Systematic review with meta‐analysis: efficacy and safety of treatments for opioid‐induced constipation

Abstract

Summary Background When 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). Aim To 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. Methods A 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. Results We 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. Conclusions Therapeutic 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.

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].…”

Can Naloxegol Therapy Improve Quality of Life in Patients with Advanced Cancer?

“…Laxative therapy is the first-line in OIC treatment [19,20], and its application is recommended from the beginning of opioid therapy (Figure 1). If laxative therapy is not effective, a change to target therapy with peripheral acting µ-opioid receptor antagonists (PAMORAs) is required [19][20][21][22]. Naloxegol, a PEGylated naloxone derivative, was approved by the European Medicines Agency (EMA) in 2014 for the treatment of OIC in patients with or without cancer.…”

Review article: diagnosis, management and patient perspectives of the spectrum of constipation disorders

“…126 Meta-analysis of the safety and efficacy of current OIC treatments has recently been published. 127…”

“…These guidelines recommend traditional laxatives (including PEG) as first‐line treatment for OIC, while peripherally acting µ‐opioid receptor antagonists and other prescription therapies are recommended for patients who fail traditional laxatives 126 . Meta‐analysis of the safety and efficacy of current OIC treatments has recently been published 127 …”