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Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations

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Abstract

Opioid analgesics have become a cornerstone in the treatment of moderate to severe pain, resulting in a steady rise of opioid prescriptions. Subsequently, there has been a striking increase in the number of opioid-dependent individuals, opioid-related overdoses, and fatalities. Clinical use of opioids is further complicated by an increasingly deleterious profile of side effects beyond addiction, including tolerance and opioid-induced hyperalgesia (OIH), where OIH is defined as an increased sensitivity to already painful stimuli. This paradoxical state of increased nociception results from acute and long-term exposure to opioids, and appears to develop in a substantial subset of patients using opioids. Recently, there has been considerable interest in developing an efficacious treatment regimen for acute and chronic pain. However, there are currently no well-established treatments for OIH. Several substrates have emerged as potential modulators of OIH, including the N-methyl-D-aspartate and γ-aminobutyric acid receptors, and most notably, the innate neuroimmune system. This review summarizes the neurobiology of OIH in the context of clinical treatment; specifically, we review evidence for several pathways that show promise for the treatment of pain going forward, as prospective adjuvants to opioid analgesics. Overall, we suggest that this paradoxical state be considered an additional target of clinical treatment for chronic pain.

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Author contributions

C.A. Arout, E. Edens, I. Petrakis, and M. Sofuoglu have each significantly contributed to the concept, formulation, writing, and revision of this manuscript.

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  1. Department of Psychiatry, Yale University School of Medicine, VA Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT, 06516, USA

    Caroline A. Arout, Ellen Edens, Ismene L. Petrakis & Mehmet Sofuoglu

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  1. Caroline A. Arout
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  2. Ellen Edens
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  3. Ismene L. Petrakis
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Correspondence to Caroline A. Arout.

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I. L. Petrakis reports a conflict of interest due to her role as a consultant for Alkermes. C. A. Arout, E. Edens, and M. Sofuoglu declare no conflicts of interest.

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This manuscript was prepared for publication during C. A. Arout’s postdoctoral fellowship (Grant # NIDA T32 DA007238; Principal Investigator: I. L. Petrakis), and is supported by Mental Illness Research, Education and Clinical Centers (MIRECC).

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Arout, C.A., Edens, E., Petrakis, I.L. et al. Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations. CNS Drugs 29, 465–486 (2015). https://doi.org/10.1007/s40263-015-0255-x

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