Developing non-opioid therapeutics to alleviate pain among persons with opioid use disorder: a review of the human evidence

Abstract

The opioid crisis remains a major public health concern, causing significant morbidity and mortality worldwide. Pain is frequently observed among individuals with opioid use disorder (OUD), and the current opioid agonist therapies (OAT) have limited efficacy in addressing the pain needs of this population. We reviewed the most promising non-opioid analgesic therapies for opioid-dependent individuals synthesising data from randomised controlled trials in the Medline database from December 2022 to March 2023. Ketamine, gabapentin, serotoninergic antidepressants, and GABAergic drugs were found to be the most extensively studied non-opioid analgesics with positive results. Additionally, we explored the potential of cannabinoids, glial activation inhibitors, psychedelics, cholecystokinin antagonists, alpha-2 adrenergic agonists, and cholinergic drugs. Methodological improvements are required to advance the development of novel analgesic strategies and establish their safety profile for opioid-dependent populations. We highlight the need for greater integration of experimental pain methods and abuse liability assessments, more granular assessments of prior opioid exposure, greater uniformity of pain types within study samples, and a particular focus on individuals with OUD receiving OAT. Finally, future research should investigate pharmacokinetic interactions between OAT and various non-opioid analgesics and perform reverse translation basic experiments, particularly with methadone and buprenorphine, which remain the standard OUD treatment.

Keywords:

• Non-opioid analgesics
• pain sensitivity
• opioid use disorder
• experimental pain
• pharmacotherapy development

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

JPD is supported by the National Institute on Drug Abuse (NIDA) Grants K23DA052682 and R21DA057240, and by the VISN 1 Mental Illness Research Education Clinical Centre (MIRECC). MS is supported by the New England Veterans Administration VISN 1 Mental Illness Research, Education and Clinical Centre (MIRECC). Other than providing funding, NIDA, and the VA had no role in the conception and conduction of this project, nor the interpretation or reporting of its findings.