• Priya Vijayvargiya, Michael Camilleri, Pooja Vijayvargiya, Patricia Erwin, and M Hassan Murad.
• Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, MN, USA.
• Aliment. Pharmacol. Ther. 2020 Jul 1; 52 (1): 37-53.

BackgroundWhen opioid-induced constipation is treated with centrally acting opioid antagonists, there may be opioid withdrawal or aggravation of pain due to inhibition of μ-opioid analgesia. This led to the development of peripherally acting μ-opioid receptor antagonists (PAMORAs).AimTo evaluate the efficacy of available PAMORAs and other approved or experimental treatments for relieving constipation in patients with opioid-induced constipation, based on a systematic review and meta-analysis of published studies.MethodsA search of MEDLINE, EMBASE and EBM Reviews Cochrane Central Register of Controlled Trials was completed in July 2019 for randomised trials compared to placebo. FDA approved doses or highest studied dose was evaluated. Efficacy was based on diverse endpoints, including continuous variables (the bowel function index, number of spontaneous bowel movements and stool consistency based on Bristol Stool Form Scale), or responder analysis (combination of >3 spontaneous bowel movements or complete spontaneous bowel movements plus 1 spontaneous bowel movement or complete spontaneous bowel movements, respectively, over baseline [so-called FDA endpoints]). Adverse effects evaluated included central opioid withdrawal, serious adverse events, abdominal pain and diarrhoea.ResultsWe included 35 trials at low risk of bias enrolling 13 566 patients. All PAMORAs demonstrated efficacy on diverse patient response endpoints. There was greater efficacy with approved doses of the PAMORAs (methylnaltrexone, naloxegol and naldemidine), with lower efficacy or lower efficacy and greater adverse effects with combination oxycodone with naloxone, lubiprostone and linaclotide.ConclusionsTherapeutic response in opioid-induced constipation is best achieved with the PAMORAs, methylnaltrexone, naloxegol and naldemidine, which are associated with low risk of serious adverse events.© 2020 John Wiley & Sons Ltd.

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