Development of peripheral opioid antagonists' new insights into opioid effects.
ABSTRACT 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 mu-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.
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ABSTRACT: The treatment of cancer-associated pain as well as chronic non-cancer-related pain (CNCP) is an increasingly relevant topic in medicine. However, it has long been recognized that opiates can adversely affect many organ systems, most notably the gastrointestinal system. These are referred to as the spectrum of "opioid-induced bowel dysfunction" (OBD) or what we will refer to as "opioid-induced bowel disease" (OIBD) which include constipation, nausea, vomiting, delayed gastric emptying, and gastro-esophageal reflux disease (GERD), and a newer entity known as narcotic bowel syndrome (NBS). Opioid analgesics are increasingly being used for the treatment of cancer pain, non-cancer-associated pain, and postoperative pain. As we achieve our goals towards pain control, we need to be cognizant of and competent in how to prevent and treat OIBD. The basis is due in part to µ-receptor activation, decreasing the peristaltic contraction and leading to sequelae of OIBD. Treatment beyond lifestyle interventional strategy will employ laxatives and stool softeners. However, studies performed while patients were already using laxativies and stool softeners have elicited the necessity of peripherally acting agents such as methylnaltrexone (MNTX) and alvimopan. Patients responded dramatically to both medications, but these studies were limited to patients that were deemed to have advanced illness. Lubiprostone, while different in its mechanism of action from MNTX and alvimopan, has proven effective and should be considered for use in OIBD. Further investigational research will promulgate more information and allow for better and more efficient treatment options for OIBD.Current Gastroenterology Reports 07/2013; 15(7):334.
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ABSTRACT: Gastrointestinal dysmotility and constipation are common problems in critical care patients. The majority of critical care patients are treated with opioids, which inhibit gastrointestinal (GI) motility and lead to adverse outcomes. We reasoned that methylnaltrexone (MNTX), a peripheral opioid antagonist approved for the treatment of opioid-induced constipation in patients with advanced illness receiving palliative care when response to laxative therapy has not been sufficient, could improve GI function in critically ill patients. The present study included all patients in our intensive care unit who required rescue medication for GI stasis during the 10-week period from September 1 to November 15, 2009. We compared conventional rescue therapy with subcutaneous MNTX. We performed a retrospective chart review of the 88 nonsurgical critical care patients receiving fentanyl infusions, 15 (17%) of whom met the criteria of absence of laxation within 72 hours of intensive care unit admission despite treatment with senna and sodium docusate. Eight of these 15 patients subsequently received conventional rescue therapy (combination of sodium picosulfate [5 mg] and 2 glycerin suppositories [4-g mold]), and 7 patients received MNTX (subcutaneous injection, 0.15 mg/kg). Laxation occurred within 24 hours in 6 of the 7 MNTX patients (86%) but in none of the 8 patients receiving conventional rescue therapy (P=.001). The median difference in time to laxation between the 2 groups was 3.5 days (P<.001). Although not statistically significant, all 7 patients treated with MNTX, but only 4 of 8 (50%) who received conventional rescue therapy, progressed to full target enteral feeding (P=.08). Intensive care unit mortality was 2 of 7 MNTX patients (29%) vs 4 of 8 (50%) in the standard therapy group (P=.61). We hypothesize that MNTX may play an important role in restoration of bowel function in critically ill patients.Mayo Clinic Proceedings 03/2012; 87(3):255-9. · 5.79 Impact Factor
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ABSTRACT: The in vivo preclinical pharmacodynamic profile of TD-1211, a selective opioid receptor antagonist currently under development for the treatment of opioid-induced constipation, was compared to that of the clinically studied opioid antagonists, naltrexone, alvimopan, and ADL 08-0011 (the primary active metabolite of alvimopan). The oral activity of TD-1211 was evaluated in models of gastrointestinal (GI) and central nervous system (CNS) function in the rat and dog. Oral administration of TD-1211, naltrexone, and ADL 08-0011 reversed loperamide-induced inhibition of gastric emptying and castor oil-induced diarrhea in rats and nonproductive GI circular smooth muscle contractility in dogs. Alvimopan was only efficacious in the castor oil model. Oral administration of naltrexone and ADL 08-0011, but not TD-1211 or alvimopan, was associated with a CNS withdrawal response in morphine-dependent mice, inhibition of morphine-induced anti-nociception in rat and dog hot plate tests, and hypothermia and sedation in dogs. It is concluded that TD-1211 has potent in vivo GI activity, consistent with opioid receptor antagonism, but has no significant CNS activity. The data from these studies support the clinical development of TD-1211 as a novel treatment for opioid-induced GI dysfunction.Archiv für Experimentelle Pathologie und Pharmakologie 03/2013; · 2.15 Impact Factor