VA/DoD CLINICAL PRACTICE GUIDELINE FOR 

OPIOID THERAPY FOR CHRONIC PAIN

Department of Veterans Affairs

Department of Defense

QUALIFYING STATEMENTS

The Department of Veterans Affairs and the Department of Defense guidelines are based upon the best 

information available at the time of publication. They are designed to provide information and assist 

decision making. They are not intended to define a standard of care and should not be construed as one. 

Neither should they be interpreted as prescribing an exclusive course of management. 

This Clinical Practice Guideline is based on a systematic review of both clinical and epidemiological 

evidence. Developed by a panel of multidisciplinary experts, it provides a clear explanation of the logical 

relationships between various care options and health outcomes while rating both the quality of the 

evidence and the strength of the recommendation. 

Variations in practice will inevitably and appropriately occur when clinicians take into account the needs of 

individual patients, available resources, and limitations unique to an institution or type of practice. Every 

healthcare professional making use of these guidelines is responsible for evaluating the appropriateness of 

applying them in the setting of any particular clinical situation.

These guidelines are not intended to represent TRICARE policy. Further, inclusion of recommendations for 

specific testing and/or therapeutic interventions within these guidelines does not guarantee coverage of 

civilian sector care. Additional information on current TRICARE benefits may be found at www.tricare.mil 

or by contacting your regional TRICARE Managed Care Support Contractor.

Version 3.0 – 2017
VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

February 2017 Page 2 of 198

Prepared by:

The Opioid Therapy for Chronic Pain

Work Group

With support from:

The Office of Quality, Safety and Value, VA, Washington, DC

& 

Office of Evidence Based Practice, U.S. Army Medical Command

Version 3.0 – 2017 

Based on evidence reviewed through December 2016
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Table of Contents

I. Introduction..................................................................................................................................... 5

II. How to Use This Clinical Practice Guideline ...................................................................................... 6

7

10

11

12

13

14

15

15

16

16

19

20

21

21

26

26

27

27

31

III. Recommendations...........................................................................................................................

IV. Algorithm ......................................................................................................................................

A. Module A: Determination of Appropriateness for Opioid Therapy.................................................

B. Module B: Treatment with Opioid Therapy......................................................................................

C. Module C: Tapering or Discontinuation of Opioid Therapy .............................................................

D. Module D: Patients Currently on Opioid Therapy ............................................................................

V. Background....................................................................................................................................

A. Opioid Epidemic................................................................................................................................. 

B. Paradigm Shift in Pain and Its Treatment.........................................................................................

C. Prioritizing Safe Opioid Prescribing Practices and Use.....................................................................

D. Taxonomy...........................................................................................................................................

E. Epidemiology and Impact..................................................................................................................

F. Chronic Pain and Co-occurring Conditions.......................................................................................

G. Risk Factors for Adverse Outcomes of Opioid Therapy....................................................................

VI. About this Clinical Practice Guideline .............................................................................................

A. Scope of this Clinical Practice Guideline ...........................................................................................

B. Highlighted Features of this Clinical Practice Guideline...................................................................

C. Methods.............................................................................................................................................

D. Implementation................................................................................................................................. 

E. Summary of Patient Focus Group Methods and Findings................................................................31

32

33

34

34

35

37

38

39

39

F. Conflict of Interest.............................................................................................................................

G. Patient-centered Care .......................................................................................................................

H. Shared Decision Making ....................................................................................................................

I. Stepped Care Model for Pain Management.....................................................................................

J. Transfer of Care ................................................................................................................................. 

K. Clinical Decision Support Tools.........................................................................................................

VII. Guideline Work Group ...................................................................................................................

VIII. Discussion of Recommendations....................................................................................................

A. Initiation and Continuation of Opioids .............................................................................................
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B. Risk Mitigation ...................................................................................................................................46

51

70

71

75

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75

80

81

81

88

99

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105

105

110

116

116

120

122

C. Type, Dose, Duration, Follow-up, and Taper of Opioids..................................................................

D. Opioid Therapy for Acute Pain..........................................................................................................

Appendix A: VA Signature Informed Consent.........................................................................................

Appendix B: Urine Drug Testing.............................................................................................................

A. Benefits of Urine Drug Testing ..........................................................................................................

B. Types of Urine Drug Testing ..............................................................................................................

Appendix C: Diagnostic and Statistical Manual of Mental Disorders for Opioid Use Disorders................

Appendix D: Drug Tables.......................................................................................................................

A. Short-acting, Orally Administered Opioids.......................................................................................

B. Long-acting/Extended-release Opioids.............................................................................................

C. Morphine Milligram Equivalent Doses .............................................................................................

D. Methadone Dosing Guidance..........................................................................................................

Appendix E: Evidence Review Methodology ........................................................................................

A. Developing the Scope and Key Questions......................................................................................

B. Conducting the Systematic Review................................................................................................. 

C. Convening the Face-to-face Meeting..............................................................................................

D. Grading Recommendations.............................................................................................................

E. Recommendation Categorization ...................................................................................................

F. Drafting and Submitting the Final Clinical Practice Guideline........................................................

Appendix F: Patient Focus Group Methods and Findings...................................................................... 123

123

124

127

16

132

3

165

165

173

182

185

A. Methods...........................................................................................................................................

B. Patient Focus Group Findings..........................................................................................................

Appendix G: Evidence Table ................................................................................................................

Appendix H: 2010 Recommendation Categorization Table...................................................................

Appendix I: Participant List..................................................................................................................

Appendix J: Literature Review Search Terms and Strategy...................................................................

A. Topic-specific Search Terms............................................................................................................

B. Search Strategies .............................................................................................................................

Appendix K: Abbreviation List..............................................................................................................

References ..........................................................................................................................................
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I. Introduction

The Department of Veterans Affairs (VA) and Department of Defense (DoD) Evidence-Based Practice Work 

Group (EBPWG) was established and first chartered in 2004, with a mission to advise the “...Health 

Executive Council on the use of clinical and epidemiological evidence to improve the health of the 

population across the Veterans Health Administration and Military Health System,” by facilitating the 

development of clinical practice guidelines (CPGs) for the VA and DoD populations.[1] This CPG is intended 

to provide healthcare providers with a framework by which to evaluate, treat, and manage the individual 

needs and preferences of patients with chronic pain who are on or being considered for long-term opioid 

therapy (LOT). 

In 2010, the VA and DoD published the Clinical Practice Guideline for Management of Opioid Therapy for 

Chronic Pain (2010 OT CPG), which was based on evidence reviewed through March 2009. Since the 

release of that guideline, there has been growing recognition of an epidemic of opioid misuse and opioid 

use disorder (OUD) in America, including among America’s Veterans, as documented in the Background

section. At the same time, there is a mounting body of research expanding detailing the lack of benefit and 

severe harms of LOT. 

Consequently, a recommendation to update the 2010 OT CPG was initiated in 2015. The updated CPG, 

titled Clinical Practice Guideline for Opioid Therapy for Chronic Pain (OT CPG), includes objective, evidencebased information on the management of chronic pain. It is intended to assist healthcare providers in all 

aspects of patient care, including, but not limited to, diagnosis, treatment, and follow-up. The system-wide 

goal of this guideline is to improve the patient’s health and well-being by providing evidence-based 

guidance to providers who are taking care of patients on or being considered for LOT. The expected 

outcome of successful implementation of this guideline is to:

• Assess the patient’s condition, provide education, and determine the best treatment methods in

collaboration with the patient and a multidisciplinary care team

• Optimize the patient’s health outcomes and function and improve quality of life

• Minimize preventable complications and morbidity

• Emphasize the use of patient-centered care
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II. How to Use This Clinical Practice Guideline

This guideline can be used in a variety of ways. It can be used by general clinicians or specialists to study 

and consider the latest information on opioid therapy (OT) and how and whether to incorporate that 

information or recommendations into their practice. It can be used to provide specific information to guide 

a patient encounter, such as looking up the dosing of a medication used less frequently or the meaning of 

the urine drug testing (UDT) result. The section on tapering and its accompanying appendix can be used to 

assist in the development of a framework for guiding an individualized, informed discussion when tapering 

is being considered. Patients can examine the guideline to educate themselves and better understand 

their care. A health care system can use the CPG to assure that its clinicians and patients have the 

resources available to compassionately, effectively, and safely evaluate and deliver LOT in a timely, 

culturally sensitive manner. The guideline can also be used to suggest specific education for identified 

gaps. 

This guideline is not intended as a standard of care and should not be used as such. Standards of care are 

determined on the basis of all clinical data available for an individual case and are subject to change as 

scientific knowledge and technology advances and patterns evolve. Today there is variation among state 

regulations, and this guideline does not cover the variety of ever-changing state regulations that may be 

pertinent. The ultimate judgement regarding a particular clinical procedure or treatment course must be 

made by the individual clinician, in light of the patient’s clinical presentation, patient preferences, and the 

available diagnostic and treatment options. As noted previously, the guideline can assist care providers, 

but the use of a CPG must always be considered as a recommendation, within the context of a provider’s 

clinical judgment and patient values and preferences, in the care for an individual patient.
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III. Recommendations

The following recommendations were made using a systematic approach considering four domains as per 

the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach as detailed 

in the section on Methods and Appendix E. These domains include: confidence in the quality of the 

evidence, balance of desirable and undesirable outcomes (i.e., benefits and harms), patient or provider 

values and preferences, and other implications, as appropriate (e.g., resource use, equity, acceptability). 

Given the relevance of all four domains in grading recommendations, the Work Group encountered 

multiple instances in which confidence in the quality of the evidence was low or very low, while there was 

marked imbalance of benefits and harms, as well as certain other important considerations arising from 

the domains of values and preferences and/or other implications. In particular, the harms due to the 

potential for severe adverse events associated with opioids, particularly overdose and OUD, often far 

outweigh the potential benefits. As such, in accounting for all four domains, these factors contributed to

Strong recommendations in multiple instances. 

# Recommendation Strength* Category†

Initiation and Continuation of Opioids

1. a) We recommend against initiation of long-term opioid therapy for 

chronic pain. 

b) We recommend alternatives to opioid therapy such as selfmanagement strategies and other non-pharmacological treatments. 

c) When pharmacologic therapies are used, we recommend nonopioids over opioids.

a) Strong 

against 

b) Strong for

c) Strong for

Reviewed, Newreplaced

2. If prescribing opioid therapy for patients with chronic pain, we 

recommend a short duration. 

Note: Consideration of opioid therapy beyond 90 days requires reevaluation and discussion with patient of risks and benefits.

Strong for Reviewed, Newadded

3. For patients currently on long-term opioid therapy, we recommend 

ongoing risk mitigation strategies (see Recommendations 7-9), 

assessment for opioid use disorder, and consideration for tapering when 

risks exceed benefits (see Recommendation 14).

Strong for Reviewed, Newreplaced

4. a) We recommend against long-term opioid therapy for pain in 

patients with untreated substance use disorder. 

b) For patients currently on long-term opioid therapy with evidence of 

untreated substance use disorder, we recommend close 

monitoring, including engagement in substance use disorder

treatment, and discontinuation of opioid therapy for pain with 

appropriate tapering (see Recommendation 14 and 

Recommendation 17).

a) Strong 

against 

b) Strong for

Reviewed, 

Amended

5. We recommend against the concurrent use of benzodiazepines and 

opioids. 

Note: For patients currently on long-term opioid therapy and 

benzodiazepines, consider tapering one or both when risks exceed 

benefits and obtaining specialty consultation as appropriate (see 

Recommendation 14 and the VA/DoD Clinical Practice Guideline for the 

Management of Substance Use Disorders). 

Strong against Reviewed, Newadded
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# Recommendation Strength* Category†

6. a) We recommend against long-term opioid therapy for patients less 

than 30 years of age secondary to higher risk of opioid use disorder

and overdose. 

b) For patients less than 30 years of age currently on long-term opioid 

therapy, we recommend close monitoring and consideration for 

tapering when risks exceed benefits (see Recommendation 14 and 

Recommendation 17).

a) Strong 

against 

b) Strong for

Reviewed, Newreplaced

Risk Mitigation

7. We recommend implementing risk mitigation strategies upon initiation 

of long-term opioid therapy, starting with an informed consent 

conversation covering the risks and benefits of opioid therapy as well as 

alternative therapies. The strategies and their frequency should be 

commensurate with risk factors and include:

 Ongoing, random urine drug testing (including appropriate 

confirmatory testing)

 Checking state prescription drug monitoring programs

 Monitoring for overdose potential and suicidality

 Providing overdose education 

 Prescribing of naloxone rescue and accompanying education 

Strong for Reviewed, Newreplaced

8. We recommend assessing suicide risk when considering initiating or 

continuing long-term opioid therapy and intervening when necessary.

Strong for Reviewed, 

Amended

9. We recommend evaluating benefits of continued opioid therapy and risk 

for opioid-related adverse events at least every three months.

Strong for Reviewed, Newreplaced

Type, Dose, Follow-up, and Taper of Opioids

10. If prescribing opioids, we recommend prescribing the lowest dose of 

opioids as indicated by patient-specific risks and benefits. 

Note: There is no absolutely safe dose of opioids.

Strong for Reviewed, Newreplaced

11. As opioid dosage and risk increase, we recommend more frequent 

monitoring for adverse events including opioid use disorder and 

overdose. 

Note:

 Risks for opioid use disorder start at any dose and increase in a dose 

dependent manner.

 Risks for overdose and death significantly increase at a range of 20-

50 mg morphine equivalent daily dose.

Strong for Reviewed, Newreplaced

12. We recommend against opioid doses over 90 mg morphine equivalent 

daily dose for treating chronic pain. 

Note: For patients who are currently prescribed doses over 90 mg 

morphine equivalent daily dose, evaluate for tapering to reduced dose 

or to discontinuation (see Recommendations 14 and 15).

Strong against Reviewed, Newreplaced

13. We recommend against prescribing long-acting opioids for acute pain, as 

an as-needed medication, or on initiation of long-term opioid therapy. 

Strong against Reviewed, Newreplaced

14. We recommend tapering to reduced dose or to discontinuation of longterm opioid therapy when risks of long-term opioid therapy outweigh 

benefits. 

Note: Abrupt discontinuation should be avoided unless required for 

immediate safety concerns.

Strong for Reviewed, Newadded
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# Recommendation Strength* Category†

15. We recommend individualizing opioid tapering based on risk assessment 

and patient needs and characteristics. 

Note: There is insufficient evidence to recommend for or against specific 

tapering strategies and schedules.

Strong for Reviewed, Newadded

16. We recommend interdisciplinary care that addresses pain, substance 

use disorders, and/or mental health problems for patients presenting 

with high risk and/or aberrant behavior.

Strong for Reviewed, Newreplaced

17. We recommend offering medication assisted treatment for opioid use 

disorder to patients with chronic pain and opioid use disorder. 

Note: See the VA/DoD Clinical Practice Guideline for the Management of 

Substance Use Disorders.

Strong for Reviewed, Newreplaced

Opioid Therapy for Acute Pain

18. a) We recommend alternatives to opioids for mild-to-moderate acute 

pain. 

b) We suggest use of multimodal pain care including non-opioid 

medications as indicated when opioids are used for acute pain. 

c) If take-home opioids are prescribed, we recommend that 

immediate-release opioids are used at the lowest effective dose 

with opioid therapy reassessment no later than 3-5 days to 

determine if adjustments or continuing opioid therapy is indicated. 

Note: Patient education about opioid risks and alternatives to opioid 

therapy should be offered.

a) Strong for

b) Weak for

c) Strong for

Reviewed, Newadded

*For additional information, please refer to the section on Grading Recommendations. 

†For additional information, please refer to the section on Recommendation Categorization and Appendix H. 
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IV. Algorithm

This CPG follows an algorithm that is designed to facilitate understanding of the clinical pathway and 

decision making process used in management of LOT. The use of the algorithm format as a way to 

represent patient management was chosen based on the understanding that such a format may promote 

more efficient diagnostic and therapeutic decision making and has the potential to change patterns of 

resource use. Although the Work Group recognizes that not all clinical practices are linear, the simplified 

linear approach depicted through the algorithm and its format allows the provider to assess the critical 

information needed at the major decision points in the clinical process. It includes:

• An ordered sequence of steps of care 

• Recommended observations and examinations

• Decisions to be considered 

• Actions to be taken

For each guideline, the corresponding clinical algorithm is depicted by a step-by-step decision tree. 

Standardized symbols are used to display each step in the algorithm, and arrows connect the numbered 

boxes indicating the order in which the steps should be followed.[2] 

Rounded rectangles represent a clinical state or condition.

Hexagons represent a decision point in the guideline, formulated as a question 

that can be answered Yes or No.

Rectangles represent an action in the process of care.
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A. Module A: Determination of Appropriateness for Opioid Therapy

Note: Non-pharmacologic and non-opioid pharmacologic therapies are preferred for chronic pain. 
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B. Module B: Treatment with Opioid Therapy
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C. Module C: Tapering or Discontinuation of Opioid Therapy
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D. Module D: Patients Currently on Opioid Therapy
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V. Background 

A. Opioid Epidemic

Chronic pain is a national public health problem as outlined in the 2011 study by the National Academy of 

Medicine (previously the Institute of Medicine [IOM]).[3] At least 100 million Americans suffer from some 

form of chronic pain. Until recently, the treatment of chronic pain with opioids was increasing at an 

alarming rate. The increase in prescriptions of these medications has been accompanied by an epidemic of 

opioid-related adverse events.

From 2000 through 2010, the proportion of pain visits during which opioid and non-opioid pharmacologic 

therapies were prescribed increased from 11.3% to 19.6% and from 26% to 29%, respectively.[4] In 2012, 

for every 100 persons in the United States (U.S.), 82.5 opioid prescriptions and 37.6 benzodiazepine 

prescriptions were written by healthcare providers.[5] In the emergency department, at least 17% of 

discharges included prescriptions for opioids.[6,7] 

There has been limited research on the effectiveness of LOT for non-end-of-life pain. At the same time, 

there is mounting evidence of the ill effects of LOT, including increased mortality, OUD, overdose, sexual 

dysfunction, fractures, myocardial infarction, constipation, and sleep-disordered breathing.[8-10] Despite 

increasing awareness of the known harms of opioids, 259 million opioid prescriptions were still written in 

2012.[11] 

The increase in opioid prescribing is matched by a parallel increase in morbidity, mortality, opioid-related 

overdose death rates, and substance use disorders (SUD) treatment admissions from 1999 to 2008.[12,13] 

In 2009, drug overdose became the leading cause of injury-related death in the U.S., surpassing deaths 

from traffic accidents.[14] In 2014, 1.9 million Americans were affected by an OUD related to non-medical 

use of prescription pain relievers,[15] and in the same year, 18,893 individuals died as a result of a 

prescription drug overdose.[16] There has been a four-fold increase in the absolute number of deaths 

associated with use of opioids since 2000, and a 14% increase between 2013 and 2014 alone.[17] In a 

survey of patients prescribed opioids for chronic non-cancer pain (CNCP) and their family members, 34% of 

patients reported that they thought they were “addicted” or “dependent” on opioid pain medication, 34% 

said that they used the medication for “fun” or to “get high,” while 22% used the medication to relieve 

day-to-day stress.[18] 

Concurrent with the increase in prescription opioid use, the rate of heroin overdose deaths increased 

nearly four-fold between 2000 and 2013.[19] According to a survey of patients entering SUD treatment for 

heroin use, the prescription opioid epidemic has resulted in a marked shift in how and which opioids are 

abused. In the 1960s, 80% of people entering treatment for heroin use started using heroin as their first 

opioid, while in the 2000s, 75% of people entering treatment for heroin use started using prescription 

opioids as their first opioid.[20] This increase in the use of opioids, as well as associated morbidity, 
VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

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mortality, and other adverse outcomes, has called attention to the need for a paradigm shift in pain and in 

the way it is treated. Consult the VA/DoD Clinical Practice Guideline for the Management of Substance Use 

Disorders (VA/DoD SUD CPG)1 for further information.

B. Paradigm Shift in Pain and Its Treatment

The U.S. is in the midst of a cultural transformation in the way pain is viewed and treated. The biomedical 

model of pain care, in which the pain experience is reduced to a pain generator and pain treatment is 

aimed at fixing or numbing pain with medications, interventions, or surgery, dominated the 1990s and the 

first decade of the 2000s. As the cost, potential harm, and limited effectiveness of this approach to chronic 

pain was becoming apparent, the National Academy of Medicine issued a call for the transformation of 

pain care to a biopsychosocial, multimodal, interdisciplinary model.[3] 

A paradigm shift in the use of OT for chronic non-terminal pain has paralleled this transformation in pain 

care. Prior to the 1980s, OT was rarely used outside of severe acute injury or post-surgical pain, primarily 

due to concern for tolerance, physical dependence, and addiction. As the hospice and palliative care 

movement began defining end-of-life care in the U.S. during the 1980s and emphasizing the importance of 

pain relief, OT increasingly became a mainstay for cancer and end-of-life pain. Efforts to destigmatize the 

use of prescription opioids for chronic non-terminal pain encompassed primary care providers and the 

public. The efforts led to an unprecedented increase in opioid prescribing for chronic non-terminal pain. 

Chronic pain management became synonymous with LOT in the 1990s and the first decade of the 2000s 

with significant numbers of patients in pain clinics receiving LOT.[21] Despite the absence of long-term 

safety or efficacy data, OT for chronic non-terminal pain became a mainstay of therapy. However, as 

observational and epidemiologic data of harm from LOT accumulated, a much more cautious approach to 

OT for chronic non-terminal pain has emerged in the decade of the 2010s. 

The accumulation of evidence of harms and the absence of evidence of long-term benefits has warranted 

a newly cautious approach to LOT that prioritizes safety. This approach coupled with the evidence of both 

the safety and efficacy for non-pharmacologic and non-opioid pharmacologic pain therapies has led to the 

current transformation in the way in which pain is viewed and treated. The biopsychosocial model of pain 

recognizes pain as a complex multidimensional experience that requires multimodal and integrated care 

approaches. Within this context, non-pharmacologic treatments and non-opioid medications are the 

preferred treatments for chronic non-terminal pain. OT has a limited role, primarily in the treatment of 

severe acute pain, post-operative pain, and end-of-life pain. 

C. Prioritizing Safe Opioid Prescribing Practices and Use 

The increasing use of opioids, as well as the accompanying rise in morbidity and mortality associated with 

opioid use, has garnered increasing attention from federal and local officials as well as other policy makers. 

 

1 See the VA/DoD Clinical Practice Guideline for the Management of Substance Use Disorders. Available at: 

http://www.healthquality.va.gov/guidelines/mh/sud/index.asp. 
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This public health issue, which has been labelled an epidemic,[22] became a focus of the President’s 

National Drug Control Strategy in 2010 and has since remained a focus. Two main goals introduced in the 

2010 strategy included curtailing illicit drug consumption in America and improving the health and safety 

of the American people by reducing the consequences of drug abuse.[23] The 2015 strategy, and an 

accompanying presidential memorandum on preventing prescription drug abuse and heroin use, released 

in October 2015, encouraged the improvement of health and safety using evidence-based methods by 

calling for change in a number of key areas including preventing drug use in communities, seeking early 

intervention opportunities, and integrating SUD treatment and supporting recovery.[24,25] 

With the passage of the Patient Protection and Affordable Care Act (PPACA) in March 2010, the 

Interagency Pain Research Coordinating Committee was created to coordinate pain research efforts 

throughout federal government agencies. The Committee was tasked with summarizing advances in pain 

care research, identifying gaps in research, and developing recommendations regarding ways to minimize 

duplicative efforts, disseminate pain care information, and expand public/private research partnerships 

and collaborations. The Committee published the National Pain Strategy in March 2016 in response to the 

call from the National Academy of Medicine to increase awareness of pain as a significant public health 

issue in the U.S.[3] The strategy made recommendations in a number of areas including prevention and 

care, professional education and training, and population research. The plan is aimed at decreasing the 

prevalence of all types of pain (acute and chronic) in the U.S., as well as the disability and morbidity 

associated with pain.[26] 

Government agencies, including the VA, DoD, and Substance Abuse and Mental Health Services 

Administration (SAMHSA), have also launched initiatives to improve the study and treatment of pain and 

adverse events associated with opioid analgesics such as OUD and overdose.[27] By August 2013, the VA 

deployed the Opioid Safety Initiative (OSI) requirements to all Veterans Integrated Service Networks 

(VISNs) with the aim of ensuring opioids are used in a safe, effective, and judicious manner. The goals of 

the OSI related to such topics as increased education, monitoring, use of safe and effective prescribing and 

management methods, tool development, collaboration, and use of alternative pain treatment. The OSI 

uses the Veterans Health Administration (VHA’s) electronic health record to identify patients who may be 

high-risk for adverse outcomes with use of opioids and providers whose prescribing practices do not 

reflect best evidence so that patient care can be improved. The OSI requirements include specific 

indicators (e.g., the number of unique pharmacy patients dispensed an opioid, the unique patients on LOT

who have received UDT).[28] As part of the OSI, the VA launched the Opioid Overdose Education and 

Naloxone Distribution (OEND) program, which was implemented as a risk mitigation strategy aimed at 

reducing deaths from opioid overdose. The program components included education and training 

regarding the following topics: opioid overdose prevention, recognition, and rescue response; risk 

mitigation strategies; and issuing naloxone kits, which can be used as an antidote to opioid 

overdose.[29,30] 

Other initiatives are aimed at improving the safe use of opioids, including the OSI Toolkit and the patient 

guide Taking Opioids Responsibly for Your Safety and the Safety of Others: Patient Information Guide on 

Long-term Opioid Therapy for Chronic Pain. The OSI Toolkit was developed to provide clinicians with 

materials to inform clinical decision-making regarding opioid therapy and safe opioid prescribing.[31] The 

toolkit materials can be found at the following link: 
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https://www.va.gov/PAINMANAGEMENT/Opioid_Safety_Initiative_Toolkit.asp. Taking Opioids Responsibly 

for Your Safety and the Safety of Others: Patient Information Guide on Long-term Opioid Therapy for 

Chronic Pain is aimed at providing information to patients as well as their providers regarding the safe use 

of opioids. More information can be found at the following link: 

http://www.healthquality.va.gov/guidelines/Pain/cot/OpiodTheraphyforChronicPainPatientTool20May20

13print.pdf. To further promote safety and patient centered care, the VHA issued a policy in 2014 requiring 

standardized education and signature informed consent for all patients receiving LOT for non-cancer 

pain.[32] 

The aforementioned presidential memorandum of October 2015 mandated that executive departments 

and agencies shall, to the extent permitted by law, provide training on the appropriate and effective 

prescribing of opioid medications to all employees who are health care professionals and who prescribe 

controlled substances as part of their federal responsibilities and duties. The DoD Opioid Prescriber Safety 

Training Program, launched accordingly, includes modules on pain management and opioid prescribing 

safety, the recent Centers for Disease Control and Prevention (CDC) guideline (see the below paragraph),

and the identification of substance misuse and referral to specialized services. Defense Centers of 

Excellence for Psychological Health and Traumatic Brain Injury is sponsoring the training and related 

management support. Training is available online at http://opstp.cds.pesgce.com/hub.php. 

The CDC released its Guideline for Prescribing Opioids for Chronic Pain, directed toward primary care 

physicians, on March 15, 2016.[33] The aim of the guideline is to assist primary care providers in offering 

safe and effective treatment for patients with chronic pain in the outpatient setting (not including active 

cancer treatment, palliative care, or end-of-life care). It is also aimed at improving communication 

between providers and patients and decreasing adverse outcomes associated with LOT. The CDC guideline, 

similar to the VA/DoD OT CPG, covered topics including initiation and continuation of OT, management of 

OT, and risk assessment and use of risk mitigation strategies. It also used the GRADE system to assign a 

grade for the strength for each recommendation which includes assessment of the quality of the evidence 

and consideration of the balance of desirable and undesirable outcomes, patient values and preferences, 

and other considerations (e.g., resource use, equity) during recommendation development (see Grading 

Recommendations for more information on the use of GRADE in updating this CPG).

On July 22, 2016, the Comprehensive Addiction and Recovery Act (CARA) was enacted with the aim of 

addressing the epidemic of overdoses from prescription opioids and other prescription drugs and 

heroin.[34] While this act was primarily focused on opioid abuse treatment and prevention, it also gave 

specific instruction to the VA in regard to broad aspects of OT including consideration of the CDC guideline 

in revising the prior VA/DoD OT CPG and adopting it for the VA. There are, however, some important 

distinctions between the CDC guideline and the VA/DoD OT CPG.

The VA/DoD OT CPG was developed with a specific patient population in mind—Service Members, 

Veterans, and their families—that has unique characteristics and needs related to the military culture and 

communities to which they return. Throughout the VA/DoD OT CPG, attention is paid to the characteristics 

and needs of these patients, particularly regarding specific risk factors such as risk for suicide, SUD, and 

other medical and mental health co-occurring conditions that may complicate management of pain for 

these patients. Further, these recommendations were made keeping in mind the implications they would 

have within the VA/DoD healthcare settings, particularly regarding considerations such as resource use, 
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accessibility, and equity related to each recommendation. Finally, the recommendations were developed 

keeping in mind the urgent need for rigorous attention to the balance of risks and benefits for patients 

within the VA/DoD specifically.

There were also some differences in the methodology used between the development of the VA/DoD OT 

CPG and the CDC guideline. Along with a clinical evidence review, during which the evidence was 

evaluated using GRADE, the CDC guideline developers also considered the findings of a contextual 

evidence review. Further, the CDC Core Expert Group, which consisted of subject matter experts, 

representatives of primary care professional societies and state agencies, and an expert in guideline 

methodology, reviewed recommendations drafted by the CDC and evaluated how the evidence was used 

in the development of the recommendations, rather than developing the recommendations themselves 

(as was the VA/DoD OT Work Group’s role in development of the VA/DoD OT CPG). While experts 

provided feedback on the CDC recommendations and their development, the CDC determined the final 

recommendations. CDC also used a review process considering and incorporating feedback from federal 

partners (e.g., SAMHSA, VA, DoD), stakeholders (e.g., professional organizations, delivery systems, 

community organizations), and other constituents (e.g., clinicians, prospective patients). The CDC guideline 

development process included notice in the Federal Register for a public review and comment period as 

well as peer review. Thus, the recommendations made in the CDC guideline, although similar to those 

made in this CPG, were likely based on a slightly different evidence base and revised based on the 

feedback of individuals who were considering a larger group of potential patients relative to the VA/DoD.

Thus, while the VA/DoD OT Work Group was aware of the release of the CDC guideline and considered 

potential implications, the CDC guideline did not form the basis of the deliberations on the strength or 

direction of these recommendations. The Work Group followed the VA/DoD Guideline for Guidelines, a 

document that details the process by which VA/DoD guidelines will be developed, including the use of the 

GRADE methodology.[1] As required by Congress in CARA, the Work Group reviewed and considered the 

CDC guideline and its inclusion in the VA/DoD OT CPG.[34] 

D. Taxonomy

Pain is defined as “an unpleasant sensory and emotional experience associated with actual or potential 

tissue damage, or described in terms of such damage...Pain is always subjective...It is unquestionably a 

sensation in a part or parts of the body, but it is also always unpleasant and therefore also an emotional 

experience.”[3,35] All of these facets signify the complexity of pain as a condition by itself and how it 

relates to both the brain and the body.[36] Pain as a symptom is multifaceted and is described and 

characterized by many factors such as its quality (e.g., sharp versus dull), intensity, timing, location, and 

whether it is associated with position or movement. 

Chronic pain is defined as pain lasting three months or more.[37] It is often associated with changes in the 

central nervous system (CNS) known as central sensitization.[38] Whereas acute and subacute pain are 

thought to involve primarily nociceptive processing areas in the CNS, chronic pain is thought to be 

associated with alterations in brain centers involved with emotions, reward, and executive function as well 

as central sensitization of nociceptive pathways across several CNS areas.[39-41] 

There are many causes of chronic pain. Pain arising from persistent peripheral stimulation could be 

mechanical or chemical/inflammatory in nature typically leading to well-localized nociceptive mechanism 
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pain. Mechanical or inflammatory pain with a visceral origin may produce a less localized pain. 

Neuropathic pain due to injury or disease of the central or peripheral nervous system (e.g., spinal cord 

injury, diabetic neuropathy, radiculopathy) may lead to poorly localized symptoms such as diffuse pain, 

burning, numbness, or a feeling of skin sensitivity. 

A comprehensive pain assessment includes a biopsychosocial interview and focused physical exam.

Elements of the biopsychosocial pain interview include a pain-related history, assessment of pertinent 

medical and psychiatric comorbidities including personal and family history of SUD, functional status and 

functional goals, coping strategies, and a variety of psychosocial factors such as the patient’s beliefs and 

expectations about chronic pain and its treatment.[36] Patients with chronic pain may also experience 

worsened quality of life, mental health, immune system function, physical function, sleep, employment 

status, and impaired personal relationships.[3,42-44] Worsening of some of these factors (e.g., quality of 

life, change in employment status) seems to also be associated with pain severity and the presence of 

psychiatric comorbidities.[45,46] Patients with chronic pain report psychological complaints (e.g., 

depression, anxiety, poor self-efficacy, poor general emotional functioning) more often than patients 

without chronic pain.[47] Further, there can be social and psychological consequences such as decreased 

ability to successfully maintain relationship and career roles and increased depression, fear, and anxiety as 

a result of pain.[3,11] 

E. Epidemiology and Impact

a. General Population

Chronic pain is among the most common, costly, and disabling chronic medical conditions in the U.S.[48-

50] In the U.S., approximately 100 million adults experience chronic pain, and pain is associated with 

approximately 20% of ambulatory primary care and specialty visits.[3,4,11] As noted above (see Opioid 

Epidemic), since the late 1990s and early 2000s, the proportion of pain visits during which patients 

received opioids has increased significantly, as have opioid-related morbidity, mortality, overdose death, 

and SUD treatment admissions.[4,12,13] Approximately one in five patients with non-cancer pain or painrelated diagnoses is prescribed opioids in office-based settings.[4] According to the CDC, sales of 

prescription opioids U.S. quadrupled from 1999 and 2014.[12] The absolute number of deaths associated 

with use of opioids has increased four-fold since 2000, including by 14% from 2013 to 2014 alone.[17] 

Between 1999 and 2015, more than 183,000 people died from overdoses related to prescription 

opioids.[51] In one survey, approximately one-third of patients receiving OT for CNCP (or their family 

members) indicated thinking that they were “addicted” to or “dependent” on the medication or used the 

medication for “fun” or to “get high.”[18] From 2000 through 2013, the rate of heroin overdose deaths 

increased nearly four-fold.[19] In the 2000s, the majority of people entering treatment for heroin use used 

prescription opioids as their first opioid.[20] 

b. VA/DoD Population

From fiscal years 2004 to 2012, the prevalence of opioid prescriptions among Veterans increased from 

18.9% to 33.4%, an increase of 76.7%. The groups with the highest prevalence of opioid use were women 

and young adults (i.e., 18-34 years old).[52] In a sample of non-treatment-seeking members of the military 

who were interviewed within three months of returning from Afghanistan, 44% reported chronic pain and 

15% reported using opioids—percentages much higher than in the general population.[53,54] Chronic pain 
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was also associated with poorer physical function, independent of comorbid mental health concerns in 

Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans.[55] 

In a study of Veterans with chronic pain who had been on opioids for at least 90 days, over 90% continued 

to use opioids one year later and nearly 80% continued to use opioids after completion of the 3.5 year 

follow-up period; while, in a study of civilian patients who had been on opioids for at least 90 days, 

approximately 65% remained on opioids through the 4.8 year follow-up period.[56,57] Rates of 

continuation in Veterans, based on this study, appeared to be related to age, marital status, race, 

geography, mental health comorbidity, and dosage. Compared to others, those who were age 50-65 years, 

were married, were a race other than African American, and who lived in a rural setting were more likely 

to continue using opioids. Veterans on higher doses of opioids were more likely to continue their use. 

Notably, those with mental health diagnoses were less likely to continue opioids, including those with 

schizophrenia and bipolar diagnoses.[56] 

F. Chronic Pain and Co-occurring Conditions

Individuals with conditions that result in or co-occur with chronic pain may have different needs or 

respond to treatment differently than individuals with chronic pain alone. Many different physical and 

psychological conditions have a pain component that can be difficult to distinguish from the underlying 

mechanism of illness. Furthermore, the treatment of co-occurring pain and other conditions may vary or 

require special considerations during their management. Readers are encouraged to consult other VA/DoD 

CPGs for further information (see VA/DoD Clinical Practice Guidelines website: www.healthquality.va.gov).

G. Risk Factors for Adverse Outcomes of Opioid Therapy

The risk factors with the greatest impact for development of opioid-related adverse events are the 

duration and dose of opioid analgesic use. Beyond duration and dose of OT, many factors increase the risk 

of adverse outcomes and must be considered prior to initiating or continuing OT (Box 1). 

Given the insufficient evidence of benefit for LOT, the clinician must carefully weigh harms and benefits 

and educate the patient as well as his or her family or caregiver prior to proceeding with treatment. As 

patient values and preferences may be impacted by other clinical considerations, some patients with one 

or more risk factors for adverse outcomes may differ with the clinician’s assessment that the risks of OT 

outweigh the potential for modest short-term benefits. Thus, it is important to consider patients’ values 

and concerns, address misconceptions, express empathy, and fully explain to patients with one or more 

risk factors that they may not benefit from, and may even be harmed by, treatment with OT. 

Conditions that significantly increase the risk of adverse outcomes from LOT are listed below. Patients for 

whom LOT is initiated should be carefully monitored, and ongoing assessment of risk should be performed 

with vigilance for the development of additional risk factors and adverse outcomes (see Recommendations 

7-9). Consider consultation with appropriate specialty care providers if there is uncertainty about whether 

benefits of OT, such as improved function (e.g., return-to-work), outweigh the risks. 
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Box 1: Selected Significant Risk Factors

 Duration and dose of OT

 Severe respiratory instability

 Sleep disordered breathing (e.g., sleep apnea)

 Acute psychiatric instability or intermediate to high acute suicide risk

• Suicidality (see Recommendation 8; VA/DoD Clinical Practice Guideline for Assessment and 

Management of Patients at Risk for Suicide [VA/DoD Suicide CPG], available at: 

http://www.healthquality.va.gov/guidelines/MH/srb/) 

 Mental disorders 

• Current or history of SUD (see VA/DoD SUD CPG, available at: 

http://www.healthquality.va.gov/guidelines/mh/sud/index.asp) 

 Untreated SUD confers additional risk (see Recommendation 4) 

• Depression or history of depression (see VA/DoD Clinical Practice Guideline for the Management of 

Major Depressive Disorder [VA/DoD MDD CPG] as appropriate, available at: 

http://www.healthquality.va.gov/guidelines/MH/mdd/) 

• Generalized anxiety disorder

• Borderline personality disorder

• Antisocial personality disorder

• Posttraumatic stress disorder (PTSD) (see VA/DoD Clinical Practice Guideline for the Management of 

Posttraumatic Stress Disorder and Acute Stress Disorder [VA/DoD PTSD CPG], available at: 

http://www.healthquality.va.gov/guidelines/MH/ptsd/) 

 History of drug overdose

 Under 30 years of age (see Recommendation 6) 

 Co-administration of a drug capable of inducing fatal drug-drug interactions (e.g., see Recommendation 5) 

 QTc interval >450 milliseconds (ms) for using methadone

 Evidence for or history of diversion of controlled substances 

 Intolerance, serious adverse effects, or a history of inadequate beneficial response to opioids

 Impaired bowel motility unresponsive to therapy

 Traumatic brain injury 

 Pain conditions worsened by opioids (e.g., fibromyalgia, headache)

 True allergy to opioid agents (that cannot be resolved by switching agents)

a. Significant Risk Factors

• Duration and dose of OT: See Recommendation 2 for more guidance on duration of OT and 

Recommendations 10-12 for more guidance on dosing of OT.

• Severe respiratory instability or sleep disordered breathing: This would include any cooccurring condition that significantly affects respiratory rate or function such as chronic 

obstructive pulmonary disease (COPD), asthma, pneumonia, sleep apnea, or a neuromuscular 

condition (e.g., amyotrophic lateral sclerosis). Two large observational studies of patients with a 

history of COPD and sleep apnea who were prescribed opioids showed a weak but positive 

association with opioid-related toxicity/overdose and overdose-related death.[58,59] 

• Acute psychiatric instability or intermediate to high acute suicide risk: Intermediate to high 

acute suicide risk, severe depression, unstable bipolar disorder, or unstable psychotic disorder

precludes the safe use of self-administered LOT.[60] Im et al. (2015) (n=487,462) found that a 

diagnosis of a mood disorder was significantly associated with suicide attempts for the chronic 

use of short-acting and long-acting opioids compared with no diagnosis of a mood disorder.[61] 
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In a study of patients on opioids, Campbell et al. (2015) reported that those with bipolar 

disorder had 2.9 times the odds of a suicidal ideation within the past 12 months as well as 3.2 

times the odds of a lifetime suicide attempt compared to those with no bipolar disorder.[62] See 

Recommendation 8 and the VA/DoD Suicide CPG2 for more information on suicidality. See the 

VA/DoD Clinical Practice Guideline for Management of Bipolar Disorder in Adults (VA/DoD BD 

CPG) for more information on bipolar disorder.3 Merrill and colleagues found that high dose 

chronic opioid therapy for pain was associated with depressed mood.[63] Treatment for chronic 

pain with movement, exercise and cognitive-behavioral therapy for pain may have benefit in 

treating depression, PTSD, and in reducing suicide risk.[64] 

• Mental health disorders: 

 Current or history of SUD: For patients with untreated SUD, see Recommendation 4. For 

patients with diagnosed OUD, see Recommendation 17. Frequent requests for early refills or

atypically large quantities required to control pain can signal an emerging SUD as well as 

diversion (see Evidence for or history of diversion of controlled substances). See the VA/DoD 

SUD CPG.4

 Depression or history of depression: Zedler et al. (2014) reported that among patients 

being treated by the VHA system that received opioids, a history of depression was 

significantly associated with opioid-related toxicity/overdose compared to no history of 

depression.[58] LOT has been associated with worsening depressive symptoms.[63] See the 

VA/DoD MDD CPG.5

 PTSD: Seal et al. (2012) (n=15,676) noted that among patients on OT, a prevalence of selfinflicted injuries was significantly higher among patients with a history of PTSD (with or 

without other mental health diagnoses) as compared to patients with other (or no) mental 

health diagnoses.[65] For more information, see the VA/DoD PTSD CPG.6

 

• History of drug overdose: A history of overdose is a red flag and providers should proceed with 

utmost caution when considering LOT for these patients.

• Under 30 years of age: See Recommendation 6. 

 

2 See the VA/DoD Clinical Practice Guideline for Assessment and Management of Patients at Risk of Suicide. Available at: 

http://www.healthquality.va.gov/guidelines/MH/srb/ 3 See the VA/DoD Clinical Practice Guideline for Management of Bipolar Disorder in Adults. Available at: 

http://www.healthquality.va.gov/guidelines/MH/bd/ 4 See the VA/DoD Clinical Practice Guideline for the Management of Substance Use Disorders. Available at: 

http://www.healthquality.va.gov/guidelines/mh/sud/index.asp. 5 See the VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder. Available at: 

http://www.healthquality.va.gov/guidelines/MH/mdd/ 6 See the VA/DoD Clinical Practice Guideline for the Management of Posttraumatic Stress Disorder and Acute Stress Disorder. 

Available at: http://www.healthquality.va.gov/guidelines/MH/ptsd/
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• Co-administration of a drug capable of inducing fatal drug-drug interactions: Providers should

carefully rule out and avoid potential drug interactions prior to initiating LOT. For example, the

following combinations are dangerous:[66]

 Opioids with benzodiazepines (compared to patients with no prescription, the odds ratio

[OR] and 95% confidence interval [CI] for drug-related death was OR: 14.92, 95% CI: 7.00-

31.77 for patients who filled a prescription for opioids and benzodiazepines; OR: 3.40, 95% 

CI: 1.60-7.21 for patients who filled only an opioid prescription, and 7.21, 95% CI: 3.33-15.60

for patients who filled only a benzodiazepine prescription) (see Recommendation 5) [66,67] 

 Fentanyl with CYP3A4 inhibitors

 Methadone with drugs that can prolong the QT interval (the heart rate’s corrected time 

interval from the start of the Q wave to the end of the T wave) (e.g., CYP450 2B6 inhibitors) 

• QTc interval >450 ms for using methadone: Unlike most other commonly used opioids,

methadone has unique pharmacodynamic properties that can prolong the QTc interval (the

heart rate’s corrected time interval from the start of the Q wave to the end of the T wave) and

precipitate torsades de pointes, a dangerous or fatal cardiac arrhythmia. Patients who may be at

risk include those with other risk factors for QTc prolongation, current or prior

electrocardiograms (ECGs) with a prolonged QTc >450 ms, or a history of syncope. Therefore,

ECGs before and after initiating methadone are highly advised (see Methadone Dosing

Guidance).

• Evidence for or history of diversion of controlled substances: The clinician should communicate

to patients that drug diversion is a crime and constitutes an absolute contraindication to

prescribing additional medications. Because suspicion is subjective and may be based on

impression, bias, or prejudice, it is important that providers who suspect diversion base

treatment plans on objective evidence. Suspicions may be confirmed by a negative mass

spectrometry/liquid chromatography UDT for the substance being prescribed in the absence of

withdrawal symptoms in someone who is receiving opioids. A negative UDT for the prescribed

opioid could also by itself be a sign of diversion. Signs of diversion may also include frequent

requests for early refills or atypically large quantities required to control pain. Routine UDT,

however, may not reliably detect synthetic opioids (e.g., methadone, fentanyl, tramadol) or

semi-synthetic opioids (e.g., oxycodone, hydrocodone, hydromorphone). When there is

evidence that the patient is diverting opioids, discontinue opioids according to

Recommendations 14 and 15 and assess for underlying OUD and/or psychiatric comorbidities.

Consultation with a pain specialist, psychiatrist, or SUD specialist may be warranted. Also

consider consultation with local risk management and/or counsel. For patients with OUD, keep

in mind that sudden discontinuation of opioids due to suspected diversion may place them at

high risk for illicit opioid use and resulting opioid overdose (see Recommendation 17).

• Intolerance, serious adverse effects, or a history of inadequate beneficial response to opioids:

Serious harm may occur should patients be prescribed additional (or different) opioids if prior

administration of opioids led to serious adverse effects or was not tolerated. It is also

inadvisable to prescribe opioids to patients who already have had an adequate opioid trial (of
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sufficient dose and duration to determine whether or not it will optimize benefit) without a 

positive response.

• Impaired bowel motility unresponsive to therapy: Opioids inhibit bowel peristalsis. Their use 

with patients with impaired bowel motility can increase the risk of severe 

constipation/impaction or possible obstruction.

• Headache not responsive to other pain treatment modalities: LOT is an ineffective treatment 

modality for patients with migraine headaches (with or without aura), tension-type headaches, 

occipital neuralgia, or myofascial pain and may result in worsening of the underlying headache 

condition through factors such as central sensitization and withdrawal.

• Traumatic brain injury (TBI): Patients with a history of TBI who use chronic short-acting and 

long-acting opioids are more likely to attempt suicide.[61] 

• True allergy to opioid agents: Morphine causes a release of histamine that frequently results in 

itching, but this does not constitute an allergic reaction. True allergy to opioid agents 

(e.g., anaphylaxis) is not common, but does occur. Generally, allergy to one opioid does not 

mean the patient is allergic to other opioids; many times, rotating to a different opioid may be 

effective. When an opioid allergy is present and OT is being considered, consultation with an 

allergist may be helpful.
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VI. About this Clinical Practice Guideline

This OT CPG is in line with the efforts described above to improve our understanding and treatment of 

pain, as well as to mitigate the inappropriate prescribing and ill effects of opioids. It is intended for VA and 

DoD healthcare practitioners including physicians, nurse practitioners, physician assistants, physical and 

occupational therapists, psychologists, social workers, nurses, clinical pharmacists, chaplains, addiction 

counselors, and others involved in the care of Service Members and their beneficiaries, retirees and their 

beneficiaries, or Veterans on or being considered for LOT. In conjunction with other efforts already under 

way, this CPG is aimed at improving safe and appropriate prescribing and use of opioids to treat chronic 

pain. 

As with other CPGs, there are limitations, including significant evidence gaps. Further, there is a need to 

develop effective strategies for guideline implementation and evaluation of the effect of guideline 

adherence on clinical outcomes. Thus, as stated in the qualifying statements at the beginning of the CPG, 

this CPG is not intended to serve as a standard of care. Standards of care are determined on the basis of all 

clinical data available for an individual patient and are subject to change as scientific knowledge and 

technology advance and patterns evolve. This CPG is based on evidence available by December 2016 and is 

intended to provide a general guide to best practices. The guideline can assist healthcare providers, but 

the use of a CPG must always be considered as a recommendation, within the context of a provider’s 

clinical judgment and patient values and preferences, for the care of an individual patient. 

A. Scope of this Clinical Practice Guideline

This OT CPG is designed to assist healthcare providers in managing or co-managing patients on or being 

considered for LOT. Specifically, this CPG is intended for adults, including Veterans as well as deployed and 

non-deployed Active Duty Service Members, their beneficiaries, and retirees and their beneficiaries, with 

chronic pain who are receiving care from the VA or DoD healthcare delivery systems. This CPG is not 

intended for and does not provide recommendations for the management of pain with LOT in children or 

adolescents, in patients with acute pain, or in patients receiving end-of-life care. As is so for any 

pharmacotherapy, any decision about prescribing opioids, or alternative medications for pain, for pregnant 

women should be made with due caution and cognizance of applicable U.S. Food and Drug Administration 

(FDA) labeling. Any patient in the VA or DoD healthcare system should be offered access to the 

interventions that are recommended in this guideline after taking into consideration the patient’s specific 

circumstances. 

While these guidelines are broadly recommended, their implementation is intended to be patientcentered. Thus, treatment and care should take into account a patient’s needs and preferences. Good 

communication between healthcare professionals and the patient about the patient’s pain experience, 

treatment goals, and challenges is essential and should be guided by evidence-based information tailored 

to the patient’s needs. An empathetic and non-judgmental (versus a confrontational or adversarial) 

approach to communication with a patient is highly recommended in order to build trust and facilitate

frank discussions relating to the social, economic, emotional, and cultural factors that influence patients’ 

perceptions, behaviors, and decision making.

The information that patients are given about treatment and care should be culturally appropriate and 

also available to people with limited literacy skills. It should also be accessible to people with additional 
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needs such as physical, sensory, or learning disabilities. Family involvement should be considered if 

appropriate.

The systematic review conducted for the update of this CPG encompassed interventional studies (primarily 

randomized controlled trials [RCTs]) published between March 2009 and December 2016 and targeted

nine key questions (KQs) focusing on the means by which the delivery of healthcare could be optimized for 

patients on or being considered for LOT. Because a comprehensive review of the evidence related to LOT

was not feasible, the nine selected KQs were prioritized from many possible KQs. Therefore, many of the 

2010 OT CPG recommendations were considered for inclusion in the updated version of the guideline 

without an updated review of the evidence. The section on Recommendations delineates whether or not 

the current CPG recommendations were based on an updated evidence review. Appendix H delineates 

whether the 2010 OT CPG recommendations were considered for inclusion in the update based on an 

updated evidence review or based on the evidence included in the 2010 OT CPG. The section on 

Recommendation Categorization further describes the methodology used for the categorization. 

B. Highlighted Features of this Clinical Practice Guideline

The 2017 version of the VA/DoD OT CPG is the second update to the original CPG. It provides practice 

recommendations for the care of populations with chronic pain already on or being considered for LOT. 

Although there are many other approaches to the treatment of chronic pain, the scope of this CPG is to 

focus on the use of opioids for chronic pain rather than being comprehensive about all treatment options. 

A particular strength of this CPG is the multidisciplinary stakeholder involvement from its inception, 

ensuring representation from the broad spectrum of clinicians engaged in the treatment and management 

of patients with chronic pain on or being considered for LOT. 

The framework for recommendations in this CPG considered factors beyond the strength of the evidence, 

including balancing desired outcomes with potential harms of treatment, equity of resource availability, 

the potential for variation in patient values and preferences, and other considerations (see Methods for 

more information). Applicability of the evidence to VA/DoD populations was also taken into consideration. 

A structured algorithm (see Algorithm) accompanies the guideline to provide an overview of the 

recommendations in the context of the flow of patient care and clinician decision making and to assist with 

training providers. The algorithm may be used to help facilitate translation of guideline recommendations 

into effective practice.

C. Methods

The current document is an update to the 2010 VA/DoD Clinical Practice Guideline for the Management of 

Opioid Therapy for Chronic Pain. The methodology used in developing the 2017 CPG follows the VA/DoD 

Guideline for Guidelines,[1] an internal document of the VA and DoD EBPWG. The VA/DoD Guideline for 

Guidelines can be downloaded from http://www.healthquality.va.gov/policy/index.asp. This document 

provides information regarding the process of developing guidelines, including the identification and 

assembly of the Guideline Champions (“Champions”) and other subject matter experts from within the VA 

and DoD, known as the “Work Group,” and ultimately, the development and submission of an updated OT 

CPG. The VA Office of Quality, Safety and Value, in collaboration with the Office of Evidence Based 

Practice, U.S. Army Medical Command, the proponent for CPGs for the DoD, identified two clinical leaders, 
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Jack Rosenberg, MD, FASAM from the VA and Christopher Spevak, MD, MPH, JD from the DoD, as 

Champions for the 2017 CPG. 

The Champions and Work Group for this CPG were charged with developing evidence-based clinical 

practice recommendations and writing and publishing a guideline document to be used by providers 

within the VA and DoD healthcare systems. Specifically, the Champions and the Work Group were 

responsible for identifying the KQs – those considered most clinically relevant, important, and interesting 

with respect to the management of patients with chronic pain on or being considered for LOT. The 

Champions and the Work Group also provided direction on inclusion and exclusion criteria for the 

evidence review and assessed the level and quality of the evidence. The amount of new scientific evidence 

that had accumulated since the previous version of the CPG was taken into consideration in the 

identification of the KQs. In addition, the Champions assisted in:

• Identifying appropriate disciplines of individuals to be included as part of the Work Group

• Directing and coordinating the Work Group

• Participating throughout the guideline development and review processes

The Lewin Team, including The Lewin Group, Duty First Consulting, ECRI Institute, and Sigma Health 

Consulting, LLC, was contracted by the VA and DoD to support the development of this CPG and conduct 

the evidence review. The first conference call was held in October 2015, with participation from the 

contracting officer’s representative (COR), leaders from the VA Office of Quality, Safety and Value and the 

DoD Office of Evidence Based Practice, and the Champions. During this call, participants discussed the 

scope of the guideline initiative, the roles and responsibilities of the Champions, the project timeline, and 

the approach for developing and prioritizing specific research questions on which to base a systematic 

review about the management of LOT. The group also identified a list of clinical specialties and areas of 

expertise that were important and relevant to the management of LOT, from which Work Group members 

were recruited. The specialties and clinical areas of interest included: Anesthesiology, Addictive Disorders 

and Addiction Medicine, Clinical Neurophysiology, Family Medicine, Geriatrics, Internal Medicine, 

Mental/Behavioral Health, Neurology, Nursing, Pain Management, Pain Medicine, Pain Psychology, 

Palliative Care, Pharmacy, Physical Medicine and Rehabilitation, Physical Therapy, Primary Care, 

Psychiatry, Psychology, and Social Work. 

The guideline development process for the 2017 CPG update consisted of the following steps:

1. Formulating and prioritizing KQs (or evidence questions) 

2. Conducting the systematic review of the literature

3. Convening a face-to-face meeting with the CPG Champions and Work Group 

4. Drafting, revising, and submitting a final CPG about the management of LOT to the VA/DoD 

EBPWG

Appendix E provides a detailed description of each of these tasks.
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b. Grading Recommendations

The Champions and Work Group used the GRADE system to assess the quality of the evidence base and 

assign a grade for the strength for each recommendation. The GRADE system uses the following four 

domains to assess the strength of each recommendation:[68] 

• Confidence in the quality of the evidence 

• Balance of desirable and undesirable outcomes 

• Patient or provider values and preferences

• Other implications, as appropriate, e.g.,:

 Resource use

 Equity

 Acceptability

 Feasibility

 Subgroup considerations

Using this system, the Champions and Work Group determined the direction (for or against) and relative 

strength (strong or weak) of each recommendation.[68] The direction indicates that the desirable effects 

of the recommendation outweigh the undesirable effects of the recommendation (for) or that the 

opposite is true (against). The strength indicates the Work Group’s level of confidence in the balance of 

desirable and undesirable effects of the recommendation among the intended patient population.[69] A 

strong recommendation indicates the Work Group is confident in this balance (e.g., that the desirable 

effects outweigh the undesirable effects). A weak recommendation indicates that the balance is still likely, 

but the Work Group’s confidence in the balance is lower than for a strong recommendation. 

Using these elements, the grade of each recommendation is presented as part of a continuum:

• Strong For (or “We recommend offering this option ...”)

• Weak For (or “We suggest offering this option ...”)

• Weak Against (or “We suggest not offering this option ...”)

• Strong Against (or “We recommend against offering this option ...”)

The grade of each recommendation made in the 2017 OT CPG can be found in Recommendations. 

Additional information regarding the use of the GRADE system can be found in Grading Recommendations. 

c. Reconciling 2010 Clinical Practice Guideline Recommendations

Evidence-based CPGs should be current, which typically requires revisions of previous guidelines based on 

new evidence or as scheduled, subject to time-based expirations.[70] For example, the United States 

Preventive Services Task Force (USPSTF) has a process for refining or otherwise updating its 

recommendations pertaining to preventive services.[71] Further, the inclusion criteria for the National 

Guideline Clearinghouse specify that a guideline must have been developed, reviewed, or revised within

the past five years. 
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The 2017 OT CPG is an update of the 2010 CPG. Thus, the structure and content of the 2017 CPG is 

reflective of the previous version of the CPG, but modified where necessary to reflect new evidence and 

new clinical priorities.

The Work Group focused largely on developing new and updated recommendations based on the 

evidence review conducted for the priority areas addressed by the KQs. In addition to those new and 

updated recommendations, the Work Group considered the current applicability of other 

recommendations that were included in the previous 2010 OT CPG without complete review of the 

relevant evidence, subject to evolving practice in today’s environment. 

To indicate which recommendations were developed based on the updated review of the evidence versus 

recommendations that were carried forward from the 2010 version of the CPG, a set of recommendation 

categories was adapted from those used by the National Institute for Health and Care Excellence 

(NICE).[72,73] These categories, along with their corresponding definitions, were used to account for the 

various ways in which older recommendations could have been updated. In brief, the categories took into 

account whether or not the evidence that related to a recommendation was systematically reviewed, the 

degree to which the recommendation was modified, and the degree to which a recommendation is 

relevant in the current patient care environment and inside the scope of the CPG. Additional information

regarding these categories and their definitions can be found in the section on Recommendation 

Categorization. The categories for the recommendations included in the 2017 CPG can be found in the 

Recommendations section. The categorizations for each 2010 CPG recommendation can be found in 

Appendix H. 

Between the development of the 2010 and 2017 versions of the OT CPG, VA/DoD adopted a new evidence 

rating system. The CPG Work Group recognized the need to accommodate this transition in evidence 

rating systems from the USPSTF system in the 2010 CPG to the GRADE system in the 2017 CPG. In order to 

report the strength of all recommendations using a consistent format (i.e., the GRADE system) the Work 

Group converted the USPSTF evidence grades accompanying the carryover recommendations from the 

2010 guideline to the GRADE system. As such, the CPG Work Group considered the strength of the 

evidence cited for each recommendation in the 2010 OT CPG as well as harms and benefits, values and 

preferences, and other implications, where possible. 

In cases where a 2010 OT CPG recommendation was covered by a 2017 KQ, peer-reviewed literature 

published since the 2010 OT CPG was considered along with the evidence base used for the 2010 CPG. 

Where new literature was considered in converting the strength of the recommendation from the USPSTF 

to the GRADE system, it is referenced in the discussion following the corresponding recommendation, as 

well as in Appendix G. 

The CPG Work Group recognizes that, while there are practical reasons for incorporating findings from a 

previous systematic review, previous recommendations, or recent peer-reviewed publications into an 

updated CPG, doing so does not involve an original, comprehensive systematic review and, therefore, may 

introduce bias.[74] 
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d. Peer Review Process 

The CPG was developed through an iterative process in which the Work Group produced multiple drafts of 

the CPG. The process for developing the initial draft is described in more detail in Drafting and Submitting 

the Final Clinical Practice Guideline. 

Once a near-final draft of the guideline was agreed upon by the Champions and Work Group, the draft was 

sent out for peer review and comment. The draft was posted on a wiki website for a period of 14 business 

days. The peer reviewers comprised individuals working within the VA and DoD health systems as well as 

experts from relevant outside organizations designated by the Work Group. External organizations that

participated in the peer review included the following:

• American Academy of Addiction Psychiatry (AAAP)

• American Academy of Pain Medicine (AAPM)

• American Physical Therapy Association (APTA)

• American Society of Addiction Medicine (ASAM)

• University of Kentucky

• University of Minnesota

VA and DoD Leadership reached out to both the internal and external peer reviewers to solicit their 

feedback on the CPG. Reviewers were provided a hyperlink to the wiki website where the draft CPG was 

posted. For transparency, all reviewer feedback was posted in tabular form on the wiki site, along with the 

name of the reviewer. All feedback from the peer reviewers was discussed and considered by the Work 

Group. Modifications made throughout the CPG development process were made in accordance with the 

evidence. 

D. Implementation

This CPG, including its recommendations and algorithm, is designed to be adapted by healthcare providers 

for the treatment of individual patients, bearing in mind patient-level considerations as well as local needs 

and resources. The algorithm serves as a tool to prompt providers to consider key decision points in the 

course of care.

Although this CPG represents the recommended practice on the date of its publication, medical practice is 

evolving and this evolution requires continuous updating based on published information. New technology 

and more research will improve patient care in the future. Identifying areas where evidence was lacking 

for the 2017 CPG can help identify priority areas for future research. Future studies examining the results 

of OT CPG implementation may lead to the development of new evidence particularly relevant to clinical 

practice. 

E. Summary of Patient Focus Group Methods and Findings

When forming guideline recommendations, consideration should be given to the values of those most 

affected by the recommendations: patients. Patients bring perspectives, values, and preferences into their 

healthcare experience, and more specifically their pain care experience, that can vary from those of 

clinicians. These differences can affect decision making in various situations, and should thus be 
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highlighted and made explicit due to their potential to influence a recommendation’s 

implementation.[75,76] Focus groups can be used as an efficient method to explore ideas and perspectives 

of a group of individuals with an a priori set of assumptions or hypotheses and collect qualitative data on a 

thoughtfully predetermined set of questions. 

Therefore, as part of the effort to update this CPG, VA and DoD Leadership, along with the OT CPG Work 

Group, held a patient focus group on December 14, 2015, at the Washington DC VA Medical Center. One 

additional family caregiver was interviewed separately at a later date. The aim of the focus group and 

interview was to further the understanding of the perspectives of patients receiving OT within the VA 

and/or DoD healthcare systems. The focus group and interview explored patient perspectives on a set of 

topics related to management of OT in the VA and DoD healthcare systems, including knowledge of OT and 

other pain treatment options, delivery of care, and the impact of and challenges with OT and chronic pain. 

It is important to note the focus group was a convenience sample and the Work Group recognizes the 

limitations inherent in the small sample size. Less than 10 people were included in the focus group 

consistent with the requirements of the federal Paperwork Reduction Act, 1980. The Work Group 

acknowledges that the sample of patients included in this focus group may not be representative of all VA 

and DoD patients on or being considered for OT for chronic pain. Further, time limitations for the focus 

group prevented exhaustive exploration of all topics related to pain care in the VA and DoD and the 

patients’ broader experiences with their care. Thus, the Work Group made decisions regarding the priority 

of topics to discuss at the focus group and interview. These limitations, as well as others, were considered 

as the information collected from the discussion was used for guideline development. Recruitment for 

participation in the focus group was managed by the Champions and VA and DoD Leadership, with 

assistance from coordinators at the facility at which the focus group took place. 

The following concepts are ideas and suggestions about aspects of care that are important to patients and 

family caregivers and that emerged from the discussion. These concepts were needed and important parts 

of the participants’ care and added to the Work Group’s understanding of patient values and perspectives. 

Additional details regarding the patient focus group methods and findings can be found in Appendix F. 

OT CPG Focus Group Concepts

A. Using shared decision making, consider all treatment options and develop treatment plan based on the 

balance of risks, benefits, and patient-specific goals, values, and preferences

B. Modify treatment based on patient response, considering patient-specific goals, values, and preferences

C. Involve family caregivers in accordance with patient preferences and maintain open, trusting, and respectful 

relationship with patients and family caregivers

D. Educate patients regarding treatment plan, alternative treatment options, and monitoring

E. Within and between healthcare systems, work with appropriate providers to ensure continuity of high quality 

care

F. Organize treatment to encourage patient adherence and participation

G. Acknowledge and minimize effects of potential medical error and take action to prevent future medical error

F. Conflict of Interest

At the start of this guideline development process and at other key points throughout, the project team 

was required to submit disclosure statements to reveal any areas of potential conflict of interest (COI) in 
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February 2017 Page 33 of 198

the past 24 months. Verbal affirmations of no COI were also used as necessary during meetings 

throughout the guideline development process. The project team was also subject to random web-based 

surveillance (e.g., ProPublica). 

If a project team member reported a COI (actual or potential), measures were in place to mitigate the 

introduction of bias into the guideline development process. Identified COIs would be reported to the 

Office of Evidence Based Practice and disclosed to the CPG Work Group in tandem with their review of the 

evidence and development of recommendations. The Office of Evidence Based Practice and the OT CPG 

Work Group would then determine whether or not action, such as restricting participation and/or voting 

on sections related to the conflict or removal from the Work Group, was necessary. If deemed necessary, 

action would have been taken by the co-chairs and the Office of Evidence Based Practice, based on the 

level and extent of involvement, to mitigate the COI. 

No OT CPG Work Group members reported relationships and/or affiliations which had the potential to 

introduce bias; thus, no further action was taken to mitigate COIs for this particular CPG.

G. Patient-centered Care

VA/DoD CPGs encourage clinicians to use a patient-centered care approach that is tailored to the patient’s 

capabilities, needs, goals, prior treatment experience, and preferences. Regardless of setting, all patients in 

the healthcare system should be offered access to evidence-based interventions appropriate to that 

patient. When properly executed, patient-centered care may decrease patient anxiety, increase trust in 

clinicians,[77] and improve treatment adherence.[78] Improved patient-clinician communication through 

patient-centered care can be used to convey openness to discuss any future concerns. 

As part of the patient-centered care approach, clinicians should review the patient’s history including 

previous treatment approaches, their results, and any other outcomes with the patient. They should ask 

the patient about his or her willingness to accept a referral to an addiction or other behavioral health 

specialist when appropriate. Lastly, they should involve the patient in prioritizing problems to be 

addressed and in setting specific goals regardless of the selected setting or level of care. The below 

approach may be used in setting SMART (Specific, Measurable, Action Oriented, Realistic, Timed) goals for 

the patient (Table 1).
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Table 1. Guide in Setting SMART Goals [79] 

Specific

A goal should be clear and concise. It is difficult to know when action 

toward a goal has been started and when it has been completed if it is 

not specific. 

Measurable

A goal should be measurable so that Veterans can track their progress. 

Veterans need to have clear criteria for progress and completion when 

taking action on a goal. Keeping tabs on progress can be inspiring.

Action

Oriented

A goal should include action. And that action should be in direct 

control of the Veteran.

Realistic

A goal should be largely within the reach of the Veterans. It is best to 

work on small lifestyle changes that are doable. Avoid the pitfalls of 

having Veterans see only the big picture and not the small steps.

Timed A goal should be tied to a timetable for completing specific, 

measurable and realistic action.

H. Shared Decision Making

The shared decision making process for chronic pain treatment planning is based on the foundation of a 

patient-centered assessment of risks and benefits and a clinical synthesis performed by the provider 

(Figure 1). The patient-centered assessment incorporates a patient-centered interview, and exploration of 

patient values, goals, questions, concerns, and expectations. Next, the clinician performs a biopsychosocial 

assessment and determines clinically appropriate therapeutic options in which benefits are likely to 

outweigh risks. The process culminates in a shared decision making process to develop a patient-centered 

treatment plan by the patient selecting from the clinically appropriate treatment options generated in the 

first two steps. 

Figure 1. Shared Decision Making for Chronic Pain Treatment and Long-Term Opioid Therapy

I. Stepped Care Model for Pain Management

The Stepped Care Model for Pain Management, developed by VA, has been implemented within both the 

VHA and Military Health System (MHS) with the aim of providing a continuum of effective, coordinated, 

and patient-centered treatment to patients with pain. With education, self-care, and whole-health 

approaches to wellness as the foundation, this model provides progressively more intensive 

biopsychosocial care within increasingly specialized settings as patients become more complex, have a 

greater degree of comorbidity, and present higher risk. Psychological, physical, complementary and 
VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

alternative, and medication therapies are often combined to create a multimodal pain care plan. The goals 

of the Stepped Care Model for Pain Management include functional rehabilitation, improvement in quality 

of life, and prevention of the pain becoming chronic and associated deterioration in function (Figure 2).

Figure 2. Stepped Care Model for Pain Management* 

*Adapted from the Interagency Pain Research Coordinating Committee’s National Pain Strategy (2016) [26] 

Abbreviations: BPS: biopsychosocial; CAM: complementary and alternative medicine; CARF: Commission on 

Accreditation of Rehabilitation Facilities; MH-PC: Primary Care-Mental Health; OEF: Operation Enduring Freedom; 

OIF: Operation Iraqi Freedom; PACT: Patient Aligned Care Team; SUD: substance use disorders

J. Transfer of Care

As the entire medical community is moving toward a greater understanding of the need for opioid safety, 

it is possible that a provider may receive, as a result of a transfer of care, a patient on a high-risk opioid 

regimen that raises concerns related to the provider’s and patient’s current understanding of opioid risks. 

Some universal approaches should be used in the management of care for the patient regardless of the 

location from which that patient is transferred. 

• Clinicians should provide each new patient with a full evaluation, understanding that chronic 

pain is a complex process that requires a comprehensive assessment of the whole individual as 

well as their social circumstances. The general goals of the interview with the patient are to do 

more than just gather information. This process should build a therapeutic relationship as well 

as facilitate behavior change when necessary. It is important to understand the situation from 

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the patient’s perspective, elicit a pain-specific history to aid in establishing the correct pain 

diagnosis, identify patient-specific coping strategies, identify patient-specific pain interference 

with functioning, and identify important co-occurring conditions. The transferring provider 

should also communicate the patient’s medical history to the receiving provider to ensure it is 

taken into account along with the patient’s perspective. This can aid the clinician in synthesizing 

the full biopsychosocial story.

• Clinicians should review previous medical records to determine what diagnostic and therapeutic 

options have already been tried. In addition, previous medical records can help to determine the 

patient’s risk of a non-overdose opioid-related adverse event, overdose risk, and risk of having 

developed or developing OUD. It can also help to determine co-occurring conditions that will 

need to be evaluated and treated in order to put together a comprehensive approach to this 

patient’s pain. 

• Clinicians should determine what the patient knows about current concerns related to OT and 

how comfortable he or she is with an approach that will be addressing opioid safety along with 

an integrated whole person approach to pain. Each patient may arrive from other providers with 

a different understanding of the current concerns related to OT, and educational gaps will need 

to be acknowledged and addressed. 

• Clinicians should offer all new patients a physical exam to help to determine the cause of the 

pain as well as co-occurring conditions that may complicate pain symptoms and/or treatment. 

• Clinicians should provide each patient an assessment that outlines the specifics related to opioid 

safety. 

 What is the diagnosis for which opioids are prescribed?

 What non-opioid therapies have been trialed and/or is the patient currently using? 

 Are there co-occurring conditions or medication doses/combinations that would increase 

the risk of OT? 

• Clinicians should use standard opioid risk mitigation strategies such as checking the Prescription 

Drug Monitoring Programs (PDMPs); making sure the patient has participated in shared-decision 

making about OT and signed and understands the opioid informed consent (see Appendix A); 

obtaining consent for and performing a UDT (see Appendix B); and offering OEND. See 

Recommendation 7 for more information on risk mitigation.

One frequently asked question is how to proceed when a patient requests to transfer an opioid 

prescription that the receiving provider has determined to be too risky to continue. For patients 

transferred from within the VA and/or DoD system, clinicians should employ risk stratified tapering 

strategies (see Recommendations 14 and 15). Clinicians should engage patients in shared decision making 

including consideration of the patient’s values, goals, concerns, and preferences prior to tapering. It is also 

important that clinicians asses for and treat OUD when present (see Recommendation 17). 
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For patients who are transferring from outside of the VA and/or DoD, there may be some unique issues to 

consider. 

• Are complete medical records available that would inform treatment planning? Until full record 

review and communication with the previous prescriber are completed, there are significant 

risks of taking over opioid prescribing even if it is with intent to taper. 

• Has the new plan of care been communicated to the previous prescriber and the patient? If it is 

felt that the regimen is too risky to take over the management with the resources available, 

then it is important to communicate this to the patient as well as the previous prescriber so that 

they can begin an exit plan for the patient as indicated. If the new provider feels comfortable 

taking over the OT, even if it is to start a taper, then this needs to be communicated to the 

previous prescriber as soon as possible to avoid duplication of prescriptions. 

K. Clinical Decision Support Tools 

There are electronic tools to facilitate clinical risk assessment and adherence to risk mitigation. Two tools 

currently used in the VA are the Opioid Therapy Risk Report (OTRR) and the Stratification Tool for 

Opioid Risk Mitigation (STORM). The OTRR allows VA providers to review clinical data related to opioid 

pain treatment within the electronic medical record (EMR), providing an efficient way of monitoring the 

data. The STORM tool incorporates co-occurring medical and mental health conditions, SUD, opioid dose, 

co-prescribed sedatives, and information about prior adverse events and generates estimates of patients’ 

risk or hypothetical risk when considering initiation of opioid therapy. It quantifies risk for poisoning or 

suicide-related events and for drug-related events, accidents, falls, and drug-induced conditions over a 

three-year window. Further, it provides suggestions as to what alternative treatments have not been tried 

and what risk mitigation strategies need to be applied. Evidence supporting their use is poor but they 

facilitate providers’ determination of current, past and potential therapies and strategies.
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VII. Guideline Work Group

Guideline Work Group*

Department of Veterans Affairs Department of Defense

Jack Rosenberg, MD, FASAM (Champion) Christopher Spevak, MD, MPH, JD (Champion)

Michael O. Chaffman, PharmD, BCPS Elizabeth Rees Atayde, RN, MSN, FNP, CCM, CPHM

Karen Drexler, MD LTC Robert Brutcher, PharmD, PhD 

Franz Macedo, DO Corinne Devlin, MSN, RN, FNP-BC

Aram Mardian, MD LTC William Grief, MD

Anthony J. Mariano, PhD James Hardin, LCSW-C, MAC

Ilene Robeck, MD Connie Kurihara, RN

Friedhelm Sandbrink, MD CDR Marisol Martinez, PharmD, MBA 

Maria Silveira, MD, MA, MPH Capt Erick C. Messler, PhD

Nancy Wiedemer, MSN, RN, ANP-BC LTC Jason Silvernail, DPT, DSc, FAAOMPT

CAPT Necia Williams, MD

Office of Quality, Safety and Value

Veterans Health Administration

Office of Evidence Based Practice

U.S. Army Medical Command 

Eric Rodgers, PhD, FNP-BC 

James Sall, PhD, FNP-BC

Rene Sutton, BS, HCA

Corinne K. B. Devlin, MSN, RN, FNP-BC 

Lewin Group ECRI Institute

Clifford Goodman, PhD

Christine Jones, MS, MPH, PMP

Erika Beam, MS

Anjali Jain, MD

Kristen E. D'Anci, PhD

Nancy M. Sullivan, BA

James Reston, PhD, MPH

Mrin Joshi, MS

Erin Payne, MS

Raj Stewart, PhD

Stacey Uhl, MS

Allison Gross, MLS

Sigma Health Consulting, LLC Duty First Consulting

Frances Murphy, MD, MPH Anita Ramanathan, BA

Megan McGovern, BA

*Additional contributor contact information is available in Appendix I.
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VIII. Discussion of Recommendations

A. Initiation and Continuation of Opioids

Recommendation

1. a) We recommend against initiation of long-term opioid therapy for chronic pain. (Strong against)

b) We recommend alternatives to opioid therapy such as self-management strategies and other

non-pharmacological treatments. (Strong for)

c) When pharmacologic therapies are used, we recommend non-opioids over opioids. (Strong for)

(Reviewed, New-replaced)

Discussion

As outlined in this CPG, there is a rapidly growing understanding of the significant harms of LOT even at 

doses lower than 50 mg oral morphine equivalent daily dose [MEDD], including but not limited to 

overdose and OUD. At the same time there is a lack of high quality evidence that LOT improves pain, 

function, and/or quality of life. The literature review conducted for this CPG identified no studies 

evaluating the effectiveness of LOT for outcomes lasting longer than 16 weeks. Given the lack of evidence 

showing sustained functional benefit of LOT and moderate evidence outlining harms, non-opioid 

treatments are preferred for chronic pain. Patient values, goals, concerns, and preferences must be 

factored into clinical decision making on a case-by-case basis. When considering the initiation or 

continuation of LOT, it is important to consider whether LOT will result in clinically meaningful 

improvements in function such as readiness to return to work/duty and/or measurable improvement in 

other areas of function, such that the benefits outweigh the potential harms.

While there is currently no evidence in the literature documenting the benefit of LOT that demonstrates 

improvement in pain and function, we recognize that in a rare subset of individuals a decision to initiate 

LOT may be considered (e.g., for intermittent severe exacerbations of chronic painful conditions). If a 

decision is made to initiate LOT, a careful assessment of benefits and risks should be made to ensure that 

the benefits are expected to outweigh the well-documented risks. In addition, prior to this consideration, a 

multimodal treatment plan should be integrated into the patient’s care. Once opioid therapy is initiated, 

all opioid risk mitigation strategies outlined in this guideline (see Recommendation 7) should be put into 

place. 

In 2011, in response to the recognition of pain and its management as a public health problem, the 

National Academy of Medicine investigated and reported on the state of pain research, treatment, and 

education in the U.S. The report called for a cultural transformation in the way pain is viewed and 

treated.[3] Accordingly, the U.S. Department of Health and Human Services (HHS) National Pain Strategy 

(March 2016) recommends a biopsychosocial approach to pain care that is multimodal and 

interdisciplinary.[26] The underlying concepts of the biopsychosocial model of pain include the idea that 

pain perception and its effects on the patient’s function is mediated by multiple factors (e.g., mood, social 

support, prior experience, biomechanical factors), not just biology alone. With this overall change in 

construct, a biopsychosocial assessment and treatment plan should be tailored accordingly. 

Psychological therapies (e.g., cognitive behavioral interventions such as Cognitive Behavioral Therapy 

[CBT], biofeedback) have been found to be effective for pain reduction in multiple pain conditions.[80-82] 
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Exercise treatments, including yoga, also have evidence of benefit for reducing pain intensity and disability 

when compared to usual care in the treatment of chronic pain conditions.[83-85] Exercise and 

psychological therapies may each exert their influence through multiple mechanisms including but not 

limited to the reduction in fear-avoidance, reduction in catastrophizing, and/or enhancing mood.[80] 

Similarly, multidisciplinary biopsychosocial rehabilitation (described as a combination of a physical 

intervention such as graded exercise and a psychological, social, or occupational intervention) has been 

shown to be more effective than usual care in improving pain and disability.[81] These interventions are 

safe and have not been shown to increase morbidity or mortality. 

In light of the low harms associated with exercise and psychological therapies when compared with LOT

these treatments are preferred over LOT, and should be offered to all patients with chronic pain including 

those currently receiving LOT. There is insufficient evidence to recommend psychological over physical 

therapies or vice versa; the choice of which to try first should be individualized based on patient 

assessment and a shared decision making process (see Patient Focus Group Methods and Findings).[80] 

In addition to non-pharmacological therapies (e.g., exercise, CBT), appropriate mechanism and conditionspecific non-opioid pharmacologic agents should be tried and optimized before consideration of opioid 

medications (e.g., gabapentin in neuropathic pain states).[83] Potential contraindications and long-term 

risks of use should be considered for non-opioid pharmacologic agents as well, as these also can carry risk 

of harm, depending on the specific patient and chosen medication.

Patient access to physical, psychological, and pain rehabilitation modalities should be considered. In some 

cases access to care may be limited; all VA and DoD clinics may not have access to multidisciplinary pain 

services. Still, all avenues for obtaining these treatments (e.g. Internet based CBT) and all appropriate nonopioid medications should be exhausted before consideration of LOT.[82] 

Further studies may help determine earlier in the course of treatment which patients are most likely to 

benefit from a specific non-pharmacologic therapy (physical, psychological, and pain rehabilitation) or nonopioid pharmacologic therapies alone or as part of a multimodal approach.

Recommendations

2. If prescribing opioid therapy for patients with chronic pain, we recommend a short duration.

(Strong for| Reviewed, New-replaced)

Note: Consideration of opioid therapy beyond 90 days requires re-evaluation and discussion with

patient of risks and benefits.

3. For patients currently on long-term opioid therapy, we recommend ongoing risk mitigation

strategies (see Recommendations 7-9), assessment for opioid use disorder, and consideration for

tapering when risks exceed benefits (see Recommendation 14).

(Strong for| Reviewed, New-replaced)

Discussion

The support for these recommendations is two-fold: a paucity of research showing benefit for LOT and the 

strength of the evidence demonstrating the potential for life-threatening harm. Of utmost concern is the 
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heightened risk for developing OUD in patients who receive OT beyond 90 days (see Appendix C for 

Diagnostic and Statistical Manual of Mental Disorders [DSM] 5 diagnostic criteria for OUD). 

Similar to other risk factors, continuing OT beyond 90 days’ duration should be weighed heavily in the riskbenefit calculus for LOT. Continuing OT for longer than 90 days is not an absolute contraindication to LOT. 

There may be some situations where the benefits of LOT clearly outweigh the risks. That must be 

determined through individual clinical assessment. 

Moderate quality evidence demonstrates that the prevalence of OUD in patients with CNCP is related to 

duration of opioid use as well as dose (see Recommendations 7-9).[86-88] There are two studies of 

patients with CNCP which support the current recommendations. Edlund et al. (2014) conducted a large 

retrospective cohort study where they examined claims data from a health insurance database between 

2000 and 2005 to examine factors predictive of developing OUD.[86] Days’ supply of opioids was 

categorized as none, acute duration (1-90 days), or chronic duration (91+ days). Average daily dose was 

defined as none, low (1-36 mg MEDD), medium (36-120 mg MEDD), or high (>120 mg MEDD). The OR of 

developing OUD ranged based on dose and duration (OR: 3.03, 95% CI: 2.32-3.95 for low dose, acute 

opioid prescription; OR: 14.92, 95% CI: 10.38-21.46 for low dose, chronic opioids prescriptions; OR: 3.10, 

95% CI: 1.67-5.77 for high dose, acute opioid prescriptions; OR: 122.45, 95% CI: 72.79-205.99 for high 

dose, chronic opioid prescriptions). They found that even greater than opioid dose, duration of OT was the 

strongest predictor of developing OUD. Additionally, a study by Boscarino et al. (2011) examined medical 

records from a large healthcare system.[89] Through interviews with a random sample of patients on LOT, 

they examined factors associated with and the prevalence of OUD (using DSM IV and 5 criteria). These 

results showed that the prevalence of lifetime OUD for patients on LOT was 34.9% (based on DSM-5 

criteria) and 35.5% (based on DSM-IV criteria). 

The relationship between OUD and duration of therapy is magnified when patients have a history of 

previous opioid or non-opioid SUD. A cross-sectional cohort study found that provision of LOT (four 

prescriptions within a 12 month period) to CNCP patients who had a history of severe OUD resulted in 

increased odds of developing OUD (OR: 56.36, 95% CI: 32.49-97.76).[88] 

Patients should be informed that progression from acute to long-term OT is associated with little evidence 

for sustained analgesic efficacy but a substantial increase in risk for OUD. Providers should discuss this

information with patients at initiation of OT and continuously thereafter to ensure that the patient 

understands the associated risks and benefits of LOT. Fully informed, some patients may desire 

continuation of OT while others may decline its continued provision. 

Research is necessary to more accurately determine how long it takes for OUD to occur and whether the 

nature of the pain is one of the factors that can influence either of this phenomena. 
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Recommendation

4. a) We recommend against long-term opioid therapy for pain in patients with untreated substance 

use disorder. (Strong against)

b) For patients currently on long-term opioid therapy with evidence of untreated substance use 

disorder, we recommend close monitoring, including engagement in substance use disorder

treatment, and discontinuation of opioid therapy for pain with appropriate tapering (see 

Recommendation 14 and Recommendation 17). (Strong for)

(Reviewed, Amended)

Discussion

Opioids carry a significant risk for OUD, overdose, and death, especially among patients with untreated 

SUD. The recommendation against LOT for patients with SUD is supported by five large studies (four 

retrospective case cohort studies and one case cohort study).[59,61,66,86,87] Individually, these studies 

are of moderate strength; however, the combined weight of their results is strongly supportive of this 

recommendation. Clinicians should note that this recommendation does not refer to patients whose sole 

SUD relates to tobacco misuse.

The Edlund et al. (2014) study of 568,640 commercial health plan patients (see Recommendation 2 and 3) 

found that those diagnosed with CNCP and an alcohol use or non-opioid drug use disorder had higher rates 

of OUD (OR: 3.22, 95% CI: 1.79-5.80 for patients with pre-index alcohol use disorder compared to no 

alcohol use disorder; OR: 8.26, 95% CI: 4.74-14.39 for patients with pre-index non-opioid drug use 

disorders compared to no non-opioid drug use disorders).[86] Moreover, Huffman et al. (2015) found that 

the presence of a lifetime history of SUD for patients with CNCP was associated with 28 times increased 

odds of therapeutic opioid addiction compared to patients with CNCP without a lifetime history of SUD

(OR: 28.58, 95% CI: 10.86-75.27).[87] 

The following three studies concern the serious risks of overdose and death. A study of 206,869 health 

maintenance organization patients who received opioid prescriptions and who had a diagnosis of an 

alcohol or drug use disorder were also found to have a significantly higher risk of overdose.[66] The VHA’s 

National Patient Care Database case cohort study of 154,684 patients also found that patients diagnosed 

with SUD and CNCP had a significantly elevated risk of overdose death (hazard ratio [HR]: 2.53, 95% CI: 

1.99-3.22) compared to patients with no SUD diagnosis.[59] The third study used a VHA database to 

review the outcomes of patients who had been prescribed chronic short-acting or long-acting opioids.[61] 

This study found that patients who received chronic short-acting or long-acting opioids and who were 

diagnosed with SUD had an increased risk of suicide attempts compared to those without an SUD diagnosis 

(OR: 2.42, standard error [SE]: 0.035 for chronic short-acting for patients with drug use disorder; OR: 2.83, 

SE: 0.057 for chronic long-acting for patients with drug use disorder; OR: 1.99, SE: 0.033 for chronic shortacting for patients with alcohol use disorder; OR: 1.87, SE: 0.056 for chronic long-acting for patients with 

alcohol use disorder).

Some patients with SUD may disagree with the recommendation to use non-opioid modalities in lieu of 

LOT to treat their pain. However, the lack of evidence of efficacy of LOT and considerable evidence of 

significant harms of overdose, death from overdose, and increased risk of suicide outweigh any potential 

modest benefit of prescribing LOT in this population. See Recommendation 7 for additional information 
VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

February 2017 Page 43 of 198

regarding UDT and risk mitigation. See the VA/DoD SUD CPG for guidance on management of SUD.

7

Given the increasing use of cannabis among patients with chronic pain and the lack of RCTs comparing 

outcomes of prescribing LOT versus other therapies for patients with and without cannabis use and 

cannabis use disorder, future research is needed to optimize care for these patients. Research is also 

needed to determine which subpopulations of patients with active SUD are at greatest risk of OUD, 

overdose, and death. Finally, further research is needed on the efficacy of alternative treatments for pain 

and ways to mitigate risks of opioid-related adverse events in patients with SUD and pain. 

Recommendation

5. We recommend against the concurrent use of benzodiazepines and opioids.

(Strong against | Reviewed, New-added)

Note: For patients currently on long-term opioid therapy and benzodiazepines, consider tapering

one or both when risks exceed benefits and obtaining specialty consultation as appropriate (see

Recommendation 14 and the VA/DoD Clinical Practice Guideline for the Management of

Substance Use Disorders).

Discussion

Harms may outweigh benefits for the concurrent use of benzodiazepines and LOT. There is moderate

quality evidence that concurrent use of benzodiazepines with prescription opioids increases the risk of 

overdose and overdose death.[66] In a retrospective cohort study, the adjusted odds ratio (AOR) for drug 

overdose was highest for individuals on LOT for chronic pain (without anxiety or PTSD) who also received 

concurrent long-term benzodiazepine therapy.[66] In another retrospective study that involved over 

200,000 participants (not included in the evidence review), Veterans receiving both opioids and 

benzodiazepines were at an increased risk of death from drug overdose.[90] Furthermore, there is a lack of 

evidence in favor of long-term therapy with benzodiazepines and opioids for chronic pain.[91] 

There is a large variation in patient preference regarding the concurrent use of benzodiazepines and LOT. 

This is especially true for patients who are already accustomed to receiving both medications (see Patient 

Focus Group Methods and Findings). Concurrent benzodiazepine and LOT use is a serious risk factor for 

unintentional overdose death and should be weighed heavily in the risk-benefit evaluation for tapering 

versus continuing one or both agents. Once initiated, benzodiazepines can be challenging to discontinue

due to symptoms related to benzodiazepine dependence, exacerbations of PTSD, and/or anxiety.[91] 

Moreover, abrupt discontinuation of benzodiazepines should be avoided, as it can lead to serious adverse 

effects including seizures and death. Tapering benzodiazepines should be performed with caution and 

within a team environment when possible (see Recommendation 26 in the VA/DoD SUD CPG).7 Due to the 

difficulty of tapering or discontinuing benzodiazepines, particular caution should be used when considering 

7 See the VA/DoD Clinical Practice Guideline for the Management of Substance Use Disorders. Available at: 

http://www.healthquality.va.gov/guidelines/mh/sud/index.asp
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February 2017 Page 44 of 198

initiating benzodiazepines for Veterans with PTSD who have co-occurring chronic pain. The VA/DoD PTSD 

CPG8 recommends against benzodiazepines for the prevention of PTSD and cautions against their use in 

treatment of PTSD. Benzodiazepines to treat acute anxiety symptoms after trauma are associated with a 

higher incidence of PTSD symptoms. For treatment of PTSD, there is evidence of lack of efficacy from small 

clinical trials and evidence of harm from observational studies of benzodiazepines for PTSD. Although 

anxiety may initially improve with benzodiazepines, the improvement is short-lived and may result in 

tolerance to increasing doses and eventual failure of the treatment. Even gradual benzodiazepine taper 

may result in exacerbation of severe PTSD symptoms. Concomitant use of benzodiazepines is considered a 

contraindication to initiation of OT. 

In addition to benzodiazepines, the addition of other psychoactive medications to LOT must be made with 

caution. While the evidence for harm associated with the combination of opioids and Z-drugs (e.g., 

zolpidem, eszopiclone) is not as strong as the evidence for harm associated with the combination of 

opioids and benzodiazepines, we suggest not prescribing Z-drugs to patients who are on LOT, as moderate 

quality evidence demonstrates that the combination of zolpidem and opioids increases the AOR of 

overdose.[66] The evidence reviewed also identifies potential adverse outcomes (e.g., risk of overdose) 

with the combined use of antidepressants and opioids in patients who do not have depression.[66] This 

particular study did not differentiate between classes of antidepressants, limiting the ability of the Work 

Group to recommend for or against prescribing opioids and a specific class of antidepressants. As such, 

there is no recommendation in this guideline with respect to using specific classes of antidepressants and 

LOT. 

Recommendation

6. a) We recommend against long-term opioid therapy for patients less than 30 years of age 

secondary to higher risk of opioid use disorder and overdose. (Strong against)

b) For patients less than 30 years of age currently on long-term opioid therapy, we recommend 

close monitoring and consideration for tapering when risks exceed benefits (see Recommendation 

14 and Recommendation 17). (Strong for)

(Reviewed, New-replaced) 

Discussion

All patients who take opioids chronically are at risk for OUD and overdose, but especially those who are 

younger than 30 years of age. Seven studies were identified that examined age as a predictor of OUD, 

respiratory/CNS depression, and/or overdose. Four of the seven studies were rated as fair quality 

evidence,[59,86,88,92] while three were rated as poor quality evidence.[58,62,87] Six of the seven studies 

demonstrated that age was inversely associated with the risk of OUD and overdose.[59,62,86-88,92] One 

 

8 See the VA/DoD Clinical Practice Guideline for the Management of Posttraumatic Stress Disorder and Acute Stress Disorder. 

Available at: http://www.healthquality.va.gov/guidelines/MH/ptsd/
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February 2017 Page 45 of 198

of the three low quality studies showed that older subjects had a higher HR of overdose.[58] The Work 

Group’s overall confidence in the quality of the evidence was moderate. 

Similar to other risk factors, age <30 years should be weighed heavily in the risk-benefit determination for 

initiating LOT. Age <30 years is not an absolute contraindication to LOT. There may be some situations 

where the benefits of LOT clearly outweigh the risks of OUD and overdose. Hospitalized patients 

recovering from battlefield injuries, for example, are known to have less chronic pain, depression, and 

PTSD when their pain is aggressively managed starting soon after injury.[93] In those cases, LOT may be 

appropriate only if risk mitigation strategies are employed and patients are titrated off LOT as soon as it is 

appropriate (see Recommendations 14 and 15).

The added risk that younger patients using opioids face for OUD and overdose is great. Edlund et al. (2014) 

found that, compared to patients ≥65 years old, patients 18-30 years old carried 11 times the odds of OUD 

and overdose. Patients 31-40 years old carried 5 times the odds of OUD and overdose compared to those 

≥65 years old.[86] Bohnert et al. (2011) found that, compared to subjects 18-29 years old, patients 30-39 

years old had roughly half the risk of developing OUD or overdose (HR: 0.56, 95% CI: 0.27-1.17). Compared 

to the subjects 18-29 years old, patients ≥70 years old had a far less risk (nearly 1/17) of developing OUD 

or overdose (HR: 0.06, 95% CI: 0.02, 0.18).[59] 

Younger patients are also at a higher risk of opioid misuse (as suggested by a UDT indicating high-risk 

medication-related behavior). Turner et al. (2014) showed that patients in the 45-64 year age group were 

significantly less likely to have an aberrant UDT (detection of a non-prescribed opioid, non-prescribed 

benzodiazepine, illicit drug, or tetrahydrocannabinol [THC]) in comparison to patients in the 20-44 age 

group.[94] Patients in the 45-64 and ≥65 age groups were significantly less likely than 20-44 year olds to 

have non-detection of a prescribed opioid as well (indicating possible diversion).[94] 

An age of 30 years was chosen based on how age was categorized in the six studies that showed an inverse 

relationship between age and OUD or overdose. One of those six studies found that patients with OUD 

were younger than patients without OUD, but did not find a statistically significant relationship.[87] Two of 

those six studies examined age as a continuous predictor, and neither reported a specific age where the 

risk of OUD or overdose changed markedly.[62,92] One study examined age as a dichotomous (<65 and 

≥65) predictor.[88] In the two remaining studies, the highest risk included ages ranging from 18 to 30 

years.[59,86] As such, the Work Group chose 30 years of age as a clinically reasonable threshold. 

Some may interpret the recommendation to limit opioid use by age as arbitrary and potentially 

discriminatory when taken out of context; however, there is good neurophysiologic rationale explaining 

the relationship between age and OUD and overdose. Studies in other areas (e.g., use of different 

substances) indicate that developing brains (age <30 years) are at increased risk of abnormalities and 

addiction when exposed to substance use early in life.[95-98] 

Toward augmenting this evidence base, we recommend that future observational research examine age as 

a continuous predictor of adverse outcomes. Additionally, we recommend that future trials examine which 

risk mitigation strategies can reduce the additional risk of OUD and overdose in younger patients on LOT. 

Lastly, a deeper understanding of the mechanisms for addiction to opioids in young brains is needed.
VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

February 2017 Page 46 of 198

B. Risk Mitigation

Recommendation

7. We recommend implementing risk mitigation strategies upon initiation of long-term opioid 

therapy, starting with an informed consent conversation covering the risks and benefits of opioid 

therapy as well as alternative therapies. The strategies and their frequency should be 

commensurate with risk factors and include:

• Ongoing, random urine drug testing (including appropriate confirmatory testing)

• Checking state prescription drug monitoring programs

• Monitoring for overdose potential and suicidality

• Providing overdose education 

• Prescribing of naloxone rescue and accompanying education 

(Strong for | Reviewed, New-replaced)

Discussion

Risk mitigation for LOT should begin before the opioids are prescribed, through an informed consent 

discussion, reviewing the patient’s history, checking state PDMPs, or instructing patients about using drug 

take back programs to dispose of unused medication. It should also occur concurrently with the therapy 

(e.g., ongoing UDT, OEND) and in response to adverse events (e.g., needle exchange programs for those 

who develop an intravenous drug use disorder). The 2010 OT CPG recommended use of an opioid pain 

care agreement, monitoring for appropriate opioid use, and, with patients’ consent, obtaining a UDT. A 

literature search was conducted dating back to the original 2010 recommendation to identify studies 

comparing the effectiveness of different risk mitigation strategies for patients on or being considered for 

LOT. One identified study was a systematic review of 11 studies looking at opioid treatment agreements 

(OTAs) and UDT strategies utilizing opioid misuse risk reduction as the main outcome measure.[99] The 

study revealed weak evidence to support the use of OTAs and UDT. A second study, a retrospective 

database study, demonstrated decreased risk of suicide attempts in various cohorts with frequent UDT, 

regular follow-up (including follow-up within four weeks for patients with new opioid prescription), and 

rehabilitative services are offered.[61] The confidence in the quality of the evidence was moderate for the 

outcome of attempted suicide risk. The third study was a retrospective cohort study that looked at the 

intervention of a clinical pharmacist guidance team versus control.[100] Outcome measures included 

adverse events, pain management, and quality of life. Details of the actual intervention were vague and 

did not necessarily include OTAs or UDT. Thus, the confidence in the quality of the evidence was very low. 

The confidence in the quality of the evidence was moderate for UDT and frequent follow-up and was low 

for OTAs. The frequency of follow-up and monitoring should be based on patient level of risk as 

determined by an individual risk assessment. 

There may be some variation in patient values and preferences. Certain patients may appreciate the use of 

risk mitigation strategies and others may not. Participants in the patient focus group expressed an 

understanding of why various risk mitigation strategies were used (see Patient Focus Group Methods and 

Findings).

Implementing more extensive risk mitigation strategies entails an investment of resources. Primary care 

providers may require more time with patients to allow for shared decision making and treatment 
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February 2017 Page 47 of 198

planning. More frequent follow-up of patients on LOT can affect access to care for all empaneled patients. 

VHA providers must also follow VHA policy regarding education and signature informed consent when 

providing LOT for patients with non-cancer pain.[101] 

Written Informed Consent and Opioid Treatment Agreements

There is a paradigm shift occurring in approaches to ensuring and documenting patient and provider 

understanding and expectations regarding the risks and benefits of LOT. The 2010 OT CPG reflected prior 

practice of using opioid treatment (or pain care) agreements. OTAs have been described as coercive rather 

than therapeutic, lack respect for individual autonomy, can be a barrier to pain care, and may be harmful 

to the patient-provider relationship.[102-105] 

Given the recognized risks of opioid therapy, an optimal approach to care should include a robust, 

signature informed consent process that is patient-centered and provides patients with information about 

known benefits and harms of OT and treatment alternatives. In 2014, VA established a requirement for 

signature informed consent, consistent with VA policy for other treatments or procedures with a 

significant risk of complications or morbidity. See Appendix A, Taking Opioids Responsibly for Your Safety 

and the Safety of Others: Patient Information Guide on Long-term Opioid Therapy for Chronic Pain (found 

at 

http://www.healthquality.va.gov/guidelines/Pain/cot/OpiodTheraphyforChronicPainPatientTool20May20

13print.pdf), and 38 C.F.R. §17.32 (2012).

Patients may decline offered treatments (e.g., OT) and may also decline risk mitigation strategies (e.g., 

UDT, pill counts) that are recommended in the course of clinical care. However, providers should discuss 

this decision with the patient, including the likelihood that their decision may result in the risks of LOT 

outweighing its potential benefits. This would require a consideration of patient’s safety, and a clinical 

decision may be made not to initiate OT or to discontinue ongoing OT through tapering (see 

Recommendation 14 and Recommendation 17).

State Prescription Drug Monitoring Programs

State database queries for detection of multi-sourcing of controlled substances are used throughout the 

country. Data comparing states with an implemented state database program to states without one 

showed 1.55 fewer deaths per 100,000 people.[106] The CDC currently recommends at least quarterly 

checks of the state database system.[33] 

Urine Drug Testing and Confirmatory Testing

As substance misuse in patients on LOT is more than 30% in some series,[107] UDT and confirmatory 

testing is used as an additional method of examining for patient substance misuse and adherence to the 

prescribed regimen. UDTs, used in the appropriate way, help to address safety, fairness, and trust with OT. 

Availability of accurate and timely confirmatory testing (e.g., gas chromatography-mass spectrometry 

[GCMS]) is critical due to the false positive and negative rates associated with UDTs.[53] Interpretation of a 

UDT and confirmatory results requires education and knowledge of the local procedures and clinical 

scenario. Local education and access to expert interpretation is necessary.

UDT results are helpful and can help identify active SUD or possible diversion. Accordingly, clinicians should 
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February 2017 Page 48 of 198

obtain UDT prior to initiating or continuing LOT and periodically thereafter. When a patient is referred for 

SUD treatment or is engaged in on-going treatment there should be close communication between the 

SUD and pain management providers. The ideal approach is an interdisciplinary format (see 

Recommendation 16). 

For more information, see Appendix B on UDT and confirmatory testing.

Prescribing of Naloxone Rescue and Accompanying Education

Naloxone administration has been identified as a life saving measure following opioid overdose. A 

systematic review of 22 observational studies provided moderate quality evidence that take home 

naloxone programs are effective in improving overdose survival and decreasing mortality, with a low rate 

of adverse events.[108] One meta-analysis of nine studies determined that take home naloxone kits were 

used approximately nine times within the first three months of follow-up for every 100 individuals 

trained.[109] Further, studies have shown that naloxone administration has been efficacious whether 

given by medical personnel or lay people, with more than 26,000 reversals documented by the CDC from 

1996-2014.[110,111] In addition, prescription of naloxone rescue and accompanying education has also 

been found to reduce opioid-related emergency department visits.[112] Distribution of naloxone for 

reversal is supported by SAMHSA, the American Medical Association (AMA), and other medical societies, 

and is facilitated through the VA via Pharmacy Benefits Management. Clinical efficacy has been established 

for its use on short-acting opioids, but not for its use on long-acting opioids such as methadone or 

exceptionally potent opioids.[108] 

Synthetic opioids such as fentanyl analogs, potent opioid receptor agonists, are responsible for a recent 

rise in death rates. Fentanyl analogs that may be used to create counterfeit opioid analgesic pills can cause 

a toxidrome characterized by significant CNS and profound respiratory depression requiring multiple 

naloxone doses for reversal.[113] 

Patients at High Risk for Opioid Use Disorder

Those patients receiving opioid analgesics who do not meet DSM-5 criteria for OUD may benefit from an 

alternative management strategy: close follow-up and CBT. Jamison et al. (2010) randomized patients at 

high-risk for OUD (as measured by standard rating scales) to receive either standard pain management or 

close follow-up with CBT for pain.[114] Both of these groups were compared to a low-risk, chronic pain 

control group receiving standard management. The authors report that, compared to a matched high-risk 

group receiving standard care, patients receiving additional monitoring and CBT exhibited significantly 

reduced illicit substance use over six months (percentage of patients with positive drug misuse index 

scores: 73.7% versus 26.3% versus 25.0%; p<0.01). At six months, there was no difference between the 

high-risk group receiving close follow-up and the low-risk group receiving standard therapy. Authors also 

reported that pain perception was less in the high-risk group receiving additional monitoring and behavior 

therapy; however, analysis of activity interference reporting reflected no significant difference between 

study groups. 
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February 2017 Page 49 of 198

Other Risk Mitigation Strategies

Take Back Programs

Returning unused opioid medications has been explored as a strategy to reduce the amount of opioids in 

the community, as it has been estimated that 70% of opioid prescriptions are left unused.[115] 

Accordingly, the National Drug Control Strategy advocates take back programs as an effective tool.[24] For 

example, in a 2013 medication take back event in a Michigan community, 3,633 containers containing 345 

different prescription medications were collected in four hours. The top five most common medications 

collected were pain relievers.[116] System-wide efficacy of a nationwide program is unknown.[117] 

Community-based Needle Exchange Programs or Syringe Service Programs 

Nearly 80% of new users of injectable opioids had previously used prescription oral opioid pain 

medication.[118,119] Illicit use of injectable opioids is accompanied by an increased rate of human 

immunodeficiency virus (HIV) and hepatitis infection. Community-based needle exchange programs have 

been shown to be an effective risk mitigation strategy for reducing high-risk behaviors (e.g., sharing 

needles) and infectious disease transmission among injection drug users.[120] For those patients who 

develop OUD and progress to intravenous drug use, the first recommendation should be for medicationassisted treatment (MAT) for OUD (see Recommendation 17). For patients who decline MAT for OUD, 

clinicians should consider educating the patient regarding sterile injection techniques and communitybased needle exchange programs, if programs are available. The 2015 outbreak of HIV/hepatitis in rural 

Indiana and subsequent successful implementation of a needle exchange program is an example of the 

threat to rural communities from non-prescription opioid use and the potential benefits of needle 

exchange programs for use as a risk mitigation strategy.[121,122] 

Recommendation

8. We recommend assessing suicide risk when considering initiating or continuing long-term opioid

therapy and intervening when necessary.

(Strong for | Reviewed, Amended)

Discussion

Opioid medications are potentially lethal and an assessment of current suicide risk should be made at 

every phase of treatment. The VA/DoD Suicide CPG9 recommends restricting the availability of lethal 

means for patients considered to be at intermediate or high acute risk of suicide (determined by presence 

and severity of suicidal ideation, level of intention to act, existence of risk factors, limited or absent 

protective factors, etc.). Accordingly, suicidality is considered to be an important risk factor for OT (see Risk 

Factors for Adverse Outcomes of Opioid Therapy).

9 See the VA/DoD Clinical Practice Guideline for Assessment and Management of Patients at Risk of Suicide. Available at: 

http://www.healthquality.va.gov/guidelines/MH/srb/ 
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February 2017 Page 50 of 198

A number of studies suggest certain chronic pain conditions represent an independent risk factor for 

suicide.[123-130] A recent large retrospective cohort study also suggests an association with prescribed 

opioid dose and suicide risk among Veterans receiving OT for CNCP.[131] Suicide risk is not static, and 

many factors influence an individual’s risk of suicide at any given point in time, as noted in the VA/DoD 

Suicide CPG.10 Thus, ongoing assessment of suicide risk is important whether one is initiating, maintaining, 

or terminating LOT. 

There is moderate quality evidence that intensification of monitoring helps mitigate the risk of suicide 

among patients on LOT. Im et al. (2015) found moderate quality evidence that, at the facility level, patients 

on LOT within facilities ordering more drug screens than the comparison group were associated with 

decreased risk of suicide attempt (chronic short-acting opioid group: OR: 0.2, 95% CI: 0.1-0.3; chronic longacting opioid group: OR: 0.3, 95% CI: 0.2-0.6). In addition, patients on long-acting opioids within the 

facilities providing more follow-up after new prescriptions were associated with decreased risk of suicide 

attempt (OR: 0.2, 95% CI: 0.0-0.7).[61] 

Some patients on LOT who suffer from chronic pain and co-occurring OUD, depression, and/or personality 

disorders may threaten suicide when providers recommend discontinuation of opioids. However, 

continuing LOT to “prevent suicide” in someone with chronic pain is not recommended as an appropriate 

response if suicide risk is high or increases. In such cases, it is essential to involve behavioral health to 

assess, monitor, and treat a patient who becomes destabilized as a result of a medically appropriate 

decision to taper or cease LOT. 

Further research is needed to identify strategies for safely managing patients at elevated risk of suicide 

who demand opioid medications or become further destabilized during tapering. 

Recommendation

9. We recommend evaluating benefits of continued opioid therapy and risk for opioid-related

adverse events at least every three months.

(Strong for | Reviewed, New-replaced)

Discussion 

Prior to initiating OT, an individualized assessment of potential opioid-related harms relative to realistic 

treatment goals must be completed. After initiating OT, frequent visits contribute to the appropriate use 

and adjustment of the planned therapy. 

The Work Group recommends follow-up at least every three months or more frequently (see 

Recommendation 7 and Recommendation 11) due to the balance of benefits and harms associated with 

this recommendation. Although the 2010 OT CPG recommended follow-up every six months, this 

10 See the VA/DoD Clinical Practice Guideline for Assessment and Management of Patients at Risk of Suicide. Available at: 

http://www.healthquality.va.gov/guidelines/MH/srb/ 
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recommended interval for follow-up and reassessment has not been sufficient to reduce the potential 

harm associated with LOT or adequately implement comprehensive, biopsychosocial pain care. More 

frequent follow-up is needed in order to increase the impact of risk mitigation strategies and enhance the 

delivery of comprehensive, biopsychosocial pain care. Frequency of visits should thereafter be based on 

risk stratification. Similarly, the CDC guideline for OT recommends re-evaluating harms versus benefits 

within one to four weeks of starting OT or at any dose change, and at least every three months or more 

frequently if needed.[132] 

At follow-up visits, a clinician should re-examine the rationale for continuing the patient on OT. Clinicians 

should take into account changes in co-occurring conditions, diagnoses/medications, and functional status 

when conducting the risk/benefit analysis for LOT. Alcohol use, pregnancy, nursing of infants, and lab 

abnormalities may change the risk/benefit calculus for LOT. Ongoing OT prescribing practice may include 

pharmacy review, informed consent, UDTs, and checking state PDMPs. A clinician should also be mindful 

of signs of diversion during follow-up (see Risk Factors for Adverse Outcomes of Opioid Therapy). The 

longer the patient is on opioids, the greater the potential for change in patient status and development of 

opioid-related harms.

C. Type, Dose, Duration, Follow-up, and Taper of Opioids

Recommendations 

10. If prescribing opioids, we recommend prescribing the lowest dose of opioids as indicated by

patient-specific risks and benefits.

(Strong for | Reviewed, New-replaced)

Note: There is no absolutely safe dose of opioids.

11. As opioid dosage and risk increase, we recommend more frequent monitoring for adverse events

including opioid use disorder and overdose.

• Risks for opioid use disorder start at any dose and increase in a dose dependent manner.

• Risks for overdose and death significantly increase at a range of 20-50 mg morphine

equivalent daily dose.

(Strong for | Reviewed, New- replaced) 

12. We recommend against opioid doses over 90 mg morphine equivalent daily dose for treating

chronic pain.

(Strong against | Reviewed, New-replaced)

Note: For patients who are currently prescribed doses over 90 mg morphine equivalent daily dose,

evaluate for tapering to reduced dose or to discontinuation (see Recommendations 14 and 15).

Discussion

There is moderate quality evidence from retrospective cohort and retrospective case control studies 

indicating that risk of prescription opioid overdose and overdose death exists even at low opioid dosage 

levels and increases with increasing doses. Significant risk (approximately 1.5 times) exists at a daily dosage 

range of 20 to <50 mg MEDD and further increases (approximately 2.6 times) at a range of 50 to <100 mg 
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February 2017 Page 52 of 198

MEDD compared to risk at <20 mg MEDD. Risk continues to increase at higher dosage ranges (≥100 mg 

MEDD) (Table 2).[58,59,66,133] 

Table 2. Risks of Prescription Opioid Overdose and Overdose Death at Selected Morphine 

Equivalent Daily Dose Intervals [58,59,66,133] 

Study Expression 

of risk

MEDD (mg)

0 1 to 19 20 to <50 50 to <100 ≥100

Turner and 

Liang (2015)1

[66] 

AOR

(95% CI) 1 

0.80

(0.50-1.27)

1.54

(1.23-1.94)

2.08

(1.61-2.69)

4.34

(3.37-5.57)

Zedler et al. 

(2014)1,2,3 [58] 

OR

(95% CI) - 1 

1.5

(1.1-1.9)

2.2

(1.5-3.2)

4.1

(2.6-6.5)

Dunn et al. 

(2010)1 [133] 

HR

(95% CI)

0.19

(0.05-0.68) 1 

1.19

(0.40-3.60)

3.11

(1.01-9.51)

11.18

(4.80-26.03)

Bohnert et al. 

(2011)1,3 [59] 

HR

(95% CI) - 1 

1.88

(1.33-2.67)

4.63

(3.18-6.74)

7.18

(4.85-10.65)

Bohnert et al. 

(2011)2,3 [59] 

HR

(95% CI) - 1 

1.74

(0.69-4.35)

6.01

(2.29-15.78)

11.99

(4.42-32.56)

1

Chronic non-cancer pain; 2Chronic cancer pain; 3Study conducted in U.S. Veterans

Abbreviations: AOR: adjusted odds ratio; 95% CI: 95% confidence interval; HR: hazard ratio; MEDD: morphine 

equivalent daily dose; OR: odds ratio

In a nested case-control study of U.S. Veterans (not included in our evidence review as it was published 

after the end of the search date range), Bohnert et al. (2016) examined the association between 

prescribed opioid dose as a continuous measure (in 10 mg MEDD increments) and overdose.[134] 

Prescribed opioid dosage was a moderately good predictor of overdose death, but the study did not reveal 

a specific dosage cut point or threshold above which risk of overdose increased dramatically. Lower 

prescribed opioid dosages were associated with reduced risk for overdose, but risk was not completely 

eliminated at lower doses; approximately 40% of overdoses were observed in patients who were 

prescribed <50 mg MEDD. 

In a prospective cohort study (not included in the evidence review as it did not include information on 

acute versus chronic pain in the patient population), Dasgupta et al. (2015) compared residents of North 

Carolina who had received an opioid prescription in the last year to residents who had not. The study 

examined the outcome of population-based rates of opioid overdose mortality by opioid dose, without use 

of a presupposed threshold (Table 3).[135] There was no safe dose of opioid. Among the over nine million 

individuals followed for one year, 629 died from opioid overdose. Of these 629 individuals, 151 had no 

record of having been dispensed an opioid. It is possible these opioids were obtained through illicit 

channels or social sharing/diversion. Of the 478 patients who died from an opioid overdose who were 

prescribed opioids, 235 (49%) had been prescribed <80 mg MEDD. Overdose incidence rate ratios (IRRs) 

doubled each time the MEDD ranges increase from 60.0-79.9 mg to 80.0-99.9 mg (IRR 2.9 to 6.2), then to 

120-139.9 mg (IRR 14.1), 160-179.9 mg (IRR 29.5), and 350-399.9 mg (IRR 63.2). 
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Table 3. Incidence Rate Ratios for Opioid Overdose Deaths, by Average Milligrams Morphine 

Equivalent Daily Dose[135] 

MEDD

(mg) Deaths Person-Years Sample Size IRR 95% CI

Unexposed 151 3,554,850 7,377,860 0.57 0.44-0.73

>0 - 39.9 98 1,305,835 1,305,969 1

40 - 59.9 90 457,227 457,322 2.6 2.0-3.5

60 - 79.9 47 213,816 213,868 2.9 2.1-4.1

80 - 99.9 34 72,448 72,483 6.2 4.2-9.2

100 - 119.9 23 45,536 45,559 6.7 4.3-10.6

120 - 139.9 22 20,699 20,721 14.1 8.9-22.5

140 - 159.9 14 14,586 14,599 12.8 7.3-22.4

160 - 179.9 15 6,769 6,784 29.5 17.1-50.7

180 – 199.9 11 9,604 9,615 15.2 8.2-28.4

200 – 249.9 24 11,653 11,678 27.4 17.5-42.8

250 – 299.9 20 7,406 7,425 35.9 22.2-58.0

300 – 349.9 17 4,495 4,512 50.2 30.0-84.0

350 – 399.9 17 3,563 3,580 63.2 37.8-105.7

400 – 499.9 14 3,527 3,541 52.7 30.1-92.2

500 – 5000 32 4,684 4,718 90.4 60.7-134.6

Total 629 5,736,696 9,560,234 -- --

Abbreviations: 95% CI: 95% confidence interval, IRR: incidence rate ratios; MEDD: morphine equivalent daily dose; 

mg: milligram(s)

Achieving an improved understanding of the factors contributing to prescription opioid-related overdose is 

an essential step toward addressing this epidemic problem. Although it is widely accepted that 

progressively higher doses of prescribed opioids result in correspondingly higher risks of opioid overdose, 

patients using any dose of opioids can still experience life-threatening respiratory or CNS depression, 

especially when opioid-naïve. This risk begins to increase with MEDD as low as 20-50 mg. Risk is further 

increased when certain concomitant demographic factors, co-occurring medical or psychiatric conditions, 

or interacting medications or substances exist. 

Recognizing the lack of evidence of long-term benefit associated with LOT used alone and the risks of 

harms with use of opioids without risk mitigation, dosing determinations should be individualized based 

upon patient characteristics and preferences, with the goal of using the lowest dose of opioids for the 

shortest period of time to achieve well-defined functional treatment goals. Understandably, there will be 

greater mortality, co-occurring medical conditions, and other adverse events in patients who require 

higher doses of opioids, even in those who benefit from such therapy. When closer follow-up is needed, 

healthcare resources and patient adherence should be considered. 

Subgroups at higher risk

Risk of prescription opioid overdose is elevated across MEDD dosage levels in patients with co-occurring

depression (moderate quality evidence).[66,133] Following an elevated baseline adjusted risk ratio (ARR) 

of 3.96, depressed patients taking 1-19 mg, 20 to <50 mg, 50 to <100 mg, and ≥100 mg MEDD had 
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respective odds of overdose of 4.75, 5.47, 6.44, and 7.06, compared to those taking an opioid at the same 

dosage level without a diagnosis of depression.[66] 

Similarly, a history of or active SUD increases risk for serious prescription opioid-related toxicity or 

overdose across opioid dosages (moderate quality evidence).[58,87,133] A retrospective cohort review of 

patients with CNCP receiving LOT at least five days per week for 90 days determined that those with a 

history of non-opioid SUD had 28 times the odds of developing OUD.[87] Each 50 mg increase in MEDD 

nearly doubled the odds while each 100 mg MEDD increase tripled the risk for OUD. Concurrent 

prescribing of sedative-hypnotics and benzodiazepines increases risk of fatal or non-fatal opioid overdose 

2-10 fold across opioid dose ranges.[66,133,135] 

There is moderate quality evidence to support that opioids taken PRN (as needed) for chronic cancer pain 

versus regularly scheduled doses, or simultaneous PRN plus regularly scheduled, places patients at 

elevated risk for opioid overdose (HR: 2.75, 95% CI: 1.31-5.78 for as needed; HR: 1.00 for regularly 

scheduled; HR: 1.84, 95% CI: 0.83-4.05 for simultaneous PRN plus regularly scheduled).[59] 

In patients receiving LOT, moderate quality evidence indicated that men are 50% more likely (HR: 1.44, 

95% CI: 1.21-1.70) to escalate to high-dose opioids (defined as >200 mg MEDD) and twice as likely to 

experience an opioid-related death (adjusted HR: 2.04, 95% CI: 1.18-3.53) compared to women.[136] Risk 

of opioid overdose morbidity or mortality is also increased in non-Hispanic white versus non-Hispanic black 

patients (moderate quality evidence).[59,136]

Future Research

Future research is needed to better determine the impact of systematic reductions in MEDD in terms of 

pain relief, specific pain and medical conditions, overdose morbidity and mortality as well as potential 

adverse outcomes (e.g., the incidence of associated OUD, infectious diseases related to intravenous drug 

use disorder, and drug-related crime and diversion) and to determine whether/which conditions may be 

appropriately treated with LOT. Research is also needed to determine how frequency of monitoring should

be impacted by dose.

Recommendation

13. We recommend against prescribing long-acting opioids for acute pain, as an as-needed

medication, or on initiation of long-term opioid therapy.

(Strong against| Reviewed, New- replaced)

Discussion 

Long-acting opioids, as further discussed below, should not be used for treatment of acute pain, on an asneeded basis, or during initiation of LOT (see Short-acting versus Long-acting Opioids). In general, 

however, no single opioid or opioid formulation is preferred over the others. However, individuals may 

have a better response, degree of safety, or tolerability depending on their individual characteristics and 

preferences. Additional information for use when deciding on appropriate pharmacological treatment of 

pain for a specific patient can be found in Appendix D. 
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There was insufficient evidence to recommend for or against any specific opioid or opioid formulation, 

specifically the following:

• Short-acting versus long-acting opioids (for LOT for chronic pain) 

• Route of administration/delivery among alternatives such as transdermal, buccal, sublingual, or 

pumps

• Abuse deterrent formulations of opioids compared to non-abuse deterrent formulations 

• Tramadol and other dual-mechanism opioids

• Buprenorphine for pain (compared to other opioids)

• Methadone (with QT monitoring)

Short-acting versus Long-acting Opioids

Avoid use of long-acting agents for acute pain (with exception of oxycodone/acetaminophen extendedrelease [ER] tablets), on an as-needed basis, or for initiation of OT.[10,137-139] There is very low quality 

evidence to recommend for or against short-acting versus long-acting opioids for maintenance of OT. 

There were two RCTs included in the evidence review that looked at safety and efficacy. One RCT 

comparing long-acting to short-acting dihydrocodeine found no statistically or clinically significant 

differences in stability of pain intensity between the two groups, as well as no difference in adverse events.

Although study results may be inconclusive due to poor study design, the authors state that they do not 

support the use of long-acting agents for chronic non-malignant pain.[140] 

A second non-inferiority RCT compared once-daily hydromorphone ER to twice-daily oxycodone 

controlled-release in patients with moderate-to-severe cancer pain. The primary efficacy endpoint was 

patient assessment of “Brief Pain Inventory (BPI) worst pain in the past 24 hr.” Results demonstrated 

similar improvements in BPI and that the once-daily hydromorphone formulation was non-inferior to the 

twice-daily oxycodone formulation. Treatment-emergent adverse events were comparable between the 

groups as well.[141] The efficacy of long-acting opioids used once-daily is non-inferior to twice-daily use.

There was a lack of statistical analysis of the outcomes and a lack of statistical power in both studies, and a 

small sample size in one study. 

There is concern for additional overdose risk associated with long-acting versus short-acting opioids. A 

study (not included in the evidence review due to its design) suggests increased risk for non-fatal overdose 

in VA patients with initiation of a long-acting opioid compared with immediate-release opioids.[137] Also, 

recent research demonstrates that patients with CNCP on long-acting OT have a significantly increased risk 

of all-cause mortality compared to patients with CNCP who are taking an analgesic anticonvulsants or a 

low-dose antidepressant.[10] 

Route of Administration/Delivery

The systematic evidence review for this CPG did not find any studies that compared alternative delivery 

systems (e.g., fentanyl transdermal, fentanyl buccal) to other delivery systems (e.g., oral, intravenous) 

(information on transdermal and sublingual buprenorphine is included in the following section on 

Buprenorphine for Pain). The concomitant use of oral and transdermal opioids or oral and intrathecal 
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pumps should be approached with extreme caution and warrants specialty consultation. Discussions of 

intrathecal pumps are beyond the scope of this guideline.

Although some patients may prefer either transdermal or buccal opioid delivery for opioids, there is 

significant potential for harm from OT with these delivery mechanisms, with no evidence of benefit over 

traditional opioid delivery systems in patients with chronic pain. Clinicians need to be especially aware of 

the risks associated with a fentanyl transdermal delivery system (or patch) (Appendix D) including its:

• Unique pharmacokinetic profile

• Continuous delivery, even after the patch is removed due to depot effect

• Increased rate of delivery

• Unpredictable variation in rate of delivery 

 Due to alterations in temperature due to external heat, skin integrity, and amount of 

adipose tissue 

 Among patients with fever, skin damage, or cachexia 

Given the potential serious risks with starting fentanyl and challenges with tapering, clinicians intent on 

prescribing transdermal fentanyl for chronic pain are encouraged to consult with other clinicians (e.g., pain 

specialists, pharmacists) and to be familiar with the unique properties of fentanyl. Specific safety 

precautions that all clinicians should be aware of regarding transdermal fentanyl include: 

• Transdermal fentanyl should not be used in opioid-naïve patients

• Patients need to be informed that:

 Heat (e.g., sun exposure, heating pad, febrile condition) can increase the rate and quantity 

of absorption

 Proper application includes: being sure to take old patch off; never applying damaged patch 

or a patch to non-intact skin; proper disposal to avoid exposure to children and pets, and 

precautions taken against possible diversion of remaining drug in used patch

• Adjusted dose (i.e., decreased patch size) should be used in patients with renal or hepatic 

insufficiency and considered in elderly patients and those with febrile illness

Abuse Deterrent Formulations of Opioids

The aim of most abuse deterrent formulations is to present a physical barrier to prevent chewing, 

crushing, cutting, grating, or grinding of the dosage form, or present a chemical barrier, such as a gelling 

agent, that will resist extraction of the opioid with use of a common solvent. Alternatively, an opioid 

antagonist (naloxone or naltrexone) can be added to interfere with, reduce, or defeat the euphoria 

associated with abuse of an agent intended for oral use when taken nasally or parenterally.[142] While 

these properties deter abuse they do not fully prevent abuse; no opioid formulation prevents consumption 

of a large number of intact capsules or tablets which continues to be the most common method of abuse. 

We do not recommend for or against abuse deterrent formulations for LOT. Our searches identified two 

RCTs in which the benefits of co-prescribing of naloxone with opioids were examined.[143,144] However, 
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both RCTs were rated as low to very low quality with short-term follow-up. One open-label RCT enrolling 

453 patients with chronic low back pain considered the safety and tolerability of an abuse deterrent

formulation of oxycodone/naloxone relative to oxycodone or morphine at 12-week follow-up.[143] 

Another RCT considered the safety and efficacy of oxycodone/naloxone prolonged-release relative to 

oxycodone prolonged-release in 184 patients with moderate-to-severe chronic cancer pain at four-week 

follow-up.[144] An observational study (not included in the evidence review) suggested that the 

introduction of abuse deterrent opioid formulations did not help reduce abuse of opioids as a class and 

that patients may switch from one opioid to another based on the availability or the lack of availability of 

abuse deterrent formulations.[145] 

Future research is needed to ascertain whether abuse deterrent formulations actually reduce OUD when 

used for chronic pain, and whether said formulations differ across clinical outcomes such as pain, function, 

and adverse events. 

Dual-Mechanism Opioids

Dual-mechanism opioids include formulations of an opioid medication with a selective serotonin reuptake 

inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI). Two common examples are 

tramadol and tapentadol. While both are dual-mechanism opioids, they differ in their affinity for the mu 

opioid receptor, resulting in partial versus full agonist effects, and as such are discussed separately. 

Tramadol

There is low quality evidence that tramadol may be more effective than placebo for pain relief. In one 

short-term study, compared to placebo, tramadol was more effective for pain.[146] There is no long-term 

evidence of the comparative efficacy of tramadol versus another opioid or a non-opioid comparison such 

as non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen. Due to tramadol’s partial mu 

agonist activity and demonstrated safety profile when used in conjunction with acetaminophen in elderly 

patients, it may be a preferred agent in that patient group.[147,148]

Tapentadol

In long-term studies, compared to placebo, low quality evidence indicates that tapentadol is more 

effective for pain-related primary and secondary outcomes, but results were mixed for several different 

self-reported quality of life measures in these studies.[149-151] Compared to oxycodone, moderate 

quality evidence suggests that tapentadol might be more effective for pain relief. Low quality evidence 

suggests there is no difference in serious adverse events. Moderate quality evidence suggests tapentadol 

might be superior for avoiding non-serious adverse events or discontinuation of treatment due to adverse 

events; however, the clinical implications of these findings are unclear.[149] 

Safety and Risk Mitigation

All recommendations in this CPG apply to dual-mechanism opioid products, including the 

recommendations regarding safety measures and risk mitigation strategies (e.g., to monitor for suicidality, 

accidental overdose, and OUD).

Dual-mechanism opioid medications have additional considerations as a result of their dual action. They 

include a lowering of seizure threshold in susceptible patients and the risk of serotonin syndrome. 
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Evidence related to safety of dual-mechanism opioids versus placebo was reviewed. No evidence on the 

safety of tramadol met our inclusion criteria, and no new evidence was reviewed. Tramadol may be 

considered lower-risk than tapentadol due to its mechanism of action and existing safety profile as noted 

above. Evidence on the safety of tapentadol was reviewed for this guideline update. In long-term studies, 

there is low quality evidence that, when compared to placebo, patients experience more adverse events 

when taking tapentadol. Some severe adverse events experienced by a small portion of patients receiving 

tapentadol included chest pain,[150,151] coronary artery disease,[151] and severe upper abdominal pain 

possibly related to the study drug.[150] There was one death due to myocardial ischemia but this was not 

likely related to tapentadol. In one study comparing tapentadol versus placebo, minor adverse events 

observed in patients treated with tapentadol included nausea and vomiting in 21.1% and 12.7% of 

patients, respectively.[151] In short-term studies, there is overall low to very low quality evidence that, 

when compared to placebo, patients receiving tapentadol experience more adverse events (e.g., vomiting, 

tiredness, dry mouth, dizziness, sweating, constipation, nausea) and drop out of treatment more often 

than the placebo groups.[146,152-154] 

Buprenorphine for Pain

There is insufficient evidence to recommend buprenorphine over other opioids for the treatment of 

chronic pain. Transdermal buprenorphine was found to be efficacious and well-tolerated for the shortterm treatment of chronic, moderate-to-severe low back pain.[155] In patients with chronic, moderate-tosevere osteoarthritis (OA) pain of the hip and/or knee, short-term use of seven-day low-dose 

buprenorphine patches were an effective and well-tolerated analgesic.[156] Furthermore, during a 28-day 

assessment period, seven-day low-dose transdermal buprenorphine patches were as effective as 

sublingual (SL) buprenorphine, with a better tolerability profile.[157] In terms of dosing, transdermal 

buprenorphine provides effective analgesia with an acceptable tolerability profile when initiated at 10 

micrograms (mcg)/hour (hr) and titrated upward to a maximum of 40 mcg/hr.[158] One study suggested 

efficacy for two-thirds of elderly OA patients (whose pain responds to opioids) at a seven-day low-dose 

buprenorphine patch at 5-20 mcg/hr when surgery was not possible and when NSAIDs were not 

recommended. Focus on and management of side effects is necessary.[159] 

Buprenorphine has several properties that make it a potentially desirable as an analgesic. It is a synthetic 

opioid analgesic with partial mu opioid agonist and kappa opioid antagonist properties.[157] It has high 

affinity to the opiate receptor and a long duration of action (24-72 hr). Buprenorphine is a partial agonist 

agent and as such may be associated with less euphoria and easier withdrawal. Buprenorphine should not 

be added to patients that are on a full mu agonist as it will precipitate withdrawal. In addition, caution 

should be exercised when adding full mu agonists to patients on buprenorphine as the efficacy and side 

effect profiles may vary. 
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Pregnancy and liver disease require consideration of monotherapy (buprenorphine without naloxone).

Other considerations for buprenorphine may be found in the VA/DoD SUD CPG.11 Consideration should be

given to specialty consultation when patients on buprenorphine have acute or post-operative pain

conditions. Practitioners who prescribe SL buprenorphine or SL buprenorphine/naloxone for pain are not

required to have an X Drug Enforcement Administration (DEA) number. However, practitioners do not

need an X DEA license to prescribe buprenorphine patches labeled for pain. When buprenorphine is used 

for pain, higher doses should be used with caution in opioid-naïve patients. Split dosing is often preferred

as the duration of pain relief may be 8-12 hr. All safety measures discussed in this guideline apply to

buprenorphine products. For additional information, see Table 4 and Table 5 below. 

Buprenorphine for Opioid Use Disorder

Patients on LOT may meet DSM-5 criteria for OUD. In addition, patients on LOT may have undiagnosed 

OUD that may manifest at the time of taper. The lifetime prevalence of any prescription OUD in patients

on LOT may be as high as 41.3%.[160] In these cases, abrupt changes or discontinuation of the prescription 

opioid may result in increased risk of adverse events. Provision of SL buprenorphine may assist the

provider and patient in meeting therapeutic goals for both pain and management of OUD. Specialty

consultation is suggested in cases where pain and OUD are being treated concurrently. Further research is

needed for managing patients with OUD and pain. There is substantial evidence for improved outcomes

with MAT, which includes frequent drug use monitoring and counseling/psychotherapy at initiation of

treatment in addition to medication (see Recommendation 17). Use of buprenorphine products for OUD is 

detailed in the VA/DoD SUD CPG.11 Under the Drug Addiction Treatment Act of 2000 (DATA 2000), in order 

to prescribe buprenorphine for OUD, physicians must qualify for a physician waiver, which includes

completing eight hours of required training and an application to SAMHSA.[161] Waivered physicians are

provided with an X DEA number and there are limits regarding the number of patients that one provider

can treat with buprenorphine for OUD.

11 See the VA/DoD Clinical Practice Guideline for the Management of Substance Use Disorders. Available at:

http://www.healthquality.va.gov/guidelines/mh/sud/index.asp
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Table 4. Buprenorphine Formulations [162]

Route Dosage Form Strengths

Brand 

Name Use

Topical Transdermal 

System

5 mcg/hr

7.5 mcg/hr

10 mcg/hr

15 mcg/hr

20 mcg/hr

Butrans® Management of pain severe enough to require aroundthe-clock, long-term, opioid treatment and for which 

alternative treatment options are inadequate

Buccal Film 75 mcg

150 mcg

300 mcg

450 mcg

600 mcg

750 mcg

900 mcg

Belbuca® Management of pain severe enough to require aroundthe-clock, long-term, opioid treatment and for which 

alternative treatment options are inadequate

Parenteral Injection 0.3 mg/mL Buprenex® Management of moderate-to-severe pain

Sublingual Tablets 2 mg

8 mg

Subutex® Treatment of opioid dependence

Abbreviations: hr: hour(s); mcg: microgram(s); mg: milligram(s); mL: milliliter(s)

Table 5. Buprenorphine/Naloxone Formulations [162] 

Route

Dosage 

Form

Strengths (listed as 

buprenorphine/naloxone) Brand Name Use

Buccal Film 2.1 mg/0.3 mg

4.2 mg/0.7 mg

6.3 mg/1.0 mg

Bunavail® Treatment of opioid dependence

Sublingual Film 2 mg/0.5 mg

4 mg/1 mg

8 mg/2 mg

12 mg/3 mg

Suboxone® Treatment of opioid dependence

Sublingual Tablets 2 mg/0.5 mg

8 mg/2 mg

generic Treatment of opioid dependence

Sublingual Tablets 1.4 mg/0.36 mg

2.9 mg/0.71 mg

5.7 mg/1.4 mg

8.6 mg/2.1 mg

11.4 mg/2.9 mg

Zubsolv® Treatment of opioid dependence

Abbreviations: hr: hour(s); mg: milligram(s)

Methadone

There is insufficient evidence to recommend methadone over other opioids for the treatment of chronic 

pain.[163] The only study included in the evidence review was limited to patients with cancer pain and 

suggested greater adverse effects with methadone than with other opioids.[166] An epidemiologic study

suggests that the use of methadone contributes disproportionately to opioid overdose deaths relative to 

the frequency with which methadone has been prescribed.[164] 
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An analysis of opioid prescriptions by VA from 2010 to 2012 concluded that the prescribing of any longacting/ER opioid medication, including methadone, was predictive of overdose or serious opioid-induced 

respiratory depression.[165] Studies comparing treatment of pain with methadone to treatment with 

other opioids describe inconsistent results and indicate that the risks associated with use of methadone 

vary greatly with treatment settings and management, monitoring, and risk mitigation strategies. A 

retrospective study of Tennessee Medicaid records (for years 1997 to 2007), documented an increased risk 

for overdose for non-institutionalized patients with non-cancer pain receiving methadone, including at low 

dosages.[166] A retrospective cohort study among Oregon Medicaid recipients (for years 2000 to 2004) 

found no statistically significant differences between methadone and long-acting morphine in risk for 

death. However, for the subgroup of patients with non-cancer pain, methadone was associated with 

greater risk of overdose symptoms, but not mortality or hospitalization.[167] A retrospective observational 

study of a large cohort drawn from VA healthcare databases (for years 2000 to 2007) documents that 

propensity-adjusted mortality was lower for methadone than for morphine. The study found no evidence 

of excess all-cause mortality among VA patients who received methadone compared with those who 

received long-acting morphine.[168] 

Yet the unique pharmacologic properties of methadone make it particularly risky to prescribe. Methadone 

carries a risk of cardiac arrhythmia, and risk assessment for QT prolongation and electrocardiographic 

monitoring is essential. Methadone has a variable half-life with peak respiratory depressant effect 

occurring later and lasting longer than peak analgesic effect. Dose escalation to improve pain relief may 

lead to unintentional intoxication and corresponding respiratory depression or arrest.[166] Additionally, 

the metabolism of methadone varies by dose and individual, making dosing unpredictable. Plus, there are 

medications that interact with methadone and should not be prescribed concurrently (see Table D-2). 

Only clinicians who are experienced with methadone and who are prepared to implement appropriate 

precautions, risk mitigation strategies, and patient/caregiver education should initiate, titrate, or taper

methadone for chronic pain. Prescribers and patients should be familiar with these unique characteristics 

and institute appropriate safety precautions. 

Specific guidance for clinicians about the risks of methadone is summarized below and detailed in 

Appendix D: 

• Monitoring for cardiotoxicity [169]

 Inform patients of the arrhythmia risk

 Ask patients about heart disease, arrhythmia, and syncope

 Obtain baseline ECG and regularly thereafter in intervals appropriate to risk/dosage

 If the QTc interval is greater than 450 ms, but less than 500 ms, reevaluate and discuss with 

the patient the potential risks and benefits of therapy and the need for monitoring the QTc 

more frequently

 If the QTc interval exceeds 500 ms, discontinue or taper the methadone dose and consider

using an alternative therapy; other contributing factors, such as drugs that cause 

hypokalemia or QT prolongation, should be eliminated whenever possible
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 Be aware of interactions between methadone and other drugs that may prolong QTc 

interval or slow the elimination of methadone, and educate patients about potential drug 

interactions 

• Conservative dosing

 Methadone should not be initiated in opioid-naïve patients in the outpatient setting

 Primary care clinicians should never rotate from another opioid to methadone without

guidance from an experienced clinician regarding the starting dose of methadone

 When initiating or increasing dosage, close follow-up is recommended (e.g., within five to 

seven days) to assess signs of methadone toxicity, such as excess sedation or delirium

 Wait at least one week on a particular dose of methadone before increasing dosage of 

methadone to make sure that the full effects of the previous dosage are evident

Recommendations 

14. We recommend tapering to reduced dose or to discontinuation of long-term opioid therapy

when risks of long-term opioid therapy outweigh benefits.

(Strong for | Reviewed, New-added)

Note: Abrupt discontinuation should be avoided unless required for immediate safety concerns.

15. We recommend individualizing opioid tapering based on risk assessment and patient needs and

characteristics.

(Strong for | Reviewed, New-added)

Note: There is insufficient evidence to recommend for or against specific tapering strategies and

schedules.

Discussion

Clinicians should reassess the use of LOT in all patients currently receiving the therapy and consider 

tapering or discontinuing opioids in all patients on LOT when the risks exceed the benefits of therapy. 

Treatment of chronic pain with LOT in general is associated with considerable risk and must be justified by 

attainment of benefit that outweighs those risks in any individual patient. Non-pharmacologic therapies 

and non-opioid pharmacologic therapies are preferred and should be optimized. See Recommendation 1

for additional information on recommended treatments for chronic pain. 

Observational studies (not included in the evidence review) suggest that when opioids are tapered or 

discontinued within the context of a multi-modal pain rehabilitation care plan, patients can experience an 

improvement in their pain, function, and mood.[170,171] Although the confidence in the quality of the 

evidence was low, the Work Group’s determination that the benefits of individualized tapering of OT 

(when risks of LOT outweigh benefits) greatly outweigh the harms of tapering, as well as their 

consideration of individual patients’ values and preferences, supported strong recommendations. 

Indications for Tapering

If risks of OT outweigh benefits, OT should be tapered to a reduced dose or tapered to discontinuation. In 

the context of shared decision making, patient-specific goals, values, and preferences, the following should 
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be taken into consideration when determining the balance of risks and benefits of OT, recognizing that 

multiple risk factors increase cumulative risk:[172,173] 

• Concomitant use of medications that increase risk of overdose

• Co-occurring medical or mental health conditions that increase risk

• Concerns about OUD or other SUD

• Patient adherence with opioid safety measures and opioid risk mitigation strategies

• Patient non-participation in a comprehensive pain care plan 

• Prescribed dose higher than the maximal recommended dose (which increases risk of adverse 

events) (see Recommendations 10-12) 

• Pain condition not effectively treated with opioids (e.g., back pain with normal magnetic 

resonance imaging [MRI]; fibromyalgia)

• Improvement in the underlying pain condition being treated

• Lack of clinically meaningful improvement in function

• Unmanageable side effects

When there is strong concern for diversion, opioids should be discontinued. For all patients, the 

prescribing clinician should regularly inquire about the patient’s preference to taper OT to a reduced 

dose or discontinuation and explore ambivalence. OT should be tapered when patients voice their 

preference to reduce dosage and/or discontinue LOT. 

There is large variation in patient preferences regarding continuing versus tapering OT and regarding the 

various processes that can be used when tapering opioids. Participants in the patient focus group 

expressed concern that when patients are receiving LOT, they may experience impaired judgement 

regarding decisions about opioid discontinuation due to the reinforcing nature of OT. Patients, therefore, 

may benefit from the outside perspective of their family members and healthcare providers. Such 

involvement should occur in accord with patient’s preferences and within applicable privacy requirements

(see Patient Focus Group Methods and Findings). 

Low frequency of follow-up in primary care and limited access to comprehensive interdisciplinary specialty 

pain, rehabilitation, mental health, and addiction services may be barriers to tapering LOT that may need 

to be addressed. 

Assessment/Follow-up

A biopsychosocial assessment including evaluation of medical, psychiatric, and co-occurring substance use 

conditions, as well as the patient’s social support system, should be completed prior to the initiation of an 

opioid taper. The risks and benefits of the current opioid regimen should be weighed with the risks and

benefits associated with a reduction in opioid dose. Periodic re-evaluation of risks and benefits coupled 

with a biopsychosocial assessment should occur when implementing an opioid taper and on follow-up. The 

frequency and type of follow-up is determined by risk assessment performed by the healthcare team. 

Follow-up should occur within a range of one week to one month after any opioid dosage change. Each 

follow-up interaction with the patient is an opportunity to provide education about self-management 
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strategies and the risks associated with OT while optimizing whole person approaches to pain care and

treatment of co-occurring medical and mental health conditions. Following discontinuation of opioids,

consider continuing risk mitigation strategies. Tapering may unmask underlying OUD. Therefore, frequent

assessment for OUD is recommended (for more information on diagnosis and treatment of OUD see the 

VA/DoD SUD CPG).12 

Referral

Clinicians should consider using an interdisciplinary, team-based approach that may include primary care,

mental health, pain specialty/rehabilitation, pharmacy, physical therapy, and/or SUD services during the

opioid tapering process. The treatment setting should be selected based on safety and the availability of 

services while also incorporating patient preferences.

It is important to recognize that some patients who are undergoing an opioid taper may experience 

symptoms of OUD that were not present or had not been previously identified prior to the taper. Opioid 

prescribers and the treatment team should remain vigilant for signs and symptoms of OUD for patients 

receiving LOT; particular attention is warranted during the tapering process. When there is concern for 

OUD or other SUD in a patient undergoing opioid tapering, clinicians should recommend SUD assessment 

and treatment to the patient in a setting that corresponds to the patient’s level of risk and availability of 

services, while considering patient preferences (see the VA/DoD SUD CPG).12 The possibility exists that 

some patients may be able to be seen in the primary care setting while others may be more appropriate 

for specialty care.

Patients on LOT with OUD are at increased risk of overdose when opioids are either continued or 

discontinued without appropriate treatment for OUD. We recommend MAT for OUD (e.g., MAT using 

methadone, buprenorphine/naloxone, or ER injectable naltrexone) (see the VA/DoD SUD CPG12 and 

Recommendation 17). Treatment of OUD with MAT can occur in SUD programs as well as in primary care, 

specialty pain care, and mental health settings when the necessary resources are available. In patients with 

OUD, the opioid prescriber should ensure that OEND has been offered. The opioid prescriber may consider 

slowing the taper until a smooth hand-off to OUD treatment can be accomplished; however, close 

monitoring must occur for all patients during this transition process. Expediting the taper process and 

continuing to offer OUD treatment may be appropriate in some situations (e.g., if patient is not adherent 

to opioid taper and declines OUD treatment).

Additionally, underlying mental health disorders may be exacerbated by opioid use and/or opioid tapering

and may require ongoing interdisciplinary care that includes mental health services.

The care team should take great efforts to ensure that the patient does not feel abandoned during the

opioid tapering process. This includes clear communication with the patient that the care team will 

12 See the VA/DoD Clinical Practice Guideline for the Management of Substance Use Disorders. Available at: 

http://www.healthquality.va.gov/guidelines/mh/sud/index.asp
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maintain frequent contact with the patient during the opioid taper and emphasizing that the care team 

will continue to pursue non-opioid pain care options during and after opioid tapering. 

Clinicians should also educate the patient/family about 

acute and protracted opioid withdrawal symptoms and 

provide treatment strategies to mitigate these symptoms 

as appropriate.[174] To foster patient engagement with 

the taper plan, clear written and verbal instructions should 

Strongly caution patients that it takes 

as little as a week to lose tolerance to 

their prior opioid dose and that they 

are at risk of an overdose if they 

resume their prior dose. be given to the patient/family regarding the tapering 

protocol, strategies to mitigate withdrawal symptoms, and 

additional non-opioid treatments for the patient’s pain condition. 

Regardless of the initial speed of taper, the rate of taper may need to be adjusted during the course of 

lowering the opioid dose. The pace of taper should be reevaluated after each dose change. 

If patients are receiving both long-acting and short-acting opioids, the decision regarding which 

formulation to be tapered first needs to be individualized based on safety, medical history, mental health 

diagnoses, and patient preference. However, it should be kept in mind when making this decision that 

long-acting opioids may be associated with higher overdose, overdose death, and all-cause mortality rates 

when compared to short-acting opioids, which may suggest tapering long-acting opioids first.[10,137] 

There may also be times when tapering both formulations simultaneously is appropriate.

If an opioid dose reduction is the initial treatment goal, ongoing assessment of the balance of risks and 

clinically meaningful benefits should be performed once the original treatment goal is achieved. If this 

assessment determines that the benefits of continuing OT do not outweigh risks, additional dose reduction 

and/or tapering to discontinuation should be pursued.

Tapering Process

The goal of opioid tapering is to improve the balance of risks and clinically meaningful benefits for patients 

on LOT. The risks and benefits of the current opioid regimen should be weighed with the risks and benefits 

associated with a reduction in opioid dose. If the provider determines a patient to be at significant risk of 

adverse outcomes due to the use of LOT, and if either the patient or the clinician is concerned about 

potential destabilizing effects of opioid tapering, referral to, or consultation with, specialty services 

including mental health, SUD, pain medicine, and rehabilitation should be strongly considered.

Abrupt discontinuation of opioids may be justified in certain high-risk circumstances. When there is 

evidence for diversion, the clinician may need to discontinue OT, frequently assess for withdrawal 

symptoms, and offer necessary support for withdrawal symptoms and treatment of SUD, if present. When 

a patient exhibits dangerous behaviors (e.g., threatening behaviors, persistent and serious disruptive 

behavior, suicidal ideation or behaviors), the clinician may consider abruptly discontinuing OT while 

providing urgent or emergent psychiatric referral and medical care for the management of opioid 

withdrawal. When relevant, dangerous or illegal behavior should be documented accurately and 

completely in the EMR to guide future care. When ongoing pain is suspected, non-opioid treatment for 

pain should be implemented.[175] 
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The characteristics that will determine the speed of tapering include opioid dose, duration of therapy, type 

of opioid formulation, and co-occurring psychiatric, medical, and substance use conditions. The tapering 

treatment plan should be individualized and should address the pace of tapering, setting of care, and 

frequency of follow-up. When determining the pace of opioid tapering, factors that would suggest a more 

gradual taper include higher opioid dose and longer duration of OT; factors that would suggest a more 

rapid taper include non-adherence to the treatment plan and escalating high-risk medication-related 

behaviors. When safety permits, gradual tapers are often better tolerated. In addition, for some patients, 

pauses in the taper for weeks or months may allow the patient time to acquire new skills for management 

of pain and emotional distress while also allowing time for neurobiological equilibration. 

The rate of taper takes into account many factors that include initial dose, formulations available, and risk 

factors that increase harm. A gradual taper over months or even years for patients starting on very high 

opioid doses involves reducing by 5-20% every four weeks. In some patients, a faster taper may be needed 

when risks are too high to consider a gradual taper; consider tapering the dose by 5-20% per week in this 

patient population. 

When it is determined that patient risks are significantly high to warrant a rapid taper over a period of days 

or weeks, then specialty consultation should be obtained to determine the rate of taper and resources 

needed. These patients will need frequent follow-up and reevaluation of SUD, mental health, and/or cooccurring medical conditions with every dose change. 

Patients Receiving Very High Dose Opioid Therapy

For patients currently prescribed ≥90 mg MEDD, a comprehensive assessment that recognizes the 

increased risk of high dose OT should be performed. Tapering to a reduced dose or tapering to 

discontinuation should be pursued when clinically meaningful functional benefit is not demonstrated or 

when significant risk factors in addition to the prescribed opioid dose are present. It should be recognized 

that elevated dose alone poses increased risk of overdose, overdose death, adverse effects, and the 

development of OUD. Assessing clinically meaningful functional benefit should be individualized and 

incorporate the use of SMART goals and considered in the context of patient-specific goals, values, and 

preferences (see table Guide in Setting SMART Goals). 

Mental health and SUD comorbidities that were previously unrecognized or that may worsen should be

assessed and addressed with an interdisciplinary approach. Interdisciplinary care including mental health,

rehabilitation, and SUD treatment services may be necessary to support the tapering process. Use of MAT,

which includes behavioral approaches, should be offered for patients in whom a diagnosis of OUD is made 

(see the VA/DoD SUD CPG).13

13 See the VA/DoD Clinical Practice Guideline for the Management of Substance Use Disorders. Available at: 

http://www.healthquality.va.gov/guidelines/mh/sud/index.asp
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Naloxone

Overdose education should be provided and naloxone should be offered as an antidote to all patients at 

risk for an opioid overdose including those who are in the process of tapering. During and following an 

opioid taper, patients may still be using opioids from other sources such as saved opioids, other 

prescribers, friends and family, as well as illicit sources. Continued surveillance for OUD and assessment for 

naloxone is suggested in patients who are no longer on opioids but who remain at risk for opioid use from 

unknown sources. For more information, see Recommendations 7-9. 

Future Research

Additional research is needed to identify the opioid tapering processes that are associated with the best 

patient outcomes among a broad range of domains including general functioning, psychosocial 

functioning, mood, pain related disability, and adverse outcomes assessed in the short, medium, and longterm. 

Recommendation

16. We recommend interdisciplinary care that addresses pain, substance use disorders, and/or

mental health problems for patients presenting with high risk and/or aberrant behavior.

(Strong for| Reviewed, New-replaced)

Discussion

A variety of high-risk medication-related behaviors (e.g., early refills, lost or stolen medications, 

problematic findings on urine tests) may suggest the presence of SUD (also known as opioid addiction, 

abuse, or dependence). Non-adherence to treatment plans or repeated failure to show for clinic 

appointments can add to the challenge of safely providing LOT in the primary care setting. The presence of 

co-occurring SUD or psychiatric conditions in some patients can make prescribing LOT an overwhelming 

problem for primary care providers. Chronic pain is a complex human experience influenced by physical, 

psychological, and social factors. Multidisciplinary care that addresses these influences is helpful for all 

patients, but is absolutely essential when pain is accompanied by co-occurring conditions, impaired 

function, or psychological problems.

Low quality evidence supports the benefits of providing brief behavioral interventions and close

monitoring to patients at high risk for prescription opioid misuse.[114] Some evidence suggests that 

patients referred to highly structured opioid-renewal programs that provide patients with frequent UDT 

monitoring, frequent clinic visits, smaller quantities of medications, and ongoing counseling/education is 

helpful for patients and primary care providers. Meghani et al. (2009) found that high-risk medicationrelated behaviors resolved in 45.6% of patients managed in a pharmacist-run opioid renewal clinic.[176] 

Although the confidence in the quality of the evidence was low, the Work Group’s determination that the 

benefits of interdisciplinary care for patients with pain and other comorbidities (e.g., SUD, mental health 

problems) contributed to a strong recommendation. 

Consider referring patients with co-occurring substance use or psychiatric conditions to addiction 

medicine/psychiatry or other behavioral health specialists. Coordination of care between pain care and 

other specialty care, including SUD clinicians, is advised. If structured comprehensive programs are not 

available, coordination among individual healthcare providers is essential to address the full range of high-
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risk behaviors. Chronic pain in general, and LOT in particular, requires consideration of all of the patient’s 

life problems. If resources do not exist to address co-occurring SUD and psychiatric conditions or if the 

patient declines to participate, treatment with LOT should be reconsidered. 

Research is needed to identify the efficacy and feasibility of providing multidisciplinary care to patients 

demonstrating significant high-risk medication-related behaviors when prescribed LOT in primary care 

settings.

Recommendation

17. We recommend offering medication assisted treatment for opioid use disorder to patients with

chronic pain and opioid use disorder.

(Strong for | Reviewed, New-replaced)

Note: See the VA/DoD Clinical Practice Guideline for the Management of Substance Use Disorders.

Discussion 

OUD (also known as opioid addiction, abuse, or dependence) is a chronic brain disease that impairs one’s 

ability to control opioid use. Opioids disrupt the functioning of brain circuits that mediate a complex array 

of functions involved in obtaining natural rewards such as food and water that are essential for survival.

Because opioids activate these circuits more powerfully than natural rewards, the primitive brain learns to 

prioritize attention to and motivation for opioids over other natural rewards.[177] Repeated opioid use 

over time can lead to OUD. While there are some risk factors such as other substance use or co-occurring 

mental illness that can increase the risk of developing an OUD among those taking opioid analgesics, by far 

the most powerful risk factor for developing OUD is long-term opioid analgesics use. All persons using 

opioid analgesics are at-risk for developing an OUD. Persons who become addicted to opioids gradually 

become more and more preoccupied with opioid use and spend more of their time seeking the drug, using 

it, or recovering from its effects. They may continue to use opioids even though they:

• Know that opioid use is harmful

• Often use more than they intended

• Engage in risky behaviors such as driving while intoxicated or combining opioids with alcohol or

other sedatives

• Have multiple unsuccessful attempts to cut down or control opioid use

• Report strong craving or urges to use opioids in response to withdrawal symptoms, stress,

negative emotions, or simply cues that the drug is available

OUD is associated with premature death from opioid overdose and other medical complications such as 

acquired immunodeficiency syndrome (AIDS), hepatitis C, and sepsis. On average, OUD carries a 40-60% 

20-year mortality rate.[178] Persons with OUD are at high-risk for premature death, not only from opioid 
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overdose, but from other consequences. Thus, providing first-line treatment is important to save lives as 

well as to improve the quality of life of patients. 

Strong evidence supports the use of opioid agonist therapy (e.g., methadone, buprenorphine/naloxone) as 

first-line treatment for moderate-to-severe OUD (see VA/DoD SUD CPG).14 However, because this 

research has been conducted primarily on persons addicted to heroin, the populations studied have had a 

higher prevalence of co-occurring SUD and lower prevalence of chronic pain. Patients and their treating 

clinicians may be concerned that treatments proven effective in different OUD populations may not be 

effective for patients with chronic pain, or may not be necessary for patients who have become addicted to 

prescription opioid analgesics. This concern has been unfounded and was addressed by Weiss and 

colleagues in the Prescription Opioid Abuse Treatment Study (POATS).[179] 

Early research suggested that patients with prescription OUD may have a better prognosis than those who 

are primarily addicted to heroin, implying that those with prescription OUD may not need MAT.[180,181] 

However, in studies with patients with DSM-IV opioid dependence (which were conducted prior to use of 

DSM-5), buprenorphine maintenance therapy is more effective than a four-week taper. One multicenter 

RCT tested the hypothesis that patients with prescription OUD would respond well to a four-week tapering 

of buprenorphine/naloxone to discontinuation plus two regimens of outpatient counseling.[179] Those 

who did not achieve successful outcomes after buprenorphine taper in phase one were invited to 

participate in phase two consisting of 12-weeks treatment using buprenorphine/naloxone followed by 

taper to discontinuation. During both phases, patients were randomized to receive a manualized, 

physician-delivered psychosocial intervention known as Standard Medical Management or Standard 

Medical Management plus manually-driven opioid drug counseling delivered by a trained therapist. Only 

6.6% of these patients achieved a successful outcome after tapering in phase one with no difference 

between the groups. In phase two, while taking buprenorphine/naloxone, 49% of patients achieved a 

successful outcome again with no difference between the counseling groups. Eight weeks after tapering 

again, only 8.6% of patients achieved a successful outcome. This suggests that MAT with moderate dose 

buprenorphine/naloxone and brief, structured counseling by the prescribing physician can be successful 

for about half of selected patients with prescription OUD, whereas withdrawal management alone, even 

with close weekly follow-up and counseling is successful for less than 10% of patients.

Furthermore, the presence of chronic pain does not seem to interfere with the success of MAT. The RCT by 

Weiss et al. (2011) and a meta-analysis by Dennis et al. (2015) reached the same conclusion that the 

presence of chronic pain did not influence response to opioid agonist therapy.[179,182] Given the high 

mortality associated with OUD and the safety and efficacy of MAT for OUD in multiple clinical trials and 

meta-analyses, we recommend MAT for those chronic pain patients who meet DSM-5 criteria for OUD. 

Those who do not respond to minimal counseling may benefit from a comprehensive assessment and 

more intensive treatment of OUD and any co-occurring conditions in SUD specialty care settings.

14 See the VA/DoD Clinical Practice Guideline for the Management of Substance Use Disorders. Available at: 

http://www.healthquality.va.gov/guidelines/mh/sud/index.asp
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D. Opioid Therapy for Acute Pain

Recommendation

18. a) We recommend alternatives to opioids for mild-to-moderate acute pain. (Strong for)

b) We suggest use of multimodal pain care including non-opioid medications as indicated when

opioids are used for acute pain. (Weak for)

c) If take-home opioids are prescribed, we recommend that immediate-release opioids are used at

the lowest effective dose with opioid therapy reassessment no later than 3-5 days to determine if 

adjustments or continuing opioid therapy is indicated. (Strong for)

(Reviewed, New-added)

Note: Patient education about opioid risks and alternatives to opioid therapy should be offered.

Discussion 

As this guideline is related to LOT, the use of opioids for acute pain is not reviewed in detail. However, 

because acute OT can be a gateway to LOT, it is part of this CPG. A review of the literature indicates that 

LOT can result from acute opioid use initially intended for short-term therapy. Further, there is a risk of 

opioid-related overdose even during acute OT. While it is understood that acute OT for severe pain due to 

injuries or surgery is the most effective option for many patients, the risks associated with acute therapy 

must be addressed when opioids are prescribed or considered. 

The risks of acute OT extending into LOT are increased in patients with mood disorders, those who refill 

the initial prescription, higher prescribed dose (greater than 120 mg MEDD), and initiation using longacting opioids.[183-185] The risk of acute post-operative OT progressing into LOT is increased with a 

history of depression, SUD, catastrophizing, higher preoperative total body pain, history of back pain, and 

preoperative use of sedative-hypnotics or antidepressants.[186,187] 

In addition, the risk of overdose includes the use of opioids for acute pain. Factors that increase overdose 

risk when opioids are used for acute pain include high prescribed dose, history of SUD, and history of 

mental health concerns. While the risk of overdose increases at doses above 20 mg MEDD or greater, this 

risk increases even further as doses increase to over 50 or 100 mg MEDD.[58,59,188] 

There are situations in which opioids may be necessary therapy for acute pain, even when substantial risk 

factors exist. It is important to incorporate opioid risk mitigation strategies into opioid prescribing for acute 

pain. These strategies should include patient education, use of non-opioid adjunctive therapy, and 

structured reassessment of opioid risks and benefits for all on acute OT. Also, consider checking the PDMP 

and performing a UDT. 

For those at higher risk of adverse events related to opioid therapy, the following strategies may help to 

decrease opioid-related overdose events and unintended long-term use: checking the PDMP, performing a 

UDT, placement in an inpatient setting or monitored environment, and/or providing OEND. 

Monitoring standards with administration of OT for acute pain vary depending on a number of factors 

including the setting, specifics of the painful insult, patient medical factors, and selected medication 

potency/dose/route of administration/adjunct selection. 
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Appendix A: VA Signature Informed Consent

For the most current information on informed consent, see the VA National Center for Ethics in Health 

Care website (http://www.ethics.va.gov/).
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Appendix B: Urine Drug Testing

A. Benefits of Urine Drug Testing

Substance misuse in patients on LOT is more than 30% in some series.[107] The inaccuracies inherent to 

patient self-report coupled with the evident mortality and morbidity to the treated patients, their families, 

and others require additional methods to ascertain patient and public safety. UDT and confirmatory 

testing is an additional method of examining for patient substance misuse and adherence to the 

prescribed regimen as well as the development of trust within the provider-family-patient relationship. It is 

critical that the UDT and confirmatory testing be done in a timely, confidential, accurate, and easily 

available manner to assure the prescribers, patients, and public that safety, fairness, and trust are being 

addressed. 

Within the VA, verbal informed consent is required prior to UDT. While a patient can decline to consent to 

UDT, a provider can factor that declination into their thinking about whether it is safe to continue with OT 

for that patient which is ultimately required if LOT is to be instituted/continued. For more information, see 

the VA National Center for Ethics in Health Care website (http://www.ethics.va.gov/).

B. Types of Urine Drug Testing

There are three main types of UDT currently being utilized in clinical settings: immunoassay, GCMS 

confirmatory testing, and liquid chromatography-mass spectrometry confirmatory testing. Immunoassay 

screening is inexpensive, fast and widely available. However, there are a number of drawbacks for using 

this test alone. There is a higher potential for false positives and negatives as well as lack of specificity of 

the actual opiate or benzodiazepine being tested. GCMS is highly sensitive and specific; however, it is 

expensive and time consuming. LCMS is less expensive than GCMS but more expensive than 

immunoassay. It can give a confirmation for a large number of medications, substances and drugs at one 

time and may be helpful in many patients at initiation of OT, periodically during OT, and following 

cessation of OT if SUD is a possibility. See Table B-1 through Table B-4 and Figure B-1 for more 

information. 

Table B-1. Urine Toxicology Specimen Validity and Normal Characteristics of a Urine Sample

[189-191] 

Urine Toxicology Specimen Validity Normal Characteristics of a Urine Sample

 Urine samples that are adulterated, substituted, or 

diluted may avoid detection of drug use

 Urine collected in the early morning is most 

concentrated and most reliable

 Excessive water intake and diuretic use can lead to 

diluted urine samples (creatinine<20 mg/dL) 

 THC assays are sensitive to adulterants (e.g., eye

drops)

Temperature within 4 minutes of voiding: 90-1000F

pH: 4.5-8.0

Creatinine: >20 mg/dL

Specific gravity: >1.003

Nitrates: <500 mcg/dL

Volume: ≥30 mL

Abbreviations: 0F: degrees Fahrenheit; dL: deciliter(s); mcg: microgram(s); mg: milligram(s); mL: milliliter(s); THC: 

tetrahydrocannabinol
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Table B-2. Urine Toxicology Screening Federal Work Place Cut Off Values [189-195]

Agent

Initial drug test 

level

(immunoassay) (ng/mL)

Confirmatory 

drug test 

level

(GCMS) 

(ng/mL)

Confirmatory test

analyte

Detection Period 

after Last Dose 

(days)1

2-8 single use

20-30 chronic use Marijuana metabolites 2 50 15 THCA

ST UralguRe

STd UndeetxE

Cocaine metabolites 300 150 Benzyolyecgonine 1-3 

Opioid

metabolites 20003 20003 

Codeine

Morphine

6-MAM

2-3 days opiates

3-5 minutes heroin

12-24 hr 6-MAM

Oxycodone 2-4 

Amphetamines 1000 500

Amphetamine

Methamphetamine

MDMA, MDA, 

MDEA

1-3 

Methamphetamine Incomplete data 500 3-4 

Benzodiazepines 300 200 3 short-acting

30 long-acting

Barbiturates 300 200 1 short-acting

21 long-acting

Methadone 300 200 EDDP 3-6 

Alcohol EtG, EtS 12 hr

1

Detection time for most drugs in urine is 1-3 days 2

Long-term use of lipid-soluble drugs (THC, diazepam, ketamine) can be detected for a longer period of time 3

Testing levels for opiates were raised from 300 ng/mL to 2000 ng/mL to reduce detection from foods containing 

poppy seeds

Abbreviations: 6-MAM: 6-monoacetylmorpine; EDDP: 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine; EtG: ethyl 

glucuronide; EtS: ethyl sulfate; GCMS: gas chromatography-mass spectrometry; hr: hour(s); MDA: 3,4-

methylenedioxy-amphetamine; MDEA: 3,4-methylenedioxy-N-ethyl-amphetamine; MDMA: 3,4-methylenedioxymethamphetamine; mL: milliliter(s); ng: nanogram(s); THC: tetrahydrocannabinol; THCA: delta-9-

tetrahydrocannabinol-9-carboxylic acid; UTS: urine toxicology screening
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Table B-3. Summary of Agents Potentially Contributing to False Positives [189-194] 

Agent Summary of Agents Potentially Contributing to False Positives

Marijuana metabolites  dronabinol

 efavirenz

 NSAIDs1

 proton pump inhibitors

 hemp foods: tea, oil2

Cocaine metabolites  coca leaf teas  topical anesthetics containing cocaine

Opioid

metabolites

 dextromethorphan

 fluoroquinolones

 levofloxacin

 ofloxacin

 poppy seeds 

 poppy oil

 rifampin

 quinine

Amphetamines/

Methamphetamine 

(high rate of false 

positives)

 amantadine

 benzphetamine

 brompheniramine

 bupropion

 chlorpromazine

 desipramine

 dextroamphetamine

 doxepin

 ephedrine

 fluoxetine

 isometheptene

 isoxsuprine 

 labetalol

 l-methamphetamine (OTC 

nasal inhaler)

 methylphenidate

 MDMA

 phentermine

 phenylephrine

 propanolamine

 promethazine

 pseudoephedrine 

 ranitidine

 selegiline

 thioridazine

 trazodone

 trimethobenzamide 

 trimipramine

Benzodiazepines  oxaprozin  sertraline

Barbiturates  ibuprofen  naproxen

Methadone  chlorpromazine

 clomipramine

 diphenhydramine

 doxylamine

 ibuprofen

 quetiapine

 thioridazine

 verapamil

Alcohol  mouthwash  short-chain alcohols  OTC cough products 

(isopropyl alcohol)

1

Detection time for most drugs in urine is 1-3 days 2

Long-term use of lipid-soluble drugs (THC, diazepam, ketamine) can be detected for a longer period of time

Abbreviations: NSAIDs: non-steroidal anti-inflammatory drugs; MDMA: 3,4-methylenedioxy-methamphetamine; 

OTC: over the counter; THC: tetrahydrocannabinol
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Table B-4. Interpreting Urine Toxicology Screening [189-191,196] 

Drug or Class Expected Results Considerations

Non-opioids

Alcohol Alcohol  Testing for ethanol metabolites, 

ethyl glucuronide or ethyl sulfate, 

can identify alcohol up to 80 hr

after consumption

Amphetamines Immunoassay – Amphetamines, 

methamphetamines or MDMA

Confirmatory – Amphetamines, 

methamphetamines or MDMA

 Immunoassay tests are highly crossreactive; therefore confirmatory

testing is required and can identify 

which amphetamine is present

Benzodiazepines Immunoassay – Unconjugated

oxazepam or its metabolites

Confirmatory – Alprazolam, 

diazepam, clonazepam, 

lorazepam, etc. 

 Immunoassays for benzodiazepines 

have a 28% overall false negative 

rate

 Confirmatory testing is needed when 

use is expected or suspected 

(alprazolam, clonazepam and 

lorazepam often not detected by 

immunoassay) 

Barbiturates Immunoassay – Barbiturates  N/A

Cocaine metabolites Immunoassay – Cocaine or 

benzoylecgonine

 Cocaine’s primary metabolite, 

benzoylecgonine, has low crossreactivity with other substances and 

is highly predictive of cocaine use

 A positive result should be 

interpreted as recent exposure to 

cocaine

Opioids or 

“Opiates”-

Natural (From 

Opium)

Codeine (Tylenol

#2,3/4)

Opiates Immunoassay – Positive

Confirmatory – Codeine, 

possibly morphine & 

hydrocodone

 Immunoassays for “opiates” are 

responsive to morphine and 

codeine but do not distinguish 

which

 Codeine is metabolized to morphine 

and small quantities of 

hydrocodone

Morphine (Avinza, 

Embeda, MS Contin, 

Kadian)

Opiates Immunoassay – Positive

Confirmatory – Morphine, 

possibly hydromorphone

 Immunoassays for “opiates” are 

responsive to morphine and 

codeine but do not distinguish 

which

 Morphine (<10%) may be 

metabolized to hydromorphone

Heroin Opiates Immunoassay – Positive

Confirmatory – Heroin (6-

MAM), morphine, possibly 

codeine

 6-MAM is pathognomonic for heroin 

use, detection 12-24 hr

 Heroin is metabolized to morphine
VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

Drug or Class Expected Results Considerations

OpioidsSemisynthetic 

(Derived from 

Opium)

Hydrocodone 

(Lorcet, Lortab, 

Norco, Vicodin)

Opiates Immunoassay – Positive

Confirmatory – Hydrocodone, 

possibly hydromorphone

 “Opiates” immunoassay may detect 

semisynthetic opioids

 hydrocodone >hydromorphone 

>oxycodone

 Negative result does not exclude use 

and confirmatory testing (GCMS) is 

required

 Hydrocodone is metabolized in small 

amounts to hydromorphone, both 

may be found in urine

 Oxycodone is metabolized to 

oxymorphone, both may be found 

in urine 

 Hydromorphone and oxymorphone 

use does not result in positive 

screens for hydrocodone and 

oxycodone, respectively

Hydromorphone 

(Dilaudid, Exalgo)

Opiates Immunoassay –May be 

positive

Confirmatory – Hydromorphone

Oxycodone (Roxicet, 

OxyContin)

Opiates Immunoassay – May be 

positive

Oxycodone Immunoassay – 

Positive

Confirmatory – Oxycodone 

possibly oxymorphone

Oxymorphone 

(Opana)

Oxycodone Immunoassay – 

Positive 

Confirmatory – Oxymorphone

Opioids – 

Synthetic 

(Man-made)

Buprenorphine Immunoassay – Buprenorphine

LCMS, GCMS – Buprenorphine, 

norbuprenorphine

 Current “opiates” immunoassays do 

not detect synthetic opioids

 Confirmatory testing (GCMS or 

LCMS) is needed Fentanyl GCMS – Fentanyl, norfentanyl

Meperidine 

(Demerol)

GCMS – Normeperidine, 

possibly meperidine

Methadone 

(Methadose)

Methadone Immunoassay – 

Positive

GCMS – Methadone, EDDP

Note: Each facility may have its own order sets and lab policies and procedures. Contact your lab for additional 

details.

Abbreviations: 6-MAM: 6-monoacetylmorpine; EDDP: 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine; GCMS: gas 

chromatography-mass spectrometry; LCMS: liquid chromatography-mass spectrometry; MDMA: 3,4-

methylenedioxy-methamphetamine

Figure B-1. Opioid Metabolic Pathways [190-193] 

Abbreviations: 6-MAM: 6-monoacetylmorpine

February 2017 Page 79 of 198
VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

February 2017 Page 80 of 198

Appendix C: Diagnostic and Statistical Manual of Mental Disorders for 

Opioid Use Disorders

DSM-5 diagnostic criteria for OUD: A problematic pattern of opioid use leading to clinically significant 

impairment or distress, as manifested by at least two of the symptoms in Table C-1, occurring within a 12-

month period.[197] 

Table C-1: DSM-5 Diagnostic Criteria for OUD [197] 

DSM-5 Diagnostic Criteria for OUD

1. Craving or strong desire or urge to use opioids

2. Recurrent use in situations that are physically hazardous

3. Tolerance

4. Withdrawal (or opioids are taken to relieve or avoid withdrawal)

5. Using larger amounts of opioids or over a longer period than initially intended

6. Persisting desire or unable to cut down on or control opioid use

7. Spending a lot of time to obtain, use, or recover from opioids

8. Continued opioid use despite persistent or recurrent social or interpersonal problems related to opioids

9. Continued use despite physical or psychological problems related to opioids

10. Failure to fulfill obligations at work, school, or home due to use

11. Activities are given up or reduced because of use

Table C-2: DSM-5 Diagnostic Criteria for Severity of OUD [197] 

Severity of OUD Number of Symptoms

Mild Presence of 2-3 symptoms

Moderate Presence of 4-5 symptoms

Severe Presence of 6 or more symptoms
February 2017 Page 81 of 198

Appendix D: Drug Tables

A. Short-acting, Orally Administered Opioids

Table D-1: Use of Short-acting, Orally Administered Opioids in Adults [198] 

Short-Acting Opioids1 

Initial Oral 

Dosage

(in opioid-naïve)

Additional Dosage 

Information

Analgesic

Onset (min)

Peak (min)

Duration (hr)

Dosing In Special 

Populations Other Considerations

Codeine (alone or in 

combination with 

APAP or ASA) 

 Codeine available as 

15, 30 and 60 mg 

tablets

 Combination 

products vary in 

codeine content 

from 15 to 60 

mg/dose unit

 15 to 30 mg 

every 4 to 6 hr

 Initial dose 

based upon 

codeine 

component, 

maximum 

dose based 

upon nonopioid 

component

 Maximum APAP 

dose: 4000 mg/d 

(2000 mg/d in 

chronic alcoholics or 

in hepatic 

impairment)

 Analgesic ceiling 

effect occurs with 

codeine at doses 

>60 mg/dose

 Codeine alone is a 

weak analgesic; 

more effective 

alternatives are 

available (including 

codeine in 

combination with 

APAP or ASA) 

15 to 30

30 to 60

4 to 6

 Elderly or debilitated: Use 

with caution

 Hepatic dysfunction: 

Conversion to active 

metabolite (morphine) 

may be reduced in 

patients with cirrhosis; 

avoid use in patients with 

liver disease

 Renal dysfunction: Use 

lower dosage or an 

alternative analgesic

 Codeine may be less effective in 

patients with decreased CYP2D6 activity (due to poor CYP2D6 metabolism or CYP-2D6 

inhibiting drugs2

) because of 

decreased conversion to the 

active metabolite, morphine

 CYP-2D6 ultra-rapid 

metabolizers3 can have 

extensive conversion to 

morphine with increase in 

opioid-mediated effects
February 2017 Page 82 of 198

Short-Acting Opioids1 

Initial Oral 

Dosage

(in opioid-naïve)

Additional Dosage 

Information

Analgesic

Onset (min)

Peak (min)

Duration (hr)

Dosing In Special 

Populations Other Considerations

Hydrocodone (in 

combination with 

APAP, ASA, or IBU)

 Combination 

products vary in 

hydrocodone 

content (2.5 to 10 

mg per dosage unit)

 5 to 10 mg

every 6 hr 

(hydrocodone 

component)

 Initial dose 

based upon 

hydrocodone

component

 Maximum dose 

based upon 

non-opioid 

component

 Maximum dose:

• 60 mg/d (4000 

mg/d APAP; 2000 

mg/d APAP in

chronic alcoholics 

or hepatic

impairment) for

hydrocodone +

APAP

combination

OR

• 37.5 to 50 mg/d

(1000 mg/d IBU) 

for hydrocodone

+ IBU 

combination

10 to 20

60 to 100

4 to 8

 Elderly or debilitated: Use 

with caution; start with 

reduced dose (2.5-5 mg) 

of hydrocodone 

component

 Hepatic dysfunction: Use 

with caution

 Conversion to the active 

metabolite, hydromorphone, 

may be decreased in patients 

with decreased CYP-2D6 activity 

(due to poor CYP-2D6 

metabolism or CYP-2D6 

inhibiting drugs2

) 

 CYP-2D6 ultra-rapid 

metabolizers3 can have 

extensive conversion to 

hydromorphone with potential 

increase in opioid-mediated 

effects

Hydromorphone

 Available as oral 

liquid 1 mg/ml, and 

2, 4, and 8 mg 

tablets

 2 mg every 4 to 

6 hr

 May give an 

initial dose of 

4 to 8 mg for 

severe pain

 There is no optimal 

or maximum dose of 

hydromorphone; 

patients on LOT are 

likely to become 

tolerant 4 and 

require doses higher 

than the usual 

dosage range to 

maintain the desired 

effect

15 to 30

30 to 60

3 to 4

 Elderly or debilitated: Use 

with caution, start at 25% 

to 50% of usual dose at 

low end of dosing range

 Hepatic / Renal 

dysfunction: Reduce initial 

dose for moderate 

impairment, more with 

severe impairment
February 2017 Page 83 of 198

Short-Acting Opioids1 

Initial Oral 

Dosage

(in opioid-naïve)

Additional Dosage 

Information

Analgesic

Onset (min)

Peak (min)

Duration (hr)

Dosing In Special 

Populations Other Considerations

Morphine

 Available as oral 

solution (10 or 20 

mg/5 ml, or 100 

mg/5 ml for opioidtolerant patients 

only) or as 15 or 30 

mg tablets

 10 to 30 mg 

every 4 hr 

 There is no optimal 

or maximum dose of 

morphine; patients 

on LOT are likely to 

become tolerant 4

and require doses 

higher than the 

usual dosage range 

to maintain the 

desired effect

30 

60

3 to 5

 Elderly or debilitated: Give 

with extreme caution; use 

lower dose

 Hepatic dysfunction: Use 

carefully in patients with 

cirrhosis and consider 

reducing dose or 

extending dosing interval 

by 1.5 to 2 times; half-life 

may be doubled (3 to 4 hr) 

and bioavailability is 

increased

 Renal dysfunction: Reduce 

dose or, if severe renal 

impairment exists, avoid 

use (see Other 

Considerations) 

 M6G, an active metabolite, may

accumulate in renal impairment

 M3G, a metabolite without 

analgesic activity, may

accumulate in renal impairment; 

this metabolite has been 

implicated in morphine-induced 

neurotoxicity, hyperalgesia, and 

allodynia
February 2017 Page 84 of 198

Short-Acting Opioids1 

Initial Oral 

Dosage

(in opioid-naïve)

Additional Dosage 

Information

Analgesic

Onset (min)

Peak (min)

Duration (hr)

Dosing In Special 

Populations Other Considerations

Oxycodone (alone or 

in combination with 

APAP or ASA)

 Single-agent 

oxycodone available 

as oral solution 5 

mg/5 ml, 20 mg/1

ml, and oral tablet 5, 

10, 15, 20, and 30 

mg

 Combination 

products vary in 

oxycodone content, 

2.5 to 10 mg per 

dose unit

 5 to 15 mg 

every 4 to 6 hr

 Initial dose 

based upon 

oxycodone 

component

 Maximum dose 

based upon 

non-opioid 

component

 For combination 

products, maximum 

dose is limited by 

APAP or ASA 

content (4000 mg/d 

for both; 2000 mg/d 

APAP in chronic 

alcoholics or 

patients with 

hepatic impairment) 

 There is no optimal 

or maximum dose of 

oxycodone; patients 

on LOT are likely to 

become tolerant 4

and require doses 

higher than the 

usual dosage range 

to maintain the 

desired effect

10 to 15

30 to 60

3 to 6

 Elderly or debilitated:

reduce dosage

 Hepatic / Renal: Use with 

caution; consider reducing 

dose and increasing 

frequency of dosing

 Conversion to the active 

metabolite, oxymorphone, may 

be decreased in patients with 

decreased CYP-2D6 activity (due 

to poor CYP-2D6 metabolism or 

CYP-2D6 inhibiting drugs2

) 
February 2017 Page 85 of 198

Short-Acting Opioids1 

Initial Oral 

Dosage

(in opioid-naïve)

Additional Dosage 

Information

Analgesic

Onset (min)

Peak (min)

Duration (hr)

Dosing In Special 

Populations Other Considerations

Oxymorphone

 Available as 5 or 10 

mg tablets

 5 mg every 4 to 

6 hr 

 There is no optimal 

or maximum dose of 

oxymorphone; 

patients on LOT are 

likely to become 

tolerant 4 and 

require doses higher 

than the usual 

dosage range to 

maintain the desired 

effect

30 to 45

N/A

4 

 Elderly or debilitated: Use 

with caution and start at 

low end of dosing range; 

levels are increased 40% 

in patients ≥65 years

 Hepatic dysfunction

• Mild hepatic

impairment: Use 

cautiously, start at low 

end of dosing range

• Moderate and severe

hepatic impairment:

Contraindicated

 Renal dysfunction: 

Bioavailability is increased 

57-65% in moderate and

severe impairment; start 

at lower doses and adjust

slowly

 Food has been shown to increase 

peak levels of oxymorphone 

immediate-release by 38%; must 

be taken on an empty stomach 

at least 1 hr before or 2 hr after 

a meal

 Must NOT be taken 

concomitantly with alcohol; 

alcohol (240 ml of 4% to 40% 

ethanol) can cause highly 

variable effects on peak drug 

levels, ranging from a decrease 

of 50% to an increase of 270% 

(demonstrated with ER 

oxymorphone)
February 2017 Page 86 of 198

Short-Acting Opioids1 

Initial Oral 

Dosage

(in opioid-naïve)

Additional Dosage 

Information

Analgesic

Onset (min)

Peak (min)

Duration (hr)

Dosing In Special 

Populations Other Considerations

Tapentadol

 Available as 50, 75, 

or 100 mg tablets

 50 mg every 4

to 6 hr

 Subsequent dose is 

50, 75, or 100 mg 

every 4 to 6 hr, 

adjusted to 

analgesia and 

tolerability

 Second dose may be 

given 1 hr after the 

first dose if 

necessary

 Max recommended 

dose: 700 mg on 

first day, 600 mg on 

subsequent days

 Use tapentadol only 

under careful 

medical supervision 

at lowest effective 

dose

 Patients on LOT are 

likely to become 

tolerant 4 and 

require doses higher 

than the usual 

dosage range to 

maintain the desired 

effect

N/A (rapid)

60

4 to 6

 Elderly: Consider starting at 

the lowest recommended 

dose

 Hepatic dysfunction: 

• Mild hepatic

impairment: No

dosage adjustment

• Moderate hepatic

impairment: Start at

50 mg and give 

subsequent doses at

least 8 hr apart (max.

3 doses in 24 hr)

• Severe hepatic

impairment: Use is not 

recommended

 Renal dysfunction: No 

dosage adjustment for 

mild or moderate renal 

impairment; not 

recommended in severe 

renal impairment

 Respiratory dysfunction: 

Use with caution because 

of respiratory depressant 

effects; consider non–mu 

opioid agonist analgesics

 Must NOT be taken

concomitantly with alcohol 

which can increase serum 

tapentadol concentration

 If used in combination with other 

CNS depressants, consider dose 

reduction of one or both agents

 Use with or within 14 days of 

MAOIs is contraindicated
February 2017 Page 87 of 198

Short-Acting Opioids1 

Initial Oral 

Dosage

(in opioid-naïve)

Additional Dosage 

Information

Analgesic

Onset (min)

Peak (min)

Duration (hr)

Dosing In Special 

Populations Other Considerations

Tramadol (alone or in 

combination with 

APAP)

 Tramadol available as 

50 mg tablet, or in 

tablet combination 

with APAP (325 mg 

APAP, 37.5 mg 

tramadol)

 25 mg every 

morning

 May increase by 25 

mg per day every 3 

days to 100 mg 

tramadol/d (25 mg 

every 6 hr)

 Subsequent 

increments of 50 

mg/d may then be 

made every 3 days 

to 200 mg/d (50 mg 

every 6 hr)

 After titration, may 

give 50 to 100 mg 

every 4 to 6 hr

 Maximum daily dose 

of tramadol: 400 

mg/d

 Combination 

product: maximum 

4000 mg/d APAP; 

2000 mg/d APAP in 

chronic alcoholics or 

in hepatic 

impairment

<60

~120 to 240

6 

 Elderly or debilitated: In 

elderly patients >75 years: 

give <300 mg/d in divided 

dose; use with caution in 

debilitated patients

 Hepatic dysfunction: 

Decrease dosage to 50 mg 

once every 12 hr in 

patients with cirrhosis

 Renal dysfunction: 

• CrCl >30 ml/min: No

change in dose or 

frequency required

• CrCl <30 ml/min:

Increase dosing 

interval to 12 hr and

decrease maximum 

daily dose to 200 mg 

 Dialysis patients: Can 

receive their regular dose 

on the day of dialysis (<7% 

of a dose is removed by 

hemodialysis)

 Slower initiation and titration 

improves tolerability

 Inhibits reuptake of serotonin 

and norepinephrine; 

concomitant use with MAOIs or 

SSRIs may increase risk of 

seizures, serotonin syndrome

 Dose carefully or use another 

agent in patients on 

serotonergic agents

 Seizures reported within the 

recommended dosage range; 

increased risk above 

recommended dosage range 

and in patient with seizure 

disorder, history of seizures, in 

conditions with increased risk of 

seizures, or with other drugs 

that increase seizure risk; 

observe maximum dose limits

 Serious anaphylactoid reactions 

reported, often following first 

dose; patients with a history of 

anaphylactoid reaction to 

codeine and other opioids may 

be at increased risk

1 Check local formulary for available formulations. 2 CYP-2D6 Inhibiting Drugs: Antiarrhythmics (amiodarone, propafenone, quinidine [strong inhibitor]); analgesics (methadone [weak inhibitor], propoxyphene); 

antihistamines (diphenhydramine, chlorpheniramine [in vitro], brompheniramine [in vitro], triprolidine [in vitro]); histamine2 receptor antagonists (cimetidine); 

neuroleptics (chlorpromazine, haloperidol, methotrimeprazine, perphenazine, thioridazine); protease inhibitors (ritonavir), quinine compounds 

(hydroxychloroquine, quinacrine, quinine); selective serotonin reuptake inhibitors (fluoxetine, fluvoxamine, paroxetine, sertraline), miscellaneous compounds 

(clomipramine, ketoconazole, ticlopidine) 3 CYP-2D6 ultra-rapid metabolizers include 1% of Asian and Hispanic, 1-10% of Caucasians, 3% of African-Americans, and 16-28% of N. African and Arabic

populations. 
February 2017 Page 88 of 198

4 Opioid tolerance is assumed in patients already taking fentanyl 25 mcg/hr OR daily doses of the following oral agents for ≥ 1 week: ≥ 60 mg oral morphine, 30 mg 

oxycodone, 8 mg hydromorphone, 25 mg of oxymorphone or equianalgesic dose of another opioid. 

Abbreviations: APAP: acetaminophen; ASA: acetylsalicylic acid; CNS: central nervous system; CrCl: creatinine clearance; d: day(s); ER: extended-release; hr: 

hour(s); IBU: ibuprofen; LOT: long-term opioid therapy; M3G: morphine-3-glucuronide; M6G: morphine-6-glucuronide; MAOIs: monoamine oxidase inhibitors; 

mg: milligram(s); min: minute(s); mL: milliliter(s); SSRIs: selective serotonin reuptake inhibitors

B. Long-acting/Extended-release Opioids

Table D-2. Use of Long-acting/Extended-release Opioids in Adults [198] 

• Long-acting/ER opioids expose patients and other users to the risks of opioid misuse and OUD, which can lead to overdose and death,

even when used at recommended dosages. Long-acting/ER opioids should be reserved for patients for whom alternative analgesic

treatment options (e.g., non-opioid analgesics or immediate-release opioid analgesics) are ineffective, not tolerated, or provide

inadequate control of pain. Assess each patient’s risk prior to prescribing long-acting/ER opioids and institute risk mitigation strategies.

• The FDA has mandated that long-acting/ER opioids be subject to a structured Risk Evaluation and Mitigation Strategy (REMS) program to

manage known or potential serious risks associated with their use (see http://www.er-la-opioidrems.com/IwgUI/rems/home.action).

• Most abuse deterrent technologies have been designed to make manipulation more difficult or to make abuse of the manipulated

product less attractive or less rewarding. In spite of these efforts, no opioid formulation prevents consumption of a large number of

intact capsules or tablets, which continues to be the most common method of abuse.

• Long-acting/ER opioids should not be used for management of acute pain (with exception of oxycodone/acetaminophen ER tablets), as

an as-needed medication, or on initiation of LOT (see Recommendation 13).
February 2017 Page 89 of 198

Long-Acting/ER

Opioids1

Initial Dosage (in opioidnaïve, unless specified) Other Dosing InformationDosing In Special 

Populations Other Considerations

Buprenorphine buccal 

film

 Available in strengths 

of 75, 150, 300, 450, 

600, 750 and 900 

mcg/film for twice 

daily administration

 75 mcg once or twice 

daily for at least 4 

days, then increase 

dose to 150 mcg every 

12 hr

 There is potential for 

buprenorphine to 

precipitate withdrawal 

in patients already on 

opioids; to reduce risk, 

the dose of other 

opioid should be 

tapered to ≤30 mg 

MEDD before initiating 

buprenorphine

 After initial dosing, dosing 

changes as necessary can 

proceed in increments of 150 

mcg every 12 hr, no more 

frequently than every 4 days

 Patients on prior dose of 

opioid 30 to 89 mg MEDD 

may initiate buprenorphine 

film at 150 mcg every 12 hr, 

90 to 160 mg MEDD may 

initiate at 300 mcg every 12 

hr; if prior opioid is >160 mg 

MEDD – consider an 

alternative analgesic

 Time to steady state ~3 days 

with every 12 hr dosing

 Elderly: Initiation at the 

low end of the dosing 

range is 

recommended

 Renal dysfunction: No 

dose adjustment 

recommended

 Hepatic dysfunction: 

Patients with severe 

hepatic impairment

should have starting 

and titration doses 

reduced by half that 

of patients with 

normal liver function 

 QTc prolongation reported with 

recommended doses of 

buprenorphine; maximum dose of 

900 mcg every 12 hr established 

due to the potential for this 

adverse effect; avoid in patients 

with Long QT Syndrome, family 

history of Long QT Syndrome, or 

those taking Class IA or Class III 

antiarrhythmic drugs

 Buprenorphine buccal film is a 

potential treatment option for 

patients with significant renal 

impairment and those with 

gastrointestinal structural or 

functional abnormality that 

interferes with swallowing or 

absorption of orally administered 

medications

Buprenorphine TDS

 Available in every 7 

day patch 

formulation that 

delivers transdermal 

buprenorphine at 

the following rates: 

5 mcg/hr, 7.5 

mcg/hr, 10 mcg/hr, 

15 mcg/hr, and 20 

mcg/hr

 In opioid-naïve or in 

patients on <30 mg 

MEDD of alternate 

agent: Initiate 

treatment with 5 

mcg/hr patch

 There is potential for 

buprenorphine to 

precipitate withdrawal 

in patients already on 

opioids; to reduce risk, 

the dose of other 

opioid should be

tapered to ≤30 mg 

MEDD before initiating 

buprenorphine; the 10 

mcg/hr patch may 

then be initiated at the 

next dosing interval

 The maximum dose of 

buprenorphine TDS 20 

mcg/hr may not provide 

adequate analgesia for 

patients requiring greater 

than 80 mg MEDD; an 

alternate analgesic should be 

considered

 Steady state achieved in ~3 

days

 Dosage does not need 

to be adjusted in 

patients with mild or 

moderate hepatic 

impairment, renal 

impairment, or in the 

elderly

 Potential treatment 

option for patients 

with significant renal 

impairment or those 

with gastrointestinal 

structural or 

functional 

abnormality that 

interferes with 

swallowing or 

absorption of oral 

medications

 Buprenorphine patch 10 mcg/hr is 

approximately equivalent to an 

oral MEDD of 18-28 mg; the 20 

mcg/hr patch is approximately 

equivalent to a MEDD of 36-55 mg

 Dose of one 20 mcg/hr patch per 

week should not be exceeded due 

to risk of QTc prolongation

 Avoid use in patients with Long QT 

Syndrome, family history of Long 

QT Syndrome, or those taking 

Class IA or Class III antiarrhythmic 

medications

 Advise patients that application of 

external heat (e.g., hot baths, 

sunbathing, saunas, heating pads) 

increases maximum plasma 

concentration of buprenorphine 

and risk of fatal overdose
February 2017 Page 90 of 198

Long-Acting/ER

Opioids1

Initial Dosage (in opioidnaïve, unless specified) Other Dosing InformationDosing In Special 

Populations Other Considerations

Fentanyl TDS

 Available in every 3 

day patch 

formulation that 

delivers transdermal 

fentanyl at the 

following rates: 12 

mcg/hr, 25 mcg/hr, 

50 mcg/hr, 75 

mcg/hr, and 100 

mcg/hr

 Fentanyl TDS is 

contraindicated in 

non-opioid-tolerant 

patients

 Fentanyl TDS is 

contraindicated in the 

management of mild 

or post-operative pain, 

and as an “as-needed” 

analgesic

 The initial dose of 

fentanyl TDS in opioidtolerant patients 2 is 

25 mcg/hr, applied 

every 72 hr; the 12 

mcg/hr dose has not 

been evaluated as an 

initial dose

 Fentanyl TDS must be used 

only on intact skin

 Dose change increments 

should be based on 

supplemental opioid doses, 

using a ratio of fentanyl TDS 

12 mcg/hr for every 45 

mg/24 hr of supplemental 

oral MEDD

 Dosing changes, as necessary, 

should occur at least 3 days

after the initial dose; 

thereafter, not more often 

than every 6 days

 Elderly: Twice as 

sensitive to fentanyl 

as younger patients; 

avoid initiation at 

doses >25 mcg/hr

unless patient is 

already taking >135 

mg oral morphine or 

equivalent

 Hepatic / Renal 

dysfunction: Reduce 

dose by 50% in mildmoderate impairment 

and avoid use if 

impairment is severe

 Patients with fever: 

Increased body 

temperature may 

increase release of 

fentanyl from the TDS; 

monitor patients for 

opioid adverse effects 

and modify dosage as 

necessary

 Consider fentanyl TDS in patients 

with persistent, moderate-tosevere pain who cannot take oral 

ER morphine or oral ER oxycodone

 Avoid application of external heat 

sources (e.g., heating pads, electric 

blankets, heat lamps, saunas, hot 

tubs, hot baths, sunbathing, 

heated water beds) to the 

application site while the patch is 

worn as heat may increase release 

and speed absorption of fentanyl

 Using damaged or cut fentanyl TDS 

patches can lead to rapid release 

of the contents of the patch and 

fatal overdose

 Use of fentanyl TDS with CYP3A4 

inhibitors3 can result in increased 

fentanyl plasma concentrations, 

increased or prolonged opioid 

effects, including fatal respiratory 

depression; use extreme caution 

and frequent monitoring in 

patients receiving these 

combinations

 CYP 3A4 inducers may increase 

fentanyl clearance
February 2017 Page 91 of 198

Long-Acting/ER

Opioids1

Initial Dosage (in opioidnaïve, unless specified) Other Dosing InformationDosing In Special 

Populations Other Considerations

Hydrocodone ER

 ER tablets contain 20, 

30, 40, 60, 80, 100 

or 120 mg 

hydrocodone for 

once daily 

administration

 ER capsules contain 

10, 15, 20, 30, 40 or 

50 mg hydrocodone 

for every 12 hr

administration

 Opioid-naïve patients:

20 mg ER tablet once 

daily

 Opioid-naïve patients:

10 mg ER capsule 

every 12 hr

 Opioid tolerant 2 

patients: Convert

current opioid to 

equianalgesic daily 

dose of 

hydromorphone ER; 

reduce the calculated 

amount by 33-50% for 

initial start dose (see 

Table D-3) 

 For opioid-experienced, both 

ER tablets and capsules:

Convert current opioid to 

equianalgesic hydrocodone 

dose then reduce that dose 

by 25%; initiate at nearest 

whole-tablet or capsule 

strength, rounding down as 

necessary 

 For both tablets and capsules:

Dose change increments of 

20 mg per day may be made 

every 3 to 7 days

 Steady state achieved in ~3 

days of dosing

 Elderly: No significant 

pharmacokinetic 

differences

 Patients with renal 

impairment:

Hydrocodone plasma 

concentrations are 

increased in moderate 

or severe impairment; 

use low initial dose 

and monitor closely 

for adverse events 

such as excessive 

sedation and 

respiratory depression

 Patients with hepatic 

impairment: no 

dosage adjustment is 

required in mild or 

moderate hepatic 

impairment; start with 

the lowest dose, 10 

mg, in patients with 

severe hepatic 

impairment, and 

monitor closely

 CYP3A4 inhibitors3 may decrease 

clearance of hydrocodone, 

increase plasma concentrations, 

and increase risk of overdose; 

CYP3A4 inducers4 may increase 

clearance and reduce opioid effect

 Both ER tablets and ER capsules are 

formulated with polyethylene 

oxide which imparts ER properties

 Hydrocodone ER tablets or capsules 

must be swallowed intact and 

should not be cut, broken, 

chewed, crushed or dissolved due 

to risk of fatal overdose

 ER tablet has abuse deterrent 

labeling related to resistance to 

crushing and high viscosity when 

dissolved in aqueous solution

 ER capsule has abuse deterrent 

properties but is not FDA-labeled 

as an abuse deterrent formulation
February 2017 Page 92 of 198

Long-Acting/ER

Opioids1

Initial Dosage (in opioidnaïve, unless specified) Other Dosing InformationDosing In Special 

Populations Other Considerations

Hydromorphone ER 

Tablets 

 Available as 8, 12, 16, 

and 32 mg tablets 

for once daily 

administration

 Not indicated in opioidnaïve patients due to 

the risk of respiratory 

depression

 Opioid tolerant.2

patients: Convert

current opioid to 

equianalgesic daily 

dose of 

hydromorphone ER; 

reduce the calculated 

amount by 33-50% for 

initial start dose (see 

Table D-3) 

 Dosage adjustments may be

made in increments of 4 to 8 

mg every 3 to 4 days as 

needed to achieve adequate 

analgesia

 Steady state reached after 3 

to 4 days of once-daily dosing

 Elderly: No specific 

guidance; monitor 

closely, particularly 

when initiating or 

titrating dosage

 Patients with renal 

impairment: Start 

patients with 

moderate impairment 

at 50% of usual dose, 

and patients with 

severe impairment at 

25% of usual dose

 Patients with hepatic 

impairment: Start 

patients with 

moderate impairment 

at 25% of usual dose 

in non-impaired 

patients

 Hydromorphone ER tablets must be 

swallowed intact and should not 

be cut, broken, chewed, crushed 

or dissolved due to risk of fatal 

overdose

 Hydromorphone ER contains 

sulfites

 Hydromorphone ER has abuse 

deterrent properties but is not 

FDA-labeled as an abuse deterrent 

formulation
February 2017 Page 93 of 198

Long-Acting/ER

Opioids1

Initial Dosage (in opioidnaïve, unless specified) Other Dosing InformationDosing In Special 

Populations Other Considerations

Methadone

 Available as 5 and 10

mg tablets and oral 

solution, 5 or 10 

mg/5 ml, for every 8 

to 12 hr 

administration

 Should not be used for 

as-needed 

supplemental OT

 Initial dose: 2.5 to 5 mg

orally every 8 to 12 hr; 

more frequent 

administration (every 

6 hr) may be necessary 

during initiation to 

maintain analgesia

 START LOW AND GO

SLOW

 See Appendix D for 

detailed dosing 

information including 

dosing 

recommendations in 

patients previously 

exposed to opioids

 Monitor patients

carefully during 

initiation, conversions 

to and from other 

opioids, and dose 

titration

 Dose change increments of

 2.5 mg every 8 hr may be 

made every 5 to 7 days

 Delayed analgesia or toxicity 

may occur because of drug 

accumulation after repeated 

doses, e.g., on days 2 to 5; if 

patient has excessive

sedation during this 

timeframe, consider 

temporarily holding dose(s), 

lowering the dose, and/or 

slowing the titration rate

 Once a stable analgesic dose is 

reached, the dosing interval 

may be extended to every 8 

to 12 hr or longer

 Elderly or debilitated: 

Consider reduced 

dosing in elderly or 

debilitated patients 

who may be more 

sensitive to opioid 

adverse effects

 Hepatic dysfunction: 

No dosage 

adjustments required 

in patients with stable 

chronic liver disease 

or mild-to-moderate 

hepatic dysfunction; 

avoid in severe liver 

disease

 Renal dysfunction: 

Methadone and its 

metabolites do not 

accumulate in patients 

with renal failure; 

however, dosage 

reduction by up to 50-

75% is recommended 

in patients with CrCl 

<10 mL/min

 Prescribers of methadone should 

be thoroughly familiar with its 

complex pharmacokinetic and 

pharmacodynamic properties or 

consult a clinician with experience 

in dosing methadone

 Plasma half-life (22 to 128 hr shortterm; 24 to 48 hr at steady-state) 

may be longer than the analgesic 

duration

 Methadone has little crosstolerance with other opioids; 

therefore, even patients with a 

high degree of opioid tolerance 

may be at risk for overdose when 

switched to methadone

 Methadone is the only long-acting 

opioid available as an oral solution

 Methadone may be subject to drug 

interactions with agents that can 

influence CYP2B6 (e.g., ticlopidine)

 May prolong QTc intervals on ECG; 

risk of torsade de pointes; see 

Appendix D for detailed QTc 

monitoring information
February 2017 Page 94 of 198

Long-Acting/ER

Opioids1

Initial Dosage (in opioidnaïve, unless specified) Other Dosing InformationDosing In Special 

Populations Other Considerations

Morphine CR or SR 

 Available in 15, 30, 

60, 100, and 200 mg 

strengths for every 8 

to 12 hr 

administration

 Morphine ER 

capsules available in 

10, 20, 30, 40, 50, 

60, 70, 80, 100, 130, 

150, and 200 mg 

capsule strengths for 

once daily 

administration

Morphine and 

Naltrexone ER Capsule 

 Available as 20/0.8, 

30/1.2, 50/2, 60/2.4, 

80/3.2, and 100/4 

capsule strengths 

(mg morphine/mg 

naltrexone) for once 

or twice-daily 

administration

 Opioid-naïve patients:

Morphine CR or SR 15 

mg every 8 to 12 hr

 Total daily increments 

of <30 to 40 mg/d may 

be made every 2 days

 Opioid-naïve patients:

Morphine ER capsules 

are not indicated in 

opioid-naïve patients

 Patients who are not 

opioid tolerant: Start 

morphine ER at 30 mg 

daily, may adjust every 

1 to 2 days

 Opioid-naïve patients:

Initiate at the lowest 

dose, 20 mg/0.8 mg 

once daily

 Opioid tolerant 2 

patients: Convert

current opioid to 

equianalgesic daily 

dose of morphine; 

reduce the calculated 

amount by 33-50% for 

initial start dose (see 

Table D-3) 

 Dose may be up 

titrated no more 

frequent than every 

other day

 Morphine CR or SR tablets 

should be swallowed whole,

not broken, chewed, or 

crushed

 For patients who have 

difficulty swallowing, SR and 

ER capsules may be opened 

and the pellets may be

sprinkled onto a small 

amount of soft food (for 

administration without 

chewing) or administered via 

16F gastrostomy tube

 Steady state achieved with 

morphine ER within 24 to 36 

hr

 Morphine/naltrexone must be 

swallowed whole or the 

contents of the capsules 

sprinkled on apple sauce; 

crushing, dissolving, or 

chewing pellets may cause a 

fatal overdose (particularly in 

the opioid-naïve patient) and 

the absorption of naltrexone 

could increase the risk of 

precipitating withdrawal in 

opioid tolerant patients

 Morphine/naltrexone: If once 

daily administration results in 

inadequate analgesia, may 

switch to twice daily dosing

Information applies to all 

formulations of morphine 

listed

 Elderly: Use with 

caution and at lower 

dose

 Patients with renal 

dysfunction:

Bioavailability is 

increased and 

clearance is 

decreased; 

metabolites M3G and 

M6G accumulate

significantly

 Reduce dose or, if 

severe renal 

impairment exists, 

avoid use

 Patients with hepatic 

dysfunction: Clearance 

decreases and half-life 

increases; M3G and 

M6G to morphine 

ratios are reduced; 

use carefully in 

patients with cirrhosis 

and consider reducing 

dose or extending 

dosing interval by 1.5 

to 2 times

 Morphine SR is preferred first-line 

long-acting agent because of 

similar efficacy to other longacting opioids, comparable safety 

profile, provider familiarity with 

use, and lower cost

 M6G, an active metabolite, may 

accumulate in renal impairment 

and contribute to excessive opioid 

effects

 M3G, a metabolite without 

analgesic activity, may accumulate 

in renal impairment; this 

metabolite has been implicated in 

morphine-induced neurotoxicity, 

hyperalgesia, and allodynia

 Morphine/naltrexone ER capsule 

has abuse deterrent labeling 

related to potential to precipitate 

withdrawal if drug is taken by 

other than oral route
February 2017 Page 95 of 198

Long-Acting/ER

Opioids1

Initial Dosage (in opioidnaïve, unless specified) Other Dosing InformationDosing In Special 

Populations Other Considerations

Oxycodone ER

 Tablets available in 

10, 15, 20, 30, 40, 

60, and 80 mg 

strengths for every 

12 hr administration

 Capsules available in

9, 13.5, 18, 27 and 

36 mg strengths for 

every 12 hr

administration

 Opioid-naïve patients:

10 mg (tablets) or 9 

mg (capsules) orally 

every 12 hr

 Opioid tolerant.2 

patients: Convert

current opioid to 

equianalgesic daily 

dose of oxycodone ER; 

reduce the calculated 

amount by 33-50% for 

initial start dose (see 

Table D-3) 

 Dose change increments: May 

increase to 20 mg (tablets) or 

18 mg (capsules) every 12 hr 

after 1 or 2 days; thereafter, 

the total daily dose may be 

increased by 25-50% of the 

current dose every 1 or 2 

days

 ER tablets are not 

bioequivalent to ER capsules; 

10 mg oxycodone HCl (ER 

tablet) = 9 mg oxycodone 

base (ER capsule)

 Steady state achieved with 

tablets or capsules in 24 to 36 

hr with repeat dosing

 Elderly: Plasma 

concentrations of 

oxycodone are 

increased ~15% in the 

elderly; however, 

usual dosing and 

dosing intervals may 

be appropriate

 Patients with renal 

dysfunction: Plasma 

concentrations of 

oxycodone are 

increased ~50% in 

patients with CrCl <60 

ml/min; dose 

conservatively and 

adjust according to 

clinical situation

 Patients with hepatic 

dysfunction: Reduce 

initial dose to 1/3 to 

1/2 of the usual dose 

and monitor closely

 Recommended for patients who 

experience intolerable, 

unmanageable adverse effects to 

long- acting morphine

 Both ER tablets and ER capsules 

have abuse deterrent labeling 

related to resistance to abuse by 

intranasal and intravenous means

 ER tablets should be swallowed 

whole, not broken, chewed, or 

crushed

 ER capsules may be opened and 

sprinkled on soft food or 

administered via feeding tube
Long-Acting/ER

Opioids1

Initial Dosage (in opioidnaïve, unless specified) Other Dosing InformationDosing In Special 

Populations Other Considerations

Oxycodone/APAP ER

 Available as tablets 

containing 

oxycodone 7.5 mg 

and APAP 325 mg

for every 12 hr 

administration

 Opioid-naïve patients:

May initiate therapy 

with the standard 

dose of 2 tablets every 

12 hr 

 A standard, single dose 

consists of 2 tablets 

totaling 15 mg 

oxycodone/650 mg 

APAP

 This is the only longacting/ER opioid to 

have an acute pain 

indication

 The polyethylene oxide 

content causes the tablet to 

swell and become sticky 

when wet. This has the 

potential to cause 

obstruction of the airway or 

GI obstruction

 Steady state concentration of 

both components are 

reached within 24 hr of 

product initiation

 Elderly: Take 

precautions when 

determining the 

dosing amount and 

frequency in geriatric 

patients since a 

greater sensitivity to 

oxycodone may be 

observed in this 

patient population 

when compared to 

younger patients

 Patients with renal or 

hepatic dysfunction:

Patients with renal 

dysfunction (CrCl <60 

ml/min) or hepatic 

dysfunction should 

initiate therapy with 1 

tablet every 12 hr and 

adjust as needed

 This long-acting/ER opioid is an 

exception to the REMS 

requirements due to the relatively 

low amount of oxycodone

contained in each tablet

 Oxycodone/APAP ER tablets are 

formulated with PEO which is 

responsible for its ER in addition to 

labeled abuse deterrent properties

 Patients should be instructed not to 

pre-soak, lick, or otherwise wet 

tablets prior to swallowing and to 

take one tablet at a time with 

adequate water to insure 

complete and immediate 

swallowing

February 2017 Page 96 of 198
February 2017 Page 97 of 198

Long-Acting/ER

Opioids1

Initial Dosage (in opioidnaïve, unless specified) Other Dosing InformationDosing In Special 

Populations Other Considerations

Oxymorphone ER 

Tablets

 Available as 5, 7.5, 

10, 15, 20, 30 and 40

mg tablets for every 

12 hr administration

 Opioid-naïve patients: 

Initiate at 5 mg every 

12 hr 

 Opioid tolerant.2 

patients: Convert

current opioid to 

equianalgesic daily 

dose of oxycodone; 

reduce the calculated 

amount by 33-50% for 

initial daily start dose 

(see Table D-3)

 Dose change increments: May 

increase by 5 to 10 mg every 

12 hr every 3 to 7 days

 Oxymorphone ER tablets must 

be taken whole, one tablet at 

a time, with enough water to 

ensure complete swallowing 

immediately after placing in 

the mouth

 Steady-state plasma levels are 

achieved after 3 days of 

multiple dose administration

 Elderly: Plasma drug 

levels are about 40% 

higher in elderly 

versus younger 

subjects; use caution, 

starting at the low end 

of dosing range and 

titrating slowly

 Patients with renal 

dysfunction:

Bioavailability is 

increased by 57% in 

moderate impairment 

and by 65% in severe 

impairment; in 

patients with CrCl <50 

mL/min, 

oxymorphone should 

be started with the 

lowest dose and 

titrated slowly

 Patients with hepatic 

dysfunction: Use with 

caution in patients 

with mild hepatic 

impairment, starting 

with lowest dose and 

titrating slowly

 Contraindicated in 

patients with 

moderate or severe 

hepatic impairment

 Must be taken on an empty 

stomach at least 1 hr before or 2 

hr after a meal; food has been 

shown to increase peak levels of 

oxymorphone ER by 50%

 Must NOT be taken concomitantly 

with alcohol, which can cause 

highly variable effects on peak 

drug levels, ranging from a 

decrease of 50% to an increase of 

270%
February 2017 Page 98 of 198

Long-Acting/ER

Opioids1

Initial Dosage (in opioidnaïve, unless specified) Other Dosing InformationDosing In Special 

Populations Other Considerations

Tapentadol ER

 Available as tablets 

containing 50, 100, 

150, 200, or 250 mg 

tapentadol for twice 

daily dosing

 In opioid-naïve and 

non-tolerant patients:

Initiate therapy with 

50 mg twice daily; use 

of higher starting 

doses in patients who 

are not opioid tolerant 

may cause fatal 

respiratory depression

 There are no 

established conversion 

ratios for conversion 

from other opioid to 

tapentadol ER; convert

current opioid to an 

estimated 

equianalgesic daily 

dose of tapentadol; 

reduce the calculated 

amount by 33-50% for 

initial daily start dose 

(see Table D-3) 

 Dose change increments: May 

increase dose by no more 

than 50 mg twice daily every 

3 days

 Maximum daily dose: 500 mg 

daily

 Tapentadol ER tablets must be 

taken whole; crushing, 

chewing, or dissolving tablets 

will result in uncontrolled 

delivery of tapentadol and 

can lead to overdose or 

death

 Steady state is attained after 

the third dose (24 hr after the 

first twice daily multiple dose 

administration)

 Elderly: No dosing 

adjustment needed, 

consider starting at 

lowest recommended 

dosage

 Patients with renal 

dysfunction: No 

dosage adjustment for 

mild or moderate 

renal impairment; not 

recommended in 

severe renal 

impairment

 Patients with hepatic 

dysfunction: Use not 

recommended in 

severe hepatic 

impairment

 Must NOT be taken concomitantly 

with alcohol which can increase 

serum tapentadol concentration

and cause fatal overdose

 Use with or within 14 days of 

MAOIs is contraindicated

Tramadol ER

 Available as 100, 200 

and 300 mg tablets 

for once daily 

administration

 Patients not currently 

on tramadol: 100 mg 

once daily

 Converting from 

tramadol IR: Start at

24 hr dosage 

equivalent rounded 

down to closest 100

mg increment

 Dose change increments: May 

increase by 100 mg every 5 

days based on analgesia and 

tolerability

 Maximum dose: 300 mg/day

 Elderly: Start at low 

end of dosing range; 

use particular caution, 

especially in patients 

>75 years

 Renal dysfunction:

Avoid use if CrCl <30 

ml/min

 Hepatic dysfunction:

Avoid use in severe 

hepatic impairment 

(Child- Pugh Class C)

 Must be swallowed whole and must 

not be chewed, crushed, or split

 See warnings and precautions 

under Other Considerations for 

tramadol IR (Table D-1) 

1

Check local formulary for available formulations.

2 Opioid tolerance is assumed in patients already taking fentanyl 25 mcg/hr OR daily doses of the following oral agents for ≥ 1 week: ≥ 60 mg oral morphine, 30 mg 

oxycodone, 8 mg hydromorphone, 25 mg of oxymorphone or equianalgesic dose of another opioid. 
3

CYP3A4 inhibiting agents include: ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, 

aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, verapamil 4 CYP3A4 inducing agents include: carbamazepine, phenobarbital, phenytoin, primidone, rifampin

Abbreviations: APAP: acetaminophen; CR: morphine controlled; CrCl: creatinine clearance; CYP2B6: cytochrome P450 2B6; CYP3A4: cytochrome P450 3A4; ECG: 

electrocardiogram; ER: extended-release; GI: gastrointestinal; HCl: hydrochloride; hr: hour(s); IR: immediate release; M3G: morphine-3-glucuronide; M6G: 

morphine-6-glucuronide; MAOIs: monoamine oxidase inhibitors; mcg: microgram(s); MEDD: morphine equivalent daily dose; mg: milligram(s); min: minute(s); 

mL: milliliter(s); OT: opioid therapy; PEO: polyethylene oxide; TDS: transdermal system; QTc: the heart rate’s corrected time interval from the start of the Q 

wave to the end of the T wave; REMS: Risk Evaluation and Mitigation Strategy; SR: sustained release

C. Morphine Milligram Equivalent Doses

Table D-3: Morphine Milligram Equivalent Doses for Commonly Prescribed Opioids[33] 

Morphine Milligram Equivalent Doses (MME)

Opioid Agent Conversion Factor

Codeine1 0.15

Tapentadol2 0.4

Morphine 1 

Hydrocodone 1 

Oxycodone 1.5

Oxymorphone 3 

Hydromorphone 4 

 All doses in mg/d except for fentanyl.

 Multiply the daily dosage for each opioid by the conversion factor to determine the equianalgesic 

dose in MME. Equianalgesic dose conversions are only estimates and cannot account for 

individual variability in genetics and pharmacokinetics.

 Do not use the calculated dose in MME to determine the doses to use when converting one 

opioid to another. When converting opioids, the new opioid is typically dosed at substantially 

lower than the calculated MME dose (33-50% less) to avoid accidental overdose due to 

incomplete cross-tolerance and individual variability in opioid pharmacokinetics.

 Use particular caution with fentanyl because it is dosed in mcg/hr instead of mg/d, and 

absorption is affected by heat and other factors.

 See Table D-2 for conversion guidance for buprenorphine-containing agents.

1

When converting from weak opioid analgesics to more potent opioids, use the recommended initial doses of the new opioid for opioid-naïve patients. 2

The conversion factor estimate for tapentadol is based upon μ-receptor agonist activity in animal models where tapentadol has been shown to be 2-3 times less 

potent than morphine.

Abbreviations: d: day(s); hr: hour(s); mcg: microgram(s); mg: milligrams; MME: morphine milligram equivalent dose

February 2017 Page 99 of 198
VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

February 2017 Page 100 of 198

D. Methadone Dosing Guidance

a. Summary

• Methadone is not a first-line agent for the treatment of chronic pain.[33] It is an alternative

long-acting opioid analgesic that may be useful in managing pain severe enough to require

continuous daily treatment for which alternative treatment options are inadequate.

• In general, as with other opioids, methadone should be used as one aspect of a comprehensive

pain management plan, as agreed upon by the practitioner and the patient.

• Methadone should be initiated and adjusted by, or in consultation with, a practitioner who has

the relevant knowledge and expertise;[33]if a provider with clinical experience is not available,

then another long-acting opioid may be used until such consultation is obtained.

• The general principles utilized in the dosing of methadone are different than those of other

opioids; these differences are due to methadone’s unique pharmacokinetic and

pharmacodynamic properties and include, but are not limited to:

 Dose titration should occur after at least 5-7 days on a designated dose (in the large

majority of cases) 

 Careful consideration must be given to potential drug interactions and to the potential for 

QT prolongation 

• Methadone is considered to be safe in patients with renal and/or hepatic impairment but should

be used with caution in end-stage disease cases of these conditions.

• There are a number of methods available that use conversion ratios to initiate or titrate

methadone; no single method is considered superior to others. Titration should be based on

patient response and not solely based on equianalgesic dosing tables.

• Monitoring ECG for QTc interval prolongation is recommended based upon certain clinical

scenarios.

b. Overview

Methadone is indicated for persistent, moderate-to-severe chronic pain in patients requiring continuous, 

around-the-clock opioid administration over an extended time. Methadone’s pharmacokinetic properties

are complex and incompletely documented.[199,200]It has a long elimination half-life that has wide interpatient variability (mean or median half-life, depending on subject type, ranges from 3-128 hr) [201-214] 

and does not reflect duration of analgesia.[210,215]Initially, methadone duration of analgesia ranges from 

4-6 hr; however, with repeated dosing, duration of analgesia can extend to 8-12 hr. Accordingly, while

initial dosing may require more frequent administration (three times per day [TID]) to achieve adequate

analgesia,[216,217] once steady-state levels are established, reducing dosing frequency to two times per

day (BID) can be considered. In elderly and frail patients, consideration may be given to starting with BID

dosing. Also, as a result of the dissociation between half-life and analgesic duration, tissue accumulation of

methadone can occur. It may take ten days for plasma levels to stabilize; thus, as a general rule, dose

titration should not be more frequent than every 5-7 days.[218] Patients should be reassessed more

frequently (e.g., every few days) when methadone is initiated and when the dose is increased.[33] Once

stable dosing is established, follow-up can be as clinically warranted.
VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

February 2017 Page 101 of 198

While methadone is an alternative to ER morphine or oxycodone for treatment of moderate-to-severe

pain, a number of authors have cautioned about the complexities of dosing and suggested the drug be

prescribed by practitioners with relevant experience, in an adequately monitored

setting.[33,216,217,219-225] Significant toxicity has occurred particularly when doses were increased 

too frequently, conversion doses were too high, or dosing intervals too close.[222,226-228]

 

In 2014, a methadone safety guideline was developed by the American Pain Society and College of 

Problems of Drug Dependence, in collaboration with the Heart Rhythm Society, which made 

recommendations for safer prescribing of methadone.[169] Table D-4 outlines baseline and monitoring 

recommendations based on categorization of patients for risk of QTc prolongation. Palliative care patients 

with the goal of comfort care may require less vigilance with ECG monitoring. 

Table D-4: Baseline and Monitoring Recommendations Based on Categorization of Patients for 

Risk of QTc Prolongation [169]

Category Baseline ECG Follow Up ECGs1Action

Patients with risk 

factors for QTc 

prolongation, any 

prior QTc >450, 

or history of 

syncope

Obtain baseline

 ECG within last 3 

months is sufficient

 Strong 

recommendation 

 Low quality

evidence

 2-4 weeks after initiation

 With significant dose increases

 When methadone dose reaches 

30-40

2 mg/d

 When methadone dose reaches 

100 mg/d2

 When new risk factors arise or 

signs or symptoms of 

suggestive arrhythmia

 Avoid use if

QTc >500 ms3

 Consider alternative to 

methadone for QTc 450-

5003

 Evaluate and correct 

reversible causes of QTc 

prolongation

Patients not 

known to be at 

higher risk of QTc 

prolongation 

Consider baseline

 ECG within the last 

12 months is 

sufficient

 Weak 

recommendation 

 Low quality

evidence

 When methadone dose reaches 

30-40

2 mg/d

 When dose reaches 100 mg/d2

 When new risk factors arise or 

signs or symptoms of 

suggestive arrhythmia

 Avoid use if

QTc >500 ms3

 Consider alternative to 

methadone for QTc 450-

5003

 Evaluate and correct 

reversible causes of QTc 

prolongation

1

Consider obtaining yearly ECGs once a stable dose is reached. 2

Doses this high are not recommended for chronic pain and are typically observed only for patients receiving 

methadone for MAT for OUD. 3

For patients on stable doses of methadone in whom a prolonged QTc has been noted (QTc >450 ms), consider 

tapering the dose of methadone and repeating the ECG. Other QT prolonging medications should be evaluated 

and cardiology specialty care should be consulted for expert opinion. 

Abbreviations: d: day(s); ECG: electrocardiogram; MAT: medication assisted treatment; ms: millisecond(s); mg: 

milligram(s); OUD: opioid use disorder; QTc: QTc interval (the heart rate’s corrected time interval from the start of 

the Q wave to the end of the T wave)

Special caution is recommended with concurrent benzodiazepines and drugs that prolong the QT 

interval.[229] 

Methadone is primarily metabolized by CYP450 2B6 to inactive/nontoxic metabolites.[230-236] CYP2B6 is 

a highly polymorphic gene[237] and may help to explain why the pharmacokinetics of methadone can be 

extremely variable from individual to individual. Currently, it is unclear whether cytochrome P450 3A has 
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any influence on methadone metabolism and caution is encouraged when using drugs that interact with 

both enzymes. 

c. Dosing Strategies

The dosing recommendations listed below (in Table D-5) are provided to offer guidance on using

methadone in the treatment of patients with chronic pain, particularly when converting from another

opioid to methadone. The use of methadone for pain should be done in the context of a pain clinic or with 

assistance of local pain management experts, including healthcare providers or pharmacists, who have 

experience with methadone’s use. If such resources are not readily available, other long-acting opioids 

should be considered (e.g., morphine sustained action [SA], or oxycodone SA). 

Various methadone dosing strategies have been employed [224,238,239] and methods are still evolving.

Older, prospective studies found no evidence to support the superiority of one dosing strategy over 

another.[220,240,241] The lack of prospective and comparative studies concerning methadone dosing 

strategies highlights the need to carefully individualize the dosing regimen of methadone. 

For opioid tolerant patients, a number of different equianalgesic dose ratio tables can be used to determine 

the dose of methadone.[220,223,242-245] This VA/DoD OT CPG includes one of the more conservative 

equianalgesic dose ratio tables as a reference for providers to discuss and/or consider (Table D-3).[245]

Local subject matter experts may prefer, or be more familiar with, other accepted (evidence-based) 

equianalgesic dose ratio tables. No equianalgesic dose ratio table is considered superior and all have 

similar limitations. When converting to methadone, lower MEDDs have lower conversion ratios than 

higher MEDDs. As compared to lower MEDDs, higher MEDDs may convert to smaller methadone doses 

than one might expect. For example, 60 mg MEDD would be ~15 mg of methadone/day (a ratio of ~4:1); 

whereas 180 mg MEDD would be ~22.5 mg/day (a ratio of ~8:1). Methadone dose conversion is not a 

linear process. Furthermore, while the equianalgesic dose ratio tables account for cross-tolerance,[218]

some subject matter expertsfeel the calculated methadone dose should be further decreased for incomplete 

cross-tolerance, especially for patients on higher MEDDs. [169,246]

Table D-5: Dosing Recommendations for Patients Receiving Codeine Preparations or No 

Previous Opioids [247,248] 

Dosing Strategy

Initial

Methadone 

Dose Increments Comments

Gradual titration

(For CNCP and situations

necessitating less frequent

monitoring) 

2.5 mg every 12 hr

or 8 hr

2.5 mg every 12 hr or 8 hr, no 

more often than every 5 to 7 d

As a general rule, start 

Faster titration low and go slow

(For cancer pain and situations 

where frequent monitoring is 

possible)

2.5-5 mg every 8 

hr

2.5 to 5 mg every 8 hr as often 

as every third day

Note: All doses refer to oral administration

Abbreviations: CNCP: chronic non-cancer pain; d: day(s); hr: hour(s); mg: milligram(s)
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Table D-6: Equianalgesic Dose Ratios [245,246] 

Morphine Dose 

(mg/d)

<30 31-99 100-299 300-499 500-999 1000-1200 >1200

Morphine: 

Methadone

2:1 4:1 8:1 12:1 15:1 20:1 Consult

Note: The conversion ratio increases as the morphine equivalent dose increases [33,220-222,249] 

Abbreviations: d: day(s); mg: milligram(s)

The equianalgesic dose ratio is only one component of the process for appropriate dosing of methadone

and other opioids. Once the dose is determined, there are two different methods to make the switch: a 

rapid conversion method and a stepwise/phased conversion. Again, no one conversion method has been

determined to be superior to the others. 

• For rapid conversion, the previous opioid is discontinued and the calculated methadone dose is

started on day one.

• For the stepwise/phased conversion, the dose of the previous opioid is decreased by 1/3 and

replaced with 1/3 of the calculated methadone dose (given in three divided doses). Then the

previous opioid dose is decreased by an additional 1/3 and the methadone dose is increased by

1/3. Finally, the remaining 1/3 of the previous opioid dose is discontinued and the methadone

dose is increased to the initial calculated dose. This can be done over several days or

weeks.[218,250]

For breakthrough pain, a short-acting opioid preparation (e.g., acetaminophen with hydrocodone,

oxycodone with or without acetaminophen, or immediate-release morphine) may be used until steady 

state is achieved (i.e., 5-7 days). As-needed methadone has also been used in a palliative care 

setting;[224,238,240] however, it is generally discouraged to avoid drug accumulation. It is important to 

note that use of breakthrough pain medications in patients with CNCP is controversial. If opioid

medications for breakthrough pain are indicated, following titration to a stable methadone dose in CNCP

patients, they should be used sparingly.[241] 

d. Converting from Methadone to Oral Morphine

Switching from methadone to another opioid is not simply the reverse process; the equianalgesic dose 

ratio tables previously mentioned are not bi-directional and cannot be used in reverse (i.e., the morphine 

to methadone conversion ratio may not be the same as the methadone to morphine ratio).[251] There is 

no widely accepted conversion strategy for switching from methadone to another opioid. A proposed safe 

and conservative approach is a 1:3 methadone to morphine ratio (10 mg methadone/day = 30 mg oral 

morphine/day).[218] However, literature suggests patients may end up on as high as 1:4.7 methadone to 

morphine ratio (10 mg methadone = 47 mg morphine).[252] 

e. Special Patient Populations

Patients 65 years and older may have decreased clearance of methadone.[212] Dosage adjustments do 

not appear necessary in patients with stable chronic liver disease; in addition, methadone and its 

metabolites do not accumulate in patients with renal failure.[253] However, two prospective studies on 

methadone dosing strategies excluded patients with liver or renal disease,[220,240] thus caution should 
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be observed when dosing methadone in these populations. Dosage adjustments may be necessary in

patients with end-stage liver or renal disease. 

f. Patient Education

Discuss the following information with patients prior to and during treatment with methadone:[243] 

• Methadone must be taken only as directed. Patients should never take extra doses without

getting approval from the prescriber.

• Taking methadone as frequently as other opioids may produce a fatal overdose.

• Patients should use other CNS depressants (especially benzodiazepines) with caution and only as

directed by a healthcare provider.

• Patients should only use methadone in combination with other opioids as prescribed by a

healthcare provider.

• The use of illicit drugs and/or alcohol with methadone may be fatal.

• Pain relief builds gradually and usually takes 5-7 days to see the full effects of a particular dose.

• Patients should tell all medical providers that they are taking methadone. Adding medications or

changing dosing of other medications can affect methadone and should be coordinated with the

methadone prescriber.

• Patients should avoid activities requiring mental alertness or coordination (such as driving or

using machinery) until the effects of methadone are realized, typically a week or longer.

• Patients should rise slowly from a sitting/supine position, as methadone may cause dizziness.

• Methadone, like other opioids, can cause significant constipation. Patients should take a

prescribed laxative as directed.

• Patients should report any of the following symptoms immediately and/or seek

urgent/emergent care: dizziness or lightheadedness, irregular heartbeat (palpitations), falls or

near falls, chest pain/pressure, and shortness of breath.

• Patients should avoid abrupt discontinuation of methadone without first consulting a healthcare

provider.
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Appendix E: Evidence Review Methodology

A. Developing the Scope and Key Questions

The CPG Champions, along with the Work Group, were tasked with identifying KQs to guide the systematic 

review of the literature on LOT. These questions, which were developed in consultation with the Lewin 

Team, addressed clinical topics of the highest priority for the VA and DoD populations. The KQs follow the 

population, intervention, comparison, outcome, timing, and setting (PICOTS) framework for evidence 

questions, as established by the Agency for Healthcare Research and Quality (AHRQ). Table E‐1 provides a 

brief overview of the PICOTS typology.

Table E-1. PICOTS [254] 

P 

Patients, 

Population, or 

Problem

A description of the patients of interest. It includes the condition(s), populations or subpopulations, disease severity or stage, co-occurring conditions, and other patient 

characteristics or demographics.

I Intervention or 

Exposure

Refers to the specific treatments or approaches used with the patient or population. It 

includes doses, frequency, methods of administering treatments, etc.

C Comparison

Describes the interventions or care that is being compared with the intervention(s) of 

interest described above. It includes alternatives such as placebo, drugs, surgery, lifestyle 

changes, standard of care, etc.

O Outcome

Describes the specific results of interest. Outcomes can include short, intermediate, and 

long-term outcomes, or specific results such as quality of life, complications, mortality, 

morbidity, etc.

(T) Timing, if 

applicable

Describes the duration of time that is of interest for the particular patient intervention and 

outcome, benefit, or harm to occur (or not occur).

(S) Setting, if

applicable

Describes the setting or context of interest. Setting can be a location (such as primary, 

specialty, or inpatient care).

The Champions, Work Group, and evidence review team carried out several iterations of this process, 

each time narrowing the scope of the CPG and the literature review by prioritizing the topics of interest.

Due to resource constraints, all developed KQs were not able to be included in the systematic review. 

Thus, the Champions and Work Group determined which questions were of highest priority, and those 

were included in the review. Table E-4 contains the final set of KQs used to guide the systematic review 

for this CPG. 

a. Population(s)

Adults 18 years or older with chronic cancer or non-cancer pain treated in any clinical setting were covered 

in this systematic review. 

b. Intervention(s)

Table E-2 lists the interventions that were covered in this systematic review. The interventions are listed 

according to the KQs they address.
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Table E-2. Key Question Specific Interventions

Question Interventions

1 

Patients with a co-occurring medical or psychological condition on the following opioids:

 Buprenorphine

 Codeine 

 Hydrocodone 

 Hydromorphone 

 Morphine 

 Oxycodone 

 Oxymorphone 

 Tapentadol 

 Tramadol 

 Fentanyl 

 Methadone

2 

Opioid dosage

Length of opioid use

Other risk factors (others may be included)[255] 

 Age

 Days with physical healthcare visits

 Degree of pain

 Gender

 History of sexual abuse

 History of abuse (including emotional, physical, or cyber bullying) or domestic violence 

 History of SUD—Self or familial

 Marital status

 Mental disorders

 Non-opioid substance abuse

 Race

 Social status

 Work status

3 See list of opioids under KQ1; non-pharmacological interventions

4 See list of opioids under KQ1; non-pharmacological interventions
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Question Interventions

5 

Short-acting opioids 

 Codeine

 Fentanyl

 Hydrocodone (only in combination with acetaminophen and ibuprofen) 

 Hydromorphone

 Morphine sulfate (tablet/liquid) 

 Oxycodone (alone or in combination with acetaminophen, ibuprofen, or aspirin)

 Oxymorphone

 Tramadol

Long-acting/ER opioids

 Buprenorphine transdermal system

 Fentanyl transdermal system

 Hydrocodone bitartrate ER capsules/tablets

 Hydromorphone hydrochloride ER tablets

 Methadone hydrochloride tablets

 Morphine sulfate and naltrexone ER capsules

 Morphine sulfate ER capsules/tablets

 Oxycodone hydrochloride and naloxone hydrochloride ER tablets

 Oxycodone hydrochloride ER tablets

 Oxymorphone hydrochloride ER tablets

 Tapentadol ER oral tablets

 Transdermal, buccal, sublingual, or pumps

See main list of opioids.

 Abuse deterrent formulations

 Buprenorphine/Naloxone

 Morphine/Naltrexone

 OROS hydromorphone (Osmotic ER Oral delivery System) 

 Oxycodone Controlled Release 

 Oxymorphone

 Additional medications

 Tramadol and other dual-mechanism opioids

 Buprenorphine

 Methadone

6 

Opioid therapy plus other psychoactive medications such as CNS depressants/antidepressants, nonopioid analgesics, benzodiazepines, stimulants, muscle relaxers, medical marijuana, Z-drugs (e.g., 

Zolpidem [Ambien], Eszopiclone [Lunesta], Zaleplon [Sonata]), and over-the-counter sleep medications 

(e.g., diphenhydramine hydrochloride or doxylamine succinate) 
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Question Interventions

7 

Naloxone rescue with one form of naloxone

Informed consent

Use of written informed consent (previously called contracts)

Risk assessment instruments

Opioid management plans

Patient education

UDT

PDMP

Monitoring instruments

More frequent monitoring

Pill counts

Use of abuse–deterrent formulations

Diversion prevention interventions (e.g., properly securing drugs, medication take back programs, public 

health education)

Pharmacogenetic testing

Random call-backs

Compliance with other therapies

Case management

Periodic check of state databases

Needle exchange programs

8 

Treatment with at least one of the following:

 Buprenorphine (with or without naloxone) 

 Methadone 

 Injectable/oral naltrexone

 Medical Management 

 Contingency Management

 Individual Drug Counseling 

 Motivational interviewing

 Motivational Enhancement Therapy 

 Other motivational approaches 

9 One tapering strategy or schedule

c. Comparator(s)

Table E-3 lists the comparators of interest to this systematic review. The comparators are listed by the KQ

they address.
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Table E-3. Key Question Specific Comparators

Question Comparators

1 Patients without a co-occurring medical or mental health condition on LOT

2 Comparison groups that vary by LOT dosage and length of opioid use, other factors

3 

No OT (including placebo) or other pain management strategies

Other modalities:

 Non-opioid medications (e.g., non-steroidal including compounded topical preparations)

 Physical interventions (e.g., physical therapy, active/passive exercise, ultrasound stimulation, 

chiropractic, osteopathic manipulation therapy)

 Behavioral/mental health interventions EXAMPLES:

• CBT

• Dialectical behavior therapy (DBT)

• Mindfulness 

• Acceptance and commitment therapy (ACT)

 Complementary and alternative interventions EXAMPLES:

• Acupuncture

• Chiropractic interventions

4 

No OT (including placebo) or other pain management strategies

Other modalities:

 Non-opioid medications (e.g., non-steroidal including compounded topical preparations)

 Physical interventions (e.g., physical therapy, active/passive exercise, ultrasound stimulation, 

chiropractic, osteopathic manipulation therapy)

 Behavioral/ mental health interventions (e.g., CBT, ACT, mindfulness, DBT)

 Complementary and alternative interventions

5 

Long-acting opioid drugs or combination short and long-acting drugs (See list)

Other route of administration/delivery alternatives

Non abuse-deterrent formulations

Other opioids

No use of buprenorphine

No use of methadone

6 Opioid therapy alone

7 No mitigation strategy or other mitigation strategy

8 No treatment for OUD or other treatment for OUD

9 Different tapering strategy or schedule

d. Outcomes

For the treatment and management questions (KQ 3–9), the following outcomes were of interest in the 

systematic review:

• Pain relief

• Quality of life

• Cognitive/functional status

• Mortality

• Opioid abuse/misuse
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• Adverse events

 SUD 

 Aberrant use

 Overdose

 Non-pain use of opiates

 Abuse

 Addictions

 Cardiovascular events

 Respiratory depression

 Gastrointestinal complications (including constipation)

 Endocrinological complications (including impotence)

 Weight gain

 Cognitive performance

 Psychiatric decompensation

 Psychological symptoms (e.g., depression, loss of libido, nightmares)

 Headaches

 Suicide

 Accidents (including falls)

 Infections

 Increased risk of HIV and Hepatitis A, B, and C

 Loss to follow-up/medical care

e. Timing 

The timing considered in the systematic review was 12 weeks for studies looking at the efficacy of OT, and

any follow-up for studies reporting on the safety of OT.

f. Setting

The setting considered in the systematic review was primary care.

B. Conducting the Systematic Review

Extensive literature searches using the search terms and strategy included in Appendix J identified 15,554 

citations potentially addressing the KQs of interest to this evidence review. Of those, 11,633 were excluded 

upon title review for clearly not meeting inclusion criteria (e.g., not pertinent to the topic, not published in 

English, published prior to study inclusion publication date, not a full-length article). Overall, 3,921 

abstracts were reviewed with 2,995 of those being excluded for the following reasons: not a systematic 

review or clinical study (CS), did not address a KQ of interest to this review, did not enroll a population of 
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interest, or published prior to March 1, 2009. A total of 926 full-length articles were reviewed. Of those, 

478 were excluded at a first pass review for the following: not addressing a KQ of interest, not enrolling the 

population of interest, not meeting inclusion criteria for CS or systematic review, not meeting inclusion 

criteria for any KQ, or being a duplicate. A total of 448 full-length articles were thought to address one or 

more KQs and were further reviewed. Of these, 385 were ultimately excluded. Reasons for their exclusion 

are presented in Figure E-1 below. 

Overall, 63 articles addressed one or more of the KQs and were considered as evidence in this review. 

Table E-4 indicates the number of studies that addressed each of the questions. 

Figure E-1. Study Flow Diagram

, 

 385 Citations Excluded at 2nd Pass Full Article Level

108 Wrong study design or does not address a KQ

68 Wrong study population or chronic pain patients 

not reported separately

72 SR superseded by more comprehensive review or 

relevant studies included in report

21 No outcomes of interest

116 Other (e.g. duplicate, published prior to 2009, not 

a clinical trial or SR)

 385 Citations Excluded at 2nd Pass Full Article Level

108 Wrong study design or does not address a KQ

68 Wrong study population or chronic pain patients 

not reported separately

72 SR superseded by more comprehensive review or 

relevant studies included in report

21 No outcomes of interest

116 Other (e.g. duplicate, published prior to 2009, not 

a clinical trial or SR)

11,633 Citations Excluded at the Title Level

Citations excluded at this level were off-topic, not 

published in English, or published prior to

inclusion date

11,633 Citations Excluded at the Title Level

Citations excluded at this level were off-topic, not 

published in English, or published prior to

inclusion date

15,554 Citations Identified by Searches

3,921 Abstracts 

Reviewed

3,921 Abstracts 

Reviewed

2,995 Citations Excluded at the Abstract Level

Citations excluded at this level were not SR or CS, 

clearly did not address a KQ, did not report on an 

outcome of interest, or were outside cutoff 

publication dates

2,995 Citations Excluded at the Abstract Level

Citations excluded at this level were not SR or CS, 

clearly did not address a KQ, did not report on an 

outcome of interest, or were outside cutoff 

publication dates

448 Articles 

Reviewed

63 Included Studies

 478 Citations Excluded at 1st Pass Full Article Level

Articles excluded at this level did not: address a key 

question of interest, enroll the population of interest, 

meet inclusion criteria for clinical study or systematic 

review, meet inclusion criteria for any key question, 

or were a duplicate.

 478 Citations Excluded at 1st Pass Full Article Level

Articles excluded at this level did not: address a key 

question of interest, enroll the population of interest, 

meet inclusion criteria for clinical study or systematic 

review, meet inclusion criteria for any key question, 

or were a duplicate.

926 Full-length Articles Reviewed

Abbreviations: CS: clinical study; KQ: key question; SR: systematic review
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At the face-to-face meeting, sub-questions of KQs 3 and 4 were added assessing the safety and 

effectiveness of non-invasive treatments for chronic pain in patients not receiving OT. Searches to address 

these sub-questions were highly targeted to include systematic reviews only. Searches of EMBASE, 

PubMed, and PsycINFO were conducted through April 20, 2016. Five systematic reviews were included in 

the evidence base. Additionally, one systematic review was identified through hand searches of the 

literature and was also included in the final evidence base.

During the drafting process, two additional searches were performed. An additional search was added 

assessing the safety and effectiveness of take-home naloxone kits, a sub-question of KQ 7. Searches to 

address this intervention were highly targeted to include systematic reviews assessing use of take-home 

naloxone. Searches of EMBASE, PubMed, and PsycINFO were conducted through October 5, 2016. Two 

systematic reviews were included in the evidence base. 

An additional sub-question assessing the need for follow-up after the prescription of opioids for acute pain

was added to KQ 2 and an additional search was conducted. Searches to address this sub-question were 

broad, but the selection criteria were highly targeted to focus on prospective studies assessing risks 

associated with acute opioid use to treat acute pain. Searches of EMBASE, PubMed, and PsycINFO were 

conducted through December 20, 2016. Four retrospective cohorts and one secondary data analysis were 

included in the evidence base. Additionally, four studies already included in the evidence base for KQ 2 

were used to inform the sub-question. 
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Table E-4. Evidence Base for Key Questions

Question 

Number Question

Number and Type 

of Studies

1 

What is the evidence that the following medical or mental health conditions are 

absolute or relative contraindications of prescribing long-term opioid therapy 

(LOT)?

 Active pursuit of compensation 

 Centralized pain conditions such as fibromyalgia

 Chronic obstructive pulmonary disease

 Cognitive impairment

 Depression

 Headache

 Gastrointestinal (GI) motility problems (e.g., toxic megacolon, GI pain 

syndromes, narcotic bowel syndrome)

 Immune status changes

 Inability to participate in comprehensive treatment plan

 Incarceration (history of)

 Hepatic, renal, or pulmonary disease

 Suspected opioid misuse (e.g., overdose, early refills, diversion, taking more 

than prescribed)

 Osteoporosis

 Personality disorders

 Posttraumatic stress disorder

 Sleep disorders

 Substance use disorders (SUD) (current or history of)

 Suicidality

 Traumatic brain injury

 Use of medical marijuana 

 QT prolongation

12 cohort studies

1 case-cohort study

1 nested casecontrol study

2 

What factors increase the risk of developing misuse or opioid use disorder (OUD) 

when considering LOT?

a) What are the risks for long-term use associated with acute use of opioids 

in treating acute pain?

14 cohort studies 

1 case-cohort study 

1 nested casecontrol study

1 secondary data 

analysis

3 

What is the comparative effectiveness of LOT versus other treatment modalities?

a) What is the comparative effectiveness of LOT versus no opioid therapy or 

other treatment modalities for patients with a history of or current SUD?

b) What is the effectiveness of non-pharmacological interventions in 

patients with chronic pain? 

7 systematic reviews 

and 17 RCTs

4 

What is the safety of LOT versus other treatment modalities?

a) What is the safety of LOT versus other treatment modalities for patients 

with a history of or current SUD?

b) What is the safety of non-pharmacological interventions in patients with 

chronic pain? 
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Question 

Number Question

Number and Type 

of Studies

5 

What is the comparative effectiveness and safety of various opioid formulations?

a) Immediate-release/short-acting opioids compared to ER/long-acting 

opioids

b) Route of administration/ delivery alternatives such as transdermal, 

buccal, sublingual, pumps

c) Abuse deterrent formulations compared to non-abuse deterrent 

formulations

d) Tramadol and other dual-mechanism opioids

e) Buprenorphine

f) Methadone

2 systematic reviews 

and 7 RCTs

6 

Does additional use of benzodiazepines or other psychoactive medications 

increase the risk of adverse events compared to opioid therapy alone?

1 RCT 

1 prospective 

comparison trial

1 post-hoc pooled 

analysis

1 retrospective 

cohort study

7 

What is the comparative effectiveness of different risk mitigation strategies for 

patients either on LOT or being considered for LOT?

a) Does this differ for patients with history of or current SUD?

b) Does this differ for patients with mental health comorbidities?

c) Does this differ for patients with medical comorbidities?

d) What is the safety and effectiveness of take-home naloxone kits?

3 systematic reviews 

1 prospective cohort 

study 

1 retrospective 

database study

8 

What is the safety and effectiveness of treatment of OUD (diagnosed or 

suspected) in patients with chronic pain?

a) Do outcomes vary by severity of OUD?

1 systematic review 

and 2 RCTs

9 

What is the safety and effectiveness of different tapering strategies and 

schedules?

1 RCT

1 prospective cohort 

study

Total Evidence Base (Note, some papers were used for more than one KQ) 63 Studies

a. Criteria for Study Inclusion/Exclusion

i. General Criteria

• Clinical studies or systematic reviews published on or after March 1, 2009 to January 18, 2016. 

For sub-questions of KQs 3 and 4, systematic reviews published through April 20, 2016 were 

included. For a sub-question of KQ 7, systematic reviews published through October 5, 2016

were included. For a sub-question of KQ 2, clinical studies or systematic reviews published 

through December 20, 2016 were included. If multiple systematic reviews addressed a KQ, the

most recent and/or comprehensive review was selected. Systematic reviews were 

supplemented with clinical studies published subsequent to the systematic review.

• Studies must have been published in English.

• Publication must have been a full CS or systematic review; abstracts alone were not included. 

Similarly, letters, editorials, and other publications that were not full-length clinical studies were 

not accepted as evidence. 
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• Study must have enrolled at least 20 patients (10 per study group) unless otherwise noted (see 

Key Question Specific Criteria below).

• Study must have reported on an outcome of interest. Study must have enrolled a patient 

population in which at least 80% of patients were receiving OT for chronic pain of at least 12 

weeks’ duration (except for the sub-question of KQ 2a pertaining to risks associated with acute 

opioid use in acute pain, and KQ 7d on naloxone rescue). If the percentage is less than 80%, then 

data must have been reported separately for this patient subgroup.

• For outcomes measuring treatment effectiveness, patients must have been followed for at least 

12 weeks.

• For KQ specific criteria, in the event that one or more KQs did not have sufficient evidence from 

the study designs specified below, lower-level evidence was evaluated for that KQ(s). Lowerlevel evidence was considered on a question-by-question basis. 

ii. Key Question Specific Criteria

• For KQ 1, acceptable study designs included systematic reviews, RCTs, or prospective cohort 

studies that statistically compared outcomes for patients with chronic pain and a co-occurring 

medical or mental health condition on OT to patients with chronic pain and no additional 

medical or mental health condition on OT. Large retrospective database studies (200 patients 

minimum) that performed multivariate statistical analyses of the effect of co-occurring 

conditions on patient outcomes were also acceptable.

• For KQ 2, acceptable study designs included systematic reviews, RCTs, or prospective cohort 

studies that statistically compared outcomes for patients with chronic pain and differences in 

potential risk factors for developing opioid misuse or OUD. For LTOT, large retrospective 

database studies (200 patients minimum) that performed multivariate statistical analyses of the 

effect of risk factors on patient outcomes were also acceptable. For KQ 2a, studies were limited 

to prospective study design. 

• For KQs 3-6, 8, and 9, acceptable study designs included systematic reviews of RCTs and/or 

individual RCTs. 

• For KQ 7, acceptable study designs included systematic reviews of RCTs, individual RCTs, or 

nonrandomized comparative studies.

b. Literature Search Strategy

Information regarding the bibliographic databases, date limits, and platform/provider can be found in 

Table E-5, below. Additional information on the search strategies, including topic-specific search terms and 

search strategies can be found in Appendix J. 

Table E-5. Bibliographic Database Information

Name Date Limits Platform/Provider

Bibliographic Databases 

The Cochrane Central Register of Controlled Trials (CENTRAL) 11/24/15 Wiley

The Cochrane Database of Methodology Reviews (Methodology Reviews) 11/24/15 Wiley
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Name Date Limits Platform/Provider

The Cochrane Database of Systematic Reviews (Cochrane Reviews) 11/24/15 Wiley

Database of Abstracts of Reviews of Effects 11/24/15 Wiley

EMBASE (Excerpta Medica) 12/20/16 Elsevier

Health Technology Assessment Database (HTA) 11/24/15 Wiley

MEDLINE/PreMEDLINE 12/20/16 OVIDSP

PsycINFO 12/21/16 OVIDSP

PubMed (In-process and Publisher records) 12/20/16 NLM

Gray Literature Resources 

AHRQ 11/30/15 AHRQ

Healthcare Standards database 11/30/15 ECRI Institute

National Guideline ClearinghouseTM 11/30/15 AHRQ

National Institute of Health and Clinical Excellence 11/30/15 NHS

C. Convening the Face-to-face Meeting

In consultation with the COR, the Champions, and the Work Group, the Lewin Team convened a three and 

a half day face-to-face meeting of the CPG Champions and Work Group on April 5-8, 2016. These experts 

were gathered to develop and draft the clinical recommendations for an update to the 2010 OT CPG. 

Lewin presented findings from the evidence review of KQs 1-9 in order to facilitate and inform the process. 

Under the direction of the Champions, the Work Group was charged with interpreting the results of the 

evidence review, and asked to categorize and carry forward recommendations from the 2010 OT CPG, 

modifying the recommendations as necessary. The members also developed new clinical practice 

recommendations not presented in the 2010 OT CPG, based on the 2016 evidence review. The subject 

matter experts were divided into two smaller subgroups at this meeting. 

As the Work Group drafted clinical practice recommendations, they also assigned a grade for each 

recommendation based on a modified GRADE and USPSTF methodology. Each recommendation was 

graded by assessing the quality of the overall evidence base, the associated benefits and harms, the 

variation in values and preferences, and other implications of the recommendation.

In addition to developing recommendations during the face-to-face meeting, the Work Group also revised 

the 2010 OT CPG algorithm to reflect the new and amended recommendations. They discussed the 

available evidence as well as changes in clinical practice since 2010, as necessary, to update the algorithm.

D. Grading Recommendations

This CPG uses the GRADE methodology to assess the quality of the evidence base and assign a grade for 

the strength for each recommendation. The GRADE system uses the following four domains to assess the 

strength of each recommendation:[68] 

• Balance of desirable and undesirable outcomes

• Confidence in the quality of the evidence

• Values and preferences
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• Other implications, as appropriate, e.g.,:

 Resource Use

 Equity

 Acceptability

 Feasibility

 Subgroup considerations

The following sections further describe each domain. 

Balance of desirable and undesirable outcomes refers to the size of anticipated benefits (e.g., increased 

longevity, reduction in morbid event, resolution of symptoms, improved quality of life, decreased 

resource use) and harms (e.g., decreased longevity, immediate serious complications, adverse event, 

impaired quality of life, increased resource use, inconvenience/hassle) relative to each other. This 

domain is based on the understanding that the majority of clinicians will offer patients therapeutic or 

preventive measures as long as the advantages of the intervention exceed the risks and adverse effects. 

The certainty or uncertainty of the clinician about the risk-benefit balance will greatly influence the 

strength of the recommendation.

Some of the discussion questions that fall under this domain include:

• Given the best estimate of typical values and preferences, are you confident that the benefits 

outweigh the harms and burden or vice versa?

• Are the desirable anticipated effects large?

• Are the undesirable anticipated effects small?

• Are the desirable effects large relative to undesirable effects?

Confidence in the quality of the evidence reflects the quality of the evidence base and the certainty in 

that evidence. This second domain reflects the methodological quality of the studies for each outcome 

variable. In general, the strength of recommendation follows the level of evidence, but not always, as 

other domains may increase or decrease the strength. The evidence review used for the development of 

recommendations for LOT, conducted by ECRI, assessed the confidence in the quality of the evidence base 

and assigned a rate of “High,” “Moderate,” “Low,” or “Very Low.” 

The elements that go into the confidence in the quality of the evidence include: 

• Is there high or moderate quality evidence that answers this question?

• What is the overall certainty of this evidence?

Values and preferences is an overarching term that includes patients’ perspectives, beliefs, expectations, 

and goals for health and life. More precisely, it refers to the processes that individuals use in considering 

the potential benefits, harms, costs, limitations, and inconvenience of the therapeutic or preventive 

measures in relation to one another. For some, the term “values” has the closest connotation to these 

processes. For others, the connotation of “preferences” best captures the notion of choice. In general, 
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values and preferences increase the strength of the recommendation when there is high concordance and 

decrease it when there is great variability. In a situation in which the balance of benefits and risks are 

uncertain, eliciting the values, concerns, and preferences of patients and empowering them or their 

surrogates to make decisions consistent with patient goals of care becomes even more important. A 

recommendation can be described as having “similar values,” “some variation,” or “large variation” in 

typical values and preferences between patients and the larger populations of interest.

Some of the discussion questions that fall under the purview of values and preferences include:

• Are you confident about the typical values and preferences and are they similar across the

target population?

• What are the patient’s values and preferences?

• Are the assumed or identified relative values similar across the target population?

Other implications consider the practicality of the recommendation, including resources use, equity, 

acceptability, feasibility and subgroup considerations. Resource use is related to the uncertainty around 

the cost-effectiveness of a therapeutic or preventive measure. For example statin use in the frail elderly 

and others with multiple co-occurring conditions may not be effective and depending on the societal 

benchmark for willingness to pay, may not be a good use of resources. Equity, acceptability, feasibility, and 

subgroup considerations require similar judgments around the practically of the recommendation.

The framework below (Table E-6) was used by the Work Group to guide discussions on each domain.
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Table E-6. Evidence to Recommendation Framework

Decision Domain Judgment

Balance of desirable and undesirable outcomes

 Given the best estimate of typical values and preferences, are you 

confident that the benefits outweigh the harms and burden or vice 

versa?

 Are the desirable anticipated effects large?

 Are the undesirable anticipated effects small?

 Are the desirable effects large relative to undesirable effects?

Benefits outweigh harms/burden

Benefits slightly outweigh harms/burden

Benefits and harms/burden are balanced

Harms/burden slightly outweigh benefits

Harms/burden outweigh benefits

Confidence in the quality of the evidence

 Is there high- or moderate quality evidence that answers this 

question?

 What is the overall certainty of this evidence?

High

Moderate

Low

Very low

Values and preferences

 Are you confident about the typical values and preferences and are 

they similar across the target population?

 What are the patient’s values and preferences? 

 Are the assumed or identified relative values similar across the target 

population?

Similar values

Some variation

Large variation

Other implications (e.g., resource use, equity, acceptability, feasibility, subgroup considerations)

 Are the resources worth the expected net benefit from the 

recommendation?

 What are the costs per resource unit?

 Is this intervention generally available?

 Is this intervention and its effects worth withdrawing or not allocating 

resources from other interventions?

 Is there lots of variability in resource requirements across settings?

Various considerations

The strength of a recommendation is defined as the extent to which one can be confident that the 

desirable effects of an intervention outweigh its undesirable effects and is based on the framework above, 

which combines the four domains.[68] GRADE methodology does not allow for recommendations to be 

made based on expert opinion alone. While strong recommendations are usually based on high or 

moderate confidence in the estimates of effect (quality of the evidence) there may be instances where 

strong recommendations are warranted even when the quality of evidence is low.[256] In these types of 

instances where the balance of desirable and undesirable outcomes and values and preferences played 

large roles in determining the strength of a recommendation, this is explained in the discussion section for 

the recommendation.

The GRADE of a recommendation is based on the following elements:

• Four decision domains used to determine the strength and direction (described above)

• Relative strength (Strong or Weak)

• Direction (For or Against)
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The relative strength of the recommendation is based on a binary scale, “Strong” or “Weak.” A strong 

recommendation indicates that the Work Group is highly confident that desirable outcomes outweigh 

undesirable outcomes. If the Work Group is less confident of the balance between desirable and 

undesirable outcomes, they present a weak recommendation.

Similarly, a recommendation for a therapy or preventive measure indicates that the desirable 

consequences outweigh the undesirable consequences. A recommendation against a therapy or 

preventive measure indicates that the undesirable consequences outweigh the desirable consequences.

Using these elements, the grade of each recommendation is presented as part of a continuum:

• Strong For (or “We recommend offering this option ...”)

• Weak For (or “We suggest offering this option ...”)

• Weak Against (or “We suggest not offering this option ...”)

• Strong Against (or “We recommend against offering this option ...”)

Note that weak (For or Against) recommendations may also be termed “Conditional,” “Discretionary,” or 

“Qualified.” Recommendations may be conditional based upon patient values and preferences, the 

resources available, or the setting in which the intervention will be implemented. Recommendations may 

be at the discretion of the patient and clinician, or they may be qualified with an explanation about the 

issues that would lead decisions to vary.

E. Recommendation Categorization

a. Categorizing Recommendations with an Updated Review of the Evidence

Recommendations were first categorized by whether or not they were based on an updated review of the 

evidence. If evidence had been reviewed, recommendations were categorized as “New-added,” “Newreplaced,” “Not changed,” “Amended,” or “Deleted.” 

“Reviewed, New-added” recommendations were original, new recommendations that were not in the 

2010 OT CPG. “Reviewed, New-replaced” recommendations were in the previous version of the guideline, 

but were modified to align with the updated review of the evidence. These recommendations could have 

also included clinically significant changes to the previous version. Recommendations categorized as 

“Reviewed, Not changed” were carried forward from the previous version of the CPG unchanged. 

To maintain consistency between 2010 recommendations, which were developed using the USPSTF 

methodology, and 2017 recommendations, which were developed using the GRADE methodology, it was 

necessary to modify the 2010 recommendations to include verbiage to signify the strength of the 

recommendation (e.g., “We recommend,” “We suggest”). Because the 2010 recommendations inherently 

needed to be modified at least slightly to include this language, the “Not changed” category was not used. 

For recommendations carried forward to the updated CPG with review of the evidence and slightly 

modified wording, the “Reviewed, Amended” recommendation category was used. This allowed for the 

wording of the recommendation to reflect GRADE methodology as well as for any other non-substantive 

(i.e., not clinically meaningful) language changes deemed necessary. The evidence used to support these 
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recommendations was carried forward from the previous version of the CPG and/or was identified in the 

evidence review for the update. 

Recommendations could have also been designated “Reviewed, Deleted.” These were recommendations 

from the previous version of the CPG that were not brought forward to the updated guideline after review 

of the evidence. This occurred if the evidence supporting the recommendations was out of date, to the 

extent that there was no longer any basis to recommend a particular course of care and/or new evidence 

suggests a shift in care, rendering recommendations in the previous version of the guideline obsolete.

b. Categorizing Recommendations without an Updated Review of the Evidence

There were also cases in which it was necessary to carry forward recommendations from the previous 

version of the CPG without a systematic review of the evidence. Due to time and budget constraints, the 

update of the OT CPG could not review all available evidence on management of LOT, but instead 

focused its KQs on areas of new or updated scientific research or areas that were not previously covered 

in the CPG. 

For areas of research that have not changed, and for which recommendations made in the previous 

version of the guideline were still relevant, recommendations could have been carried forward to the 

updated guideline without an updated systematic review of the evidence. The support for these 

recommendations in the updated CPG was thus also carried forward from the previous version of the CPG. 

These recommendations were categorized as “Not reviewed.” If evidence had not been reviewed, 

recommendations could have been categorized as “Not changed,” Amended,” or “Deleted.” 

“Not reviewed, Not changed” recommendations refer to recommendations from the previous version of 

the OT CPG that were carried forward unchanged to the updated version. The category of “Not reviewed, 

Amended” was used to designate recommendations that were modified from the 2010 CPG with the 

updated GRADE language, as explained above. 

Recommendations could also have been categorized as “Not reviewed, Deleted” if they were determined 

to be out of scope. A recommendation was out of scope if it pertained to a topic (e.g., population, care 

setting, treatment, condition) outside of the scope for the updated CPG as defined by the Work Group. 

The categories for the recommendations included in the 2017 version of the guideline are noted in the 

Recommendations. The categories for the recommendations from the 2010 OT CPG are noted in 

Appendix H. 

c. Recommendation Categories and Definitions

For use in the 2017 OT CPG, a set of recommendation categories was adapted from those used by the 

United Kingdom National Institute for Health and Clinical Excellence (NICE).[72,73] These categories, along 

with their corresponding definitions, were used to account for the various ways in which 

recommendations could have been updated from the 2010 OT CPG. The categories and definitions can be 

found in Table E-7. 
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Table E-7. Recommendation Categories and Definitions 

Evidence

Reviewed*

Recommendation

Category* Definition*

Reviewed

New-added New recommendation following review of the evidence

New-replaced Recommendation from previous CPG that has been carried over to the 

updated CPG that has been changed following review of the evidence

Not changed

Recommendation from previous CPG that has been carried forward to the 

updated CPG where the evidence has been reviewed but the recommendation 

is not changed

Amended

Recommendation from the previous CPG that has been carried forward to the 

updated CPG where the evidence has been reviewed and a minor amendment 

has been made

Deleted Recommendation from the previous CPG that has been removed based on 

review of the evidence

Not reviewed

Not changed Recommendation from previous CPG that has been carried forward to the 

updated CPG, but for which the evidence has not been reviewed

Amended

Recommendation from the previous CPG that has been carried forward to the 

updated CPG where the evidence has not been reviewed and a minor 

amendment has been made

Deleted Recommendation from the previous CPG that has been removed because it 

was deemed out of scope for the updated CPG

*Adapted from the NICE guideline manual (2012) [72] and Garcia et al. (2014) [73] 

Abbreviation: CPG: clinical practice guideline

F. Drafting and Submitting the Final Clinical Practice Guideline

Following the face-to-face meeting, the Champions and Work Group members were given writing 

assignments to craft discussion sections to support each of the new recommendations and/or to update 

discussion sections from the 2010 OT CPG to support the amended “carried forward” recommendations. 

The Work Group also considered tables, appendices, and other sections from the 2010 OT CPG for 

inclusion in the update. During this time, the Champions and Work Group also made additional revisions to

the algorithm, as necessary. 

After developing the initial draft of the updated CPG, an iterative review process was used to solicit 

feedback on and make revisions to the CPG. Once they were developed, the first two drafts of the CPG

were posted on a wiki website for a period of 14-20 business days for internal review and comment by the 

Work Group. All feedback submitted during each review period was reviewed and discussed by the Work 

Group and appropriate revisions were made to the CPG. 

Draft 3 of the CPG was made available for peer review and comment. This process is described in Peer 

Review Process. After revisions were made based on the feedback received during the peer review and 

comment period, the Champions presented the CPG to the EBPWG for their approval. Changes were made 

based on feedback from the EBPWG and the guideline was finalized. 

The Work Group also produced a set of guideline toolkit materials, which included a provider summary,

pocket card, and a patient summary. The final 2017 OT CPG was submitted to the EBPWG in February 

2017. 
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Appendix F: Patient Focus Group Methods and Findings

A. Methods

On December 14, 2015, as part of the effort to update this CPG, the VA and DoD Leadership, along with 

the OT CPG Work Group, held a patient focus group at the Washington DC VA Medical Center. Focus group 

participants included six patients and two family caregivers. One additional family caregiver was 

interviewed separately at a later date. 

The aim of the focus group and interview was to further the understanding of the perspectives of patients 

receiving LOT within the VA and/or DoD healthcare systems, as these patients are most affected by the 

recommendations put forth in the updated OT CPG. The focus group and interview explored patient 

perspectives on a set of topics related to management of OT in the VA and DoD healthcare systems, 

including knowledge of OT and other pain treatment options, delivery of care, and the impact of and 

challenges with LOT. 

Participants for the focus group were recruited from the pain clinics at the Walter Reed National Military 

Medical Center and the Washington DC VA Medical Center. Patient focus group participants were not 

intended to be a representative sample of VA and DoD patients who have experienced LOT. However, 

recruitment focused on eliciting a range of perspectives likely to be relevant and informative in the 

guideline development process. Patients were not incentivized for their participation or reimbursed for 

travel expenses. 

The OT CPG Champions and Work Group developed a set of questions to help guide the focus group and 

interview. The facilitator from Lewin led the discussion using interview questions prepared by the Work 

Group as a general guide to elicit the most important information from the patients regarding their 

experiences and views about their treatment and overall care. Given the limited time and the range of 

interests and expressiveness of the participants, not all of the listed questions were addressed. 

At the time of the focus group, three patients were receiving care in the DoD healthcare system, two 

patients were receiving care in the VA healthcare system, and one patient was receiving care from a 

private pain center. Some of these patient participants had transitioned between multiple care settings, 

including from VA to DoD, from DoD to VA, and from a governmental healthcare setting to a private 

healthcare setting. Two patients stated that they were currently on LOT for pain. Four patients stated that 

they had previously been on LOT, but have since transitioned to other treatments for pain. 

The following concepts are aspects of care that are important to patients and family caregivers that 

emerged from the focus group discussion and the interview. Each of these themes was an important and 

needed aspect of participants’ healthcare. 
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B. Patient Focus Group Findings

Using shared decision making, consider all treatment options and develop treatment plan based

on the balance of risks, benefits, and patient-specific goals, values, and preferences

• Identify patient-specific goals associated with LOT (main goals of these focus group participants

included returning to work, minimizing pain, maintaining a functional life, avoiding invasive

medical procedures, and getting off opioids)

• Discuss and consider all pain management options (non-pharmacotherapy and non-opioid

pharmacotherapy) prior to starting LOT; do not default to prescribing opioids

• Use shared decision making to develop an individualized treatment plan; discuss pros and cons

(e.g., benefits, risks, side effects) of each treatment option (including non-opioid treatment

options) in conjunction with each patient’s goals, priorities, values, and preferences

• Maintain focus on patient goals throughout treatment, including any changes in those goals

over time

Modify treatment based on patient response, considering patient-specific goals, values, and

preferences

• Be prepared to adjust or otherwise change treatment (e.g., tapering opioids) subject to patient

response, preferences, and changes in priorities and goals; convey this flexibility and support

the patient and support him/her during the change in treatment

• Do not continue to prescribe opioids when patients express reluctance to take them or do not

adhere; continue to understand patient needs and preferences and adapt treatment accordingly

• Take time to develop a thorough understanding of patient needs and capabilities; develop an

individualized treatment plan; be accountable for adverse outcomes

• Even after LOT is initiated, continue to discuss and consider all pain management options (nonpharmacotherapy and non-opioid pharmacotherapy)

• Carefully consider side effects during monitoring and adjust treatment in order to minimize side

effects (e.g., depression, weight gain, headaches, nightmares, problems with intimacy,

paresthesias) pursuant to individual patient preferences

Involve family caregivers in accordance with patient preferences and maintain open, trusting,

and respectful relationship with patients and family caregivers

• Foster family, including family caregiver, involvement in shared decision making and support in

accordance with patient preferences and in a way that is beneficial to the patient

• Always treat patients and family, including family caregivers, with respect and support

• Build and maintain trust, respect, and support in relationship with the patient and family,

including family caregivers

• Ensure the patient has the capability to engage in shared decision making; recognize that

patients who are in pain or who are taking opioids or other powerful medications may be in
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suboptimal condition to make informed decisions on their own and may benefit from 

involvement of knowledgeable family members, including family caregivers

Educate patients regarding treatment plan, alternative treatment options, and monitoring

• Clinicians should be proactive and responsive in providing necessary clinical information in a 

manner comprehensible to patients and family caregivers; acknowledge that patients will seek

and acquire information from other sources (especially the Internet) and encourage patient 

proactivity

• When prescribing opioids, provide in-depth and patient-specific education on medication (e.g., 

side effects, dosing, administration, storage, safety, disposal, take back programs) during 

medical visits in conjunction with distributing or otherwise enabling access to educational 

materials

• Provide necessary information regarding changes in treatment; discuss tapering and risks of selftapering as necessary; recognize and address the challenges for patients on OT, including 

tapering

• Explain/provide education to patients as to why doctors use monitoring practices such as UDT 

when patients are using opioids; do not simply order the tests without such explanation 

Within and between healthcare systems, work with appropriate providers to ensure continuity

of high quality care

• Consult with other providers (e.g., psychologists, physical therapists) and patient advocates as 

appropriate, especially when patients express the need for more information or other clinical 

support

• Provide seamless transitions in opioid treatment and other pain management within and 

between VA, DoD, and any other healthcare systems; patients should not have to encounter 

abrupt changes in treatment regimens moving from one system to another or have to “start all 

over” when moving to another system 

• Continue transformation of pain management 

Organize treatment to encourage patient adherence and participation

• Facilitate appointment scheduling for days and times that fit the patient’s needs (e.g., try to 

avoid patient work days where possible, schedule multiple provider appointments on same day 

rather than multiple days) 

• Facilitate prescription refills and patient visits for refills in a way that fits the patient’s needs, 

lifestyle, and schedule, while maintaining safe prescribing practices 

Acknowledge and minimize effects of potential medical error and take action to prevent future 

medical error

• Acknowledge instances of potential medical error or other instances in which patient outcomes 

from previous medical procedures were less than desirable or expected (including experiences 
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of adverse events) and the consequences for the patient; consider these experiences when 

developing treatment plans

• Report potential medical errors that may have been experienced by patients and take action to 

prevent future medical error
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Appendix G: Evidence Table

#

Recommendation

2010

Grade15 Evidence16

Strength of 

Recommendation17

Recommendation 

Category18

1. a) We recommend against initiation of long-term 

opioid therapy for chronic pain.

b) We recommend alternatives to opioid therapy

such as self-management strategies and other

non-pharmacological treatments.

c) When pharmacologic therapies are used, we 

recommend non-opioids over opioids.

None

None

None

[80-83,85]

Additional References:

[3,26,84] 

a) Strong against

b) Strong for

c) Strong for

Reviewed, Newreplaced

2. If prescribing opioid therapy for patients with chronic 

pain, we recommend a short duration. 

Note: Consideration of opioid therapy beyond 90 days 

requires re-evaluation and discussion with patient of 

risks and benefits.

None [86-89]

Additional References:

[132] 

Strong for Reviewed, Newreplaced

15 The 2010 VA/DoD OT CPG used the USPSTF evidence grading system (http://www.uspreventiveservicestaskforce.org). Inclusion of more than one 2010 Grade indicates that more 

than one 2010 CPG recommendation is covered under the 2016 recommendation. The strength of recommendations were rated as follows: A- a strong recommendation that the 

clinicians provide the intervention to eligible patients; B- a recommendation that clinicians provide (the service) to eligible patients; C- no recommendation for or against the 

routine provision of the intervention is made; D- recommendation is made against routinely providing the intervention; I- the conclusion is that the evidence is insufficient to 

recommend for or against routinely providing the intervention. “None” indicates that the 2017 OT CPG recommendation replaced or amended a 2010 OT CPG recommendation 

for which there was no grade. “N/A” indicates that the 2017 OT CPG recommendation was a new recommendation, and therefore does not have an associated 2010 Grade. 16 The evidence column indicates studies that support each recommendation. For new recommendations, developed by the 2016 guideline Work Group, the literature cited 

corresponds directly to the 2016 evidence review. For recommendations that have been carried over from the 2010 VA/DoD OT CPG, slight modifications were made to the 

language in order to better reflect the current evidence and/or the change in grading system used for assigning the strength of each recommendation (USPSTF to GRADE). For 

these “modified” recommendations, the evidence column indicates “additional evidence,” which can refer to either 1) studies that support the recommendation and which were 

identified through the 2016 evidence review, or 2) relevant studies that support the recommendation, but which were not systematically identified through a literature review. 17 Refer to the Grading Recommendations section for more information on how the strength of the recommendation was determined using GRADE methodology.

18 Refer to the Recommendation Categorization section for more information on the description of the categorization process and the definition of each category. 
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#

Recommendation

2010

Grade15 Evidence16

Strength of 

Recommendation17

Recommendation 

Category18

3. For patients currently on long-term opioid therapy, we 

recommend ongoing risk mitigation strategies (see 

Recommendations 7-9), assessment for opioid use 

disorder, and consideration for tapering when risks 

exceed benefits (see Recommendation 14).

None [86-89]

Additional References:

[132] 

Strong for Reviewed, Newreplaced

4. a) We recommend against long-term opioid therapy

for pain in patients with untreated substance use

disorder.

b) For patients currently on long-term opioid therapy

with evidence of untreated substance use disorder,

we recommend close monitoring, including 

engagement in substance use disorder treatment,

and discontinuation of opioid therapy for pain with

appropriate tapering (see Recommendation 14 and

Recommendation 17).

None [59,61,66,86,87] a) Strong against

b) Strong for

Reviewed, 

Amended

5. We recommend against the concurrent use of 

benzodiazepines and opioids. 

Note: For patients currently on long-term opioid 

therapy and benzodiazepines, consider tapering one or 

both when risks exceed benefits and obtaining specialty 

consultation as appropriate (see Recommendation 14 

and the VA/DoD Clinical Practice Guideline for the 

Management of Substance Use Disorders).

N/A [66]

Additional References:

[90,91] 

Strong against Reviewed, Newadded

6. a) We recommend against long-term opioid therapy

for patients less than 30 years of age secondary to

higher risk of opioid use disorder and overdose.

b) For patients less than 30 years of age currently on

long-term opioid therapy, we recommend close 

monitoring and consideration for tapering when

risks exceed benefits (see Recommendation 14 and

Recommendation 17).

None [58,59,62,86-88,92,94]

Additional References: 

[93,95-98] 

a) Strong against

b) Strong for

Reviewed, Newreplaced
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#

Recommendation

2010

Grade15 Evidence16

Strength of 

Recommendation17

Recommendation 

Category18

7. We recommend implementing risk mitigation strategies

upon initiation of long-term opioid therapy, starting 

with an informed consent conversation covering the 

risks and benefits of opioid therapy as well as 

alternative therapies. The strategies and their 

frequency should be commensurate with risk factors 

and include: 

 Ongoing, random urine drug testing (including 

appropriate confirmatory testing)

 Checking state prescription drug monitoring 

programs

 Monitoring for overdose potential and suicidality

 Providing overdose education 

 Prescribing of naloxone rescue and accompanying 

education

None

None

None

None

None

None

B 

B 

[61,99,100,107-109,114]

Additional References:

[24,33,53,101-106,110-113,115-122] 

Strong for Reviewed, Newreplaced

8. We recommend assessing suicide risk when considering 

initiating or continuing long-term opioid therapy and 

intervening when necessary.

None

None

[61,123-128]

Additional References:

[129-131]

Strong for Reviewed, 

Amended

9. We recommend evaluating benefits of continued 

opioid therapy and risk for opioid-related adverse 

events at least every three months. 

None

None

None

None

B

Additional References:

[132] 

Strong for Reviewed, Newreplaced

10. If prescribing opioids, we recommend prescribing the 

lowest dose of opioids as indicated by patient-specific 

risks and benefits. 

Note: There is no absolutely safe dose of opioids.

None [58,59,66,87,133,136]

Additional References:

[134,135] 

Strong for Reviewed, Newreplaced

11. As opioid dosage and risk increase, we recommend 

more frequent monitoring for adverse events including 

opioid use disorder and overdose.

Note: 

 Risks for opioid use disorder start at any dose and 

increase in a dose dependent manner.

 Risks for overdose and death significantly increase 

at a range of 20-50 mg morphine equivalent daily 

dose.

None [58,59,66,87,133,136]

Additional References:

[134,135] 

Strong for Reviewed, Newreplaced
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#

Recommendation

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Grade15 Evidence16

Strength of 

Recommendation17

Recommendation 

Category18

12. We recommend against opioid doses over 90 mg 

morphine equivalent daily dose for treating chronic 

pain. 

Note: For patients who are currently prescribed doses 

over 90 mg morphine equivalent daily dose, evaluate 

for tapering to reduced dose or to discontinuation (see 

Recommendations 14 and 15).

None [58,59,66,87,133,136]

Additional References:

[134,135] 

Strong against Reviewed, Newreplaced

13. We recommend against prescribing long-acting opioids 

for acute pain, as an as-needed medication, or on 

initiation of long-term opioid therapy. 

None [140,141,143,144,146,149-

159,163,165] 

Additional References:

[10,137-

139,142,145,147,148,160,162,164,166-

169]

Strong against Reviewed, Newreplaced

14. We recommend tapering to reduced dose or to 

discontinuation of long-term opioid therapy when risks 

of long-term opioid therapy outweigh benefits. 

Note: Abrupt discontinuation should be avoided unless 

required for immediate safety concerns.

N/A Additional References:

[10,137,170-175] 

Strong for Reviewed, Newadded

15. We recommend individualizing opioid tapering based 

on risk assessment and patient needs and 

characteristics. 

Note: There is insufficient evidence to recommend for 

or against specific tapering strategies and schedules.

N/A Additional References:

[10,137,170-175] 

Strong for Reviewed, Newadded

16. We recommend interdisciplinary care that addresses 

pain, substance use disorders, and/or mental health 

problems for patients presenting with high risk and/or 

aberrant behavior.

None 

None 

None 

None 

None

[114,176] Strong for Reviewed, Newreplaced

17. We recommend offering medication assisted treatment

for opioid use disorder to patients with chronic pain 

and opioid use disorder. 

Note: See the VA/DoD Clinical Practice Guideline for 

the Management of Substance Use Disorders.

None

None

None

Additional References:

[177-182] 

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Strength of 

Recommendation17

Recommendation 

Category18

18. a) We recommend alternatives to opioids for mild-tomoderate acute pain.

b) We suggest use of multimodal pain care including 

non-opioid medications as indicated when opioids

are used for acute pain. 

c) If take-home opioids are prescribed, we

recommend that immediate-release opioids are 

used at the lowest effective dose with opioid

therapy reassessment no later than 3-5 days to

determine if adjustments or continuing opioid

therapy is indicated.

Note: Patient education about opioid risks and 

alternatives to opioid therapy should be offered.

N/A [58,59,183-188] a) Strong for

b) Weak for

c) Strong for

Reviewed, Newadded
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Appendix H: 2010 Recommendation Categorization Table

2010

Recommendation 

Location19

2010 Recommendation Text20

2010 Grade

21

Category22

2016

Recommendation (if 

applicable)23

ModuleSectionNumber

1 A 1 A trial of opioid therapy is indicated for a patient with chronic pain who meets all of the 

following criteria: 

a. Moderate to severe pain that has failed to adequately respond to indicated non-opioid

and non- drug therapeutic interventions

b. The potential benefits of opioid therapy are likely to outweigh the risks (i.e., no

absolute contraindications)

c. The patient is fully informed and consents to the therapy

d. Clear and measurable treatment goals are established

None Not reviewed, 

Deleted

1 A 2 The ethical imperative is to provide the pain treatment with the best benefit-to-harm 

profile for the individual patient.

None Not reviewed, 

Deleted

19 The first three columns indicate the location of each recommendation within the 2010 OT CPG. 

20 The 2010 Recommendation Text column contains the wording of each recommendation from the 2010 OT CPG. 

21 The 2010 VA/DoD OT CPG used the U.S. Preventive Services Task Force (USPSTF) evidence grading system. http://www.uspreventiveservicestaskforce.org The strength of 

recommendations were rated as follows: A- a strong recommendation that the clinicians provide the intervention to eligible patients; B- a recommendation that clinicians provide 

(the service) to eligible patients; C- no recommendation for or against the routine provision of the intervention is made; D- recommendation is made against routinely providing 

the intervention; I- the conclusion is that the evidence is insufficient to recommend for or against routinely providing the intervention. “None” indicates there was no grade 

assigned to the recommendation in the 2010 OT CPG. 22 The Category column indicates the way in which each 2010 OT CPG recommendation was updated. 

23 For recommendations that were carried forward to the 2010 OT CPG, this column indicates the new recommendation(s) to which they correspond. 
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1 B 1 A comprehensive patient assessment should be completed to identify clinical conditions 

that may interfere with the appropriate and safe use of opioid therapy (OT).

The comprehensive assessment should include:

a. Medical History

• Age, Sex

• History of present illness, including a complete pain assessment (see Annotation C)

• History of injury if applicable

• Past Medical and Surgical history

• Past Psychiatric history (including depression, anxiety, other emotional disorders, risk

of suicide including family history and previous suicidal attempts)

• Medications (including current and past analgesics, their effectiveness, side effects,

and tolerability, as well as drugs that may interact with opioid therapy)

• Substance use history (personal, family, peer group)

• Family history

• Social history (including employment, cultural background, social network, marital

history, and legal history, other behavioral patterns (i.e. impulse behaviors))

• Review of systems

• Allergies

• Abuse (sexual, physical and mental)

b. Physical examination

• A general examination

• A pain-focused musculoskeletal and neurologic examination

• Mental Status Examination (MSE) (Including level of alertness, ability to understand

and follow instruction, and suicidal ideation)

c. Review of diagnostic studies and assessments

d. Evaluation of occupational risks and ability to perform duty

None Not reviewed, 

Deleted

1 B 2 Information from the pain history and physical exam should be reviewed to ensure that 

the patient has had an adequate therapeutic trial of non-opioid medication therapies.

None Not reviewed, 

Deleted

1 B 3 A urine drug test (UDT) (also referred to as urine drug screen (UDS)) should be used to 

screen for the presence of illegal drugs, unreported prescribed medication, or 

unreported alcohol use prior to starting therapy. [B] 

B Reviewed, 

Deleted

1 B 4 Patients on chronic opioid therapy should be assessed for suicide risk at onset of therapy 

and regularly thereafter. High suicide risk is a relative contraindication for OT.

None Reviewed, 

Amended

Recommendation 8
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1 B 5 Opioid therapy should be used only after careful consideration of the risks and benefits. None Reviewed, 

New-replaced

Recommendation 1

Recommendation 2

Recommendation 3

1 C 1 Pain intensity should be evaluated at each visit. None Not reviewed, 

Deleted

1 C 2 Intensity of pain should be measured using a numeric rating scale (0-10 scale) for each of 

the following:

• current pain,

• least pain in last week

• “usual” or “average” pain in last week

None Not reviewed, 

Deleted

1 C 3 The patient’s response to current pain treatments should be assessed using questions 

such as:

• “What is your intensity of pain after taking (use of) your current

treatment/medication?”

• “How long does your pain relief last after taking your treatment/medication?”

• “How does taking your treatment/medication affect your functioning?”

(Note: some interventions may temporarily increase pain, so it may not be appropriate 

to ask these questions.)

None Not reviewed, 

Deleted

1 C 4 Other attributes of pain should be assessed as part of the comprehensive pain 

assessment:

• Onset and duration, location, radiation, description (quality), aggravating and

alleviating factors, behavioral manifestations of pain, and impact of pain

• Temporal patterns and variations (e.g., diurnal, monthly, seasonal)

• Current and past treatments for pain

• Patient’s expectations for pain relief

None Not reviewed, 

Deleted

1 C 5 If possible, determine the type of pain:

• Differentiate between nociceptive and neuropathic pain

• Consider further evaluation if needed (such as imaging, Electro Diagnostic Studies

(EDS) or consultation)

• Ask specifically whether the patient suffers from headache

None Not reviewed, 

Deleted
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1 C 6 Assessment of function, to obtain a baseline, should include: (Consistent evaluation tool 

is helpful in providing evaluation of response to opioid therapy over time):

• Cognitive function (attention, memory, and concentration)

• Employment

• Enjoyment of life

• Emotional distress (depression and anxiety)

• Housework, chores, hobbies, and other day to day activities

• Sleep

• Mobility

• Self-care behaviors

• Sexual function

None Not reviewed, 

Deleted

1 C 7 Information from the pain history and physical exam should be reviewed to ensure that 

the patient has had an adequate trial of non-opioid therapy.

None Not reviewed, 

Deleted

2 D 1 Opioid therapy trial should NOT be initiated in the following situations (absolute 

contraindications):

a. Severe respiratory instability

b. Acute psychiatric instability or uncontrolled suicide risk

c. Diagnosed non-nicotine Substance Use Disorder (DSM-IV criteria) not in remission and

not in treatment

d. True allergy to opioid agents (cannot be resolved by switching agents)

e. Co-administration of drug capable of inducing life-limiting drug-drug interaction

f. QTc interval > 500 millisecond for using methadone

g. Active diversion of controlled substances (providing the medication to someone for

whom it was not intended)

h. Prior adequate trials of specific opioids that were discontinued due to intolerance,

serious adverse effects that cannot be treated, or lack of efficacy

None Reviewed, 

Amended

Recommendation 4
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2 D 2 Opioid therapy trial can be initiated with caution in the following situations. Consider 

consultation with appropriate specialty care to evaluate if potential benefits outweigh 

the risks of therapy.

a. Patient receiving treatment for diagnosed Substance Use Disorder (DSM-IV criteria).

(See Annotation P1)

b. Medical condition in which OT may cause harm:

• Patient with obstructive sleep apnea not on CPAP

• Patients with central sleep apnea (See Annotation P2)

• Chronic pulmonary disease (mild-moderate asthma, COPD)

• Cardiac condition (QTc interval 450-500 milliseconds) that may increase risk of using 

methadone 

• Known or suspected paralytic ileus

• Respiratory depression in unmonitored setting

c. Risk for suicide or unstable psychiatric disorder

d. Complicated pain

• Headache not responsive to other pain treatment modalities

e. Conditions that may impact adherence to OT:

• Inability to manage opioid therapy responsibly (e.g., cognitively impaired)

• Unwillingness or inability to comply with treatment plan

• Unwillingness to adjust at-risk activities resulting in serious re-injury

• Social instability

• Mental Health disorders

None Reviewed, 

Deleted

2 D 3 Consider consultation with an appropriate specialist if legal or clinical problems indicate 

need for more intensive care related to opioid management. (See Annotation E – 

Indications for consultation).

None Not reviewed, 

Deleted

2 E 1 Refer to an Advanced Pain provider, or interdisciplinary pain clinic or program for 

evaluation and treatment a patient with persistent pain and any of the following 

conditions:

a. Complex pain conditions or polytrauma

b. Significant medical comorbidities that may negatively impact opioid therapy

c. Situation requires management beyond the comfort level of the primary provider

None Not reviewed, 

Deleted

2 E 2 Refer to SUD Specialty Provider for evaluation and treatment patient whose behavior 

suggests addiction to substances (excluding nicotine).

None Not reviewed, 

Deleted
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2 E 3 Consider consultation with a SUD specialist to evaluate the risk of recurrent substance 

abuse or to assist with ongoing management.

None Reviewed, 

New-replaced

Recommendation 16

2 E 4 Refer to Behavioral Health Specialty for evaluation and treatment a patient with any of 

the following conditions:

a. Psychosocial problems or comorbidities that may benefit from behavioral disease/case 

management

b. Uncontrolled, severe psychiatric disorders or those who are emotionally unstable

c. Patients expressing thoughts or demonstrating behaviors suggestive of suicide risk

None Not reviewed, 

Deleted

2 E 5 Refer patients with significant headache to a neurologist for evaluation and treatment. None Not reviewed, 

Deleted

2 E 6 Consider consultation with occupational health specialty if patient’s occupation requires 

a high level of cognitive function.

None Not reviewed, 

Deleted

2 F 1 The clinician should assess the ability of the patient being considered for opioid therapy 

to be able to adhere to treatment requirements, as these patients are likely to do well 

and benefit from OT.

None Not reviewed, 

Deleted

2 F 2 The appropriateness of opioid therapy as a treatment modality for chronic pain and the 

level of risk for adverse outcomes should be determined based on the initial and ongoing 

assessment of the patient.

None Not reviewed, 

Deleted

2 F 3 For patients with history of drug abuse, psychiatric issues, or serious aberrant drugrelated behaviors, initiation of a trial of OT in the primary care setting should only be 

considered if more frequent and stringent monitoring can be provided. In such 

situations, clinicians should strongly consider consultation with a mental health or 

addiction specialist.

None Not reviewed, 

Deleted

2 F 4 Young patients (less than 25 years old) are at higher risk for diversion and abuse and may 

benefit from more stringent monitoring.

None Reviewed, 

New-replaced

Recommendation 6

2 F 5 The clinician should consider referring patients who have unstable co-occurring 

disorders (substance use, mental health illnesses, or aberrant drug related behaviors) 

and who are at higher risk for unsuccessful outcomes (see Annotation E).

None Not reviewed, 

Deleted

2 G 1 Involve the patient and family/caregiver in the educational process, providing written 

educational material in addition to discussion with patient/family.

None Not reviewed, 

Deleted
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2 G 2 Discuss the opioid pain care agreement (OPCA) in detail, and reinforce in subsequent 

visits (See Annotation H).

None Reviewed, 

New-replaced

Recommendation 7

2 G 3 Provide, and document in the medical record, patient education on the following topics:

• General Information: goals and expectations, addiction, tolerance, physical

dependency, withdrawal symptoms

• Patient responsibilities: prescriptions, adherence to treatment plan, obtaining

medications from a single prescriber (or clinic) and single pharmacy, pain diary, feedback 

to the provider

• Legal Issues

• Instruction on how to take medication: importance of consistent dosing and timing,

interaction with other drugs

• Prophylactic treatment of adverse effects and management of constipation

• Discussion of an individualized comprehensive care plan that may include, in addition

to OT, physical therapy, occupational therapy, cognitive-behavioral therapy, 

acupuncture, manipulation, complementary and alternative medicine, other nonpharmacologic therapies, and other non-opioid agents.

None Reviewed, 

New-replaced

Recommendation 7

2 H 1 Discuss a trial of opioid therapy with the patient, and obtain the patient's informed 

consent in a shared decision-making discussion. Document the informed consent 

discussion.

None Not reviewed, 

Deleted

2 H 2 Review and discuss a written Opioid Pain Care Agreement (OPCA) with the patient who 

is expected to receive daily opioid therapy for the treatment of chronic pain. The signed 

agreement can serve as documentation of an informed consent discussion. (For a sample 

agreement, see Appendix C)

None Reviewed, 

New-replaced

Recommendation 7
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2 H 3 The responsibilities during therapy, of the provider and the patient, should be discussed 

with the patient and family. A discussion of patient responsibilities should be patientcentered and address the following issues :

• Goals of therapy -- Partial pain relief and improvement in physical, emotional, and/or

social functioning

• The requirement for a single prescribing provider or treatment team

• The limitation on dose and number of prescribed medications

• Proscription against the patient changing dosage without discussing with provider

• Monitoring patient adherence - discuss the role of random urine drug testing, the use 

of "pill counts"

• A prohibition on use with alcohol, other sedating medications, or illegal drugs without

discussing with provider

• Agreement not to drive or operate heavy machinery until abatement of medicationrelated drowsiness

• Responsibility to keep medication safe and secure

• Prohibition of selling, lending, sharing or giving any medication to others

• Limitations on refills: only by appointment, in person, and no extra refills for running

out early (exceptions should be considered on an individual basis)

• Compliance with all components of overall treatment plan (including consultations and

referrals)

• Adverse effects and safety issues such as the risk of dependence and addictive

behaviors

• The option of sharing information with family members and other providers, as

necessary, with the patient's consent

• Need for periodic re-evaluation of treatment

• Reasons for stopping opioid therapy

• Consequences of non-adherence with the treatment agreement.

None Reviewed, 

Deleted

2 H 4 Patient’s refusal to sign an agreement as part of the initial and ongoing assessments of 

the patient’s ability to adhere to the treatment plan and the level of risk for adverse 

outcomes (see Table 2, Annotation F). The prescription of therapy, in such cases, should 

be based on the individual patient and the benefits versus harm involved with therapy. 

The rationale for prescribing opioids without a signed agreement should be 

documented.

None Not reviewed, 

Deleted
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2 I 1 The treatment plan should be individually tailored to the patient’s circumstances and to 

the characteristics of the patient’s pain.

None Not reviewed, 

Deleted

2 I 2 Consider the use of other treatment approaches (such as supervised therapeutic 

exercise, biofeedback, or cognitive behavior approaches), which should be coordinated 

with the opioid therapy.

None Reviewed, 

New-replaced

Recommendation 1

2 I 3 Consider establishing a referral and interdisciplinary team approach, if indicated. None Not reviewed, 

Deleted

2 I 4 Establish a follow-up schedule to monitor treatment and patient progress. None Not reviewed, 

Deleted

2 I 5 The treatment plan and patient preferences should be documented in the medical 

record.

None Not reviewed, 

Deleted

3 K1 1 Chronic pain is often a complex biopsychosocial condition. Clinicians who prescribe OT 

should routinely integrate psychotherapeutic interventions, functional optimization, 

interdisciplinary therapy, and other adjunctive non-opioid pain therapies.

None Not reviewed, 

Deleted

3 K1 2 Provide written and verbal education to the patient about the specific medication, 

anticipated adverse effects, dosing and administration, possible excessive sedation and 

symptoms of opioid withdrawal.

None Not reviewed, 

Deleted

3 K1 3 With patient consent, obtain a urine drug test (UDT) prior to initiating an OT trial and 

randomly at follow-up visits to confirm the appropriate use of opioids. A patient can 

refuse urine drug testing. The provider should take into consideration a patient’s refusal 

to undergo urine drug testing as part of the ongoing assessment of the patient’s ability 

to adhere to the treatment plan and the level of risk for adverse outcomes (see 

Annotation F, Table 2).

None Reviewed, 

Deleted
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3 K1 4 There is no evidence to recommend for or against the selection of any specific opioid:

a. Using a shared decision-making process, select a specific opioid formulation, based on

experience and knowledge that matches the individual’s needs and specific medical 

conditions

b. Consider patient preference, and agent that allows administration by the least

invasive route

c. Consider the ease of drug administration, patient’s prior experience with, and level of

tolerance to opioid medications, potential risk for misuse, abuse patterns, and local 

formulary guidance

d. Transdermal fentanyl should be avoided in opioid naïve patients.

None Reviewed, 

New-replaced

Recommendation 13

3 K1 5 Start the opioid therapy trial with a low dose and with one medication at a time. None Not reviewed, 

Deleted

3 K1 6 Initiate a bowel regimen to prevent and treat constipation, which is anticipated with all 

opioids. 

None Not reviewed, 

Deleted

3 K1 7 For continuous chronic pain, an agent with a long duration of action, such as controlledrelease morphine or methadone is recommended.None Not reviewed, 

Deleted

3 K1 8 Alternatively, short-acting opioids can be started, and later converted to long acting 

opioids. (See Annotation K2 - Titration)

None Not reviewed, 

Deleted

3 K1 9 Treatment of continuous chronic pain should be initiated with opioids on a defined and 

scheduled basis.

None Not reviewed, 

Deleted

3 K1 10 For episodic chronic pain, consider short-acting opioids (such as morphine, oxycodone, 

or hydrocodone), trying one medication at a time on a PRN (as needed) basis. Longacting opioids should not be used on a PRN basis.

None Not reviewed, 

Deleted
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3 K1 11 When using methadone:

a. Inform patients of the arrhythmia risk

b. Ask patients about heart disease, arrhythmia, and syncope

c. Obtain an electrocardiogram (ECG) to measure the QTc interval before starting 

methadone and once the dose is stabilized (maintenance phase). Measure the QTc 

annually thereafter if the patient history is positive for risk factors for prolonged QTc 

interval, or has known prolonged QTc interval. Perform additional electrocardiography if 

the methadone dosage exceeds 100 mg/day, or if the patient has unexplained syncope 

or seizures

d. If the QTc interval is greater than 450ms, but less than 500ms, reevaluate and discuss

with the patient the potential risks and benefits of therapy, and the need for monitoring 

the QTc more frequently

e. If the QTc interval exceeds 500 ms, discontinue or taper the methadone dose and

consider using an alternative therapy. Other contributing factors, such as drugs that 

cause hypokalemia, or QT prolongation should be eliminated whenever possible

f. Be aware of interactions between methadone and other drugs that may prolong QTc

interval, or slow the elimination of methadone, and educate patients about drug 

interaction.

None Not reviewed, 

Deleted

3 K2 1 Maintain close communication with patients and families, explicitly discussing the 

criteria for evaluating the effects of analgesic medications; doing so can help in defusing 

the anxiety that often accompanies visits to the physician.

None Not reviewed, 

Deleted

3 K2 2 Ask the patient to keep records of the time and dose of medication, the degree of pain 

relief, and the occurrence of adverse effects.

None Not reviewed, 

Deleted

3 K2 3 Documentation is essential, and should demonstrate the evaluation process—including 

consultation, prescriptions, and periodic review of patient status. Any change and 

consequent patient response should be documented in the record.

None Not reviewed, 

Deleted

3 K2 4 Follow up with the patient in no longer than 2 to 4 weeks after dosage modifications, or 

other treatment adjustments, basing the frequency of follow-up on the clinical situation 

(also see Annotation K3 – Maintenance Phase).

None Reviewed, 

Deleted

3 K2 5 Assess the patient for changes in biopsychosocial and spiritual domains but especially 

the diagnosis, trajectory of disease, and effect of adjuvant therapies.

None Not reviewed, 

Deleted
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3 K2 6 As with initial opioid selection and dosing, titration should be individualized according to 

the patient's age, health status, previous exposure to opioids, level of pain, 

comorbidities, potential drug interactions, the particular opioid formulation, the level 

(setting) of care, attainment of therapeutic goals, and predicted or observed harms.

None Not reviewed, 

Deleted

3 K2 7 If necessary, the daily dose may be increased by 25%-100% at a time. In general, smaller 

increments are appropriate for elderly or frail patients, those with likely low opioid 

tolerance, and patients experiencing unsatisfactory pain relief in the presence of some 

adverse effects. Larger increments may be used in patients with severe uncontrolled 

pain or likely high level of opioid tolerance. If the new dose is well tolerated but 

ineffective, additional increases in dose can be considered.

None Not reviewed, 

Deleted

3 K2 8 To ensure that the full effect from a dosage change has been manifested, and to avoid 

potential toxicity due to rapid accumulation of a drug, do not increase the dose more 

frequently than every five half-lives. In the case of methadone, upward dosage titration 

should not occur more frequently than every 7 days and perhaps longer (e.g., every 1 to 

2 months), and only if there is no problem with daytime sedation, taking into 

consideration that there is wide interpatient variability in half-lives and responsiveness. 

(See Appendices E1 and F)

None Not reviewed, 

Deleted

3 K2 9 If possible, titrate only one drug at a time while observing the patient for additive 

effects. Maintain patients on as few medications as possible to minimize drug 

interactions and adverse events. Discontinue medications, especially adjuvant 

medications, which do not add substantially to patient function or comfort. Continue 

close assessment of patients prescribed multiple centrally acting/psychoactive 

medications.

None Not reviewed, 

Deleted

3 K2 10 If a medication provides less than satisfactory pain reduction despite increasing the dose 

as tolerated to a reasonable level (less than 200 mg/day morphine equivalent), evaluate 

for potential causes such as nonadherence and drug interactions (see Appendix E, Table 

E6– Drug Interactions), and consider changing to an alternate opioid medication.

None Not reviewed, 

Deleted

3 K2 11 Medication may be increased until limited by adverse effects or clear evidence of lack of 

efficacy. If a high dose of medication (greater than 200 mg/day morphine equivalent) 

provides no further improvement in function, consider consultation rather than further 

increasing the dose.

None Not reviewed, 

Deleted

3 K2 12 During the titration phase, reasonable supplemental (rescue) doses of a short acting

opioid may be considered. (See Annotation K-4-Supplemental Dosing) 

None Not reviewed,

Deleted 
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3 K2 13 Consider one or more of the following adjustments in therapy when there is an apparent 

loss of analgesic effect

a. Further optimize adjuvant therapies

b. Re-titrate the dose

• Increase dose by 25-100%.

• Do not increase the dose more frequently than every 5 half lives (for methadone or 

fentanyl no more than once a week), to ensure that the full effect from a dosage change 

has been manifested and to avoid potential toxicity due to rapid accumulation of a drug

• If possible, titrate only one drug at a time, while observing the patient for additive 

effects. Inappropriate or ineffective medications should be tapered while titrating an 

appropriate pharmacologic regimen

• Medication may be increased until treatment goals are met, intolerable adverse effects

occur, or there is clear evidence of lack of efficacy

c. Rotate to another opioid

• Rotation between opioids may help to improve efficacy, reduce side effects and reduce 

dose escalation in some patients who are receiving long-term opioid therapy

• Rotate to another agent based on equianalgesic table and titrate (see Appendix E,

Table E6 for conversion factors)

d. Refer or consult with advanced pain care (pain or palliative care specialist/pharmacist)

• If the dose of opioid is large (more than 200mg/day morphine equivalent)

• If opioid induced hyperalgesia or opioid tolerance is suspected

e. Discontinue Opioid Therapy (See Annotation X).

None Not reviewed, 

Deleted

3 K2 14 For a patient with continuous pain, an agent with a long duration of action, such as 

controlled-release morphine or methadone, is recommended.

None Not reviewed, 

Deleted

3 K2 15 If short-acting opioids are effective and well tolerated, it may be possible to achieve 

equivalent pain relief with fewer daily doses of the medication by substituting an 

equivalent dose of long-acting opioid medication (such as methadone, morphine CR, 

oxycodone CR, or transdermal fentanyl). These long- acting medications may provide 

steadier serum levels and smoother pain control. They can be supplemented with doses 

of short-acting medication to control pain exacerbation.

None Not reviewed, 

Deleted
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3 K2 16 The conversion to a long-acting opioid should be based on an equianalgesic conversion 

(see Appendix E, Table E3 for conversion factors) and consideration of the incomplete 

cross-tolerance between opioids. To allow for incomplete cross-tolerance, in most cases, 

the starting conversion dose should be 50% to 67% of the calculated equianalgesic dose.

A notable exception to this general rule is methadone, which has relatively little crosstolerance with other opioids and should be started at a conversion dose that is based on 

the previous morphine- equivalent dose. Inexperienced clinicians should consult with an 

expert before initiating methadone; even in an opioid tolerant patient (see Appendix E, 

Table E-3, and Appendix F Methadone Dosing Recommendations).

None Not reviewed, 

Deleted

3 K2 17 Base the method of rotating opioids on the clinical situation. Either of the following two 

methods may be used:

a. Step-wise Rotation: Reduce the old opioid dose by 25% to 50% decrements and

replace the amount removed with an equianalgesic conversion dose of the new opioid. 

This method may be preferable when switching large doses of opioids. A disadvantage of 

this method is that the causative opioid(s) of new or worsening adverse effects during 

rotation would be difficult to identify.

b. Single-step Rotation: Stop the old opioid and start the new opioid in an equianalgesic 

conversion dose. This method may be preferable when the old agent must be stopped 

immediately because of a hypersensitivity reaction. A disadvantage of this method is 

that pain may worsen if the new agent has a delayed peak analgesic effect (e.g., 

methadone) while the old agent has a relatively short offset of effects.

None Not reviewed, 

Deleted

3 K3 1 Maintain the lowest effective and well-tolerated dose. The optimal opioid dose is the 

one that achieves the goals of pain reduction and/or improvement in functional status 

and patient satisfaction with tolerable adverse effects.

None Reviewed, 

New-replaced

Recommendation 10

Recommendation 11

Recommendation 12

3 K3 2 Recognize that the dose may need to be titrated up or down on basis of the patient’s 

current biopsychosocial situation. (See Annotation K2 – Titration Phase)

None Not reviewed, 

Deleted
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3 K3 3 Assess patients at least every 1 to 6 months based on the following:

a. Individualize and adjust visit frequencies based on patient characteristics,

comorbidities, level of risk for potential drug misuse (i.e., diversion, addiction, abuse, 

and aberrant drug-related behavior), type of pain, and type and dose of opioids. No 

specific visit frequency applies to all patients

b. Select a frequency that allows close follow-up of the patient’s adverse effects, pain

status, and appropriate use of medication

c. The patient should be able to request an early evaluation

d. Any change in the efficacy of the maintenance dose requires a face to face encounter 

for assessment prior to modifying therapy

None Reviewed, 

Deleted

3 K3 4 Monthly renewal of the prescription for opioid medication can be facilitated by:

a. Phone call, email, or mail-in requests; and/or

b. A structured program (e.g., opioid renewal clinic) staffed by advanced care providers 

(e.g., pharmacists, nurse practitioners, PA-Cs, psychologists, RNs) with appropriate cosignatures

None Not reviewed, 

Deleted

3 K3 5 In addition to the maintenance opioid analgesic, supplemental doses of short-acting 

opioids may be considered. (See Annotation K4 – Supplemental Therapy)

None Not reviewed, 

Deleted

3 K3 6 Assess and re-educate patient’s adherence with safely storing opioid medications. None Not reviewed, 

Deleted

3 K4 1 Evaluate worsening or new pain symptoms to determine the cause and the best 

treatment approach.

None Not reviewed, 

Deleted

3 K4 2 Encourage the use of non-pharmacologic modalities (e.g., pacing activities, relaxation, 

heat, cognitive behavioral therapy).

None Reviewed, 

New-replaced

Recommendation 1

3 K4 3 Carefully evaluate the potential benefits, side effects, and risks when considering 

supplemental opioids.

None Not reviewed, 

Deleted

3 K4 4 Consider supplemental short-acting opioid, non-opioid, or a combination of both agents 

on an as- needed basis.

None Not reviewed, 

Deleted

3 K4 5 Avoid the use of rapid-onset opioids as supplemental opioid therapy in chronic pain, 

unless the time course of action of the preparation matches the temporal pattern of pain 

intensity fluctuation.

None Not reviewed, 

Deleted
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3 K4 6 Avoid use of long-acting agents for acute pain or on an as-needed basis in an outpatient 

setting.

None Not reviewed, 

Deleted

3 K4 7 When using combination products, do not exceed maximum recommended daily doses 

of acetaminophen, aspirin, or ibuprofen.

None Not reviewed, 

Deleted

3 K4 8 Avoid the use of mixed agonist-antagonist opioids, as these agents may precipitate 

withdrawal in patients who have physical opioid dependence.

None Not reviewed, 

Deleted 

3 K4 9 Whenever possible, use the same opioid for supplemental therapy as the long-acting 

opioid to avoid confusion about the cause of any adverse effects that may develop.

None Not reviewed, 

Deleted

3 K4 10 When using short-acting pure agonist opioids (alone or in combination with non-opioid 

analgesics) for supplemental therapy, give opioid doses equivalent to about 10-15%, the 

every four hourly equivalent, or 1/6th of the total daily opioid dose, as needed.

None Not reviewed, 

Deleted

3 K4 11 Use rescue short-acting opioids to assist with pain management during the titration 

process and to help determine the long-term daily opioid dose.

None Not reviewed, 

Deleted

3 K4 12 Do not use routinely for chronic pain. If necessary, use breakthrough pain therapy 

sparingly.

None Not reviewed, 

Deleted

3 K4 13 Consider adjusting the long-acting opioid regimen if pain exacerbations are interfering 

with patient function due to severity, frequency, or diurnal variations in pain intensity.

None Not reviewed, 

Deleted

3 K4 14 Educate and reassure patient, emphasizing realistic expectations about limitations of 

chronic opioid therapy, the normal cyclic nature of chronic pain, and the importance of 

pacing activities.

None Not reviewed, 

Deleted

3 K4 15 Consider providing preemptive analgesia for preventing incident pain e.g., 8 to 12 doses 

per month of short-acting opioid preparation.

None Not reviewed, 

Deleted

 3 L 1 When writing a prescription for opioid therapy, be certain to record the name of the 

drug, the strength, the number of dosage units (written numerically and in text) and how 

the drug is to be taken. (In the case of methadone, indicate on the prescription that it is 

for pain as opposed to detoxification).

None Not reviewed, 

Deleted

 3 L 2 Follow local regulations. None Not reviewed, 

Deleted
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4 M1 1 Evaluate patient for opioid adverse effects: constipation, nausea, vomiting, headache, 

dyspepsia, pruritus, dizziness, tiredness, dry mouth, sweating, hyperalgesia, sexual 

dysfunction, and sedation.

None Not reviewed, 

Deleted

4 M1 2 Many adverse effects spontaneously resolve with continued administration and 

development of tolerance. Consider individual levels of tolerability to different opioid 

agents.

None Not reviewed, 

Deleted

4 M1 3 If not already done, anticipate and consider preventive treatment for common adverse 

effects, particularly constipation and nausea.

None Not reviewed, 

Deleted

4 M1 4 Keep in mind that slowly titrating the opioid dose, modifying the dosage regimen, 

treating symptoms, and rotating the opioid agents may successfully treat most adverse 

effects.

None Not reviewed, 

Deleted

4 M1 5 Consider evaluation of possible drug-to-drug interactions with other medications that 

have been prescribed for the patient (see Appendix E: Drug Table E4 – Drug 

Interactions).

None Not reviewed, 

Deleted
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4 M2 1 At every visit and telephone contact for opioid renewal, assess and document adherence 

with appropriate use of opioid analgesics, and any evidence of misuse, abuse, or 

addiction. 

a. Evaluate how and when the patient is taking medication, use of other medications

including nonprescription and herbal preparations, and use of alcohol and illicit drugs

b. Screening aids such as random pill counts, adherence checklists, or instruments such

as the Screener and Opioid Assessment for Patients with Pain (SOAPP), may be used to 

assist the provider in assessing adherence

c. With patient consent, obtain a Urine Drug Test (UDT) before initiating opioid therapy

trial and randomly at follow-up visits to confirm the appropriate use of opioids (See 

Annotation M3 )

d. Assess and document adherence to other components of the treatment plan, such as

follow up with referrals, tests, and other therapies

e. Assess patients for behaviors that are predictive of addiction including repeated minor

variations in adherence that may indicate an increased likelihood of addiction or serious 

non-adherence

f. Assess patient’s adherence and reeducate regarding the importance of safely storing

opioid medications

g. Assess and document patient motivation and barriers to adherence

None Reviewed, 

New-replaced

Recommendation 7

Recommendation 9

4 M2 2 Based on the clinical assessment the provider should determine whether aberrant 

behavior is present and respond with appropriate action.

None Not reviewed, 

Deleted

4 M2 3 If the clinician is not sure of the meaning of the behavior, more frequent clinic visits, 

addiction or mental health specialist consultations, or periodic drug screens might be 

employed.

None Reviewed, 

New-replaced

Recommendation 7

Recommendation 9

4 M2 4 When aberrant behaviors are present, providers should not stigmatize or judge patients 

but instead simply inform the individual that the behavior is unsafe and needs evaluation 

and adjustment in treatment through increased structure and monitoring or referral.

None Not reviewed, 

Deleted

4 M2 5 A continuing pattern of repeated episodes of non-adherence following treatment 

changes designed to maximize adherence should increase prescriber concerns and 

consideration of potential cessation of opioid therapy.

None Reviewed, 

New-replaced

Recommendation 9
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4 M2 6 Consider involving family members or significant others in identifying solutions to nonadherence and in monitoring future adherence when possible. This may include a 

change in the patient’s living situation that would provide greater structure (e.g., nursing 

home, assisted living facility), potentially enhance compliance, and reduce 

nonadherence

None Not reviewed, 

Deleted

4 M3 1 Inform patients that drug testing is a routine procedure for all patients starting or on 

opioid therapy, and is an important tool for monitoring the safety of their treatment.

None Reviewed, 

New-replaced

Recommendation 7

4 M3 2 With patient consent, obtain a UDT in all patients prior to initiation of OT. [B] B Reviewed, 

New-replaced

Recommendation 7

4 M3 3 With patient consent monitor all patients on OT with periodic random UDTs to confirm 

adherence to the treatment plan. Increase the frequency of UDTs based on risk level for 

aberrant drug-related behaviors and following each dose increase. [B]

B Reviewed, 

New-replaced

Recommendation 7

4 M3 4 Take into consideration a patient’s refusal to take a UDT as part of the ongoing 

assessment of the patient’s ability to adhere to the treatment plan and the level of risk 

for adverse outcomes (see Annotation F).

None Not reviewed, 

Deleted

4 M3 5 When interpreting UDT results take into account other clinical information (e.g., past 

SUD, other risk factors, aberrant drug-related behaviors, and other conditions indicating 

risk.)

None Not reviewed, 

Deleted

4 M3 6 Understanding of lab methods for drug testing and reporting are necessary to interpret 

UDT results (i.e., screen versus confirmatory test, substances tested, cut-off levels for 

tests). Maintain a close working relationship with the clinical laboratory to answer any 

questions about the UDT or for confirming the results.

None Not reviewed, 

Deleted
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4 M4 1 Evaluate and assess the patient for the following problems or other indications for 

consultation or referral:

a. Patient with complex pain conditions

b. Patient with significant medical comorbidities that may negatively impact opioid

therapy

c. Patient with significant concurrent psychiatric illnesses

d. Patient who is unable to tolerate increased pain or physical withdrawal symptoms

arising from opioid tapering when OT is being discontinued

e. Opioid induced hyperalgesia or opioid tolerance suspected (i.e., pain increases or

changes while on chronic stable opioid dosing and with an unchanged underlying 

medical condition causing the pain)

f. Patient with conditions requiring management beyond the expertise level of the 

primary provider

None Not reviewed, 

Deleted

4 M5 1 Evaluate pain intensity at each visit.

a. Intensity of pain should be measured in the following manner using a Numeric Rating 

Scale (NSR) (0 to 10) and include the following:

• Current pain

• Least pain in last week

• “Usual” or “Average” pain in the last week

b. The patient’s response to current pain medications should be assessed each visit using 

questions such as:

• “What is your intensity of pain after taking your current treatment/medication?”

• “How long does your pain relief last after taking your medication?”

None Not reviewed, 

Deleted
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4 M5 2 Evaluate pain-related function using objective documentation whenever possible, such 

as physical therapy progress notes, employment records, exercise diaries, family reports, 

clinician observations (e.g., walking distance), or validated instruments or NRS rating 

scales on a monthly basis during the titration phase and every six months after the 

patient is on stable opioids. Assessment of function may include:

• Employment

• Enjoyment of life

• Emotional distress (depression and anxiety)

• Housework, chores, hobbies, and other day to day activities

• Sleep

• Mobility

• Self-care behaviors

• Sexual function

None Not reviewed, 

Deleted

4 M5 3 Assess overall patient satisfaction with pain therapy at each visit None Not reviewed, 

Deleted

4 M5 4 Emphasis should be given to capitalizing on improved analgesia by gains in physical and 

social function; opioid therapy should be considered complementary to other analgesic 

and rehabilitative approaches.

None Not reviewed, 

Deleted

5 N1 1 Adverse effects can usually be minimized through the use of low starting doses, slow 

titration rates, prophylactic and symptomatic treatments, and specific patient education 

provided at initiation of therapy.

None Not reviewed, 

Deleted

5 N1 2 Symptomatic treatment should be augmented with slow dosage titration, dose 

modification, and/or opioid rotation to minimize the adverse effects as follows:

a. Titrate slowly, temporarily reducing or holding doses if necessary, or modify the 

dosage regimen to allow the patient to develop tolerance to the adverse effects

b. If these measures fail to minimize the adverse effects, consider rotating to another 

opioid agent

None Not reviewed, 

Deleted

5 N1 3 If adverse effects are unmanageable and therapy is a greater detriment than benefit as 

determined by discussion with the patient and family, opioid therapy should be 

discontinued.

None Not reviewed, 

Deleted
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5 N1 4 Initial bowel regimens should generally consist of a bowel stimulant and a stool softener 

as well as general measures, such as increased fluid intake, increased dietary fiber, and 

adequate exercise.

None Not reviewed, 

Deleted

5 N1 5 Routinely initiate a stimulant-based bowel regimen at commencement of chronic opioid 

therapy.

None Not reviewed, 

Deleted

5 N1 6 If the initial regimen is inadequate, mild hyperosmotic, saline, and emollient laxatives 

may be added.

None Not reviewed, 

Deleted

5 N1 7 If possible, reduce or discontinue other drugs that may cause or contribute to 

constipation.

None Not reviewed, 

Deleted

5 N1 8 Bulk-producing laxatives, such as psyllium and polycarbophil, are not recommended and 

are relatively contraindicated as they may exacerbate constipation and lead to intestinal 

obstruction in patients with poor fluid intake.

None Not reviewed, 

Deleted

5 N1 9 Assess patients for constipation symptoms at every office visit. None Not reviewed, 

Deleted

5 N1 10 Consider prophylactic antiemetic therapy at initiation of therapy. None Not reviewed, 

Deleted

5 N1 11 Rule out other causes of nausea, and/or treat based on cause including

a. Stimulation of chemoreceptor trigger zone: dopamine or serotonin antagonist

b. Slowed GI motility: metoclopramide

c. Nausea associated with motion: dimenhydrinate or scopolamine.

None Not reviewed, 

Deleted

5 N1 12 Rule out an allergic reaction. None Not reviewed, 

Deleted

5 N1 13 Itching may resolve spontaneously despite continuation of opioid therapy. If the itching 

does not spontaneously resolve, consider treatment with antihistamines.

None Not reviewed, 

Deleted

5 N1 14 Rule out other causes. None Not reviewed, 

Deleted

5 N1 15 Reduce dose (with or without addition of a co-analgesic). Excessive sedation within the 

first few days of initiating opioids may require temporarily holding one or two doses and 

restarting at a lower dose to prevent respiratory depression.

None Not reviewed, 

Deleted
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5 N1 16 Add or increase non-opioid or non-sedating adjuvant for additional pain relief so that the 

opioid can be reduced.

None Not reviewed, 

Deleted

5 N1 17 If the above measures fail to relieve sedation adequately, consider rotating to another 

opioid agent.

None Not reviewed, 

Deleted

5 N1 18 Consider adding caffeine or a prescription psychostimulant medication. None Not reviewed, 

Deleted

5 N1 19 Rule out other causes. None Not reviewed, 

Deleted

5 N1 20 Consider reducing or stopping (tapering) the dose. None Not reviewed, 

Deleted

5 N1 21 Add or increase non-opioid or non-sedating adjuvant for additional pain relief so that the 

opioid can be reduced.

None Not reviewed, 

Deleted

5 N1 22 Rotate opioid agent. None Not reviewed, 

Deleted

5 N1 23 If patient continues to deteriorate during titration phase and presents with symptoms of 

delirium, opioid therapy should be discontinued.

None Not reviewed, 

Deleted

5 N1 24 If patient develops increased confusion or major cognitive changes (delirium) during the 

maintenance phase, consider hospitalization to investigate the cause and to continue 

treatment safely.

None Not reviewed, 

Deleted

5 N1 25 Ask all patients on opioids for chronic pain about symptoms of opioid-induced 

endocrinopathy (i.e. hypogonadism) on each visit.

None Not reviewed, 

Deleted

5 N1 26 If opioid-induced endocrinopathy symptoms are present, , and not accounted for by 

another disorder or illness (e.g., depression, chronic disease), laboratory evaluation and 

consultation with an endocrinologist should be considered

None Not reviewed, 

Deleted

5 N1 27 Insufficient data exists to recommend routine laboratory screening for endocrinopathy 

in asymptomatic patients on OT.

None Not reviewed, 

Deleted

5 N1 28 There is insufficient evidence to make recommendations regarding OT and immune 

dysfunction.

None Not reviewed, 

Deleted
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5 N1 29 Consider monitoring bone density in patients at risk for osteoporosis (See Table 6: Risk 

Factors for Osteoporosis), as patients with fractures associated with hypogonadism often 

have no other symptoms associated with hypogonadism.

None Not reviewed, 

Deleted

5 N2 1 If a medication causes unmanageable adverse effects, consider changing to an alternate 

opioid medication.

None Not reviewed, 

Deleted

5 N2 2 When therapy is a greater detriment than benefit as determined in consultation with the 

patient and family, opioid therapy should be discontinued.

None Not reviewed, 

Deleted

5 N3 1 Address safety issues immediately and apply legal mandates as appropriate. None Not reviewed, 

Deleted

5 N3 2 Dangerous or illegal behaviors may require immediate cessation of the opioid therapy 

with consideration of appropriate treatment of potential withdrawal symptoms.

None Not reviewed, 

Deleted

5 N3 3 Document and refer to behavior health specialty those patients demonstrating behaviors 

suggestive of suicide.

None Reviewed, 

Amended

Recommendation 8

5 N3 4 For a patient with evidence of diversion or dangerous or suicidal behavior the clinician 

should discontinue OT, refer as appropriate for emergency psychiatric evaluation, and 

flag the chart.

None Not reviewed, 

Deleted

5 N3 5 Consider notifying law enforcement about suspected criminal behaviors such as 

prescription fraud or diversion. Consult with counsel prior to doing so to clarify current 

confidentiality laws and regulations (e.g., VA /military police, risk manager, and/or 

regional counsel).

None Not reviewed, 

Deleted

5 N3 6 Carefully document the details of the situation in the clinical record, or not, as advised by 

risk management and/or legal counsel.

None Not reviewed, 

Deleted
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5 N4 1 Consider adjustment of the initial treatment agreement, with emphasis upon specific 

adherence issues that have been identified; a more structured approach may be 

required. Possible responses to minor nonadherence might include:

a. Reviewing, discussing, and restating the treatment plan

b. Reviewing the written opioid treatment agreement and incorporating any needed

revisions

c. Recommending consultation with a pain, addictions, or behavior health specialist

d. Administration of medications under supervision or with the assistance of others

e. Change of medication, medication dose, or amount dispensed

f. More frequent clinic contacts (telephonic, physician extenders, or clinic visits)

g. Instituting periodic or random urine toxicology screens

None Reviewed, 

New-replaced

Recommendation 9

5 N4 2 Consider setting up a grievance procedure with the patient. None Not reviewed, 

Deleted

5 N4 3 Consider involving family members or significant others in identifying solutions to nonadherence and in monitoring future adherence when possible. This may include change 

in the patient’s living situation that would provide greater structure (e.g. nursing home, 

assisted living facility) and might enhance compliance and reduce nonadherence.

None Not reviewed, 

Deleted

5 N5 1 Consider consultation with, or referral to, a behavioral health specialist if exacerbation of 

an underlying psychotic disorder is an issue, if the nonadherent behaviors may be due to 

changes in mood or increased suicidality, or if there is evidence of increased and poorly 

controlled anger and tendency to violent behaviors (see Annotation O2).

None Not reviewed, 

Deleted

5 N5 2 Consider referral to an addiction specialist if the nonadherent behaviors are those 

associated with possible addiction (see Annotation O1).

None Reviewed, 

New-replaced

Recommendation 16

5 N5 3 Patients presenting with persistent or troublesome aberrant behavior who do not 

respond to intervention by primary care should be referred for evaluation and 

management of OT to a more structured care environment (e.g., Pharmacy Pain 

Management Clinic / Opioid Renewal Pain Care Clinic/ Pain Medicine Clinic).

None Reviewed, 

New-replaced

Recommendation 16

5 N5 4 If such programs are not available, consider continuing OT with increased frequency of 

monitoring and screening, performing a comprehensive behavioral assessment, and 

addressing co-morbidities.

None Reviewed, 

New-replaced

Recommendation 16
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6 O1 1 Consider consultation or referral to addiction specialty for evaluation and treatment in 

the following conditions:

a. Demonstration of behaviors suggesting addiction to prescribed opioids or substance 

use disorders

b. Patients with a significant chronic, or substantiated pain, who develop addiction

behaviors in the context of chronic opioid therapy

c. Uncontrolled substance use disorder (excluding nicotine)

d. Behaviors characteristic of compulsive drug use (addiction) to either opioids or other

drugs or alcohol should be referred to an addiction specialty

e. Complex conditions who manifest behaviors characteristic of addiction with multiple 

co- occurring psychiatric disorders

f. Need for tapering of opioids or unable to tolerate tapering after discontinuation of OT.

None Reviewed, 

NewReplaced

Recommendation 16

6 O1 2 Consider consultation with a SUD specialist to evaluate the risk of recurrent substance 

abuse or to assist with ongoing management.

None Reviewed, 

New-replaced

Recommendation 17

6 O1 3 Refer patient for psychosocial treatments specific to prescription medication 

addiction/abuse. These can include addiction counselors comfortable with such topics, 

and self-help organizations (Pills Anonymous/PA, the National Chronic Pain Outreach 

association, and other similar organizations).

None Not reviewed, 

Deleted

6 O2 1 Consider referral to a Pain Medicine Specialist in the following situations:

a. Patient with complex pain conditions or polytrauma

b. Patient with significant medical comorbidities that may negatively impact opioid

therapy

c. Patient who is unable to tolerate increased pain or physical withdrawal symptoms

arising from opioid tapering when OT is being discontinued

d. Opioid induced hyperalgesia or opioid tolerance is suspected

e. High dose of medication (greater than 200 mg/day morphine equivalent) provides no

further improvement in function

f. Patient requiring management beyond the expertise of the primary provider

None Not reviewed, 

Deleted
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6 O2 2 Consider Referral to/consultation with a Behavioral Health Provider for evaluation and 

treatment in the following conditions:

a. Exacerbation of an underlying psychotic disorder

b. Uncontrolled, severe psychiatric disorder or those who are emotionally unstable

c. Demonstration of high-risk behaviors suggestive of suicide ideation

d. Psychosocial problems or comorbidities that may benefit from disease or case 

management

e. Adverse behavioral or cognitive effects of OT

f. Co-occurring trauma related conditions (mTBI, TBI, PTSD)

None Not reviewed, 

Deleted

7 P 1 Schedule follow-up visits at least every 2-4 weeks after any change in medication 

regimen and at least once every 1-6 months for the duration of the therapy 

(maintenance).

None Not reviewed, 

Deleted

7 P 2 Assess at each visit:

a. Comfort (degree of analgesia)

b. Opioid-related adverse effects

c. Functional status (physical and psychosocial)

d. Adherence to opioid treatment agreement and other aspects of treatment plan

e. Obtain laboratory studies (especially liver or kidney function screens), and/or order

drug screens as indicated

f. Use of self-report instruments (diary, opioid log) may be helpful but should not be

required. 

None Not reviewed, 

Deleted

7 P 3 Documentation is essential and the medical record for each encounter should 

specifically address comfort, function, adverse-effects, and treatment plan adherence.

None Not reviewed, 

Deleted

8 Q 1 Opioid therapy should be tapered off and discontinued if any of the following situations 

occur:

a. The medication fails to show partial analgesia with incremental dose titration

b. Trials with different agents provide inadequate analgesia

c. There is other evidence that the pain may not be opioid responsive

d. Real or potential harms outweigh real or potential benefits

e. Patient request.

None Not reviewed, 

Deleted

8 Q 2 Consider decreasing the opioid dose when pain level decreases in stable patients. (See 

Annotation X – Tapering)

None Not reviewed, 

Deleted
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8 R 1 Document, and offer referral to addiction specialty for patients demonstrating behaviors 

suggesting addiction to prescribed opioids or substance use disorders.

None Reviewed, 

New-replaced

Recommendation 17

8 R 2 Discuss pharmacotherapy options with all patients with opioid and/or alcohol 

dependence.

None Reviewed, 

New-replaced

Recommendation 17

8 R 3 If there are clearly unsafe or illegal behaviors, opioid prescribing should stop 

immediately and withdrawal should be addressed.

None Not reviewed, 

Deleted

8 S 1 Attempt to maintain contact with any patient who withdraws from treatment due to a 

disagreement.

None Not reviewed, 

Deleted

8 S 2 Refer patients with comorbid psychiatric disorders to appropriate mental health 

providers.

None Not reviewed, 

Deleted

8 S 3 Identify and document any co-occurring disorders (CODs) in patients with substance use 

disorders;

a. Psychiatric history, including symptoms and their relation to substance use, current

and past diagnoses, treatments and providers

b. Infectious diseases (HIV, Hepatitis C, sexually transmitted disease)

c. For patients using nicotine offer and recommend tobacco use cessation treatment

d. Medical CODs that may be related to or affected by substance use (e.g., diabetes,

cardiovascular disease, digestive disorders, skin infections, respiratory disorders, 

dementia, cerebrovascular disease)

None Not reviewed, 

Deleted

8 S 4 Individuals with SUD should be assessed for any significant, unmet psychosocial needs or 

situational stressors. These include but are not limited to:

a. Inadequate or no housing

b. Financial difficulties, especially if unable to meet basic needs

c. Problematic family relationships or situations (including caregiver burden or domestic 

violence)

d. Poor social support

e. Religious and spiritual problems

f. Occupational problems

g. Difficulties with activities of daily living or instrumental activities of daily living

None Not reviewed, 

Deleted

8 T 1 Decisions regarding tapering schedule should be made on an individual basis. Sometimes 

faster or slower tapering may be warranted.

None Not reviewed, 

Deleted
VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

February 2017 Page 160 of 198

2010

Recommendation 

Location19

2010 Recommendation Text20

2010 Grade

21

Category22

2016

Recommendation (if 

applicable)23

ModuleSectionNumber

8 T 2 For those patients who are at high risk of aberrant behaviors (parasuicidal acts, 

dealing/selling medications, or those with severe impulse control disorders), tapering 

opioid in a primary care setting is not appropriate and those patients should be referred 

to an addiction or pain specialist with expertise dealing with difficult cases.

None Not reviewed, 

Deleted

8 T 3 Patients with complicated withdrawal symptoms should be referred to a pain specialist 

or a center specializing in withdrawal treatment.

None Not reviewed, 

Deleted

8 T 4 Patient being tapered due to development of addiction should be referred for SUD 

treatment. Opioid detoxification in a primary care setting followed by ongoing substance 

use treatment may be appropriate.

None Not reviewed,

Deleted

8 U 1 Complete evaluation of treatment, comorbidity, psychological condition, and other 

relevant factors should be completed prior to the initiation of the taper.

None Not reviewed, 

Deleted

8 U 2 Clear written and verbal instructions should be given to patients/family to educate them 

about the slow taper protocol that will minimize abstinence (withdrawal) syndromes.

None Not reviewed, 

Deleted

8 U 3 Patients who are unable to tolerate the taper as described should be considered for 

referral to, or consultation with, a pain specialist, substance use specialist or other 

expert.

None Not reviewed, 

Deleted

8 U 4 Withdrawal management for addicted patients is not part of this guideline. Refer to the 

VA/DoD Guideline for the Management of Substance Use Disorders.

None Not reviewed, 

Deleted

8 V 1 Do not abandon a patient under any circumstances. None Not reviewed, 

Deleted

8 V 2 Maintain contact with any patient who withdraws from treatment due to a 

disagreement.

None Not reviewed, 

Deleted

8 V 3 Refer patients with comorbid psychiatric disorders to appropriate mental health 

providers.

None Not reviewed, 

Deleted

9 W 1 Use caution when using opioids in patients with history of substance use disorders. [B] B Reviewed, 

Deleted

9 W 2 Use an integrated treatment approach addressing both pain [B] and SUD issues with 

appropriate information sharing. [C]

C Not reviewed, 

Deleted
VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

February 2017 Page 161 of 198

2010

Recommendation 

Location19

2010 Recommendation Text20

2010 Grade

21

Category22

2016

Recommendation (if 

applicable)23

ModuleSectionNumber

9 W 3 Patients on opioid agonist therapy for DSM-IV diagnosis of opioid dependence who have 

a co- occurring chronic pain disorder should be treated for pain considering the following 

options:

a. Use non-pharmacologic interventions

b. Use other non-opioid pharmacologic treatment modalities

c. Cautious use of opioid therapy by using another opioid agonist with slow titration and

careful communication with the SUD opioid agonist therapy prescribers. [B]

B Reviewed, 

Deleted

9 W 4 Perform urine drug testing as an adjunctive tool at regular intervals. [B] B Reviewed, 

New-replaced

Recommendation 9

9 W 5 Management of OT in patients on sublingual (SL) buprenorphine (with or without 

naloxone) for DSM-IV

diagnosis of opioid dependence:

a. SL buprenorphine is FDA-approved for treatment of opioid dependence and can only

be

prescribed by a qualified and DEA-waivered physician for this purpose

b. Patients on SL buprenorphine should not receive full agonist opioids concomitantly for

routine

pain control

c. Nonopioid and nonpharmacologic strategies for pain management should be

maximized

In the event of anticipated pain ( i.e., an elective procedure or surgery) SL buprenorphine

should

be stopped for 48 hr before the scheduled event

e. For unanticipated pain (trauma, emergency surgery or procedure) the care team

managing the

acute pain should be notified that the patient is prescribed SL buprenorphine and when

the last

dose was taken.

None Not reviewed, 

Deleted

9 X 1 Be vigilant for sleep apnea during OT. If clinical suspicion exists for the presence of sleep 

apnea in a patient on OT, sleep study should be considered. [B].

B Not reviewed, 

Deleted
VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

February 2017 Page 162 of 198

2010

Recommendation 

Location19

2010 Recommendation Text20

2010 Grade

21

Category22

2016

Recommendation (if 

applicable)23

ModuleSectionNumber

9 X 2 Patients on OT who present with sleep disorder confirmed by a sleep study should be 

assessed for the appropriateness of continuing OT and should be evaluated for the risks 

(based on the severity of the sleep-disordered breathing) versus benefits of OT. If OT is 

continued, it should be titrated cautiously. Patients found to have sleep-disordered 

breathing should be followed with a repeated sleep study. [C]

C Not reviewed, 

Deleted

9 X 3 Patient with abnormal sleep study should be educated about the significant additional 

risks including breathing disruption, and instructed to avoid alcohol, or any CNSdepressant medication. [A]

A Not reviewed, 

Deleted

9 X 4 The type of sleep apnea should be evaluated to determine if it is obstructive or central.

CPAP may worsen central sleep apnea. [D]

D Not reviewed, 

Deleted

9 X 5 Patients with sleep apnea who are on OT may benefit from a reduction in the dose of 

their opioids.

None Not reviewed, 

Deleted

9 X 6 Discontinuation of opioid therapy should be considered if the sleep apnea is severe or 

life threatening.

None Not 

reviewed, 

Deleted

9 X 7 Consider more careful monitoring of OT in patients treated with methadone and/or 

benzodiazepines. [B]

B Not reviewed, 

Deleted
VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

February 2017 Page 163 of 198

Appendix I: Participant List

Elizabeth (Liz) Rees Atayde, RN, MSN, FNP, CCM, CPHM

Nursing, Medical Management 

Medical Management Consultant/CPG Coordinator 

U.S. Army Medical Command

Fort Sam Houston, TX

LTC Robert Brutcher, PharmD, PhD 

Pharmacy

Deputy Director, Department of Pharmacy

Walter Reed National Military Medical Center/ Defense

Health Agency

Bethesda, MD

Michael O. Chaffman, PharmD, BCPS

Pharmacy 

National PBM Clinical Pharmacy Program Manager, 

Veterans Health Administration

Pharmacy Benefits Management Services

Hines, IL

Corinne K. B. Devlin, MSN, RN, FNP-BC

Family Nurse Practitioner

Chief, Office of Evidence Based Practice

U.S. Army Medical Command 

Clinical Performance Assurance Directorate 

Fort Sam Houston, TX

Karen Drexler, MD 

Substance Use Disorders, Psychiatry 

National Mental Health Program Director, 

Substance Use Disorders 

Mental Health Services, VA Central Office

Atlanta, GA

LTC William Grief, MD

Family Medicine, Pain Medicine

Chief, Department of Pain Management

Madigan Army Medical Center

Joint Base Lewis-McChord, WA

James Hardin, LCSW-C, MAC

Social Work

Chief, Addiction Treatment Services

Walter Reed National Military Medical Center

Bethesda, MD

Connie Kurihara, RN

Pain Management

Research Nurse

Walter Reed National Military Medical Center 

Bethesda, MD

Franz Macedo, DO

Pain Medicine, Physical Medicine and Rehabilitation

Medical Director, Comprehensive Pain Center

Minneapolis VA Medical Center

Minneapolis, MN

Aram Mardian, MD 

Family Medicine, Primary Care

Chief, Chronic Pain Wellness Program 

Phoenix VA Health Care System

Phoenix, AZ

Anthony J. Mariano, PhD

Pain Psychology

Director, Pain Psychology, VISN 20 Pain Medicine and 

Functional Rehabilitation Center

VA Puget Sound Healthcare System

Seattle, WA

CDR Marisol Martinez, PharmD, MBA

Pharmacy 

Clinical Pharmacy Analyst 

U.S. Public Health Service Defense 

Health Agency Pharmacy Operations 

Division 

San Antonio, TX 

Capt Erick C. Messler, PhD 

Psychology

Director of Psychological Health

Malmstrom Air Force Base, MT

Ilene Robeck, MD 

Internal Medicine, Addiction Medicine, 

Mental/Behavioral Health 

Co-Chair, National Primary Care Pain Champions Initiative 

Director of Virtual Pain Care, Richmond VA Medical 

Center

Richmond, VA
VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

February 2017 Page 164 of 198

Jack Rosenberg, MD, FASAM (Champion) 

Pain Medicine, Anesthesiology, Addiction

Chair, National Pain Guidelines Group 

Member, National Pain Management Strategy 

Coordinating Committee

Co-Physician Pain Lead, VISN 10 

Staff Physician, Ann Arbor VA Medical Center 

Ann Arbor, MI

Friedhelm Sandbrink, MD 

Pain Medicine, Neurology, Clinical Neurophysiology 

Chief, Pain Management Program, Department of 

Neurology, Washington DC VA Medical Center 

Deputy National Program Director for Pain Management, 

Specialty Care Services, VHA 

Washington, DC 

LTC Jason Silvernail DPT, DSc, FAAOMPT

Physical Therapy

Chief, Physical Therapy Service

Walter Reed National Military Medical Center/ Defense 

Health Agency

Bethesda, MD

Maria Silveira, MD, MA, MPH

Palliative Care, Geriatrics 

Clinical Scientist, Geriatric Research Education Clinical 

Center, Ann Arbor VA Medical Center

Ann Arbor, MI

Christopher Spevak, MD, MPH, JD (Champion) 

Pain Medicine, Addiction Medicine

Director, Prescription Medication Misuse Program

Deputy Director, Wounded Warrior and NCRP Initiatives

Walter Reed National Military Medical Center/ Defense 

Health Agency

Bethesda, MD

Nancy Wiedemer, MSN, RN, ANP-BC 

Nursing, Primary Care, Pain Medicine

Pain Management and Opioid Safety Lead for VISN 4

Pain Management Coordinator, Corporal Michael 

Crescenz VA 

Medical Center, Philadelphia

CAPT Necia Williams, MD

Pain Medicine, Anesthesiology

Command Surgeon

Marine Special Operations Command

Camp Lejeune, NC
VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

February 2017 Page 165 of 198 

Appendix J: Literature Review Search Terms and Strategy

A. Topic-specific Search Terms

The search strategies employed combinations of free-text keywords as well as controlled vocabulary terms 

including (but not limited to) the following concepts. Strategies for each bibliographic database follow this 

table.

Table J-1. EMTREE, Medical Subject Headings (MeSH), PsycInfo, and Keywords 

Concept Controlled Vocabulary Keywords 

Patient population

Chronic Pain EMBASE

‘chronic disease’/exp

‘chronic inflammatory pain’/exp

‘chronic pain’

‘pain’/exp

MeSH

exp chronic disease/

exp pain/

PsycINFO

Exp chronic illness/

exp chronic pain/

exp pain/ 

chronic

Chronic adj3 pain*

Chronic NEXT/3 pain*

Long?term NEXT/3 pain*

months

pain

weeks

year*

Chronic Opioid Use EMBASE

‘analgesic agent’/exp

‘codeine’/de

‘drug therapy’/lnk

‘fentanyl’/de

‘morphine’/de

‘narcotic agent’/exp

‘narcotics’/exp

‘narcotic drugs’/exp

‘opiate’/de

‘opiates’/exp

MeSH

Chronic pain/drug therapy

exp analgesics, opioids

exp narcotics

PsycINFO

exp analgesic drugs

exp narcotics

exp narcotic drugs

exp opiates

Analgesic*

COT 

‘chronic NEXT/1 opi* NEXT/1 therapy’

‘chronic opi* therapy’ 

codeine

Fentanyl

heroin

Hydrocodone

Hydromorphone

Long?term

Methadone

months

morphine

narcotic* 

Opi*

Oxycodone

Oxycontin 

Oxymorphone

percocet

Tapentadol

Tramadol

Vicodin

weeks

Year*
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VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

February 2017 Page 166 of 198

Concept Controlled Vocabulary Keywords 

KQ 1

Contraindications

What is the evidence that 

the following medical or 

mental health conditions 

are absolute or relative 

contraindications of 

prescribing LOT? 

 Active pursuit of 

compensation 

 Centralized pain 

conditions such as 

fibromyalgia

 Chronic obstructive 

pulmonary disease

 Cognitive impairment

 Depression

 Headache

 GI motility problems 

(e.g., toxic 

megacolon, GI pain 

syndromes, narcotic 

bowel syndrome)

 Immune status 

changes

 Inability to participate 

in comprehensive 

treatment plan

 Incarceration (history 

of)

 Hepatic, renal, or 

pulmonary disease

 Suspected opioid 

misuse (e.g., 

overdose, early 

refills, diversion, 

taking more than 

prescribed)

 Osteoporosis

 Personality disorders

 Posttraumatic stress 

disorder

 Sleep disorders

 SUD (current or 

history of)—include 

specific disorders 

and appropriate key 

words in search

 Suicidality

 Traumatic brain injury

 Use of medical 

marijuana 

 QT prolongation

EMBASE

‘drug contraindication’/exp

‘drug interaction’/exp

‘drug safety’/exp

MeSH

analgesics, opioid/contraindications

Polypharmacy/

PsycINFO

Drug interactions/

Polypharmacy/

Safety/

Cardiovascular

CNS

COPD

Compensation*

Contraindication*

depression

Fibromyalgia

gastrointestinal

Headache* 

Heart

immune

Liver 

Lung 

Obstructive

Osteoporosis

(personality or cognitive or mental or 

neuro*) adj3 (disorder* or disease* or 

illness*))

Post?traumatic stress

PTSD

Respiratory 

Sleep 

Substance adj2 (abuse OR misuse)

Substance use disorder

SUD

Suicide

suicidality

TBI 

Traumatic brain
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VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

February 2017 Page 167 of 198

Concept Controlled Vocabulary Keywords 

KQ 2 

Risk factors for the 

continuum of misuse or 

OUD

What factors increase the 

risk of developing misuse 

or OUD when considering 

LTOT?

a) What are the risks 

for long-term use 

associated with 

acute use of 

opioids in treating 

acute pain?

EMBASE

‘analgesic agent abuse’/exp

‘bullying’/exp

‘opiate addiction’/exp

‘opioid-related disorders’/exp 

‘risk’/exp

‘sexual abuse’/exp

MeSH

‘bullying’/

‘domestic violence’/exp

‘risk assessment’/exp

‘substance-related disorders’/exp

PsycINFO

Exp addiction/

Exp at risk populations/

Exp codependency/

Exp drug abuse/

Exp drug addiction/

Exp drug overdoses/

Exp illegal drug distribution/

Exp risk assessment/

Exp risk factors 

Exp risk perception/ 

Abuse

Acute

Addict*

Assess*

Bully

Bullying 

Day*

dependency

Disorder*

Early

Initial

New 

New onset

Overdose*

Predict*

Risk*

Short term

violence
DRAFT 3 -DO NOT DISTRIBUTE

VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

February 2017 Page 168 of 198

Concept Controlled Vocabulary Keywords 

KQ 3 AND KQ 4

Effectiveness of LTOT

What is the comparative 

effectiveness of LTOT 

versus other treatment 

modalities?

a) What is the 

comparative 

effectiveness of 

LTOT versus other 

treatment 

modalities for 

patients with a 

history of or 

current SUD?

b) What is the 

effectiveness of 

nonpharmacological 

interventions in 

patients with 

chronic pain?

Safety of LTOT

What is the safety of 

LTOT versus other 

treatment modalities?

a) What is the safety 

of LTOT versus 

other treatment 

modalities for 

patients with a 

history of or 

current SUD?

b) What is the safety 

of nonpharmacological 

interventions in 

patients with 

chronic pain? 

EMBASE

‘adverse drug events’/exp

‘adverse drug reaction’/exp

‘adverse drug reaction’/lnk

‘drug overdose’/exp

‘patient safety’/exp

‘prescription drugs’/exp

‘side effect’/lnk

‘side effect’/de

‘treatment outcome’/de

MeSH

‘analgesics, opioid’/*adverse effects

‘prescription drugs’/adverse effects

‘quality of life’ 

‘risk’

‘side effect’/de

‘treatment outcome’

PsycINFO

*quality of life/

“side effects (drug)”/

*treatment outcomes/

Drug overdose/*prevention & control 

Aberrant NEXT/3 behavior*

Absence

absent

Abuse

Accident*

‘ade’

Addict*

adverse

‘adverse drug events’ 

Adverse NEXT/1 effect*

Anxiety

cardiac

cardiovascular

cognitive

complication

depression

Disorder*

Diversion

effective

effectiveness

Fall

Falls 

Harm*

Misuse

Mood

Outcome*

Overdose* 

‘pain relief’

Pain NEXT/2 relief

Pain NEXT/3 reliev*

poison*

‘quality of life’

QOL

Safety

‘side effect*’

Sleep s
DRAFT 3 -DO NOT DISTRIBUTE

VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

February 2017 Page 169 of 198

Concept Controlled Vocabulary Keywords 

KQ 5

Effectiveness of different 

opioid formulations

What is the comparative 

effectiveness and safety 

of various opioid 

formulations?

a) Immediaterelease/shortacting opioids 

compared to 

ER/long-acting 

opioids

b) Route of 

administration/ 

delivery 

alternatives such 

as transdermal, 

buccal, sublingual, 

pumps

c) Abuse deterrent 

formulations 

compared to nonabuse deterrent 

formulations

d) Tramadol and 

other dualmechanism 

opioids

e) Buprenorphine

f) Methadone

EMBASE

‘short acting analgesic agent’/exp

MeSH

‘analgesics, short-acting’

PsycINFO

*drug therapy

Abuse-deterrent

controlled

‘controlled release’

extended

‘extended release’

Formulation

immediate

‘immediate release’

LA

‘long?acting’

Medication

Medicine

Pill*

Prescription*

SA

‘short?acting’

(short* OR long* OR immediate OR 

extended OR controlled OR sustained AND 

(release* OR act*))

Sustained 
DRAFT 3 -DO NOT DISTRIBUTE

VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

February 2017 Page 170 of 198

Concept Controlled Vocabulary Keywords 

KQ 6

Added benzodiazepines

Does additional use of 

benzodiazepines or other 

psychoactive medications 

increase the risk of 

adverse events compared 

to OT alone?

EMBASE

‘antidepressant agent’/exp

‘benzodiazepine’

‘benzodiazepine derivative’/exp 

‘hypnotic sedative agent’/exp

‘narcotic analgesic agent’/exp

‘non prescription drug’

‘prescription drug’

MeSH

‘patient safety’

‘polypharmacy’/exp

‘safety’

PsycINFO

exp analgesic drugs/

Exp anesthetic drugs/

Exp anticonvulsive drugs/

Exp antidepressant drugs/

Exp antiemetic drugs/

Exp antihistaminic drugs/

Exp antihypertensive drugs/

exp benzodiazepines/

exp cns depressant drugs/

drug therapy/sh

*hypnotic drugs/

Insomnia.id.

Major depression.id.

Exp polypharmacy/

Schizophrenia.id.

Exp sedatives/

Exp self medication/

Ambien

‘anti depressant’

Antidepressant*

Anti-depressant’

Benzodiazepine*

'eszopiclone' 

Hypnotic*

lunesta 

OTC

‘over-the-counter’

‘over the counter’

prescription*

polypharmacy

psychoactive*

sonata

stimulant*

‘z drug’

‘z drugs’

'zaleplon'

'zolpidem'
DRAFT 3 -DO NOT DISTRIBUTE

VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

February 2017 Page 171 of 198

Concept Controlled Vocabulary Keywords 

KQ 7

Risk mitigation strategies

What is the comparative 

effectiveness of different 

risk mitigation strategies 

for patients either on 

LTOT or being considered

for LTOT?

a) Does this differ for 

patients with 

history of or 

current SUD?

b) Does this differ for 

patients with 

mental health 

comorbidities?

c) Does this differ for 

patients with 

medical 

comorbidities?

d) What is the safety 

and effectiveness 

of take-home 

naloxone kits?

EMBASE

‘naloxone’/exp

‘opiate addiction’/exp

‘patient education’/exp

‘prescription drug diversion’/exp

‘risk reduction’/exp

‘substance abuse’/exp

‘urinalysis’/exp

MeSH

‘contracts’

‘drug monitoring’

exp ‘patient compliance’/

exp ‘risk’/

PsycINFO

exp addiction/

Exp client education/

exp drug abuse/

drug abuse.sh.

exp drug addiction/

opiates.id.

exp monitoring/

exp naloxone/

exp patient compliance/

Exp prescription drugs/

Exp risk assessment/

Exp risk evaluation and mitigation 

strategy/

Exp risk perception/

Exp treatment compliance/

Exp urinalysis/

Abuse

Addict*

agreement

‘call back’

Call-back

Compliance

comply

consent

contract

database

diversion

divert

doctor

Detect*

Diversion

Divert

Misuse

Mitigat*

Monitor*

naloxone

Naloxone NEXT/2 rescue

office

Pill NEXT/2 count

physician

primary

Precaution*

Query

Recall

Rescue

Risk*

Risk NEXT/5 reduc*

Risk NEXT/5 mitigat*

Screen*

surveillance

Test*

Urin*
DRAFT 3 -DO NOT DISTRIBUTE

VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

February 2017 Page 172 of 198

Concept Controlled Vocabulary Keywords 

KQ 8

Treatment of OUD

What is the safety and 

effectiveness of 

treatment of OUD 

(diagnosed or suspected) 

in patients with chronic 

pain?

a) Do outcomes vary 

by severity of 

OUD? 

EMBASE

'acceptance and commitment 

therapy'/exp

‘addiction’/exp

‘analgesic agent abuse’/exp

‘cognitive therapy’/exp

‘drug abuse’/exp

‘drug dependence’/exp

‘narcotic analgesic agent’/exp

‘narcotic dependence’/exp

‘opiates’/exp

‘opiate addiction’/exp

‘psychotherapy’/exp

‘support group’/exp

MeSH

‘analgesics, opioid’/exp

‘cognitive therapy’/exp

‘counseling’/exp

‘motivational interviewing’/

‘narcotics’/exp

‘substance abuse detection’/exp

‘substance-related disorders’/exp

PsycINFO

exp addiction/

Exp adjunctive treatment/

Exp cognitive therapy/

Exp counseling/

exp drug abuse/

drug abuse.sh.

exp drug addiction/

exp drug dependence/

electrosleep treatment/

exp motivational interviewing/

exp opiates/

opiates.id. 

Exp prescription drugs/

Exp psychotherapy/

Exp support group/

Exp treatment/

Exp treatment compliance/

Exp treatment effectiveness evaluation/

Exp treatment outcomes/

aberrant

Abuse

Addict*

Behavioral

buprenorphine

Cognitive

Contingency

‘contingency management’

Counsel*

counseling

drug

interview*

methadone

misuse

motivation*

naltrexone

therapy

treat*

treatment
DRAFT 3 -DO NOT DISTRIBUTE

VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain

February 2017 Page 173 of 198

Concept Controlled Vocabulary Keywords 

KQ 9

Tapering

What is the safety and 

effectiveness of different 

tapering strategies and 

schedules?

EMBASE

‘analgesia’/exp

‘clinical protocol’/exp

‘dose response’/exp

‘drug administration’.exp

‘drug therapy’/lnk

‘pain management’/exp

MeSH

‘clinical protocols’/exp

‘drug administration schedule’/exp

PsycINFO

exp analgesic drugs/

Exp drug dosages/

Exp pain management/ 

Adjust*

administration

Decrease* 

Dose

Dosing

plan

protocol

Reduc*

Schedule

Strategy

strategies

Taper*

Titrat*

B. Search Strategies

Table J-2. MEDLINE/PSYCINFO (presented in OVID syntax) 

Set 

Number Concept Search Statement

1 Chronic pain *exp chronic pain/ OR (exp pain/ AND (chronic OR long?term)) OR (exp chronic 

illness/ AND pain?)

2 Chronic adj3 pain?.ti,ab.

3 Combine 1 OR 2

4 LTOT exp analgesic drugs/ or exp narcotics/ or exp narcotic drugs/ or exp opiates/

5 (opioid* or opiod* or opiate* or oposal or opon or narcotic*).mp. OR (morphine 

or codeine or fentanyl).mp.

6 (Oxymorphone or tapentadol or methadone or fentanyl or hydrocodone or 

oxycodone or codeine or morphine or hydromorphone or tramadol).mp. 

7 Combine 4 OR 5 OR 6

8 Combine chronic pain 

and LTOT

3 AND 7

9 Contraindications

(KQ1)

(Contraindication or COPD or cardiovascular or respiratory or obstructive or lung 

or fibromyalgia or headache or heart or liver or sleep or osteoporosis or CNS or 

immune or gastrointestinal).mp. 

10 (medic* adj1 marijuana).mp. or ("post?traumatic stress" or PTSD).mp. or 

traumatic brain.mp. or TBI.ti,ab. or (substance adj2 abuse).mp. or (substance 

adj2 misuse).mp. or (depression or suicide or suicidality).mp. or ((personality or 

cognitive or mental or neuro*) adj3 (disorder* or disease* or illness*)).mp.

11 9 OR 10

12 Workers 

compensation

exp litigation/ or exp workers’ compensation insurance/ or lawsuit.mp. or 

litigation.mp. exp insurance/ or insurance claim.mp. or exp disability evaluation/ 

or exp malingering/ or malingering.mp.

13 (worker adj2 compensation).mp. or litigation.ti. or lawsuit.ti. or claim*.ti. or 

disability*.ti. or compensation.ti. or malinger*.ti.

14 combine 11 OR 12 OR 13
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February 2017 Page 174 of 198

Set 

Number Concept Search Statement

15 Combine with chronic 

pain and LTOT

8 AND 14

16 Risk of misuse (KQ2) Exp drug abuse/ or exp addiction/ or exp codependency/ or exp drug addiction/ 

or exp drug overdoses/ or exp illegal drug distribution/ 

17 16 AND (opi* or narcotic* or hydrocodone or vicodin or oxycodone or oxycontin 

or percocet or heroin or methadone or morphine or codeine or analgesic*).mp.

18 ((opi* or narcotic* or hydrocodone or vicodin or oxycodone or oxycontin or 

percocet or heroin or methadone or morphine or codeine or analgesic*) adj2 

(addict* or abuse or misuse or disorder* or diversion)).mp.

19 Risk*.mp. or exp risk assessment/ or exp risk perception/ or exp at risk 

populations/ or exp risk factors/

20 17 OR 18

21 Combine risk and 

abuse

19 AND 20

22 Combine with chronic 

pain and LTOT

8 AND 21

23 Effectiveness and 

Safety of LTOT (KQs 3 

and 4)

exp "Side Effects (Drug)"/ or exp "side effects (treatment)"/ or exp 

"complications (disorders)"/ 

24 exp Suicide/ or exp Major Depression/ or exp Attempted Suicide/ or exp Drug 

Abuse/ or exp Drug Overdoses/ or exp Drug Addiction/ or exp Safety/ or 

overdose.mp. or adverse events.mp. or drug addiction.mp.

25 Exp pain management/ or (pain adj2 (reliev* or relief)) or exp Quality of Life/ or 

quality of life.mp. or exp treatment outcomes/ or outcomes.mp.

26 ((adverse adj1 event*) or (adverse adj1 effect*) or (aberrant adj3 

behavior*)).mp. or (overdose* or diversion or addict* or abuse or accident* or 

complication* or absence or absent or falls or fall or depression or anxiety or 

mood or sleep or cardiovascular or cardiac or cognitive).ab,ti.

27 ((work or occupation* or job) adj3 (injur* or accident or absence or 

performance)).mp. or exp safety/ or exp occupational safety/ or exp accidents/ 

or exp job performance/ or exp employee absenteeism/ or exp cognitive 

processes/ OR exp cognitive impairment/

28 exp driving behavior/ or exp drivers/ or exp risk taking/ or exp risk perception/ 

or exp highway safety/ or exp motor traffic accidents/ or exp motor vehicles/ or 

exp transportation accidents/ or exp motor traffic accidents/ or (accident* or 

crash or collison or wreck).mp. or ((drive or driving or car* or traffic or vehicle*)

and (safe* or accident* or crash* or wreck* or impair* or risk* or collison*)).mp.

29 Combine 23 OR 24 OR 25 OR 26 OR 27 OR 28

30 Combine with LTOT 7 AND 29

31 Formulations (KQ5) (*drug therapy/ or (prescription* or medication or medicine or pill*).mp. AND 

opi*

32 'immediate release' OR 'extended release' OR 'short acting' OR shortacting OR sa 

OR 'long acting' OR longacting OR la OR 'controlled release' OR (short* OR long* 

OR immediate OR extended OR controlled OR sustained AND (release* OR 

act*)).mp.

33 (formulation* or short?act* or long?act* or immediate or extended or 

controlled or sustained or abuse-deterrent or (abuse adj1 deterrent)).mp.
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Set 

Number Concept Search Statement

34 (opiate* or opioid).ti. and (formulation* or short?act* or long?act* or 

immediate or extended or controlled or sustained).mp.

35 Combine (31 AND (32 OR 33 )) OR 34

36 Combine with LTOT 7 AND 35

37 Added 

benzodiazepines 

(KQ6)

benzodiazepine*.mp. or exp benzodiazepines/

38 *hypnotic drugs/ or exp analgesic drugs/ or exp anesthetic drugs/ or exp 

anticonvulsive drugs/ or exp antiemetic drugs/ or exp antihistaminic drugs/ or 

exp antihypertensive drugs/ or exp benzodiazepines/ or exp cns depressant 

drugs/ or exp sedatives/ or exp antidepressant drugs/ or exp nonprescription 

drugs/ or exp self medication/ or exp prescription drugs/ or exp polypharmacy/

39 (insomnia or chronic pain or schizophrenia or major depression).id. and drug 

therapy.sh.

40 (zolpidem or zaleplon or eszopiclone or ambien or lunesta or sonata or 

benzodiazepine* or antidepressant* or anti-depressant* or stimulant* or 'z 

drug' or 'z drugs' or hypnotic* or psychoactive*).mp.

41 (over-the-counter or 'over the counter' or OTC).mp or (prescription* or 

prescribed).ab,ti. Or polypharmacy.mp.

42 ((medication* or medicine) and (multiple or concomitant or several)).mp.

43 Combine 37 OR 38 OR 39 OR 40 OR 41 OR 42

44 Combine with chronic 

pain and LTOT

8 AND 43

45 Risk mitigation for 

addiction (KQ7)

exp opiates/ or exp drug addiction/ or exp prescription drugs/ or exp drug 

abuse/ or exp addiction/ OR (opiates.id and drug abuse.sh.)

46 ((addict* OR abuse OR misuse OR diversion OR divert) AND (opi* OR 

oxymorphone OR tapentadol OR methadone OR fentanyl OR hydrocodone OR 

oxycodone OR codeine OR morphine OR hydromorphone OR tramadol)).mp.

47 Combine opiate 

addiction or misuse

45 OR 46 

48 Mitigation strategies urin* adj7 (screen* OR test* OR detect* OR anal* OR monitor*) OR exp 

urinalysis/ or exp drug usage screening/ 

49 Count OR 'call back' OR database OR query OR compliance OR contract* OR 

agreement OR consent OR recall OR surveillance OR call-back OR monitor* OR 

(‘pill count’ OR pill count).mp.

50 (naloxone adj2 rescue).mp.

51 'patient compliance'/exp OR (patient:ab,ti AND (compliance:ab,ti OR 

comply:ab,ti))

52 Exp treatment compliance/ or (patient and (compliance or comply)).ab,ti.

53 ((office OR doctor OR primary) adj3 (visit* OR appointment* OR check*)).mp. OR 

(exp opiates/ AND exp monitoring/)

54 Exp client education/ or patient education.mp. OR patient NEXT/3 (aware* OR 

educat*)

55 (opi* adj5 (contract OR contracts OR agreement)).mp.

56 Combine mitigation 

strategies

48 OR 49 OR 50 OR 51 OR 52 OR 53 OR 54 OR 55
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Set 

Number Concept Search Statement

57 Risk Exp risk assessment/ or exp risk perception/ or (risk* adj7 (mitigate* OR 

reduc*)).mp. or (risk evaluation and mitigation strategy).mp. 

58 Combine addiction, 

mitigation, and risk

47 AND 56 AND 57

59 Combine addiction, 

mitigation, and risk 

with LTOT

7 AND 58

60 Treatment of OUD 

(KQ8)

((addict* OR abuse OR misuse OR diversion OR divert) AND (opi* OR 

oxymorphone OR tapentadol OR methadone OR fentanyl OR hydrocodone OR 

oxycodone OR codeine OR morphine OR hydromorphone OR tramadol)).mp. 

61 Opiate addiction or 

misuse

exp opiates/ or exp drug addiction/ or exp prescription drugs/ or exp drug 

abuse/ or exp addiction/ OR (opiates.id and drug abuse.sh.)

62 (exp drug abuse/ or exp drug dependence/ or exp drug addiction/ or aberrant.ti. 

or aberrant.ab.) and (exp opiates/ or opioid*.mp. or oxymorphone.mp. or 

tapentadol.mp. or methadone.mp. or fentanyl.mp. or hydrocodone.mp. or 

oxycodone.mp. or codeine.mp. or morphine.mp. or hydromorphone.mp. or 

tramadol.mp. or analgesic*.mp.)

63 Counseling Exp psychotherapy/ OR exp cognitive therapy/ OR exp counseling/ OR exp 

support group/ OR exp motivational interviewing/ exp Adjunctive Treatment/ or 

exp Treatment Compliance/ or exp Treatment/ or exp Treatment Effectiveness 

Evaluation/ or (treat or treatment or therap* or counsel*s).ab,ti.

64 counsel OR counseling OR ((cognitive OR contingency OR drug OR behavioral OR 

motivational) adj2 (counseling OR therapy)) OR motivation* adj1 interview* OR 

(buprenorphine OR naloxone OR naltrexone OR methadone) OR contingency 

management.mp.

65 Combine addiction 60 OR 61 OR 62

66 Combine counseling 63 OR 64

67 Combine LTOT and 

addiction and 

counseling

7 AND 65 AND 66

68 Tapering (KQ9) (exp analgesia/ or exp analgesic drugs/ or exp pain management/) AND exp drug 

dosages/

69 ((dose or dosing) and (protocol* or administration or plan* or schedule* or 

strategy or strategies)).mp.

70 (taper* or decrease* or reduc* or adjust* or titrat* or dosing or dose*).mp.

71 ((taper* or decrease* or reduc* or adjust* or titrat* or dosing or dose*) and 

(protocol* or administration or plan* or schedule* or strategy or 

strategies)).mp.

72 Combine tapering sets 68 OR 69 OR 70 OR 71

73 Combine tapering and 

chronic pain and LTOT

8 AND 72

74 Combine all final sets 15 OR 22 OR 30 OR 36 OR 44 OR 59 OR 67 OR 73

75 Apply limits limit 74 to (human and english language and yr="2009 - 2016")

76 Apply publication type 

limits

75 AND (trial* or study or studies or method* or review* or analysis or compar* 

or random* or systematic*).mp.

77 limit 75 to ("0100 journal" or "0110 peer-reviewed journal" OR “journal article”)
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Set 

Number Concept Search Statement

78 75 AND (exp clinical trials/ or exp cohort analysis/ or exp followup studies/ or 

exp longitudinal studies/ or ((compar* or comparison or comparative) and 

trial*).ab,ti.

79 Combine final sets 76 OR 77 OR 78

OVID syntax:

* (within or following a term) = truncation character (wildcard)

.ab. = limit to abstract

ADJn = search terms within a specified number (n) of words from each other in any order

exp/ = “explodes” controlled vocabulary term (e.g., expands search to all more specific related terms 

in the vocabulary’s hierarchy)

.mp. = combined search fields (default if no fields are specified)

.pt. = publication type 

.ti. = limit to title 

.ti,ab. = limit to title and abstract fields 

Table J-3. EMBASE/Medline Search Strategies Conducted using EMBASE Syntax

Set 

Number Concept Search Statement

1 Chronic pain 'chronic pain'/exp OR (chronic OR 'long term') NEXT/2 pain*

2 'chronic inflammatory pain'/de OR (chronic NEXT/3 pain*):ab,ti.

3 Combine sets for 

chronic pain

1 OR 2

4 LTOT ‘narcotics’/exp OR 'narcotic agent'/exp OR 'analgesia'/exp OR 'narcotic analgesic 

agent'/exp OR 'opiate'/de

5 opioid* OR opiod* OR opiate* OR oposal OR opon OR narcotic*

6 ‘morphine’/de OR ‘codeine’/de OR ‘fentanyl’/de

7 Oxymorphone OR tapentadol OR methadone OR fentanyl OR hydrocodone OR 

oxycodone OR codeine OR morphine OR hydromorphone OR tramadol

8 ‘pain’/exp AND 'drug therapy'/lnk AND opi*

9 Combine sets for 

opioids

4 OR 5 OR 6 OR 7 OR 8

10 Combine with chronic 9 AND (chronic:ti OR 'cot':ti OR chronic NEXT/1 opi* NEXT/1 therapy OR 

longterm:ti OR 'long term':ti OR months:ab,ti OR year*:ab,ti)

11 Combine chronic pain 

with LTOT

3 AND 10

12 Contraindications 

(KQ1)

‘drug contraindication’/exp OR ‘drug interaction’/exp OR ‘drug safety’/exp OR 

‘analgesics, opioid/contraindicaitons’
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Set 

Number Concept Search Statement

13 Compensation* OR contraindication* OR copd OR cardiovascular OR respiratory 

OR 'chronic obstructive' OR lung OR fibromyalgia OR headache* OR heart OR 

liver OR sleep OR osteoporosis OR cns OR immune OR gastrointestinal OR 

medic* NEAR/1 marijuana OR 'post-traumatic stress' OR ptsd OR 'traumatic 

brain' OR tbi OR 'substance use disorder' OR sud OR depression OR suicide OR 

suicidality OR (personality OR cognitive OR mental OR neuro*) NEXT/3 

(disorder* OR disease* OR illness*)

14 Combine 

contraindications

12 OR 13

15 Combine 

contraindications with 

chronic pain and LTOT

11 AND 14

16 Risk of misuse (KQ2) ('opiate addiction'/exp OR 'analgesic agent abuse'/exp OR 'opioid-related 

disorders'/exp) AND ('risk'/exp OR risk*:ab,ti)

17 'risk'/exp OR (risk* AND (predict* OR assess*))

18 (opi* OR narcotic* OR hydrocodone OR vicodin OR oxycodone OR oxycontin OR 

percocet OR heroin OR methadone OR morphine OR codeine OR analgesic*) 

NEXT/2 (addict* OR abuse OR misuse OR disorder OR diversion)

19 History of abuse 'domestic violence'/exp OR 'sexual abuse'/exp OR 'bullying'/exp OR bully OR 

bullying OR (domestic OR spous* OR child* AND (abuse OR violence))

20 Risk of opioid 

addiction 

17 AND (18 OR 19)

21 Combine risk sets 16 OR 20

22 Combine risk of 

misuse with chronic 

pain and LTOT

11 AND 21

23 Effectiveness and 

Safety of LTOT (KQs 3 

and 4)

'adverse drug events' OR 'ade' OR overdose OR diversion OR misuse OR addict* 

OR abuse OR adverse NEXT/1 event OR adverse NEXT/1 effect* OR accident* 

OR absence OR absent OR falls OR fall OR depression OR anxiety OR mood Or 

overdose* OR poison* OR death OR harm* OR disorder* OR sleep OR aberrant 

NEXT/3 behavior* OR complication* OR cardiovascular OR cardiac OR cognitive

24 'quality of life'/exp OR 'quality of life' OR qol OR pain NEXT/2 relief OR pain 

NEXT/2 reliev* OR ‘pain relief’

25 'prescription drugs'/exp AND ('adverse drug reaction'/lnk OR 'side effect'/lnk)

26 'treatment outcome'/de OR 'side effect'/de OR 'adverse drug reaction'/exp OR 

‘drug overdose’/ OR ‘adverse outcome’/exp OR ‘opiate addiction’/exp OR 

'patient safety'/exp OR safety OR effectiveness OR effective OR outcome*

27 Combine sets for 

safety

23 OR 24 OR 25 OR 26

28 Combine with chronic 

pain and LTOT

11 AND 27

29 Formulations (KQ5) 'narcotics'/exp OR 'narcotic agent'/exp OR 'analgesia'/exp OR 'narcotic analgesic 

agent'/exp OR 'opiate'/de

30 opioid* OR opiod* OR opiate* OR oposal OR opon OR narcotic* OR 

oxymorphone OR tapentadol OR methadone OR fentanyl OR hydrocodone OR 

oxycodone OR codeine OR morphine OR hydromorphone OR tramadol

31 'morphine'/de OR 'codeine'/de OR 'fentanyl'/de

32 'pain'/exp AND 'drug therapy'/lnk AND opi*
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Set 

Number Concept Search Statement

33 Combine sets for 

opioids

29 OR 30 OR 31 OR 32

34 'immediate release' OR 'extended release' OR 'short acting' OR shortacting OR 

sa OR 'long acting' OR longacting OR la OR 'controlled release' OR (short* OR 

long* OR immediate OR extended OR controlled OR sustained AND (release* OR 

act*)) OR ‘short acting analgesic agent’/exp OR (abuse-deterrant AND formula*)

35 33 AND 34

36 'opiate'/exp OR 'narcotics'/exp OR 'narcotic agent'/exp OR 'analgesia'/exp OR 

'narcotic analgesic agent'/exp OR 'opiate'/de OR morphine OR oxycodone OR 

oxymorphone OR opi* AND (controlled OR sustained OR extended)

37 Opioid formulations 35 OR 36

38 Combine with chronic 

pain and LTOT

11 AND 37

39 Added 

benzodiazepines (KQ6)

'benzodiazepine derivative'/exp OR 'benzodiazepine' OR benzodiazepine* OR 

'antidepressant agent'/exp OR 'hypnotic sedative agent'/exp OR 'narcotic 

analgesic agent'/exp OR 'benzodiazepine derivative'/exp OR 'zolpidem'/exp OR 

'zaleplon'/exp OR 'eszopiclone'/exp

40 'zolpidem' OR 'zaleplon' OR 'eszopiclone' OR ambien OR lunesta OR sonata OR 

benzodiazepine* OR antidepressant* OR 'anti-depressant' OR 'anti depressant' 

OR stimulant* OR 'z drug' OR 'z drugs' OR hypnotic* OR psychoactive*

41 prescription* AND (otc OR 'over the counter') AND (multiple* OR added OR 

additional OR several OR concomitant)

42 'prescription drug'/exp AND 'non prescription drug'/exp OR 'polypharmacy'/exp

43 Combine medicine 

sets

38 OR 39 OR 40 OR 41

44 'treatment outcome'/de OR 'side effect'/de OR 'adverse drug reaction'/exp OR 

'patient safety'/exp OR safety OR effectiveness OR effective OR outcome*

45 Combine with 

outcomes

42 AND 43

46 Combine with chronic 

pain and LTOT

11 AND 45

47 Risk mitigation for 

addiction (KQ7)

'opiate addiction'/exp OR ‘substance abuse’/exp OR

‘drug monitoring’/exp OR ‘prescription drug diversion’/exp OR ((addict* OR 

abuse OR misuse OR diversion OR divert) AND (opi* OR oxymorphone OR 

tapentadol OR methadone OR fentanyl OR hydrocodone OR oxycodone OR 

codeine OR morphine OR hydromorphone OR tramadol))

48 urin* NEXT/7 (screen* OR test* OR detect* OR anal* OR monitor*) OR 

‘urinalysis’/exp

49 pill NEXT/2 count OR 'call back' OR database OR query OR compliance OR 

contract* OR agreement OR consent OR recall OR surveillance OR call-back OR 

monitor* OR naloxone NEXT/2 rescue

50 'patient compliance'/exp OR (patient:ab,ti AND (compliance:ab,ti OR 

comply:ab,ti))

51 'patient education'/exp OR patient NEXT/3 (aware* OR educat*)

52 (office OR doctor OR primary) NEXT/3 (visit* OR appointment* OR check*)

53 'contracts'/exp OR opi* NEXT/5 (contract OR contracts OR agreement)
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Set 

Number Concept Search Statement

54 Risk* NEXT/7 (mitigate* OR reduc*) OR ‘risk’/exp OR ‘risk reduction’/exp OR 

‘risk evaluation and mitigation strategy’ OR ‘naloxone’/exp OR naloxone OR 

rescue OR precaution*

55 Combine risk 

mitigation strategies

47 OR 48 OR 49 OR 50 OR 51 OR 52 OR 53 OR 54

56 Combine with chronic 

pain and LTOT

11 AND 55

57 Treatment of OUD 

(KQ8)

addict* OR abuse OR misuse OR disorder AND (opi* OR oxymorphone OR 

tapentadol OR methadone OR fentanyl OR hydrocodone OR oxycodone OR 

codeine OR morphine OR hydromorphone OR tramadol) OR ‘opiate use 

disorder’

58 'opiate addiction'/exp OR 'analgesic agent abuse'/exp OR ('drug abuse'/exp OR 

'drug dependence'/exp OR 'narcotic dependence'/exp OR 'addiction'/exp OR 

aberrant:ti OR aberrant:ab AND ('narcotic analgesic agent'/exp OR 'opiates'/exp 

OR opioid* OR oxymorphone OR tapentadol OR methadone OR fentanyl OR 

hydrocodone OR oxycodone OR codeine OR morphine OR hydromorphone OR 

tramadol OR analgesic*))

59 'psychotherapy'/exp OR 'cognitive therapy'/exp OR 'counseling'/exp OR 

'acceptance and commitment therapy'/exp OR 'support group'/exp OR 

'motivational interviewing'/exp

60 counsel OR counseling OR (cognitive OR contingency OR drug OR behavioral OR 

motivational) NEAR/2 (counseling OR therapy) OR 'contingency management' 

OR motivation* NEAR/1 interview* OR buprenorphine OR naloxone OR 

methadone

61 Combine opioid 

addiction set

57 OR 58

62 Combine counsel set 59 OR 60

63 Combine with chronic 

pain and LTOT

11 AND 61 AND 62

64 Tapering (KQ9) 'pain management'/exp OR 'analgesia'/exp AND ('drug administration'/exp OR 

'clinical protocol'/exp)

65 ‘dose response’/exp OR ((dose OR dosing) AND (protocol* OR administration OR 

plan* OR schedule* OR strategy OR strategies))

66 (taper* OR decrease* OR reduc* OR adjust* OR titrat* OR dosing OR dose*) 

AND (protocol* OR administration OR plan* OR schedule* OR strategy OR 

strategies)

67 Combine tapering sets 64 OR 65 OR 66

68 Combine with chronic 

pain and LTOT

11 AND 67

69 Combine all final sets 15 OR 22 OR 28 OR 38 OR 46 OR 56 OR 63 OR 68

70 Apply limits 69 AND [2009-2016]/py AND [English]/lim AND [humans]/lim

71 Apply unwanted 

publication types

70 NOT ('conference abstract'/it OR 'conference paper'/it OR 'editorial'/it OR 

'letter'/it OR 'note'/it OR 'short survey'/it)

72 Apply trials hedge 71 AND (random*:ab,ti OR trial* OR control* OR cohort OR compar*:ab,ti OR 

prospective OR retrospective OR series OR review* OR study OR studies OR 

method* OR analysis OR systematic*:ab,ti)
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Set 

Number Concept Search Statement

73 71 AND ('clinical trial'/exp OR 'clinical trial (topic)'/exp OR 'longitudinal 

study'/exp OR 'major clinical study'/exp OR 'prospective study'/exp OR 

'retrospective study'/exp OR 'controlled clinical trial'/exp OR 'controlled clinical 

trial (topic)'/exp OR 'randomized controlled trial'/exp OR ‘randomized controlled 

trial’/de OR 'comparative study'/exp OR 'methodology'/exp)

74 71 AND (‘meta analysis’/de OR 'meta analysis (topic)'/exp OR 'meta 

analysis'/exp OR 'outcomes research'/exp OR 'systematic review'/exp OR 

'systematic review (topic)'/exp OR ‘systematic review’/de OR 'meta? 

analysis':ab,ti OR 'systematic review':ab,ti)

75 Combine 72 OR 73 OR 74

EMBASE.com Syntax:

* (within or following a term) = truncation character (wildcard)

:ab = limit to abstract

:ab,ti = limit to abstract and title

NEAR/n = search terms within a specified number (n) of words from each other in any order

/exp = “explodes” controlled vocabulary term (e.g., expands search to all more specific related terms 

in the vocabulary’s hierarchy)

:it. = limit to publication type 

:ti. = limit to title 
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Appendix K: Abbreviation List

Abbreviation Definition

0F degrees Fahrenheit

AAAP American Academy of Addiction Psychiatry

AAPM American Academy of Pain Medicine

AHRQ Agency for Healthcare Research and Quality

AIDS acquired immunodeficiency syndrome

AMA American Medical Association

AOR adjusted odds ratio

APAP acetaminophen

APTA American Physical Therapy Association

ARR adjusted risk ratio

ASA acetylsalicylic acid

ASAM American Society of Addiction Medicine

BID two times per day

BPI Brief Pain Inventory

CARF Commission on Accreditation of Rehabilitation Facilities

CBT Cognitive Behavioral Therapy

CDC Centers for Disease Control and Prevention

CENTRAL The Cochrane Central Register of Controlled Trials

CI confidence interval

CNCP chronic non-cancer pain

CNS central nervous system

COI conflict of interest

COPD chronic obstructive pulmonary disease

COR contracting officer's representative

CPG clinical practice guideline

CS clinical study

DATA 2000 Drug Addiction Treatment Act of 2000

DEA Drug Enforcement Administration

dL deciliter(s)

DoD Department of Defense

DSM-IV Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition

DSM-5 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition

EBPWG Evidence-Based Practice Work Group

ECG electrocardiogram

EDDP 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine

EMR electronic medical record

FDA Food and Drug Administration

FY fiscal year

GCMS gas chromatography- mass spectrometry
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Abbreviation Definition

GI gastrointestinal

GRADE Grading of Recommendations Assessment, Development and Evaluation

HHS U.S. Department of Health and Human Services

HIV human immunodeficiency virus

HR hazard ratio

hr hour

IOM Institute of Medicine

IRR incidence rate ratios

KQ key question

LCMS liquid chromatography-mass spectrometry

LOT long-term opioid therapy

m meter(s)

M3G morphine-3-glucuronide

M6G morphine-6-glucuronide

MAOI monoamine oxidase inhibitor

MAT medication assisted treatment

mcg microgram(s)

MDA 3,4-methylenedioxy-amphetamine

MDEA 3,4-methylenedioxy-N-ethyl-amphetamine

MDMA 3,4-methylenedioxy-methamphetamine

MEDD morphine equivalent daily dose

MeSH Medical Subject Headings

mg milligram(s)

MHS Military Health System

mL milliliter(s)

MRI magnetic resonance imaging

NICE National Institute for Health and Care Excellence

NSAIDs non-steroidal anti-inflammatory drugs

OA osteoarthritis

OEF Operation Enduring Freedom

OEND Opioid Overdose Education and Naloxone Distribution

OIF Operation Iraqi Freedom

OR odds ratio

OSI Opioid Safety Initiative

OTC over the counter

OTRR Opioid Therapy Risk Report

OUD opioid use disorder

PDMP Prescription Drug Monitoring Program

PICOTS population, intervention, comparison, outcome, timing, and setting

PPACA Patient Protection and Affordable Care Act
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Abbreviation Definition

PRN as needed

PTSD posttraumatic stress disorder

QTc interval the heart rate’s corrected time interval from the start of the Q wave to the end of the T 

wave

RCT randomized controlled trial

REMS Risk Evaluation and Mitigation Strategy

SA sustained action

SAMHSA Substance Abuse and Mental Health Services Administration

SE standard error 

SL sublingual

SMART Specific, Measurable, Action Oriented, Realistic, Timed 

SNRIs serotonin-norepinephrine reuptake inhibitors

SR sustained release

SSRI selective serotonin reuptake inhibitor

STORM Stratification Tool for Opioid Risk Mitigation

SUD substance use disorders

THC tetrahydrocannabinol

THCA delta-9-tetrahydrocannabinol-9-carboxylic acid

TID three times per day

U.S. United States

UDT urine drug testing (or urine drug test)

USPSTF United States Preventive Services Task Force

UTS urine toxicology screening

VA Department of Veterans Affairs

VHA Veterans Health Administration
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References

1. U.S. Department of Veteran Affairs, Department of Defense. Guideline for guidelines. Veterans 

Health Administration, Office of Quality & Performance, Evidence Review Subgroup; Revised April 

10, 2013.

2. Society for Medical Decision Making Committee on Standardization of Clinical Algorithms. 

Proposal for clinical algorithm standards. Med Decis Making. Apr-Jun 1992;12(2):149-154.

3. Institute of Medicine Committee on Advancing Pain Research, Care Education. The National 

Academies Collection: Reports funded by National Institutes of Health. Relieving pain in America: A 

blueprint for transforming prevention, care, education, and research. Washington (DC): National 

Academies Press (US); 2011.

4. Daubresse M, Chang HY, Yu Y, et al. Ambulatory diagnosis and treatment of nonmalignant pain in 

the United States, 2000-2010. Med Care. Oct 2013;51(10):870-878.

5. Paulozzi LJ, Mack KA, Hockenberry JM. Vital signs: Variation among states in prescribing of opioid 

pain relievers and benzodiazepines - United States, 2012. MMWR Morb Mortal Wkly Rep. Jul 4 

2014;63(26):563-568.

6. Kea B, Fu R, Lowe RA, Sun BC. Interpreting the National Hospital Ambulatory Medical Care Survey: 

United States emergency department opioid prescribing, 2006-2010. Acad Emerg Med. Feb 

2016;23(2):159-165.

7. Hoppe JA, Nelson LS, Perrone J, Weiner SG. Opioid prescribing in a cross section of US emergency 

departments. Ann Emerg Med. Sep 2015;66(3):253-259.e251.

8. Chou R, Turner JA, Devine EB, et al. The effectiveness and risks of long-term opioid therapy for 

chronic pain: A systematic review for a National Institutes of Health Pathways to Prevention 

workshop. Effectiveness and risks of long-term opioid therapy for chronic pain. Annals of Internal 

Medicine. 2015;162(4):276-286.

9. Baldini A, Von Korff M, Lin EH. A review of potential adverse effects of long-term opioid therapy: A 

practitioner's guide. Prim Care Companion CNS Disord. 2012;14(3).

10. Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Prescription of long-acting opioids and mortality 

in patients with chronic noncancer pain. JAMA. Jun 14 2016;315(22):2415-2423.

11. Reuben DB, Alvanzo AAH, Ashikaga T, et al. National Institutes of Health Pathways to Prevention 

workshop: The role of opioids in the treatment of chronic painthe role of opioids in the treatment 

of chronic pain. Annals of Internal Medicine. 2015;162(4):295-300.

12. Vital signs: Overdoses of prescription opioid pain relievers---United States, 1999--2008. MMWR 

Morb Mortal Wkly Rep. Nov 4 2011;60(43):1487-1492.

13. Deer TR, Gunn J. Blood testing in chronic pain management. Pain Physician. Mar-Apr 

2015;18(2):E157-161.

14. Centers for Disease Control and Prevention. Fatal injury reports, national and regional, 1999 - 

2015. 2015; https://webappa.cdc.gov/sasweb/ncipc/mortrate10_us.html. Accessed January 6, 

2017.

15. Substance Abuse and Mental Health Services Administration, Center for Behavioral Health 

Statistics and Quality. Behavioral health trends in the United States: Results from the 2014 National 

Survey on Drug Use and Health. 2015; http://www.samhsa.gov/data/sites/default/files/NSDUHFRR1-2014/NSDUH-FRR1-2014.pdf. 

16. Center for Disease Control and Prevention, National Center for Health Statistics, National Vital 

Statistics System, Mortality File. Number and age-adjusted rates of drug-poisoning deaths 

involving opioid analgesics and heroin: United States, 2000–2014. 2015; 

http://www.cdc.gov/nchs/data/health_policy/AADR_drug_poisoning_involving_OA_Heroin_US_2

000-2014.pdf 
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17. Rudd RA, Aleshire N, Zibbell JE, Gladden RM. Increases in drug and opioid overdose deaths - 

United States, 2000-2014. MMWR Morb Mortal Wkly Rep. 2016;64(50-51):1378-1382.

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