Pharmacological Interventions for Opioid-Induced Hyperalgesia: A Scoping Review of Preclinical Trials

Background: Opioid analgesics are the most effective pharmacological agents for moderate and severe pain. However, opioid use has several limitations such as opioid-induced hyperalgesia (OIH), which refers to the increased pain sensitivity that occurs once analgesia wears off after opioid administration. Several pharmacological interventions have been suggested for OIH, but the current literature does not provide guidelines on which interventions are the most effective and whether they differ depending on the opioid that induces hyperalgesia. This scoping review aimed to identify and describe all the preclinical trials investigating pharmacological interventions for OIH caused by remifentanil, fentanyl, or morphine as the first step towards evaluating whether the most effective OIH interventions are different for different opioids. Methods: Electronic database searches were carried out in Embase, PubMed, and Web of Science. Detailed data extraction was conducted on the eligible trials. Results: 72 trials were eligible for the review. Of these, 27 trials investigated remifentanil, 14 trials investigated fentanyl, and 31 trials investigated morphine. A total of 82 interventions were identified. The most studied interventions were ketamine (eight trials) and gabapentin (four trials). The majority of the interventions were studied in only one trial. The most common mechanism suggested for the interventions was inhibition of N-methyl-D-aspartate (NMDA) receptors. Conclusion: This scoping review identified plenty of preclinical trials investigating pharmacological interventions for OIH. Using the current literature, it is not possible to directly compare the effectiveness of the interventions. Hence, to identify the most effective interventions for each opioid, the interventions must be indirectly compared in a meta-analysis.