Knowing the Enemy Is Halfway towards Victory: A Scoping Review on Opioid-Induced Hyperalgesia

Abstract

Opioid-induced hyperalgesia (OIH) is a paradoxical effect of opioids that is not consensually recognized in clinical settings. We conducted a revision of clinical and preclinical studies and discuss them side by side to provide an updated and renewed view on OIH. We critically analyze data on the human manifestations of OIH in the context of chronic and post-operative pain. We also discuss how, in the context of cancer pain, though there are no direct evidence of OIH, several inherent conditions to the tumor and chemotherapy provide a substrate for the development of OIH. The review of the clinical data, namely in what concerns the strategies to counter OIH, emphasizes how much OIH rely mechanistically on the existence of µ-opioid receptor (MOR) signaling through opposite, inhibitory/antinociceptive and excitatory/pronociceptive, pathways. The rationale for the maladaptive excitatory signaling of opioids is provided by the emerging growing information on the functional role of alternative splicing and heteromerization of MOR. The crossroads between opioids and neuroinflammation also play a major role in OIH. The latest pre-clinical data in this field brings new insights to new and promising therapeutic targets to address OIH. In conclusion, although OIH remains insufficiently recognized in clinical practice, the appropriate diagnosis can turn it into a treatable pain disorder. Therefore, in times of scarce alternatives to opioids to treat pain, mainly unmanageable chronic pain, increased knowledge and recognition of OIH, likely represent the first steps towards safer and efficient use of opioids as analgesics.

Case report: The lesson from opioid withdrawal symptoms mimicking paraganglioma recurrence during opioid deprescribing in cancer pain

“…In the long-term management of opioid analgesic therapy, opioid-induced hyperalgesia (OIH) is a paradoxical opioid effect and should not be forgotten: OIH often leads to the need to reduce or modify the therapy ( 41 ). OIH is defined as a state of nociceptive sensitization caused by opioid exposure.…”

Restoration of the Activity of the Prefrontal Cortex to the Nucleus Accumbens Core Pathway Relieves Fentanyl-Induced Hyperalgesia in Male Rats

“…OIH is a state of hypersensitivity caused by large opioid exposure that does not improve or even worsens with continuous opioid usage. 1 This paradoxical phenomenon has become a challenge in current clinical analgesic treatment, prompting an urgency for investigating the mechanism of its occurrence.…”

How do opioids control pain circuits in the brainstem during opioid-induced disorders and in chronic pain? Implications for the treatment of chronic pain

“…42,60 Recent studies, conducted in patients with chronic pain, indicate the development of OIH in patients with chronic pain on use of opioids. 150 Other treatment options include drugs such as gabapentinoids, tricyclic antidepressants, serotonin, and norepinephrine reuptake inhibitors, but these drugs only provide modest outcomes, and they also have side effects that limit their use. 42,151 Finally, when other therapeutic options have failed, for some patients, opioids remain a treatment option.…”