Adverse effects of chronic opioid therapy for chronic musculoskeletal pain


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.

Key Points

  • 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

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Figure 1: Increased prescription of opioids in million grams of medication between 1997 and 2006.
Figure 2: Tolerance versus opioid-induced hyperalgesia.


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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.

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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.

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Crofford, L. Adverse effects of chronic opioid therapy for chronic musculoskeletal pain. Nat Rev Rheumatol 6, 191–197 (2010).

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