Advances to Block the Adverse Side Effects of Opioid Analgesics on the Gastrointestinal Tract Without Blocking Their Beneficial Analgesic Effects

Advances to Block the Adverse Side Effects of Opioid Analgesics on the Gastrointestinal Tract Without Blocking Their Beneficial Analgesic Effects

Leslie John B
US Gastroenterology Review 2007 - Issue II - October 2007
Published: October 2008
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Opioid-based analgesia is considered the standard of care for post-operative pain management and is widely used for the management of chronic pain.1–3 Opioids mediate analgesia by binding to mu-opioid receptors in the central nervous system (CNS);3 however, they also bind to mu-opioid receptors in the gastrointestinal (GI) tract, resulting in opioid-induced bowel dysfunction (OBD) or contributing to post-operative ileus (POI).3,4 The most commonly reported symptom of OBD, opioid-induced constipation (OIC), is considered an expected side effect of opioid therapy; it substantially reduces patient quality of life and may interfere with optimal opioid dosing.1,5,6 POI, a transient cessation of co-ordinated bowel motility, occurs after surgical intervention and may not resolve for more than five days.7 Currently, there are no consensus guidelines or US Food and Drug Administration (FDA)-approved pharmacological agents for the management of OBD, OIC, or POI.

Laxatives are the mainstay of the pharmacological management of constipation associated with OBD; however, these agents may not address other symptoms of OBD (e.g. gastroesophageal reflux, nausea, and omiting), must often be used in combination with other treatments, and may be associated with abdominal cramping, bloating, and gas.8,9 Moreover, a substantial proportion of patients continue to experience symptoms of OBD despite treatment with laxatives. Laxatives have also not consistently been successful in the management of POI.10 Many institutions have implemented multimodal care pathways intended to accelerate GI recovery after surgery. Some techniques or pathways are not feasible for all patients or available at all institutions, and patients may still experience POI even with implementation of these pathways.10

A new class of peripherally acting mu-opioid receptor (PAM-OR) antagonists target the mechanism underlying OBD and one of the primary causes of POI: opioid activation of mu-opioid receptors within the GI tract.11–15 Two agents in this pharmacological class—alvimopan (Adolor Corporation, Exton, Pennsylvania, and GlaxoSmithKline, Philadelphia, Pennsylvania) and methylnaltrexone (Progenics Pharmaceuticals, Tarrytown, New York, and Wyeth, Madison, New Jersey)—have been investigated for the management of OBD (alvimopan), OIC (methylnaltrexone), and POI (alvimopan and methylnaltrexone). This brief report presents a short introduction to the PAM-OR antagonist class and its mechanism of action, as well as a description of the current clinical development of methylnaltrexone and alvimopan.

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