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

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, Opioidassociated 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.

What to Do and What Not to Do in the Management of Opioid-Induced Constipation: A Choosing Wisely Report

“…These agents are an attractive option for OIC as they target the cause of constipation symptoms (i.e., opioid receptors). Naldemedine, naloxegol, and methylnaltrexone are three common PAMORAs that have demonstrated good efficacy for the management of OIC but continue to be underutilized by clinicians [32]. A recent meta-analysis of available medications for OIC highlighted a body of evidence supporting the use of these three agents to treat OIC in chronic non-cancer pain [33].…”

“…PAMORAs have not demonstrated significant efficacy for OIC prevention, but physicians should be aware of their excellent utility and tolerability for OIC management [41]. Physicians should however pay careful attention to the use of PAMORAs in patients with abdominal cancer or complete or partial bowel obstruction due to the risk of precipitating cramps or colicky pain [32,42].…”

Novel Analgesics with Peripheral Targets

“…Moreover, with a prolonged inflammatory event, peripheral receptors seem to account for the majority of the analgesic effect [ 28 ]. Peripherally restricted μ-opioid receptor antagonists methylnaltrexone, alvimopan, and naloxegol could allow to reduce dose-limiting side effects of blood–brain barrier–permeable agonists, e.g., constipation [ 29 ]. A similar strategy should work for developing kappa-receptor agonists.…”

Opioid-induced Constipation

“…37 In a recent systematic review of 14 randomized controlled trials that assessed PAMORA therapy in patients with OIC, Schwenk et al 40 concluded that the PAMORAs as a drug class are effective for the treatment of OIC. Likewise, Pergolizzi et al 41 conducted a comprehensive review of PAMORAs approved for OIC, which concluded that the PAMORAs were safe and effective for the treatment of OIC. The authors tabulated safety variables and determined that adverse events commonly reported were often mild to moderate abdominal pain, flatulence, nausea, and diarrhea, for example, which are generally gastrointestinal-related, and an expected consequence of effective laxation.…”

“…The authors tabulated safety variables and determined that adverse events commonly reported were often mild to moderate abdominal pain, flatulence, nausea, and diarrhea, for example, which are generally gastrointestinal-related, and an expected consequence of effective laxation. 41 …”