A Comprehensive Review of Opioid-Induced Hyperalgesia

Opioid-induced hyperalgesia (OIH) is defined as a state of nociceptive sensitizationcaused by exposure to opioids. The condition is characterized by a paradoxical responsewhereby a patient receiving opioids for the treatment of pain could actually becomemore sensitive to certain painful stimuli. The type of pain experienced might be thesame as the underlying pain or might be different from the original underlying pain. OIHappears to be a distinct, definable, and characteristic phenomenon that could explainloss of opioid efficacy in some patients.Findings of the clinical prevalence of OIH are not available. However, severalobservational, cross-sectional, and prospective controlled trials have examined theexpression and potential clinical significance of OIH in humans. Most studies have beenconducted using several distinct cohorts and methodologies utilizing former opioidaddicts on methadone maintenance therapy, perioperative exposure to opioids inpatients undergoing surgery, and healthy human volunteers after acute opioid exposureusing human experimental pain testing.The precise molecular mechanism of OIH, while not yet understood, varies substantiallyin the basic science literature, as well as clinical medicine. It is generally thought toresult from neuroplastic changes in the peripheral and central nervous system (CNS)that lead to sensitization of pronociceptive pathways. While there are many proposedmechanisms for OIH, 5 mechanisms involving the central glutaminergic system, spinaldynorphins, descending facilitation, genetic mechanisms, and decreased reuptake andenhanced nociceptive response have been described as the important mechanisms.Of these, the central glutaminergic system is considered the most common possibility.Another is the hypothesis that N-methyl-D-aspartate (NMDA) receptors in OIH includeactivation, inhibition of the glutamate transporter system, facilitation of calciumregulated intracellular protein kinase C, and cross talk of neural mechanisms of painand tolerance.Clinicians should suspect OIH when opioid treatment’s effect seems to wane in theabsence of disease progression, particularly if found in the context of unexplained painreports or diffuse allodynia unassociated with the original pain, and increased levelsof pain with increasing dosages. The treatment involves reducing the opioid dosage,tapering them off, or supplementation with NMDA receptor modulators.This comprehensive review addresses terminology and definition, prevalence, theevidence for mechanism and physiology with analysis of various factors leading to OIH,and effective strategies for preventing, reversing, or managing OIH.Key words: Opioid-induced hyperalgesia, opioid tolerance, opioid sensitivity, adverseevents, chronic opioid therapy