Clinical benefits and risks of N-methyl-d-aspartate receptor antagonists to treat severe opioid use disorder: A systematic review.

Background: Demand for treatments for severe opioid use disorder is increasing worldwide. The current pharmacotherapy is mainly focused on opioid and adrenergic receptors. The N-methyl-d-aspartate receptor (NMDAR) is among other receptors that can also be targeted to treat the disease. Findings from randomized controlled trials (RTCs) on NMDAR antagonists to treat severe opioid use disorder amply varied. This study aimed to evaluate the clinical benefits and assess the potential risks for adverse events or side effects of NMDAR antagonists that were investigated for the treatment of severe opioid use disorder.

Methods: Articles were searched in PubMed, Scopus, Google Scholar, Proquest. Cochrane Review Database, Medline Ovid, and EMBASE from their inception to March 2019. RTCs on NMDAR antagonists for the treatment of severe opioid use disorder were independently screened and assessed by two authors. The results were synthesized qualitatively.

Results: Nineteen RTCs of 1459 participants met the inclusion criteria. There is moderate evidence suggesting that ketamine, memantine, amantadine, and dextromethorphan may be able to manage opioid withdrawal symptoms. There is little evidence suggesting that memantine may be able to reduce methadone maintenance dose in participants on methadone, reduce opioid use, and reduce craving. Dropout is noticeable among dextromethorphan's participants. Safety concerns are more likely associated with dextromethorphan and ketamine.

Conclusions: NMDAR antagonists have the potentiality to treat severe opioid use disorder. There is insufficient evidence to recommend them for the treatment of severe opioid use disorder due to several limitations inherent to the RCTs reviewed. Further exploration is needed.