I read with great interest the letter by Mehta in your December issue regarding the role of peripheral opioid antagonism in the treatment of opioid-induced bowel dysfunction. Alvimopan was reviewed by the author as a 'highly potent competitive antagonist at the human μ opioid receptor' [1]. However, there are several points made by the author that require clarification.
First, the author states that the “oral bioavailability [of alvimopan] is only 6%, restricting its activity predominantly to the gut where it is metabolised' [1]. While it is true that the oral bioavailability of alvimopan is 6%, this is not the reason for the peripheral restriction of the compound. Rather, alvimopan is a large molecular weight zwitterion, with high polarity, that does not cross the blood-brain barrier at clinically relevant concentrations [2].
Secondly, the author states that 'in patients who developed postoperative ileus after undergoing bowel resection and hysterectomy… alvimopan administration reduced the time to first bowel movement or flatus, or total time to pass flatus when compared to placebo.' Alvimopan is not administered to patients who develop postoperative ileus; rather, the patient receives the first 12 mg dose of drug 30 minutes to 5 hours before surgery followed by 12 mg twice daily for up to 7 days [3]. Further to this point, the author’s statement that 'alvimopan is licensed to prevent postoperative ileus' is incorrect. The indication for alvimopan is for the acceleration of upper and lower gastrointestinal recovery following partial large or small bowel resection with primary anastomosis, not for treatment or prevention of postoperative ileus [3]. Also, the major endpoints in the placebo-controlled alvimopan phase three clinical development program were a composite of upper and lower gastrointestinal recovery, gastrointestinal recovery 2 (the latter being the time to tolerate solid food and first bowel movement and gastrointestinal recovery 3 (the latter being time to tolerate solid food and time to first bowel movement or first flatus), rather than those stated by the author [4-7].
Finally, the author states that 'long-term efficacy studies have found an association between treatment with alvimopan and an increased risk of cardiovascular event.' Preliminary findings from a long-term safety study of alvimopan for opioid-induced bowel dysfunction (a chronic condition) demonstrated a numeric imbalance in reports of myocardial infarction [8]. However, no imbalance in myocardial infarction was observed in other clinical trials evaluating alvimopan for opioid-induced bowel dysfunction, or the population data from the postoperative ileus trials (an acute condition), that were the basis for the approval of alvimopan for short-term hospital use in patients undergoing bowel resection [9]. In addition, a causal relationship between myocardial infarction and alvimopan exposure has not been established [3]. It was subsequently found that patients who experienced cardiovascular events in the opioid-induced bowel dysfunction trials were generally older or had established cardiovascular disease and that rates of both of these traits were higher in the alvimopan group compared with placebo [9].
Lee Techner, DPM
Vice President Medical Affairs and Medical Director
Adolor Corporation
fax 484-595-1513
ltechner@adolor.com
Conflict of interest:
Lee Techner, DPM, is the Vice President of Medical Affairs and a Medical Director at Adolor Corporation, the company that developed and is co-marketing Entereg® (alvimopan).
References
1. Mehta V Peripheral opioid antagonism. Anaesthesia 2009; 64: 1279-82.
2. Viscusi ER, Gan TJ, Leslie JB, et al. Peripherally acting mu-opioid receptor antagonists and postoperative ileus: mechanisms of action and clinical applicability. Anesthesia & Analgesia 2009; 108: 1811-22.
3. Adolor Corporation. Entereg® (alvimopan) Capsules. Prescribing Information. Available at: http://www.entereg.com/pdf/prescribing-information.pdf. (accessed 05/01/2010).
4. Wolff BG, Michelassi F, Gerkin TM, et al. Alvimopan, a novel, peripherally acting mu opioid antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus. Annals of Surgery 2004; 240: 728-34; discussion 34-35.
5. Delaney CP, Weese JL, Hyman NH, et al. Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery. Diseases of the Colon and Rectum 2005; 48: 1114-25; discussion 25-26; author reply 27-29.
6. Viscusi ER, Goldstein S, Witkowski T, et al. Alvimopan, a peripherally acting mu-opioid receptor antagonist, compared with placebo in postoperative ileus after major abdominal surgery: results of a randomized, double-blind, controlled study [published erratum appears in Surg Endosc 2006; 20: 537]. Surgical Endoscopy 2006; 20: 64-70.
7. Ludwig K, Enker WE, Delaney CP, et al. Gastrointestinal tract recovery in patients undergoing bowel resection: results of a randomized trial of alvimopan and placebo with a standardized accelerated postoperative care pathway. Archives of Surgery 2008; 143: 1098-105.
8. GSK and Adolor announce preliminary results from phase 3 safety study of alvimopan (Entereg/Entrareg). GSK press release. Available at: http://us.gsk.com/html/media-news/pressreleases/2007/2007_04_09_GSK1056.htm (accessed 26/02/2010)
9. Adolor Corporation. Entereg® (alvimopan) Capsules for Postoperative Ileus (POI). FDA Advisory Panel Briefing Document. Available at: http://www.fda.gov/ohrms/DOCKETS/ac/08/briefing/2008-4336b1-02-Adolor.pdf (accessed 20/02/2010).