Investigational opioid antagonists for treating opioid-induced bowel dysfunction

ABSTRACT

Introduction: Opioids have been highlighted for their role in pain relief among cancer and non-cancer patients. Novel agents have been investigated to reduce opioid-induced constipation (OIC) as the main adverse effect that may lead to treatment discontinuation. Development of peripherally acting mu-opioid receptor antagonists (PAMORA) has resulted in a novel approach to preserve the efficacy of pain control along with less OIC.

Areas covered: Clinical evidence for investigational PAMORAs was reviewed and clinical trials on investigational agents to reduce OIC were included. TD-1211 is currently being evaluated in Phase II clinical trial. Oxycodone-naltrexone and ADL-5945 went through Phase III clinical trials, but have been discontinued.

Expert opinion: There is a substantial need to develop agents with specific pharmacokinetic properties to meet the needs of patients with underlying diseases. Holding the efficacy of a medicine with the highest selectivity on targeted receptors and the least adverse effects is the main approach in upcoming investigations to improve patients’ quality of life (QoL). Novel agents to reduce opioid-induced bowel dysfunction (OIBD) that do not reverse peripherally mediated pain analgesia are of great interest. Direct comparison of available agents in this field is lacking in the literature.

KEYWORDS:

• Clinical trial
• constipation
• mu-opioid receptor antagonists
• opioid-induced constipation

Article highlights

• Use of OPIOIDs in chronic pain management can be completed if adverse effects are minimized.

• Peripheral mu-opioid receptors are responsible for opioid-induced bowel dysfunctions (OIBD). Selective peripherally acting mu-opioid receptor antagonists (PAMORA) are novel investigational agents with promising less OIBD.

• The most prevalent opioids-associated adverse effect is constipation that has a great social and economic burden.

• Three approved agents, including methylnaltrexone, naloxegol, and oxycodone-naloxane are available in the market. Naldemedine has passed Phase IV of clinical trial and approved recently. TD-1211 is still being evaluated in Phase II clinical trial.

• Developing agents with better safety and cost-effectiveness are of value. Pharmacokinetic issues should be considered in patients with underlying diseases.

• New approaches to reduce OIBD without reversing peripherally mediated pain analgesia should be taken into account.

In order to set up a direct comparison between PAMORAs, similar outcome measures should be applied in future studies.

This box summarizes key points contained in the article.

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.

Additional information

Funding

This paper was not funded.