Elsevier

Mayo Clinic Proceedings

Volume 83, Issue 10, October 2008, Pages 1116-1130
Mayo Clinic Proceedings

SPECIAL ARTICLE
Development of Peripheral Opioid Antagonists: New Insights Into Opioid Effects

https://doi.org/10.4065/83.10.1116Get rights and content

The recent approval by the US Food and Drug Administration of 2 medications—methylnaltrexone and alvimopan—introduces a new class of therapeutic entities to clinicians. These peripherally acting μ-opioid receptor antagonists selectively reverse opioid actions mediated by receptors outside the central nervous system, while preserving centrally mediated analgesia. Methylnaltrexone, administered subcutaneously, has been approved in the United States, Europe, and Canada. In the United States, it is indicated for the treatment of opioid-induced constipation in patients with advanced illness (eg, cancer, AIDS) who are receiving palliative care, when response to laxative therapy has not been sufficient. Alvimopan, an orally administered medication, has been approved in the United States to facilitate recovery of gastrointestinal function after bowel resection and primary anastomosis. Clinical and laboratory studies performed during the development of these drugs have indicated that peripheral receptors mediate other opioid effects, including decreased gastric emptying, nausea and vomiting, pruritus, and urinary retention. Laboratory investigations with these compounds suggest that opioids affect fundamental cellular processes through mechanisms that were previously unknown. These mechanisms include modifications of human immunodeficiency virus penetration, tumor angiogenesis, vascular permeability, and bacterial virulence.

Section snippets

GASTROINTESTINAL EFFECTS OF OPIOIDS

Although respiratory depression is the most dangerous adverse effect of opioids, constipation is a far more common problem for most patients who use opioids. Opioid-induced constipation is a symptom of a more general syndrome called opioid-induced bowel dysfunction (OBD), which includes inhibition of gastric emptying, peristalsis, and secretions, as well as increased tone of intestinal sphincters.7 Slowed gastrointestinal transit, increased fluid absorption, and desiccation of stool lead to

PHARMACOTHERAPY FOR OPIOID GASTROINTESTINAL EFFECTS

The gastrointestinal effects of morphine and similar substances involve both central and peripheral mechanisms; however, the actions at μ receptors in the gut wall appear to be the most important mechanisms.23, 24, 25 Thus, a logical goal of treatment is to block these gut receptors while sparing those receptors mediating analgesia.

The first attempts to accomplish this goal involved low doses of orally administered naloxone. Naloxone, a tertiary amine that is lipid soluble and easily crosses

Delayed Gastric Emptying

Effects of PAMORAs on gastric emptying have not been as well studied as effects on bowel motility, and the potential clinical implications of delayed emptying are rather different from implications of POI or constipation. Opioids decrease the tone of gastric smooth muscle and increase the tone of sphincters—and gastric emptying is a function of both these effects. As mentioned previously, a trial of alvimopan did not show any effect on gastric emptying.57 Two studies showed that MNTX attenuates

CELLULAR EFFECTS

Four lines of preclinical investigation indicate that PAMORAs may prove useful in areas that are far removed from the problems of constipation and ileus. Many patients who are critically ill, including those with large tumors, are given high doses of opioids under the assumption that these drugs do little harm, provided that ventilation is adequate. However, increasing experimental evidence shows that opioids can produce undesirable effects on the growth of tumors and on the spread of infection

THE NEW DRUGS: FINAL THOUGHTS

Although alvimopan and MNTX work by the same mechanism, major distinctions exist between them. One important difference is the route of administration. Methylnaltrexone has been tested in oral and parenteral forms, but FDA approval is based only on the injectable form for subcutaneous administration. Oral MNTX has been tested in small volunteer protocols, but there are no peer-reviewed publications of larger-scale trials. Alvimopan has been tested only in an oral form, and it is not clear if an

CONCLUSION

Peripherally acting μ-opioid receptor antagonists have been proven useful for the relief of opioid-induced gastrointestinal dysfunction. The development of PAMORAs—including MNTX and alvimopan—has provided important insights into the peripheral effects of opioids. Methylnaltrexone has been approved by the FDA, Health Canada, and the European Medicines Agency. In the United States, it has been approved for subcutaneous injection in patients with advanced illness who are receiving palliative

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  • Cited by (0)

    Dr Moss has patent interests in methylnaltrexone and serves as a consultant to Progenics Pharmaceuticals, which has the license for methylnaltrexone's development. Wyeth Pharmaceuticals entered into an agreement with Progenics in December 2005 to develop and commercialize methylnaltrexone for the treatment of patients with opioid-induced adverse effects. Dr Rosow has received research support from Progenics Pharmaceuticals.

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