Managing Side Effects and Complications of Opioid Therapy for Chronic Pain

This fact sheet accompanies the 2017 VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain and was created to aid with 

treatment of adult populations. Department of Veterans Affairs (VA) and Department of Defense (DoD) employees who use this information 

are responsible for considering all applicable regulations and policies throughout the course of care and patient education. The goal of 

this factsheet is to explain how to properly manage side effects of opioid therapy (OT) in DoD and VA primary care settings. Co-occurring 

conditions and side effects are common consequences of OT, and may occur during both short-term and long-term opioid therapy (LOT). 

Risk Mitigation

The greatest risk factors for the development of opioid-related 

adverse events are the duration and dose of opioid analgesic use.1

Many other factors also increase the risk of adverse outcomes 

and must be considered when prescribing opioid medications (see 

Significant risk factors).

Providers should consider and implement risk mitigation strategies 

before prescribing opioid medications. The provider should discuss 

the potential risks and benefits as well as alternative therapies with 

the patient and if possible, obtain the patient’s informed consent 

regarding the patient care plan, including risk mitigation strategies. 

Risk mitigation strategies may include:

 Ongoing random urine drug testing and appropriate 

confirmatory testing

 Frequent face-to-face follow-up appointments to assess for 

co-occurring conditions and side effects

 Monitoring for overdose potential and suicidality

 Providing overdose education, including prescribing of 

naloxone rescue

 Checking state prescription drug monitoring programs

Evaluation of the benefits of continued opioid therapy and risk for 

opioid-related adverse events every three months (at a minimum) 

is recommended.

Clinical reminders: 

 Evaluate risk factors for opioid-related harms

 Conduct a suicide risk assessment and intervene when necessary 

 Check the Prescription Drug Monitoring Program (PDMP) for high dosages and prescriptions from other providers 

 Use urine drug testing to identify prescribed substances and undisclosed use

 Refer for opioid use disorder treatment if indicated

Avoid prescribing concurrent benzodiazepines and opioids

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)

 Traumatic brain injury 

 Mental disorders 

 Current or history of substance use disorder (SUD) (untreated 

SUD confers additional risk) 

 Depression or history of depression2

 Generalized anxiety disorder 

 Borderline personality disorder 

 Antisocial personality disorder 

 Posttraumatic stress disorder (PTSD)

 History of drug overdose 

 Under 30 years of age

 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 

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

 True allergy to opioid agents (that cannot be resolved by 

switching agents)

 Co-administration of a drug capable of inducing fatal drugdrug interactions
Spectrum of Side Effects

Carefully consider side effects (e.g., depression, weight gain, headaches, nightmares, problems with intimacy, paresthesias) during monitoring and 

adjust treatment in order to minimize the side effects pursuant to individual patient preferences. Slower initiation and titration improves tolerability. 

Managing Adverse Effects

It is imperative that providers discuss possible adverse effects of OT with patients and family members. If adverse effects are unmanageable 

and therapy is a greater detriment than benefit as determined by discussion with the patient and family, OT should be discontinued. See the 

chart below for more information on some of the potential adverse effects.

Adverse Effects Symptoms Protocol for Management

Respiratory 

depression

 Drowsiness

 Slow or shallow breathing

 Difficulty staying awake

 Difficulty awakening

 Loud or unusual snoring

 Administer the lowest effective opioid dose necessary to achieve satisfactory pain control – 

start low and go slow

 Avoid other central nervous system (CNS) depressants, especially benzodiazepines 

 because this combination has been identified in opioid-related deaths

 Alert family members or caretakers of the important warning signs to watch for that may 

indicate that the opioid should be decreased or stopped:

 Difficult or slow breathing

 Difficulty staying awake

 Loud or unusual snoring

 Difficulty being awakened

Mental status 

changes

 Confusion

 Bad dreams

 Hallucinations

 Restlessness

 Agitation

 Dysphoria

 Significantly depressed level of 

consciousness

 Seizures

 Evaluate underlying cause; consider role of primary therapy – hallucinations can be due to a 

variety of causes, including change in surroundings and sleep deprivation

 Evaluation of hallucinations is often performed by “trial and error” techniques – eliminate 

nonessential CNS-acting medications (e.g., steroids)

 Re-evaluate and treat underlying process if appropriate

 Dysphoria is more common with mixed opioid agonists/antagonists and antidopaminergic 

medications

 If hallucinations persist:

 Consider a trial of an antipsychotic in consultation with behavioral health specialty, or

 Switch to another opioid

Opioid-induced 

endocrinopathy

 Loss of libido

 Impotence

 Fatigue

 Mood alterations

 Loss of muscle mass and 

strength

 Abnormal menses

 Infertility

 Ask all patients on opioids about symptoms of opioid-induced endocrinopathy 

(e.g., hypogonadism) 

 Determine cause of symptoms through lab work and/or consultation with an endocrinologist

 For males, consider testosterone patch therapy, as research indicates it may 

improve androgen deficiency symptoms, sexual function, mood, depression and hematocrit 

levels

 NOTE: There is insufficient data to recommend routine laboratory screening for endocrinopathy 

in asymptomatic patients on OT

Severe respiratory 

instability or sleep 

disordered

breathing (sleep 

apnea or COPD)

 Loud snoring

 Excessive daytime sleepiness

 Fatigue

 Morning headaches (cerebral 

vasodilation)

 Depression and/or emotional 

instability

 Short-term memory loss

 Impaired concentration

 Irregular pauses in breathing

 Strongly consider discontinuing OT and obtain sleep studies

 The type of sleep apnea should be evaluated to determine if it is obstructive or central

 Central sleep apnea is a relative contraindication to OT, and discontinuation of OT should be 

considered if sleep apnea is severe or life-threatening

 Instruct patients to avoid alcohol and medications that cause drowsiness

References

1 Opioid Therapy for Chronic Pain Working Group, Department of Veterans Affairs & Department of Defense. (2017). VA/DoD Clinical Practice Guideline for Opioid 

Therapy for Chronic Pain. Version 3.0. Retrieved from https://www.healthquality.va.gov/guidelines/Pain/cot/VADoDOTCPG022717.pdf

2 Management of Major Depressive Disorder Working Group, Department of Veterans Affairs & Department of Defense. (2016). VA/DoD Clinical Practice Guideline for 

the Management of Depressive Disorder. Version 3.0. Retrieved from http://www.healthquality.va.gov/guidelines/MH/mdd/VADoDMDDCPGFINAL1.pdf

Updated June 2017 by Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury

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