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

Joseph V Pergolizzi Jr,1 Paul J Christo,2 Jo Ann LeQuang,1 Peter Magnusson3,4 1NEMA Research, Inc., Naples, FL, USA; 2Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medicine, Baltimore, ML, USA; 3Cardiology Research Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden; 4Centre for Research and Development, Uppsala University/Region, Gävleborg, SwedenCorrespondence: Joseph V Pergolizzi JrNEMA Research, Inc., Naples, FL, USAEmail jpjmd@msn.comAbstract: 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.Keywords: constipation, methylnaltrexone, naldemedine, naloxegol, opioid antagonism, opioid-associated bowel disorder, opioid-associated side effects, pain