Relative risks of adverse effects across different opioid agonist treatments—A systematic review and meta‐analysis

Abstract Background and Aims Opioid agonist treatment (OAT) is established for opioid use disorder, but limited data on adverse effects exist. We aimed to review relative risks of adverse effects across opioid agonists. Methods Systematic review with pair‐wise meta‐analysis of randomized clinical trials. A search in Embase, Medline, PsycInfo, CENTRAL and the Web of Science Core Collection was performed from inception to 11 April 2024 (PROSPERO: CRD42022322722). Two reviewers independently extracted data and used the Cochrane Risk of Bias Assessment Tool. Certainty of evidence was assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). Primary outcomes were constipation, sedation, pruritus, sweating, nausea and vomiting, headache and any non‐headache pain. Results We identified 25 eligible trials, including 4892 participants. Reported agonists were methadone, levomethadone, methadyl acetate, buprenorphine, buprenorphine/naloxone, slow‐release oral morphine (SROM), diacetylmorphine, hydromorphone and opium tincture. Buprenorphine (all formulations combined) was associated with a lower risk of sedation than methadone [risk ratio (RR) = 0.68 (95% confidence interval = 0.56–0.82)]; 1558 participants, 9 studies]. Methadone had a lower risk of sedation compared with SROM [RR = 0.63 (0.58–0.69); 356 participants, 2 studies] and a lower risk of nausea than methadyl acetate [RR = 0.56 (0.37–0.85); 913 participants, 3 studies]. There was high overall risk of bias in 92% of included trials due to limited and non‐systematic outcome assessment. Certainty of evidence was low or very low for all but one comparison with moderate certainty. Conclusions There is currently insufficient data to determine whether the rates of adverse effects differ across opioid agonist treatments for most outcomes, with several exceptions. Moreover, the certainty of evidence is currently low or very low due to a lack of rigorous outcome assessment.