Motility Disorders Constipation
Methylnaltrexone—A New Peripheral Opioid Receptor Antagonist— Clinical Considerations
Karen Kim, MD, MS1 and Jonathan Moss, MD, PhD2
1. Associate Professor of Gastroenterology, Hepatology, and Nutrition, Department of Medicine; 2. Professor, Vice Chairman for Research, Department of Anesthesia and Critical Care, and Professor of the College, University of Chicago
Abstract
Progenics Pharmaceuticals, Inc.) was recently approved by the US Food and Drug Administration (FDA) for the treatment of opioid-induced constipation (OIC) in patients with advanced illness receiving palliative care who have a suboptimal response to conventional laxative therapy. Additionally, recent studies suggest that MNTX’s therapeutic effect in treating OIC may include those with chronic pain, post-operative bowel dysfunction after orthopedic surgery, and certain intensive care unit (ICU) patients. This article describes the discovery and approval of MNTX, the results of clinical trials that have been reported since its approval, and the potential role MNTX may play in the treatment of gastrointestinal (GI) disorders.
Keywords Methylnaltrexone, constipation, opioid-induced constipation, palliative care, colonic transit, opioid antagonists
Disclosure: Jonathan Moss, MD, PhD, serves as a paid consultant to Progenics Pharmaceuticals, Inc., has a financial interest in methylnaltrexone as a patent holder through the University of Chicago, and receives stock options from Progenics Pharmaceuticals, Inc. Karen Kim, MD, MS, has no conflicts of interest to declare. Received: August 5, 2010 Accepted: October 14, 2010 Citation: US Gastroenterology & Hepatology Review, 2010;6:38–42 Correspondence: Jonathan Moss, MD, PhD, Department of Anesthesia and Critical Care, Professor of the College, University of Chicago, 5841 S Maryland Ave., MC 4028, Chicago, IL 60637. E:
jm47@midway.uchicago.edu
Support: The publication of this article was funded by Progenics Pharmaceuticals, Inc.
Constipation in patients on opioid pain medication contributes significantly to patient discomfort, co-morbidities, and length of hospital stay. This is especially pronounced among those receiving palliative care, where pain control is optimized to reduce pain and suffering. Methylnaltrexone (MNTX; Relistor®
The development of methylnaltrexone (MNTX; RELISTOR®, Progenics Pharmaceuticals, Inc.) and its approval by the US Food and Drug Administration (FDA) two years ago has provided an important option for gastroenterologists for the treatment of opioid-induced constipation (OIC) in patients with advanced illness receiving palliative care when response to laxative therapy has not been sufficient.1,2
Beyond its role in
palliative care, recent studies suggest that MNTX may have therapeutic potential in the wider population of chronic pain patients with OIC, in patients with post-operative bowel dysfunction after orthopedic surgery, and in certain intensive care unit (ICU) patients. While primary care physicians, palliative pain physicians, oncologists, and anesthesiologists all prescribe opioids, OIC can be sufficiently difficult to manage that it often merits consultation by a gastroenterologist. It is the purpose of this article to review the studies leading to the approval of MNTX and to describe potential uses that have emerged since its approval.
Development Of Methylnaltrexone
It has long been proposed that the µ opioid receptor modulates both the analgesic and gut effects3 endogenous opioids4,5
of opioids, and exogenous as well as can directly influence gut motility. Despite our
understanding of the biology of opioids and pain, few new approaches to 38
patient care have emerged. Although µ opioids are effective in pain management, their adverse effects can limit their use. Among the adverse effects of opioids, the most clinically important is OIC. Constipation occurs in more than half of patients receiving opioids for palliative care.6
may limit effective pain control.7,8
preferred pain to the severe constipation induced by opioids.9 patients do not become tolerant to the constipating effects of opioids.
It is often refractory to stool softeners and laxatives and Studies have shown that patients Moreover,
Initial attempts to separate the analgesic from the adverse effects of opioids focused on the oral use of low doses of tertiary-ammonium compounds such as naloxone. In several small trials, naloxone and similar tertiary-ammonium opioid antagonists successfully reversed the constipating effects of opioids, with only 2% reaching the circulation due to first-pass metabolism. However, because these compounds cross the blood–brain barrier, pain control was difficult to titrate.10–13
Professor
Leon Goldberg at the University of Chicago reasoned that a charged molecule with opioid antagonist properties would not penetrate the blood–brain barrier, thus preserving central analgesia when given with opioids (see Figure 1). A methyl group added to naltrexone at the ring nitrogen resulted in the positively charged molecule MNTX.
© TOUCH BRIEFINGS 2010
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100