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Peripherally Acting Mu-Opioid Receptor Antagonists and Postoperative Ileus: Mechanisms of Action and Clinical Applicability

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Peripherally Acting Mu-Opioid Receptor Antagonists and Postoperative Ileus: Mechanisms of Action and Clinical Applicability Review Article Peripherally Acting Mu-Opioid Receptor Antagonists and Postoperative Ileus: Mechanisms of Action and Clinical Applicability Eugene R. Viscusi, MD* Postoperative ileus (POI), a transient cessation of coordinated bowel function after surgery, is an important health care problem. The etiology of POI is multifactorial Tong J. Gan, MD† and related to both the surgical and anesthetic pathways chosen. Opioids used to manage surgical pain can exacerbate POI, delaying gastrointestinal (GI) recovery. John B. Leslie, MD, MBA‡ Peripherally acting mu-opioid receptor (PAM-OR) antagonists are designed to mitigate the deleterious effects of opioids on GI motility. This new class is investigational for POI management with the goal of accelerating the recovery of Joseph F. Foss, MD§ upper and lower GI tract function after bowel resection. In this review, we summarize the mechanisms by which POI occurs and the role of opioids and opioid Mark D. Talon, CRNA࿣ receptors in the enteric nervous system, discuss the mechanism of action of PAM-OR antagonists, and review clinical pharmacology and Phase II/III POI trial Wei Du, PhD¶ results of methylnaltrexone and alvimopan. Finally, the role of anesthesiologists in managing POI in the context of a multimodal approach is discussed. Gay Owens, PharmD¶ (Anesth Analg 2009;108:1811–22) Postoperative ileus (POI) is a transient cessation of (BR), often not resolving for 4 days or longer.3 Clini- coordinated bowel motility that prevents effective cally, POI is characterized by delayed passage of flatus transit of intestinal contents or tolerance of oral in- and stool, bloating, abdominal distension, abdominal take.1,2 POI occurs universally after bowel resection pain, nausea, and vomiting and is associated with an increase in postoperative morbidity and length of 4,5 From the *Department of Anesthesiology, Jefferson Medical hospital stay (LOS). The etiology of POI is multi- College, Thomas Jefferson University, Philadelphia, Pennsylvania; factorial and includes the surgical stress response †Department of Anesthesiology, Duke University Medical Center, (inhibitory reflexes resulting from sympathetic neu- Durham, North Carolina; ‡Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota; §Cleveland ral stimulation) and an acute inflammatory response Clinic, Cleveland, Ohio; ࿣Department of Anesthesiology, University associated with manipulation of the bowel.4,6–9 En- of Texas Medical Branch, Galveston, Texas; and ¶Adolor Corpora- dogenous opioids secreted within the gastrointesti- tion, Exton, Pennsylvania. nal (GI) tract in response to surgical stress and Accepted for publication November 7, 2008. administration of exogenous opioid-based analgesia Support for this study and funding for medical editorial assis- tance was provided by Adolor Corporation, Exton, PA, and Glaxo- can stimulate peripheral opioid receptors within the SmithKline, Philadelphia, PA. GI tract, which may exacerbate POI and further Dr. Viscusi received grant support from Adolor Corporation delay GI recovery.4,7,10–13 (alvimopan) and Progenics (methylnaltrexone) for the performance of clinical trials and is also a consultant for Adolor Corporation. Dr. The time required to recover GI function often 14 Gan has received research support from Schering-Plough, MGI determines the LOS. In the United States, LOS for Pharma, Edwards Lifesciences, Wyeth Pharmaceuticals, Javelin, patients undergoing BR ranges from 5 to 14 days.15,16 Aspect, and Hospira. He has served on the speakers bureaus for Edwards Lifesciences and Aspect Medical. Dr. Leslie received Mean cost per hospital stay has been estimated to be grants/research funding from Wyeth Pharmaceuticals and Progen- approximately $6000 more for patients with coded ics Pharmaceuticals and served as an advisor for Adolor Corpora- POI compared with patients without coded POI.17 tion, GlaxoSmithKline, Baxter Pharmaceuticals, Xsira, and Organon. Dr. Foss is a former employee of Adolor, holds patent rights to Therefore, accelerating GI recovery after BR via pa- methylnaltrexone, and owns stock in Progenics. He currently re- tient management or pharmacologic approaches ceives research support from MGI Pharma. Mr. Talon has nothing to disclose. Dr. Du is a former employee of Adolor Corporation and would represent a clinically important addition to the has stock options. Dr. Owens is an employee of Adolor Corporation standard of care. Current management of POI has and has stock options. included the following: nasogastric tube (NGT) inser- Address correspondence and reprint requests to Eugene R. tion, IV hydration and parenteral nutrition, laxatives Viscusi, MD, Department of Anesthesiology, Acute Pain Manage- ment Service, Thomas Jefferson University, 111 S. 11th St., Suite and off-label use of drugs, such as ceruletide, meto- G-8490, Philadelphia, PA 19107. Address e-mail to eugene.viscusi@ clopramide, somatostatin, and erythromycin.2,15,18 jefferson.edu. However, these therapies have either proven inad- Copyright © 2009 International Anesthesia Research Society equate for management of POI, increased risk for DOI: 10.1213/ane.0b013e31819e0d3a additional postoperative complications, or not been Vol. 108, No. 6, June 2009 1811 clinically validated. Accelerated GI recovery has been activity.8,34 Therefore, because of its complex intercon- reported by some health care centers with the use of necting neural networks and sophisticated functions, multimodal care pathways.1,19–24 These pathways in- the ENS is often referred to as the brain in the GI corporate patient education, the use of less-invasive tract.33 surgical techniques, and opioid-sparing analgesics or Three types of neurons mediate the regulation of techniques, such as epidural analgesia.1,19–24 How- ENS functions: sensory neurons, interneurons, and ever, some anesthetic pathways and advanced surgi- motor neurons.34,36 Enteric sensory neurons receive cal techniques are not feasible for all patients and sensory information from sensory receptors in the not available at all institutions.1,19–24 Previous phar- intestinal epithelium, mucosa, and muscle.34,36 Inter- macologic approaches, such as prokinetic drugs or neurons serve as conduits between the sensory and laxatives, have not been consistently successful for motor neurons and between different motor neurons managing POI.25,26 Furthermore, epidural analgesia to allow the ENS to function as an intercommunicat- has become less popular with the routine application ing network in the intestinal plexuses.34 Excitatory of anticoagulation for venous thromboembolism pro- and inhibitory motor neurons work in concert to phylaxis. A class of drugs known as peripherally mediate effective peristalsis through interaction and acting mu-opioid receptor (PAM-OR) antagonists tar- control of smooth muscle cells, epithelial cells, glands, get one of the main causes of POI: opioid activation of and blood vessels.34,36 The inflammatory response to mu-opioid receptors in the GI tract.1,4 Two drugs in manipulation of the intestines during abdominal sur- this PAM-OR antagonist class, methylnaltrexone and gery can also influence GI motility.6 Immune cells alvimopan, are under investigation or approved for infiltrate the intestines and secrete proinflammatory the management of POI after BR.*27–31 Methylnaltrex- cytokines, resulting in decreased smooth muscle func- one is currently approved for treatment of opioid- tion and GI dysmotility.4 induced constipation in patients with advanced illness32 and was investigated in Phase III POI trials. OPIOID RECEPTORS IN THE CNS AND ENS Alvimopan was recently approved by the US Food Opioid receptors are G protein-coupled receptors and Drug Administration (FDA) to accelerate the time that mediate a wide variety of physiologic effects to upper and lower GI recovery after partial large or through the binding of endogenous opioid peptides small BR with primary anastomosis. We present a and exogenous opioids. The three primary opioid brief background of opioid receptors and their role in receptor types (mu, ␦, and kappa) are ubiquitous in enteric physiology, the mechanisms of action of the CNS and ENS.11 Mu-opioid receptors are the PAM-OR antagonists, and a review of published clini- primary mediators of opioid analgesic effects in the cal trial data of PAM-OR antagonists in patients CNS (mu1) and GI-related effects in the GI tract undergoing BR. Finally, a discussion is presented on 11 (mu2). In the CNS, mu-opioid receptors are enriched how, as perioperative physicians, anesthesiologists in the cerebral cortex, striatum, and hippocampus in can work within the surgical team to manage POI in the brain.37 The central effects mediated by opioids in this surgical population. Table 1. Effects of Opioids on the Gastrointestinal Tract ENTERIC NEUROPHYSIOLOGY The enteric nervous system (ENS) is the neural Pharmacologic network that supplies the digestive tract and mediates action Clinical effect complex reflex activity in the GI tract independently Decreased gastric Decreased appetite, increased of the central nervous system (CNS). The ENS pro- motility and gastroesophageal reflux emptying cesses information from sensory receptors, regulates Decreased pyloric tone Nausea and vomiting neural reflex activities, and coordinates the complex Decreased enzymatic Delayed digestion; hard, dry motor patterns in the GI tract responsible for mixing secretion stools and propulsive movements and the secretory func- Inhibition of small and Delayed absorption of tions.33
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