An update on the use of pharmacotherapy for opioid-induced bowel dysfunction

ABSTRACT

Introduction

With the growing rate of aging and the incidence of chronic diseases, there has been an upsurge in opioid prescription and abuse worldwide. This has been associated with increased reports of opioid-related adverse events, particularly opioid-induced bowel dysfunction (OIBD), calling for a rational clinical management strategy.

Areas Covered

Through searching PubMed, Scopus, Cochrane Library, and Web of Science, English literature was gathered as of 1 January 2017. Furthermore, the USFDA, EMA, TGA, Clinicaltrials.Gov, WHO-ICTRP databases, and the latest guidelines were reviewed to extract ongoing clinical studies and provide an evidence-based expert opinion with detailed information on efficacy, safety, approval status, and pharmacokinetics of the currently used medications.

Expert opinion

Despite the significant burden of OIBD, the clinical development of agents lags behind disease progress. Although in most places, management of opioid-induced constipation (OIC) is initiated by lifestyle modifications followed by laxatives, opioid antagonists, and secretagogue agents, there are still major conflicts among global guidelines. The fundamental reason is the lack of head-to-head clinical trials providing inter- and intragroup comparisons between PAMORAs, laxatives, and secretagogue agents. These investigations must be accompanied by further valid biopharmaceutical and economic evaluations, paving the way for rational clinical judgment in each context.

KEYWORDS:

• Alvimopan
• linaclotide
• lubiprostone
• methylnaltrexone
• naloxone
• naloxegol
• naldemedine
• Peripherally-acting mu receptor antagonists
• prucalopride
• pharmacotherapy

Article highlights

• Opioid-induced bowel dysfunction (OIBD), which covers a range of symptoms, including opioid-induced constipation (OIC) can be clinically diagnosed if symptoms initiate/worsen upon opioid commence/titration and continue for at least two weeks.

• Most guidelines agree on initiating a laxative bowel regimen (either stimulant agents or PEG) as preventive care, along with effective patient education and individualized lifestyle modifications. Meanwhile, conducting well-designed studies to evaluate the cost-effectiveness of laxatives as prophylactic treatments is warranted.

• As the first-line treatment of OIC, laxatives, either stimulants (i.e. bisacodyl, senna, and sodium picosulfate) or, more notably, osmotic laxatives (i.e. PEG), are recommended by almost all global expert panels. In contrast, docusate, mineral oil, saline osmotic laxatives, non-absorbable sugars, and insoluble fibers should be avoided.

• If there is no adequate response, PAMORAs, especially naloxegol and naldemedine, are strongly recommended. In contrast, methylnaltrexone has low-quality and inconsistent evidence in OIC.

• There has been no evidence supporting the efficacy of miscellaneous gastrointestinal agents (i.e. lubiprostone, linaclotide, and prucalopride) in OIC; though the USFDA and PMDA approved lubiprostone for this indication.

• A recently introduced fixed-dose combination of naloxone/oxycodone with gut-restrictive effects should give insight into other combination formulations containing various opioids with different strengths.

• There is an unmet need to perform well-designed, large-scale clinical studies on PAMORAs, and laxatives, particularly head-to-head, targeting pediatrics, the elderly, cancer patients, and those with other GI complications.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.