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Review
, 8 (4), 387-92

Complications of Long-Term Opioid Therapy for Management of Chronic Pain: The Paradox of Opioid-Induced Hyperalgesia

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Review

Complications of Long-Term Opioid Therapy for Management of Chronic Pain: The Paradox of Opioid-Induced Hyperalgesia

D Eric Brush. J Med Toxicol.

Abstract

While opioids remain a valid and effective analgesic strategy for patients suffering from a wide variety of painful conditions, they are not a panacea. Increasingly, physicians must balance patient expectations of adequate pain control with known limitations of opioid pharmaceuticals including adverse effects, tolerance, addiction, withdrawal, and drug diversion. Further complicating the issue over the last decade is a growing body of evidence suggesting chronic opioid use may unexpectedly worsen the perception of pain in some individuals. This syndrome, termed opioid-induced hyperalgesia (OIH), fundamentally changes our understanding of opioid pharmacodynamics and may influence our approach to management of chronic pain. This manuscript describes the concept OIH and provides an overview of basic science and clinical research to date attempting to characterize this syndrome, as well as ascertain its clinical relevance. The potential existence of OIH in humans is framed within the context of our current understanding of opioids and our prescribing patterns so that physicians may begin to incorporate these ideas into their philosophy of pain management as further information develops. Animal studies reliably validate OIH in controlled models. Rigorous research protocols in humans are lacking, and we cannot yet confidently conclude that OIH manifests in clinically significant ways. However, clinicians should consider the possibility of OIH when evaluating outcomes of patients on chronic opioid therapy.

Figures

Fig. 1
Fig. 1
Paw withdrawal latency demonstrating OIH. Data are representative of studies conducted in rats using a thermal stimulus to the hind paw. The y-axis indicates seconds of exposure prior to paw withdrawal. Baseline measurements for control and opioid-exposed groups verify no difference in withdrawal latency. Opioid exposure on day 1 increases the withdrawal latency and indicates analgesia. Return to baseline on day 3 suggests tolerance, and subsequent decreased latency below pre–opioid exposure measurements illustrates the occurrence of OIH. Removal of opioid exposure on day 7 results in a return to baseline
Fig. 2
Fig. 2
Cold pressor test in methadone maintenance patients. This figure, adapted from Doverty et al. [17], compares the pain threshold and pain tolerance of controls with methadone maintenance subjects. Opioid withdrawal is controlled by conducting the experiment after daily dosing and by verifying methadone plasma concentrations. Placement of the forearm in an ice bath occurs at time zero. The y-axis measures seconds until subjects report pain (threshold) and again following self–termination of stimulus exposure (tolerance). Variation in pain threshold was not significant, whereas tolerance to the stimulus was markedly diminished in the methadone group

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