Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations

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.

Withdrawal-associated injury site pain (WISP): a descriptive case series of an opioid cessation phenomenon

“…6,39,60,68,73,80,112,133,134 Along with opioid, neurokinin 1, and toll-like receptor 4 antagonists, NSAIDS and gabapentinoids have been found to reduce neuroinflammation and mitigate OIH and/or WIH in some 1,5,14,18,34,45,46,61,70,83,85,94,100,121,127,135,137 but not all 50 circumstances. In our study, a subset of participants named NSAIDs most frequently and gabapentinoids third for relieving WISP, supporting a possible neuroinflammatory component.…”

“…Although these may be coincidental, there is evidence that these or related substances may mitigate OIH, WIH, or other forms of pain through modulation of one of the above mechanisms, some of which are also involved with gabapentinoids. 6,74,94,111,113,116 …”

“…It is known that opioid use itself can cause adaptations in the central nervous system that lead to increased pain sensitivity, termed opioid-induced hyperalgesia (OIH), 3,6,10,21,32,41,65,68,84,91,92 clinically first described over a century ago. 2 Opioid-induced hyperalgesia is at times confused with tolerance, which may be distinct in both mechanism and treatment.…”

“…2 Opioid-induced hyperalgesia is at times confused with tolerance, which may be distinct in both mechanism and treatment. 6,29,51 Once opioids are stopped, the pain sensitivity can continue or seem to heighten temporarily because any pain-relieving effect opioids may have provided is eliminated, and the drug-opposite effect can take time to subside. 139 Also, in preclinical models, opioid withdrawal induces central changes in neurotransmitters, along with neuroimmune and neuroinflammatory mediators involved in nociception, 43,44 thus potentially intensifying pain beyond OIH.…”

OnabotulinumtoxinA Nerve Blocks in the Treatment of Occipital Neuralgia

“…That this data did not yield significant results was perhaps unsurprising, given the recent decrease in opioid use due to dependence [18], overdose [19], and opioid-induced hyperalgesia [20]. A 2007 study examining ONA's effect on occipital neuralgia showed opioid use in all six of its patients [15]; in contrast, only 21 of 63 patients in this study had received opioid prescriptions, 19 of which were PRN dosages for short-acting relief.…”