The use of opioids for the treatment of chronic pain has increased dramatically over the past decade. Whether these drugs provide considerable benefits in terms of pain reduction and improved function to balance the risks associated with their use, however, is unclear. Of particular importance to clinicians treating chronic musculoskeletal pain is opioid-induced hyperalgesia, the activation of pronociceptive pathways by exogenous opioids that results in central sensitization to pain. This phenomenon results in an increase in pain sensitivity and can potentially exacerbate pre-existing pain. Opioids also have powerful positive effects on the reward and reinforcing circuits of the brain that might lead to continued drug use, even if there is no abuse or misuse. The societal risk of increased opioid prescription is associated with increased nonmedical use, serious adverse events and death. Patients with chronic musculoskeletal pain should avoid the long-term use of opioids unless the benefits are determined to outweigh risks, in which case, the use of chronic opioids should be regularly re-evaluated.
Increased opioid prescription is associated with increased misuse, abuse and diversion
Endogenous opioid peptides and receptors are involved in the reward and reinforcement circuitry in the brain, which is altered by taking exogenous opioid drugs
In addition to providing antinociception or analgesia, opioids activate pronociceptive pathways resulting in central sensitization called opioid-induced hyperalgesia
Opioid-induced hyperalgesia could lead to persistence or enhancement of chronic musculoskeletal pain
Opioids have a poor benefit:risk ratio in chronic, nonmalignant pain states including osteoarthritis
Long-term opioid use should be avoided in patients with chronic musculoskeletal pain; in cases where benefits are determined to outweigh risks, use of chronic opioids should be regularly re-evaluated
Subscribe to Journal
Get full journal access for 1 year
only $17.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Ives, T. J. et al. Predictors of opioid misuse in patients with chronic pain: a prospective cohort study. BMC Health Services Res. 6, 46 (2006).
Compton, W. M. & Volkow, N. D. Major increases in opioid analgesic abuse in the United States: concerns and strategies. Drug Alcohol Depend. 81, 103–107 (2006).
Becker, W. C., Sullivan, L. E., Tetrault, J. M., Desai, R. A. & Fiellin, D. A. Non-medical use, abuse and dependence on prescription opioids among US adults: Psychiatric, medical and substance use correlates. Drug Alcohol Depend. 94, 38–47 (2008).
Woodcock, J. A difficult balance—Pain management, drug safety, and the FDA. N. Engl. J. Med. 361, 2105–2107 (2009).
Joranson, D. E. & Gilsom, A. M. Drug crime is a source of abused pain medications in the United States. J. Pain Symptom Manage. 30, 299–301 (2005).
Cicero, T. J., Shores, C. N., Paradis, A. G. & Ellis, M. S. Source of drugs for prescription opioid analgesic abusers: a role for the Internet? Pain Med. 9, 718–723 (2008).
Inciardi, J. A., Surratt, H. L., Cicero, T. J. & Beard, R. A. Prescription opioid abuse and diversion in an urban community: the results of an ultrarapid assessment. Pain Med. 10, 537–548 (2009).
Fishbain, D. A., Cole, B., Lewis, J., Rosomoff, H. L. & Rosomoff, R. S. What percentage of chronic nonmalignant pain patients exposed to chronic opioid analgesic therapy develop abuse/addiction and/or aberrant dreg-related behaviors? A structured evidence-based review. Pain Med. 9, 444–459 (2008).
Turk, D. C., Swanson, K. S. & Gatchel, R. J. Predicting opioid misuse by chronic pain patients. A systematic review and literature synthesis. Clin. J. Pain 24, 497–508 (2008).
Katz, N. & Fanciullo, G. J. Role of urine toxicology testing in the management of chronic opioid therapy. Clin. J. Pain 18 (Suppl. 4), S76–S82 (2002).
Le Merrer, J., Becker, J. A., Befort, K. & Kieffer, B. L. Reward processing by the opioid system in the brain. Physiol. Rev. 89, 1379–1412 (2009).
Contet, C., Kieffer, B. L. & Befort, K. Mu opioid receptor: a gateway to drug addiction. Curr. Opin. Neurobiol. 14, 370–378 (2004).
Gieryk, A., Ziolkowska, B., Solecki, W., Kubik, J. & Przewlocki, R. Forebrain PENK and PDYN gene expression levels in three inbred strains of mice and their relationship to genotype-dependent morphine reward sensitivity. Psychpharmacology 208, 291–300 (2010).
Przewlocki, R. Opioid abuse and brain gene expression. Eur. J. Pharmacol. 500, 331–349 (2004).
Wager, T. D., Scott, D. J. & Zubieta, J. K. Placebo effects on human mu-opioid activity during pain. Proc. Natl Acad. Sci. USA 104, 11056–11061 (2007).
Qiu, Y. H., Wu, X. Y., Xu, H. & Sackett, D. Neuroimaging study of placebo analgesia in humans. Neurosci. Bull. 25, 277–282 (2009).
Matre, D., Casey, K. L. & Knardahl, S. Placebo-induced changes in spinal cord pain processing. J. Neurosci. 26, 559–563 (2006).
Eippert, F., Finsterbusch, J., Bingel, U. & Buchel, C. Direct evidence for spinal cord involvement in placebo analgesia. Science 326, 404 (2009).
Chu, L. F., Angst, M. S. & Clark, D. Opioid-induced hyperalgesia in humans. Molecular mechanisms and clinical consideration. Clin. J. Pain 24, 479–496 (2008).
Ballantyne, J. C. & Mao, J. Opioid therapy for chronic pain. N. Engl. J. Med. 349, 1943–1953 (2003).
Ueda, H. & Ueda, M. Mechanisms underlying morphine analgesic tolerance and dependence. Front. Biosci. 14, 5260–5272 (2009).
Angst, M. S. & Clark, D. Opioid-induced hyperalgesia: A qualitative systematic review. Anesthesiology 104 (2006).
Silverman, S. M. Opioid induced hyperalgesia: Clinical implications for the pain practitioner. Pain Physician 12, 679–684 (2009).
Adam, F., Dufour, E. & Le Bars, D. The glycine site-specific NMDA antagonist (+)-HA966 enhances the effect of morphine and reverses morphine tolerance via a spinal mechanism. Neuropharmacology 54, 588–596 (2008).
Cohen, S. P. et al. An intravenous ketamine test as a predictive response tool in opioid-exposed patients with persistant pain. J. Pain Symptom Manage. 37, 698–708 (2009).
Compton, P. A., Ling, W. & Torrington, M. A. Lack of effect of chronic dextromethorphan on experimental pain tolerance in methadone-maintained patients. Addiction Biol. 13, 393–402 (2008).
Baron, M. J. & McDonald, P. W. Significant pain reduction in chronic pain patients after detoxification from high dose opioids. J. Opioid Manag. 2, 277–282 (2006).
Celerier, E., Laulin, J.-P., Corcuff, J.-B., Le Moal, M. & Simonnet, G. Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: A sensitization process. J. Neurosci. 21, 4074–4080 (2001).
Juni, A., Klein, G., Pintar, J. E. & Kest, B. Nociception increases during opioid infusion in opioid receptor triple knock-out mice. Neurosci. 147, 439–444 (2007).
Watkins, L. R., Hutchinson, M. R., Johnston, I. N. & Maier, S. F. Glia: novel counter-regulators of opioid analgesia. Trends Neurosci. 28, 661–669 (2005).
Hutchinson, M. R. et al. Evidence that opioids may have Toll-like receptor 4 and MD-2 effects. Brain Behav. Immun. 24, 83–95 (2010).
Albutt, C. On the abuse of hypodermic injections of morphia. Practitioner 5, 327–331 (1870).
Chen, L. et al. Altered quantitative sensory testing oucome in subjects with opioid therapy. Pain 143, 65–70 (2009).
Pud, D., Cohen, D., Lawental, E. & Eisenberg, E. Opioids and abnormal pain perception: New evidence from a study of chronic opioid addicts and healthy subjects. Drug Alcohol Depend. 82, 218–223 (2006).
Chu, L. F., Clark, D. J. & Angst, M. S. Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: a preliminary prospective study. J. Pain 7, 43–48 (2006).
Harris, R. E. et al. Decreased central mu-opioid receptor availability in fibromyalgia. J. Neurosci. 27, 10000–10006 (2007).
Jones, A. K. et al. Changes in central opioid receptor binding in relation to inflammation and pain in patients with rheumatoid arthritis. Br. J. Rheumatol. 33, 909–916 (1994).
Younger, J. W., Zautra, A. J. & Cummins, E. T. Effects of naltrexone on pain sensitivity and mood in fibromyalgia: no evidence for endogenous opioid pathophysiology. PLoS One 4, e5180 (2009).
Younger, J. & Mackey, S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med. 10, 663–672 (2009).
Trescot, A. M. et al. Opioids in the management of chronic non-cancer pain: an update of American Society of the Interventional Pain Physicians (ASIPP) guidelines. Pain Physician 11, S5–S62 (2008).
Webster, L. R., Choi, Y., Desiah, H. & Webster, L. Sleep disordered breathing and chronic opioid therapy. Pain Med. 9, 425–432 (2008).
Ramar, K. Reversal of sleep-disordered breathing with opioid withdrawal. Pain Practitioner 9, 394–398 (2009).
Harbuz, M. Neuroendocringology of autoimmunity. Int. Rev. Neurobiol. 52, 133–161 (2002).
Mousa, S. A., Straub, R. H., Schafer, M. & Stein, C. Beta-endorphin, Met-enkaphalin, and corresponding opioid receptors within synovium of patients with joint trauma, osteoarthritis, and rheumatoid arthritis. Ann. Rheum. Dis. 66, 871–879 (2007).
Sacerdote, P. Opioid-induced immunosuppression. Curr. Opin. Support Paliat. Care 2, 14–18 (2008).
Eisenstein, T. K., Rahim, R. T., Feng, P., Thingalaya, N. K. & Meissler, J. Effects of opioid tolerance and withdrawal on the immune system. J. Neuroimmune Pharmacol. 1, 237–259 (2006).
Trescot, A. et al. Effectiveness of opioids in the treatment of chronic non-cancer pain. Pain Physician 11, S181–S200 (2008).
Nuesch, E., Rutjes, A., Husni, E., Welch, V. & Juni, P. Oral or transdermal opioids for osteoarthritis of the knee or hip. Cochrane Database of Systematic Reviews, Issue 4. Art. No.: CD003115. doi:10.1002/14651858.CD003115.pub3 (2009).
Crofford, L. J. Pain management in fibromyalgia. Curr. Opin. Rheumatol. 20, 246–250 (2008).
Charles P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.
Leslie J. Crofford declares that she has received grant or research support from Allergan, Pfizer and Wyeth. The Journal Editor J. Buckland and the CME questions author C. P. Vega declare no competing interests.
About this article
Cite this article
Crofford, L. Adverse effects of chronic opioid therapy for chronic musculoskeletal pain. Nat Rev Rheumatol 6, 191–197 (2010). https://doi.org/10.1038/nrrheum.2010.24
Pharmaceutical Biology (2020)
Negative Affect–Related Factors Have the Strongest Association with Prescription Opioid Misuse in a Cross-Sectional Cohort of Patients with Chronic Pain
Pain Medicine (2020)
Fatigue: Biomedicine, Health & Behavior (2019)