Clinical Review

What Do We Know About Opioid-Induced Hyperalgesia?



From the Massachusetts General Hospital Center for Pain Medicine, Boston, MA.


  • Objective: To review evidence from clinical and preclinical studies related to the phenomenon of opioid-induced hyperalgesia (OIH) and discuss issues relevant to clinical diagnosis and management.
  • Methods: Literature review.
  • Results: OIH is defined as a state of nociceptive sensitization caused by exposure to opioids such that a patient receiving opioids to treat pain could become more sensitive to painful stimuli. Interest in understanding OIH has grown over years and multiple mechanisms have been proposed. Both OIH and opioid tolerance can reduce opioid analgesic efficacy, complicating clinical management of chronic pain. When a diagnosis is uncertain, a trial of opioid dose escalation or tapering may be helpful in differentiating between tolerance and OIH. It is unclear whether certain types of opioids or routes of administration are more likely to lead to OIH.
  • Conclusion: Clinical outcome of opioid therapy is a dynamic balance among the opioid analgesic effect, OIH, and worsening pain due to disease progression. While OIH has been well documented over nearly 2 decades, its exact clinical characteristics and underlying mechanisms have yet to be fully determined.

Opioids, which produce analgesia through a primarily inhibitory effect on the nociceptive system, have been used for decades for the clinical management of moderate to severe pain. Opioid analgesics act on 3 major classes of opioid receptors, including the µ, k, δ (mu, kappa, and delta) receptors. Activation of opioid receptors not only produces analgesia but also other effects, such as euphoria, respiratory depression, decreased gastrointestinal motility, and cardiovascular effects. Exposure to opioids, however, can also lead to the development of opioid tolerance and opioid-induced hyperalgesia (OIH). Both opioid tolerance and OIH can decrease opioid analgesic efficacy, making chronic pain management a challenge. OIH is a state of nociceptive sensitization caused by exposure to opioids, such that a patient receiving opioids for the treatment of pain could actually become more sensitive to painful stimulation, resulting in a paradoxical adverse response to opioid therapy. In this article, we will review evidence from preclinical and clinical studies and discuss issues relevant to clinical diagnosis and management of OIH.

Evidence of OIH in Animal Studies

In early 1990s, an original preclinical study showed that there was a progressive reduction in baseline nociceptive threshold by using a foot withdraw test in rats receiving repeated intrathecal morphine administration (10-20 mg) over a 7-day period [1]. A number of animal studies later also provided similar data. A reduced baseline nociceptive threshold was observed in animals receiving subcutaneous fentanyl boluses using the Randall-Sellitto test, in which a constantly increasing pressure was applied to a rat’s hind paw. The decreased baseline nociceptive threshold lasted 5 days after cessation of 4 fentanyl bolus injections [2]. In another study, a reduced baseline nociceptive threshold was detected in animals with repeated heroin administration [3]. In other studies, rats exposed to morphine also developed a latent sensitization of visceral pain with a shift of the morphine dose-response curve to the right [4]; exposure to methadone also induced hyperalgesia in rats, which was not prevented by a weak NMDA receptor antagonist (memantine) [5]; and a partial µ-receptor agonist buprenophine produced a dose-related OIH as well [6].


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