Efficacy and Safety of Peripherally Acting Mu-Opioid Receptor Antagonists for the Treatment of Opioid-Induced Constipation: A Bayesian Network Meta-analysis

Abstract

Objective To assess the efficacy and safety of peripherally acting mu-opioid receptor antagonists (PAMORAs) for the treatment of opioid-induced constipation (OIC). Methods Randomized controlled trials (RCTs) were searched for OIC therapy comparing PAMORAs with placebo. Both a pairwise and network meta-analysis were performed. The surface under the cumulative ranking area (SUCRA) was used to determine the efficacy and safety of OIC treatment using different PAMORAs. Results The primary target outcome was a response that achieves an average of three or more bowel movements (BMs) per week. In the network meta-analysis, four PAMORAs (naldemedine, naloxone, methylnaltrexone, and alvimopan) showed a better BM response than the placebo. Naldemedine was ranked first (odds ratio [OR] = 2.8, 95% credible interval [CrI] = 2–4.5, SUCRA = 89.42%), followed by naloxone (OR = 2.9, 95% CrI = 1.6–5.3, SUCRA = 87.44%), alvimopan (OR = 2.2, 95% CrI = 1.3–3.5, SUCRA = 68.02%), and methylnaltrexone (OR = 1.7, 95% CrI = 1.0–2.8, SUCRA = 46.09%). There were no significant differences in safety found between the PAMORAs and the placebo. Conclusions We found that PAMORAs are effective and can be safely used for the treatment of OIC. In network meta-analysis, naldemedine and naloxone appear to be the most effective PAMORAs for the treatment of OIC.

Effects of opium tincture on the enteric and central nervous systems: A randomized controlled trial

“…32,33 The direct underlying mechanism behind these effects, that is, activation of μ-opioid receptors within the submucosal and myenteric plexus of the enteric nervous system, is evident by the alleviation of constipation symptoms during opioid treatment when a peripherally acting μ-opioid receptor antagonist is co-subscribed. 25,[34][35][36] The current study confirms for the first time that opium tincture possesses gastrointestinal-altering actions in healthy, which could also be beneficial in the treatment of chronic diarrhoea. Previous studies regarding segmental transit time in chronic diarrhoea patients treated with opioids are very limited, but two randomized controlled trials have shown that loperamide decreased gastric emptying time.…”

Efficacy and Safety of Methylnaltrexone for the Treatment of Opioid-Induced Constipation: A Meta-analysis of Randomized Controlled Trials

“…Several previous reviews on the similar topic have been published [22][23][24][25][26][27][28][29]. Six of them evaluated the treatment of OIC with different pharmacological therapies, mainly l-opioid receptor antagonists, including methylnaltrexone [22][23][24][25][26][27].…”

Antagonists of the Mu-Opioid Receptor in the Cancer Patient: Fact or Fiction?

“…The PAMORAs are specifically designed to avoid blood–brain barrier penetration and counteract the mu-opioid-related side effects outside the central nervous system (CNS)[ 19 ] had been studied in postoperative nausea and vomiting (PONV) and postoperative ileus (POI) [ 20 , 21 , 22 •, 23 , 24 ]. Their current main therapeutic indication is opioid-induced constipation (OIC) related to MOR activation in the gastrointestinal tract mainly in patients receiving chronic opioid therapy, considered safe, effective, and well-tolerated agents [ 25 – 27 , 28 •].…”