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Opioids are important in the treatment of acute and chronic pain in non-cancer and cancer patients. Opioid prescribing is often limited by concerns regarding the development of addiction, opioid misuse, overdose and death. Additionally there is often misunderstanding of addiction, tolerance and physical dependence. As a result, pain is often undertreated and individuals may be stigmatized for their legitimate use of opioids.1

  1. Opioids refer to substances that act on opioid receptors; an “opiate” is derived from the opium poppy.
  2. Narcotics refer to any substances federally regulated by the Drug Enforcement Agency (DEA).
  3. Addiction, also known as opioid use disorder, is defined as the inability to reduce or control drug use, coupled with continued use despite harm, social problems, and failure to fulfill major role obligation at work school or home.1,23
  4. Pseudoaddiction refers to drug-seeking behavior by patients who have severe pain and include taking medications in larger amounts than prescribed, running out early, and the presence of withdrawal symptoms. Yet, these behaviors may not be associated with true addiction, but with under treatment. These behaviors are usually eliminated after proper medication adjustments are made.2
  5. Tolerance refers to adaptation in which exposure to a drug induces changes that result in a diminution of the drug’s effects over time.1
  6. Dependence is manifested by a drug class-specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.1
  7. Abuse is the use of an illicit drug or the intentional self-administration of a medication for nonmedical purposes, such as to become euphoric or “high”.3
  8. Diversion is the use of a legitimately prescribed medication for illicit purposes, perhaps with the intent to sell or distribute. Examples include stolen, altered, or forged prescriptions, or trading for profit on medications.1


Chronic pain is defined as pain lasting greater than 3 months or longer than expected tissue healing.23 Opioid use in the short term has been shown to improve function, reduce neuropathic and nociceptive non-cancer pain.23Long-term functional improvement studies are lacking.

Prescribing physicians must find a balance between an appropriate use of opioids to reduce pain and improve function, while assessing the risks of developing opioid use disorder, overdose and drug diversion.  Opioid prescribing has increased by 7.3% from 2007 to 2012.23 Opioid related overdose death has been increasing over the last decade with over 165,000 deaths in the US from 1999 to 2014.23

Epidemiology including risk factors and primary prevention

Pain lasting at least 3 months was determined to affect 11.2% of adults according to the 2012 National Health and Nutrition Examination Survey.23There is lacking literature regarding primary prevention of chronic pain. Treatment of chronic pain with opioid medication can lead to risk, with the most substantial being overdose death.

Overdose death has been linked to high dose prescribing (greater than 200 morphine milligram equivalents per day), concurrent opioid and benzodiazepine use, extended release or long acting medications, and prior history of overdose.23 Methadone, a long acting synthetic opioid, represents less than 2% of prescribed opioids but accounts for about a third of opioid overdose related deaths.23 Important risk factors for opioid use disorder include previous illicit substance or alcohol abuse, major depression, and use of psychotropic medications.23 Between 3% and 16% of the general population has some type of substance abuse disorder.5


Opioid receptors are members of a larger superfamily of receptors with 7 transmembrane alpha helices, coupled with G proteins; G proteins rapidly undergo desensitization and internalization after exposure.

Opioid receptors are found in the peripheral and central nervous system and in immune cells.

The 4 major types of opioid receptors and their respective endogenous peptides are:

  1. mu (endorphin): these are most commonly used in clinical practice
  2. delta (enkephalin)
  3. kappa (dynorphin)
  4. orphan-like receptor

Examples of mixed agonist-antagonists include butorphanol and pentazocine. Partial agonists include buprenorphine and other buprenorphine combination products, such as buprenorphine/naloxone, which is used for the treatment of addiction and off-label used for the treatment of pain.

Significant genetic polymorphism of opioid receptors leads to changes in binding affinities and receptor densities, clinically manifested by inter-individual variability in sensitivity and response to opioid analgesic effects; this phenomenon influences efficacy, side effects, tolerance, and risk of drug abuse or addiction.6-8

Specific secondary or associated conditions and complications

Opioids have significant anxiolytic effects.9

Common adverse effects include:

  1. gastrointestinal (constipation, nausea, emesis)
  2. central nervous system (impaired cognition, decreased balance, depression, decreased reaction time)
  3. respiratory depression; which can be compounded in patients with sleep disorder breathing such as obstructive sleep apnea and should be used with caution
  4. pruritus
  5. hypogonadism. This may lead to muscle atrophy, reduced pain threshold, depression, and lethargy and osteoporosis. Screening should include free and total testosterone, cortisol, luteinizing hormone, dihydrotestosterone, and follicle stimulating hormone. Men should be screened for presence of prostate cancer. Similar endocrine abnormalities may occur in women, but are less well described in the literature

A reduction in adverse effects may be seen over time because of a “tolerance” effect.

Close management of adverse effects may include additional medications including stool softeners, anti-emetics, gastrointestinal stimulants, and central nervous system stimulants for sedation.

Sexual dysfunction may be related to direct effects of opioids or related drug-induced inhibition of production and release of gonadotropin releasing hormone and inhibition of testicular testosterone synthesis.

Changes in neural processing: Animal and human studies show that prolonged used of opioids may be associated with the development of abnormal sensitivity to pain (i.e., allodynia and hyperalgesia). Cellular adaptations may be mediated by N-methyl D-aspartate-receptor changes and other complex neuroplastic abnormalities.10,11

Opioid use in pregnancy can result in stillbirth, poor fetal growth, pre-term delivery, birth defects. For pregnant women already on long-term opioid therapy abrupt taping can result in fetus and patient undergoing withdrawal. Pregnant women on continues opioid treatment should arrange for delivery at a facility capable of treating neonatal withdrawal syndrome.

Patients greater than 65 years old have additional risk of drug accumulation due to renal or hepatic impairment. Screening for cognitive impairment and falls is beneficial for primary prevention.


Functional assessment

Pain assessment for opioids prescription: The “Four A’s” of pain assessment are:

  1. analgesia
  2. activities of daily living
  3. adverse effects
  4. aberrant drug taking, characterized by9,12
    1. euphoria
    2. taking more medication than prescribed
    3. running out of scheduled prescriptions early
    4. reporting ongoing need for greater doses
    5. selling or diverting their medications

Risk stratification for potential aberrant behaviors should be based on exploring risk factors for opioid misuse.  These include:

  1. Screener and Opioid Assessment for Patients with Pain Revised (SOAPP-R)23
  2. Opioid Risk Tool13
  3. Brief Pain Interview23
  4. CAGE for Alcohol Abuse

Assess controlled substance prescription history utilizing the state prescription drug monitoring program (PDMP) prior to opioid initiation and regularly during treatment23

  1. Assess for multiple prescribers of controlled substances
  2. Assess for early refill requests
  3. Determine opioid dosages or dangerous combinations

Laboratory studies

  1. Compliance testing and monitoring for abuse and diversion are essential. Standard testing includes both a urine screen (immunoassay) and subsequent confirmatory testing (gas chromatography/mass spectrometry) that can confirm the precise type of opiate.
  2. Urine drug testing should be performed prior to initiating therapy and at least annually. However, testing should be more frequent in high risk patients for substance abuse.23
  3. Urine screens monitor for other agents (cannabinoids, benzodiazepines, amphetamine, cocaine). Clinician need understand how to interpret the results of the drug panel tested such as positive results for medication metabolites.23
  4. The role of serum testing in opioid monitoring remains controversial.
  5. Newer strategies including testing hair, saliva, and other tissue samples is an evolving area; biological matrices, such as hair, may provide a longer window of detection than blood or urine, and be less invasive; commercially available testing is presently not widely available.
  6. There is controversial genetic screening for medication metabolism.

Supplemental assessment tools

(See Essentials of Assessment section/ClinicalFunctional Assessment/ Item C 1-5)

Professional Issues

An important balance between patient access and reasonable clinical practice is necessary. Patients need access to quality pain management, including the use of controlled substances. However, the clinician should be trained in the indications, contraindications, management of opioids while also taking the necessary steps to prevent and/or monitor for abuse and diversion.


Available or current treatment guidelines

Model Guidelines: Physiatrists cannot singularly eliminate the risk of abuse and diversion of opioids, but can play an important role in reducing risks. By law, physicians are obligated to comply with both state regulations and the federal Controlled Substances Act. The Federation of State Medical Boards developed its Model Guidelines for the Use of Controlled Substances for the Treatment of Pain16 with input from numerous stakeholders and agencies. Most state medical boards adopted the 2004 Model Policy updated with similar language.

The American Pain Society and American Academy of Pain Medicine Clinical Guidelines on the Use of Chronic Opioid Therapy was published in 2009.16 The CDC guidelines for prescribing opioid for Chronic Pain- United States from 2016 for chronic pain treatment.23

Key components of these guidelines include:

  1. Patient selection and risk stratification that focuses on ongoing “benefit versus harm” evaluation.
  2. Informed (verbal or written) consent and opioid management plans (written).
  3. Treatment goals should be discussed with patient, including opioid use, discontinuation if the risk outweighs the benefits or there is no improvement in function or pain. Reassessment of opioid therapy benefit and risk should be performed 1 to 4 weeks of initiation and at least every 3 months for continued use.
  4. Strict and organized monitoring of pain intensity, function, aberrant behaviors using drug testing and PDMP, and adverse effects.
  5. Non-opioids and non-pharmacological treatment should be combined with opioid therapy when appropriate.
  6. First short acting opioid should be trialed prior to initiation of long acting opioids. The lowest effective dose should be used. Benefits must outweigh risks with dose escalation from greater to 50mg MED/day and careful justification for increase greater than 90 mg MME/day
  7. Acute pain treatment with opioids, the lowest effective short acting opioid for the expected duration of pain severity, such as 3 to 7 days should be prescribed.
  8. Cautious observation for dose escalations, high dosing, opioid rotation, high dose-related adverse events such as hyperalgesia, neuroendocrinologic dysfunction, and immunosuppression; also change in health status and adherence.
    1. Opioids have no ceiling effect or maximum dose; a reasonable definition for high dose opioid therapy is more than 200 MED/day.
    2. Opioid rotation may be a strategy for patients who experience intolerable adverse effects or inadequate benefit.
  9. Consider offering Naloxone for patients at high risk for overdose. More frequent monitoring for high risk patients; if aberrant behaviors are observed, then organized detoxification and withdrawal of opioids. Offer or arrange medication assisted treatment and behavioral therapy for opioid use disorder.
  10. Optimize treatment of depression, anxiety and other mental health conditions with collaborated treatment with behavioral health specialist.
  11. Counseling about driving and work safety: There is conflicting evidence regarding influence of opioids when using chronic, stable dosing. Impairment risk may be greater during initiation, titration, or when used in combination with other centrally acting agents, including alcohol.
  12. Identification of one clinician who accepts primary responsibility for overall medical care: This clinician may or may not prescribe opioids but is available to coordinate consultation and communication among those involved in the patient’s care. Consideration for more formal interdisciplinary pain management team should be made when those clinicians believe the patient may benefit from additional therapy not provided by the primary prescribing clinician.

Coordination of care

Chronic pain management is a multidisciplinary treatment. Opioid use for chronic pain treatment is only one modality for treatment.  Coordination of care with physical therapist and occupational therapies can assist in improvement of function and quality of life. Psychosocial factors can be addressed by psychological and psychiatric care as well social workers. Safe opioid prescribing can be supported by referencing state prescription monitoring programs to identify aberrant behaviors. Using a multidisciplinary approach to chronic pain care can also assist is reducing opioid use.

Patient & family education

Patient and family education may improve outcomes pertinent to achieving short- and long-term goals, and may reinforce recognition of behavioral changes, adverse effects, and initiatives essential to developing a truly comprehensive pain management program.


Commonly Used Opioid Analgesics
AgentOpioid Morphine Equivalent Conversion FactorAdvantagesDisadvantagesOther Considerations
Morphine1Not metabolized via CYP450.Greater risk of allergic reaction than most other opioids.

Active metabolites can accumulate in patients with impaired renal function.

Codeine0.15Prodrug. Efficacy/toxicity may be variable depending on CYP450 polymorphism.

Greater risk of allergic reaction than most other opioids.

Meperidine0.1Risk of seizures related to neurotoxic metabolitenormeperidine. Use not recommended.

Greater risk of allergic reaction than most other opioids.

Use not recommended.
Tramadol0.1Possibly more efficacious against neuropathic pain due to norepinephrine reuptake inhibition.Risk of serotonin syndrome and seizures when taken with tricyclic antidepressants, SSRIs, SNRIs, MAOIs, triptans.

Efficacy/toxicity may be variable depending on CYP450 polymorphism.

May lower seizure threshold. Avoid use in patients with seizure disorder.
Hydrocodone1Efficacy/toxicity may be variable depending on CYP450 polymorphism.

No immediate-release formulations available without acetaminophen.

Oxycodone1.5Efficacy/toxicity may be variable depending on CYP450 polymorphism.
Hydromorphone4Not metabolized via CYP450.
Oxymorphone3Not metabolized via CYP450.
Tapentadol0.4Better tolerated, possibly more efficacious against neuropathic pain due to norepinephrine reuptake inhibition.

Not metabolized via CYP450.

Risk of serotonin syndrome when taken with tricyclic antidepressants, SSRIs, SNRIs, MAOIs, triptans.
Methadone1-20 mg/day—4

21-40 mg/day—8

41-60 mg/day—10

>61-80 mg/day—12

NMDA receptor antagonist activity may yield moreefficacy against neuropathic pain and decrease risk of opioid-induced hyperalgesia.

Safer for use in patients with impaired renal function.

Highly variable dosing, potential for QTc prolongation.

Efficacy/toxicity may be variable depending on CYP450 polymorphism.

Buprenorphine patch95Potential for QTc prolongation
Fentanyl transdermal100Safer for use in patients with impaired renal function.Efficacy/toxicity may be variable depending on CYP450 polymorphism.


Cutting edge concepts and practice

These include:

Drug formulations designed to deter or resist abusive behaviors.

Risk Evaluation and Mitigation Strategy (REMS) proposals from the DEA/FDA.

  1. The Food and Drug Administration Amendments Act (FDAAA) is currently developing a REMS to “ensure that the benefits of these drugs continue to outweigh certain risks.”17This work signals significant changes in the regulation, distribution, marketing, and post marketing surveillance of opioids.
  2. The FDAAA also recommends an expansion of the present Risk Map system into a more comprehensive and long-term plan for controlled substances with regards to premarketing study, post marketing labeling, and subsequent monitoring of misuse once the product is on the market.
  3. Elements of the REMS include that health care providers have proper training and experience, dispensers are specifically certified, drugs are dispersed in certain settings with evidence of safe use, and patients are subject to monitoring and a registry.

Federal and State Controlled Substance Laws and Resources

  1. The Pain and Policy Studies Group website18 has information on a wide range of United States and international resources.
  2. Now in its fourth edition, Achieving Balance in State Pain Policy: A Progress Report Card is a valuable resource.19
  3. Specific public law information is in the Controlled Substances Act.20,21


Formulations that are abuse deterrent or relatively resistant to abusive manipulation (crushing, snorting, injecting) are presently available and in late stages of development. Only post market studies will determine if these formulas decrease the risks of abuse, addiction, or diversion. A major recent concern has been the epidemic of drug overdose in the United States with deaths from prescription opiate overdose quadrupling from 1999 to 2014. The majority of the increase in overdose deaths has been due to prescription opiates, and it is now an area of concern that the prescription opiate medications be used and monitored appropriately.24


Gaps in the evidence-based knowledge

There is a lack of studies determining the benefit of long term opioid use greater than 1 year in the treatment of chronic pain22. There is a need for better understanding regarding the misuse and abuse of opiod medications prescribed for pain. 24


  1. Savage SR, Joranson DE, Covington EC, et al. Definitions related to the medical use of opioids: evolution towards universal agreement. J Pain Symptom Manage. 2003;26:655-667.
  2. Weissman D, Haddox J. Opioid pseudoaddiction – an iatrogenic syndrome. Pain. 1989;36:363-366.
  3. Gourlay D, Heit H, Almahrezi A. Universal precautions in pain medicine: a rational approach to the management of chronic pain. Pain Med. 2005;6:107-212.
  4. Joranson DE, Ryan KM, Gilson AM, Dahl JL. Trends in medical use and abuse of opioid analgesics. JAMA. 2000;283:1710-1714.
  5. Fishbain D, Rosomoff H, Rosomoff R. Drug abuse, dependence, and addiction in chronic pain patients. Clin J Pain. 1992;8:77-85.
  6. Landau R. Human opioid receptor A118G polymorphism affects intravenous patient-controlled analgesia morphine consumption after abdominal hysterectomy. Anesthesiology. 2006;105:235-237.
  7. Pasternak GW. Molecular biology of opioid analgesia. J Pain Symptom Manage. 2005;29(5 Suppl):S2-59.
  8. Ross JR, Rutter D, Welsh K, et al. Clinical response to morphine in cancer patients and genetic variation in candidate genes. Pharmacogenomics J. 2005;5:324-336.
  9. Christo P. Opioid effectiveness and side effects in chronic pain. Anesthesiol Clin N Am. 2003:21:699-713.
  10. Mao J, Price, DD, Mayer, DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain. 1995;62:259-274.
  11. Ballantyne J, Mao. Opioid therapy for chronic pain. N Engl J Med. 2003;349:1943-1953.
  12. Passik SD, Weinreb HJ. Managing chronic nonmalignant pain: overcoming obstacles to the use of opioids. Adv Ther. 2000;17:70-83.
  13. Webster L, Webster R. Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the opioid risk tool. Pain Med. 2005;6:432-444.
  14. Ewing J. Detecting alcoholism. The CAGE questionnaire. JAMA. 1984;252:1905-1907.
  15. Skinner H. The drug abuse screening test. Addict Behav. 1982;7:363-371.
  16. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10:113-130.
  17. Shuren, J. Department of Health and Human Services, Food and Drug Administration. Identification of drug and biological products deemed to have risk evaluation and mitigations strategies for purposes of Food and Drug Administration Administration Amendmants Act of 2007. Federal Register, March 27, 2008;73(60):16313-16314.
  18. Pain and Policy Studies Group. Pain and Policy Studies Group Web site. Available at: http://www.painpolicy.wisc.edu. Accessed May 1, 2011.
  19. Pain and Policy Studies Group. Achieving Balance in State Pain Policy: A Progress Report Card. 4th ed. Madison, WI: University of Wisconsin Paul P. Carbone Comprehensive Cancer Center; 2008.
  20. Hartney E. What are controlled drugs? About.com Guide. Updated July 15, 2011. http://addictions.about.com/od/legalissues/fcontrolleddrugs.htm
  21. The Controlled Substances Act of 1970, Pub L No. 91-513, 84 Stat 1242.
  22. Dowell, D. Haegerich, T. Chou, R. CDC Guidelines for prescribing opioids for chronic pain-United States, 2016. JAMA. Http://Jama.jamanetwork.com. March 15, 2016.
  23. Dowell, D. Haegerich, T. Chou, R. CDC Guidelines for Prescribing Opioids for Chronic Pain- United States, 2016. Morbidity and Mortality Weekly Report. Early Release Vol. 65 March 15, 2016.
  24. Centers for Disease Control and Prevention. Increases in Drug and Opioid Overdose Deaths — United States, 2000–2014. MMWR 2015; 64;1-5.

Other Online Resources – Supplemental

Office of National Drug Control Policy. Proper disposal of prescription drugs. Available at: http://www.whitehousedrugpolicy.gov/publications/pdf/prescrip_disposal.pdf. Accessed May 1, 2011.

US Drug Enforcement Administration. Drug scheduling. Available at: http://www.usdoj.gov/dea/pubs/scheduling.html. Accessed May 1, 2011.

Department of Justice Drug Enforcement Administration Office of Diversion Control. DEA pharmacist manual. Available at: http://www.deadiversion.usdoj.gov/pubs/manuals/pharm2/pharm_manual.pdf. Accessed May 1, 2011.

Department of Justice Drug Enforcement Administration Office of Diversion Control. Cases against doctors. Available at: http://www.deadiversion.usdoj.gov/crim_admin_actions/index.html. Accessed May 1, 2011.

Rannazzisi JT, Caverly MW. Department of Justice Drug Enforcement Administration Office of Diversion Control Web site. Practitioner’s manual. Available at: http://www.deadiversion.usdoj.gov/pubs/manuals/pract/index.html. Accessed May 1, 2011.

Federation of State Medical Boards of the US. Model policy for the use of controlled substances for the treatment of pain.Available at: http://www.fsmb.org/pdf/2004_grpol_Controlled_Substances.pdf. Accessed May 1, 2011.

Alliance of State with Prescription Monitoring Programs and National Association of State Controlled Substances Authorities.Prescription monitoring program model act. October 2002. Available at: http://www.nascsa.org/PDF/PMPmodelact02.pdf. Accessed May 1, 2011.

Original Version of the Topic:

William Anderson, MD. Opioid Management for Chronic Pain. Publication Date: 2011/11/11.

Author Disclosure

Monika Patel, MD
Nothing to Disclose