The Use of Peripheral μ-Opioid Receptor Antagonists (PAMORA) in the Management of Opioid-Induced Constipation: An Update on Their Efficacy and Safety

Abstract

Peripherally acting μ-opioid receptor antagonists (PAMORAs) constitute a class of drugs which reverse opioid-induced constipation (OIC) with similar opioid analgesic effects. OIC differs from other forms of constipation in that it is an iatrogenic condition that occurs when an opioid acts on the dense network of μ-opioid receptors in the enteric system, which affect a variety of functions including gastrointestinal motility, secretion, and other factors that can cause bowel dysfunction. Unfortunately, laxative products, bowel regimens, dietary changes, and lifestyle modifications have limited effectiveness in preventing OIC, Opioid-associated adverse effect which occurs in 40% to 80% of opioid patients and may led to cessation of the treatment. PAMORAs are μ-receptor opioid antagonists specifically developed so that they have very limited ability to cross the blood-brain barrier and thus they are able to antagonize peripheral but not central μ-opioid receptors. PAMORAs are designed to have no effect on the analgesic benefits of opioid pain relievers but to relieve but antagonizing the effects of the opioid in the gastrointestinal system. The three main PAMORAS are methyltrexone (oral or parenteral), naldemedine (oral only), and naloxegol (oral only). Clinical studies demonstrate the safety and efficacy of these agents for alleviating constipation without diminishing the analgesic effect of opioid therapy. The aim of this narrative review to update the current status of PAMORAs for treating OIC in terms of safety and efficacy.

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Keywords:

• constipation
• methylnaltrexone
• naldemedine
• naloxegol
• opioid antagonism
• opioid-associated bowel disorder
• opioid-associated side effects
• pain

Acknowledgments

There was no funding provided by a sponsor or other agency to produce this paper or in support of this work.

Abbreviations

CYP, cytochrome P; EMT, epithelial mesenchymal transition; ≥OIC, opioid-induced constipation; kg, kilogram; LLC, Lewis lung carcinoma; MACE, major adverse cardiovascular event; mg, milligram; NSCLC, non-small-cell lung cancerPAMORA, peripherally acting μ-opioid receptor; PAC-SYM, Patient Assessment of Constipation Symptoms; PRN, as needed; RFBM, rescue-free bowel movement; SBM, spontaneous bowel movement; TLR4, toll-like receptor 4.

Disclosure

JVP Jr is a consultant/speaker or researcher for AstraZeneca, US World Meds, BDSI, Salix, Enalare, Scilex, and Neumentum and is a principal at Native Cardio. He also reports personal fees from BDSI, during the conduct of the study; grants and/or personal fees from Salix and Astra Zeneca, outside the submitted work. PJC is on the advisory board of GlaxoSmithKline, Consumer Healthcare and is a consultant for Daichii Sankyo. He also reports personal fees from GlaxoSmithKline, Daiichi Sankyo, and BTG, assisted in media work for Algiatry, outside the submitted work. PM has received speaker fees or grants from Abbott, Alylam, Bayer, AstraZeneca, BMS, Boeringer-Ingelheim, Internetmedicine AB, Lilly, Novo Nordsik, Octupus Medical, Orion Pharma, Pfizer and Vifor Pharma. The authors report no other conflicts of interest in this work.