Turning the Tide of Chronic 

Opioid Therapy

William C. Becker, MD

Assistant Professor, General Internal Medicine

VA Connecticut Healthcare System

Yale University School of Medicine
DISCLOSURE & ACCREDITATION

I have no conflicts of interest related to the content of 

this presentation.

 
Outline

• Chronic pain: pathophysiology and epidemiology

• Opioids:

– Pharmacology, role in chronic non-cancer pain

– Evidence base

– Prescribing trends 

• Guidelines in chronic opioid therapy 

• Next steps aimed at improving quality of care 
Case #1

29-year-old man with recent back surgery for large 

intervertebral disk herniation referred for evaluation of possible 

opioid use disorder/addiction.

CC: ongoing sciatica, low back pain. 

PMHx: PTSD

Pertinent data: 

– Morphine SA 30 mg TID with oxycodone IR 5-10 mg q4 

hours; run out early twice 

– Non adherent to sertraline, mental health appointments

– Sedentary but intermittent high intensity activity

ROS: Insomnia, nightmares, agitation, inability to sit through 

classes, considering withdrawal from school
Case #2

70-year-old man with severe spinal stenosis, b/l hip/knee 

osteoarthritis referred for 2nd opinion about opioid regimen

CC: increasing frequency of low back pain paroxysms

PMHx: COPD, OSA on CPAP, obesity

Pertinent data:

– Oxycodone IR 10 mg four times a day for 3 years

– Requests a dose increase

– Lives independently, active socially in the Elks and the 

Moose clubs. Collects hats, enjoys traditional Hungarian 

dance but currently slowed by pain.

PCP worried about potential consequences of dose escalation; 

wonders if long-acting agents would be more appropriate.
Outline

Chronic pain: pathophysiology and epidemiology

Opioids:

– Pharmacology, role in chronic non-cancer pain

– Evidence base

– Trends in pharmacoepidemiology

Guidelines in chronic opioid therapy

Next steps aimed at improving quality of care

•

•

•

•
Acute pain

von Hehn CA et al. Neuron 2012
Chronic inflammatory pain 

Adapted from von Hehn CA et al. Neuron 2012
Chronic pain: neuronal plasticity

and central sensitization

Neuronal plasticity

Peripheral nerve injury  recruitment of macrophages and glial 

cells  dysregulated nerve regeneration of both AΒ and c-fibers 

Central sensitization

Excess of AΒ and c-fibers in dorsal horn  compensatory 

changes to NMDA receptors  

lowered pain thresholds

Woolf CJ. Pain 2011
Chronic pain: hyperalgesia and allodynia

C-fiber

AΒ-fiber

C-fiber

AΒ-fiber

Woolf CJ. Pain 2011
Complexity of chronic pain

Deardorff, WW. APA 2008.
Chronic pain: ubiquitous and costly

• Point prevalence: 25% in U.S. adults; 10% with disabling 

chronic pain that limits work and family activity

• Second most common reason for outpatient visits

• Annual national economic cost estimated up to $635 billion

• 2011: Five of U.S.’ 133 medical schools had 

mandatory course on pain
Outline

• Pain: pathophysiology and epidemiology

• Opioids:

– Pharmacology, role in chronic non-cancer pain

– Evidence base

– Prescribing trends

• Guidelines in chronic opioid therapy 

• Next steps aimed at improving quality of care 
Opiates 

• Naturally present in opium from seedpod 

of Papaver somniferum

• Morphine, codeine

Opioids

• Manufactured

• Semi-synthetics: hydrocodone, 

hydromorphone

• Synthetics: fentanyl, methadone

Opioid analgesics (opiates + opioids)

Morphine equivalent dose

• Method of standardizing potency across various opioid 

compounds 

• Based on equianalgesic tables from dose ranging studies

• Example:

20 mg oxycodone TID 

= 

90 mg morphine 

equivalent daily dose

Equianalgesic 

dose (MG)

Opioid

(oral)

30 Morphine

7.5 Hydromorphone

20 Oxycodone

30 Hydrocodone
Activation of mu receptors
Opioids: undisputed indications

End-of-life 

related pain

... (T. Lauder Brunton, 1899)

Acute pain 

WHO. Cancer Pain Relief. 1986
Opioids & chronic non-cancer pain
Sequelae of long-term opioids

Tolerance  higher doses required to achieve same analgesic 

effect over time

• High prevalence

• Also develops to some of the toxic effects

Withdrawal  characteristic symptoms upon abrupt cessation or 

lowering of opioid dose

Opioid-induced hyperalgesia  paradoxical worsening of pain 

with higher doses

• Prevalence unknown

• Correlation with total opioid exposure (dose x time)
Mu receptors and reward pathways
Opioid use disorder (DSM-V)

Physiologic sequelae

• Tolerance 

• Withdrawal 

• Opioid craving

Loss of control

• Greater amounts of use or longer 

period of use than intended 

• Persistent desire but unsuccessful 

efforts to cut down

• Inordinate amount of time 

obtaining, using, or recovering

 

Adverse consequences

Summary of 5 criteria:

• Important social, occupational or 

recreational activities given up or 

reduced due to opioid use or 

recurrent opioid use despite 

physical or psychological 

problems caused or worsened by 

use
Other important toxicities

• Constipation

• Itching 

• Nausea/vomiting 

• Hypogonadism 

• Opioid-induced hyperalgesia

• Sedation

• Impaired cognition

• Falls/motor vehicle accidents

• Blunted respiratory drive

• Non-fatal and fatal overdose
Odds of overdose by increasing dose 

Dunn Gomes Bohnert

Dose* 

(mg/day) HR (95% CI) OR (95% CI) HR (95% CI)

1-<20 1.00 (REF) 1.00 (REF) 1.00 (REF)

20-<50 1.2 (0.4-3.6) 1.3 (0.9-1.8) 1.9 (1.3-2.7)

50-<100 3.1 (1.0-9.5) 1.9 (1.3-2.9) 4.6 (3.2-6.7)

≥100 or 

100-199 11.2 (4.8-26.0) 2.0 (1.3-3.2) 7.2 (4.9-10.7)

≥200 2.9 (1.8-4.6)

*morphine equivalent

Dunn et al. Annals IM 2010; Gomes et al. Archives IM 2011; Bohnert et al. JAMA 2011 

Slide courtesy of JW Frank, MD, MPH
Opioids for chronic pain: important 

limitations

• Central sensitization may not be responsive to opioids

• Chronic pain has prominent psychological component; unclear 

role for opioids

• Long term therapy induces tolerance, necessitating higher 

doses

• Higher doses chronically  increased risk of opioid-induced 

hyperalgesia

• Higher doses  increased risk of toxicity, both acute and 

chronic 
Evidence base: opioids for chronic 

non-cancer pain
Opioids for chronic low back pain

Martell, BA et al. Ann Intern Med. 2007 
Evidence for long-term use

• RCTs, non-randomized trials, pre-post case series, variety of 

pain conditions examining outcomes ≥ 6 months:

• “Despite the identification of 26 treatment groups with 4768 

participants, the evidence regarding the effectiveness of longterm opioid therapy in chronic non-cancer pain is too sparse 

to draw firm conclusions...”

• Medium effect size in study completers, but they were small 

proportion of sample

• No long-term studies included functional outcomes

Noble, M. The Cochrane Collaboration. 2010 
Increase in opioid prescription

0

20

40

60

80

100

120

140

Hydrocodone Oxycodone Morphine Methadone Hydromorphone

Source: Automation of Reports and Consolidated Orders System, US DEA, slide adapted from A Gilson

Opioid sales (mg per person)

Silverberg MJ, Clin J Pain, 2012; Hansen L, J Pain Sympt Mgmt 2011
Similar trends in VA

Becker, WC et al. SGIM National Meeting. 2013. 
Increases in high-dose and long-term 

prescribing 

Becker, WC et al. SGIM National Meeting. 2013. 
0

2

4

6

8

10

'70 '74 '78 '82 '86 '90 '94 '98 '02 '06

Death rate per 100,000

38,329 drug overdose deaths in 2010

National Vital Statistics System, http://wonder.cdc.gov

Year 

Trends in opioid overdose death

16,651 (43%) involved opioid analgesics
How did we get here?

• Public health campaigns against pain

• Aggressive & sometimes deceptive marketing

• Extrapolation from cancer/acute pain data 

• Purdue pharma officials found guilty of misbranding; 

fined $600 million

• Clinical inertia
Outline

• Pain: pathophysiology and epidemiology

• Opioids:

– Pharmacology, role in chronic non-cancer pain

– Evidence base

– Trends in pharmacoepidemiology

• Guidelines in chronic opioid therapy

• Next steps aimed at improving quality of care
Key summary points:

• “Clinicians may consider a trial of chronic opioid therapy if 

chronic non-cancer pain is moderate or severe, pain is having 

an adverse impact on function or quality of life, and potential 

therapeutic benefits outweigh or are likely to outweigh 

potential harms (strong recommendation, low-quality 

evidence).”

• Multi-modal care

• Structured monitoring: Continue if safe and effective, 

discontinue if unsafe or ineffective
Gaps in the guidelines

• How do we systematically assess harm and benefit?

• What do we do once harm or absence of benefit is 

identified?

– Discontinuation protocols

– Alternative treatment options 

• What about dose?
Monitoring is lax

In a cohort of 1600+ patients on long-term opioids in primary 

care followed for up to 4 years:

• 7%  at least one urine drug test

• 49%  regular office visits

• 74%  limited early refills

Becker, WC et al. Annals of Family Medicine. 2011. 
Opioid discontinuation is rare

Martin, BC et al. JGIM. 2011.
Outline

• Pain: pathophysiology and epidemiology

• Opioids:

– Pharmacology, role in chronic non-cancer pain

– Evidence base

– Trends in pharmacoepidemiology

• Guidelines in chronic opioid therapy

• Next steps aimed at improving quality of care
Transforming VA Pain Care

The Six Essential Elements of Good Pain Care 

1. Educate Veterans/families to promote self-efficacy and shared 

decision making; provide access to relevant resources

2. Educate/train all team members to discipline specific 

competencies, including team based care 

3. Develop and integrate non-pharmacological modalities into care 

plans

4. Institute rational medication prescribing, use of pain procedures 

and safe opioid use 

5. Implement approaches for bringing the Veteran’s whole team 

together and for maintaining ongoing communication 

6. Establish metrics to monitor pain care and outcomes at both the 

individual level and the population level
Clinical research agenda

How do we systematically assess harm and benefit?

Develop an easy-to-use monitoring algorithm

What do we do once harm or absence of benefit is 

identified?

Design and test alternative treatment strategies

What about dose?

Inform guidelines on dose and duration limits

•

 

•

•

Becker WC et al. JGIM 2013
Develop an easy-to-use monitoring 

algorithm

• Starting point: brief patient-reported checklist assessing 

opioid safety, efficacy, misuse

• Universal use of treatment agreements

• Routine access to prescription monitoring programs

• Routine, judicious use of urine drug testing

Becker, WC. VA Health Services Research and Development CDA-2 (08-276) 
Brief checklist development

• Systematic review of other instruments:

– Too long, lacked safety/efficacy items

– Not validated in actual clinical care

• Safety, efficacy, misuse of opioids; 10 items or fewer

• Patient self-report, self-administered

• Every patient, every visit and perhaps between visits

• Any item endorsed should prompt clinician follow-up

Becker, WC et al. Pain 2013
Opioid treatment agreement

• Written document outlining goals of therapy, plan of care, and 

expectations for safe opioid use

• Goals: focus on function

Specific

Measureable 

Action-oriented

Realistic 

Timebound

• Frequently revisited

• When necessary, cite as evidence that harm is outweighing 

benefit of therapy
Treatment agreements reduce opioid misuse

0

10

20

30

40

50

60

Aberrant

medication

taking

behavior

Multiple

sources

Multiple

sources

Illicit drug use

Before After

Starrels, Becker et al. Ann Int Med 2010. Patients with misuse (%)
Prescription drug monitoring 

program (PDMP)

• Listing of all controlled substances filled by patient in the 

state; pharmacy reporting is state law

• Allows prescribers to track multiple fills or “doctor shopping”

• Need a DEA# to register

• Can also query yourself (as prescriber)

• Population-level data equivocal on benefit

• Prescriber level qualitative data  increased provider comfort 

and confidence
Have an exit strategy

• Treatment agreement:

– Duration of therapy and discontinuation plan

– Plan regarding dose

– What will happen if opioids are not effective

– What will happen if treatment agreement is not followed 

(e.g. taper, immediate discontinuation, transition to 

alternative treatments)
Design and test alternative 

treatment strategies
IOM’s vision for multimodal 

chronic pain care

Behavioral 

therapies

Physical

activation

Rational 

pharmaco

therapy

SELF CARE SELF EFFICACY

Promotion of Healthy Behaviors Addressing Co-Morbidities

Integrated Health System
Evidence-based non-pharmacologic 

treatments for chronic pain

Physical activation

• Low intensity aerobic exercise

• Physical therapy

• Yoga

• Tai Chi

• Aquatherapy 

Behavioral treatments

• Cognitive behavioral therapy 

• Mindfulness/meditation 

• Progressive muscle relaxation

• Biofeedback

Other techniques

• Massage

• Chiropractic 

• Acupuncture 

• Trigger point injections

• Botox injections 

• Intra-articular steroid injection

• TENS 

• Nerve blocks
Making “multi-modal” a reality 

• Integrated Pain Clinic: 2-hour, multi-disciplinary pain 

assessment (Health Psychology, Pain Medicine, Physiatry, 

Physical Therapy)

• Opioid Reassessment Clinic: longitudinal multi-disciplinary 

assessment and treatment (Addiction Psychiatry, Health 

Psychology, Internal Medicine) 

• Educational programming for PCPs: how to communicate and 

enhance motivation for multi-modal care
Novel pharmacotherapies
Buprenorphine: a partial mu agonist

100

90

80

70

60

50

40

30

20

10

0 

% 

Opioid dose

Full Agonist

Partial Agonist

(Buprenorphine)

Full Antagonist

Opioid 

effect: 

sedation, 

respiratory 

depression
Potential roles for buprenorphine

• First-line therapy for chronic non-cancer pain

• Assist with transition off of full agonist opioids when:

– Maximum duration reached

– Full agonists ineffective

– Intolerable side effects (e.g. over sedation)
SNRIs, gabapentanoids, 

?cannabinoids

Source: http://www.rationalprescribing.com/ 
Dose and adverse events
Veterans Aging Cohort Study

• Prospective, observational cohort study of HIV(+) and 

demographically matched HIV(-) veterans in the US 

• Examines role of comorbid disease in determining clinical 

outcomes in HIV infection

• Harnesses robust VA electronic health record: laboratory, 

pharmacy, diagnostic data over 14 years

• Opioids Workgroup
Opioids workgroup analyses

• Demographic and clinical correlates of any, high dose, long term 

opioid receipt (Edelman et al, JGIM 2012)

• 12-year trends analysis

• Next steps:

– Opioids and polypharmacy (D. Weisberg) 

– Association between opioid dose and important adverse 

effects:

• Falls, factures

• Sleep-disordered breathing

• Non fatal, fatal overdose

– Collaborating with VA national medication quality and safety 

office
Back to the cases...
29-year-old man 5 months after back surgery, chronic low-back 

pain on morphine long-acting with oxycodone for breakthrough; 

has run out early twice. 

Assessment: 

Case #1

1) Opioid use disorder: tolerance, withdrawal, craving, adverse 

consequences (withdrawal from school)

2) Poorly controlled pain and non-engagement with multimodal 

pain treatment plan

Treatment recommendations/plan:

Transition to buprenorphine, SA counseling

Motivational enhancement to reengage with PTSD treatment 

and physical therapy.

Gabapentin added.

Vocational counseling; Case worker assigned.
70-year-old man with severe spinal stenosis, generalized 

osteoarthritis, on oxycodone 10 mg four times a day for 3 years; 

efficacy has waned. 

Assessment:

Case #2

1) Opioid tolerance

2) Unable to achieve functional goals despite engagement in 

multimodal therapy

Treatment recommendations:

10%-20% dose increase  still results in moderate dose therapy 

Continue to encourage appropriate coping strategies

Avoid >20% dose increase and/or switch to long-acting 

formulation

 
Summary

• Despite physiologic limitations and modest evidence of 

efficacy, opioid prescribing for chronic pain has skyrocketed.

• Guidelines regarding chronic opioid therapy may not curtail 

current trends.

• Improved monitoring tools, discontinuation protocols and 

alternative treatment strategies are needed to improve safety 

and efficacy of chronic pain treatment.

• Dose and duration limits are needed to decrease opioid 

exposure.
Thank you

Robert Kerns

Liana Fraenkel

David Fiellin

VA HSR&D

Opioid Reassessment Clinic team @ VACHS

Integrated Pain Clinic team @ VACHS

Amy Justice and the Opioids Workgroup of VACS

Nancy Wiedemer and Mac Gallagher of PVAMC

VA Painiacs