-
The Oncologist Jul 2009
Review
Topics: Humans; Laxatives; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds
PubMed: 19605844
DOI: 10.1634/theoncologist.2009-0049 -
Journal of the Advanced Practitioner in... 2019Opioid-induced constipation (OIC) is a common adverse effect associated with opioid therapy, with many patients never developing tolerance to this effect. There are many... (Review)
Review
Opioid-induced constipation (OIC) is a common adverse effect associated with opioid therapy, with many patients never developing tolerance to this effect. There are many traditional laxatives available to help patients combat this symptom, yet OIC may not reliably respond to conventional treatment. Peripherally acting µ-opioid receptor antagonists (PAMORAs) have a place in the treatment of refractory OIC, when traditional laxatives have not resulted in effective laxation. There are a number of PAMORAs now available, and methylnaltrexone is the only PAMORA indicated for the treatment of OIC in adults with advanced illness, as well as for patients with chronic noncancer pain, including patients with chronic pain related to prior cancer treatment who do not require frequent opioid escalation. Advanced practitioners need to have an understanding of how and when to best use these medications for the different indications in patients with advanced illness or chronic noncancer-related pain.
PubMed: 31308989
DOI: No ID Found -
Drugs May 2010Methylnaltrexone is a selective mu-opioid receptor antagonist that has restricted ability to cross the blood-brain barrier, thus enabling reversal of opioid-induced... (Review)
Review
Methylnaltrexone is a selective mu-opioid receptor antagonist that has restricted ability to cross the blood-brain barrier, thus enabling reversal of opioid-induced peripheral effects, such as constipation, without affecting the central effects, such as pain relief. Treatment with subcutaneous methylnaltrexone 0.15-0.30 mg/kg, relative to placebo, significantly increased the rescue-free laxation response rate within 4 hours of the first dose (primary endpoint) in adult patients with opioid-induced constipation and advanced illness in two randomized, double-blind, placebo-controlled, multicentre, phase III studies; one was a single-dose study (n = 154), the other a multiple-dose study (n = 133). In the multiple-dose study, rescue-free laxation response rates within 4 hours after at least two of the first four doses (coprimary endpoint) were also significantly higher in methylnaltrexone recipients than in placebo recipients. Moreover, median time to laxation after the first dose was significantly shorter in methylnaltrexone recipients than in placebo recipients in both studies. Methylnaltrexone was not associated with any significant changes in pain scores or central opioid withdrawal in these studies. Methylnaltrexone was generally well tolerated in clinical trials; most adverse events were of mild to moderate severity.
Topics: Analgesics, Opioid; Constipation; Humans; Molecular Structure; Naltrexone; Quaternary Ammonium Compounds; Randomized Controlled Trials as Topic; Receptors, Opioid, mu; Treatment Outcome
PubMed: 20426500
DOI: 10.2165/11204520-000000000-00000 -
Drugs in R&D 2006Methylnaltrexone is a peripheral opioid receptor antagonist undergoing phase III clinical trials for the treatment of opioid-induced constipation in patients with... (Review)
Review
Methylnaltrexone is a peripheral opioid receptor antagonist undergoing phase III clinical trials for the treatment of opioid-induced constipation in patients with advanced medical illness who are being treated with narcotics for pain. The compound does not cross the blood-brain barrier in humans and reverses the opioid effects without interfering with pain relief. Some opioid-induced adverse events that the drug may potentially target include constipation, nausea/vomiting, cough suppression and urinary retention. Methylnaltrexone was discovered by researchers at the University of Chicago, Chicago, Illinois, USA and is in joint development with Progenics Pharmaceuticals and Wyeth Pharmaceuticals. Progenics is conducting clinical trials with three methylnaltrexone dosage forms: subcutaneous, IV and oral. Progenics plans to complete the clinical development of methylnaltrexone alone, after which potential pharmaceutical or biotechnology partners will be looked at to provide financial support and marketing expertise, particularly outside the US market. In December 2005, Progenics and Wyeth Pharmaceutical (Wyeth) entered into an exclusive, worldwide agreement for the joint development and commercialisation of methylnaltrexone for the treatment of opioid-induced side effects, including constipation and postoperative bowel dysfunction. Under the terms of the licensing agreement, Wyeth has worldwide rights to the compound and Progenics retains the option to co-promote methylnaltrexone in the US. The companies will collaborate on the worldwide development of methylnaltrexone. Under the terms of the agreement, Wyeth has made an up-front payment to Progenics and will also make additional milestone payments. Wyeth will also pay Progenics royalties on worldwide sales, and co-promotion fees within the US. Wyeth is also responsible for all future development and commercialisation costs. Wyeth will develop oral methylnaltrexone worldwide. Progenics will lead the US development of subcutaneous and intravenous methylnaltrexone, while Wyeth will lead development of these parenteral products outside the US.UR Labs licensed methylnaltrexone from the University of Chicago. In October 2001, Progenics in-licensed the methynaltrexone patent portfolio in exchange for rights to future methynaltrexone royalties. In December 2005, Progenics acquired a substantial portion of the royalty and milestone payments in exchange for 686,000 shares of Progenic's common stock and 2.6 million US dollars in cash. In April 2005, Progenics Pharmaceuticals made a public offering of 2 million shares of its common stock, pursuant to an effective shelf registration statement. Progenics intends to use the net proceeds from this offering to fund clinical trials of methylnaltrexone, to fund clinical trials of other product candidates and for other research and development programs. All primary and secondary endpoints were statistically significant in Progenic's second phase III trial of subcutaneous methylnaltrexone (0.15 mg/kg or 0.30 mg/kg). The trial was initiated in January 2004 in 133 patients with opioid-induced constipation at 27 nursing homes and hospices in the US. Enrollment was completed in September 2005 and results announced in February 2006. In March 2005, Progenics announced results from the pivotal phase III trial of subcutaneous methylnaltrexone for the reversal of opioid-induced constipation. This trial involved a total of 150 patients from 16 hospices in the US who had advanced medical illnesses and who were receiving occasional opioids. Progenics has completed a phase IIb dose-ranging study with subcutaneous methylnaltrexone for treatment of narcotic-induced constipation in patients with cancer or AIDS. Positive top-line results from a phase II clinical trial of methylnaltrexone in the management of postoperative bowel dysfunction were reported in January 2005. The endpoints of the study included restoration of bowel function and discharge eligibility. Reversal of urinary retention was a secondary endpoint in this study. Progenics plans to complete a more in-depth analysis of this phase II data and present the finding to the US FDA. Methylnaltrexone (IV) is scheduled to enter phase III clinical studies in this indication in 2006. An NDA is expected to be submitted for the intravenous formulation of methylnaltrexone in late 2007/early 2008. Progenics also plans to initiate a phase II study of methylnaltrexone in women who have undergone hysterectomies. This patient population is also at high risk for ileus. In May 2004, Progenics Pharmaceuticals completed phase I clinical trials using two different oral formulations of methylnaltrexone. Analysis of preliminary data from 61 healthy volunteers who received methylnaltrexone at three dose levels indicated that the drug was well tolerated and exhibited predictable pharmacokinetics. Based on these phase I studies, Progenics selected an oral formulation and dose levels of methylnaltrexone that will be tested in phase II clinical trials for relief of opioid-induced constipation in patients with chronic-pain. The technology licensed from UR Labs, Inc., is the subject of issued US and European patents and several related US and foreign patent applications relating to certain compositions, formulations and uses of methylnaltrexone filed by the University of Chicago. Progenics have continued to expand the patent coverage relating to methylnaltrexone with the filing of new patent applications.
Topics: Clinical Trials as Topic; Colic; Constipation; Flatulence; Humans; Injections, Intravenous; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Treatment Outcome
PubMed: 17073520
DOI: 10.2165/00126839-200607060-00006 -
Expert Opinion on Pharmacotherapy Jul 2018The extensive and alarming use of opioids for pain management in patients with chronic pain receiving palliative care is associated with non-tolerable gastrointestinal... (Review)
Review
The extensive and alarming use of opioids for pain management in patients with chronic pain receiving palliative care is associated with non-tolerable gastrointestinal (GI) adverse effects. Opioid-induced constipation (OIC) is the most common adverse effect impairing patient quality of life (QOL). In addition, OIC is one of the treatment limiting consequences of opioid analgesics. Management of OIC is becoming a challenge since traditional laxatives have limited efficiency. Peripherally acting mu-opioid receptor antagonists (PAMORA) have been developed for the treatment of OIC with methylnaltrexone bromide being the first approved to treat OIC in adults with advanced illness undergoing palliative care. Areas covered: The authors systematically review the clinical evidence for methylnaltrexone bromide including a review of the pharmacokinetic and pharmacodynamic data along with clinical effectiveness and cost-effectiveness. Though there is a need for further long-term clinical investigation, there is a large body of evidence for both its efficacy and safety in the treatment of OIC. Expert opinion: Methylnaltrexone has both subcutaneous injection and oral dosage forms available in the market. The lack of more evidence in specific populations such as pregnant women, pediatrics and elderly still remains. The global consumption of methylnaltrexone shows a projection of increased use since its approval worldwide in 2008.
Topics: Analgesics, Opioid; Chronic Pain; Clinical Trials as Topic; Constipation; Government Regulation; Half-Life; Humans; Naltrexone; Quality of Life; Quaternary Ammonium Compounds; Treatment Outcome
PubMed: 29979903
DOI: 10.1080/14656566.2018.1491549 -
The American Journal of Hospice &... Feb 2011Opioids have become the gold standard for treatment of severe pain in advanced disease, but adverse effects can affect the quality of life. Opioid-induced bowel... (Review)
Review
Opioids have become the gold standard for treatment of severe pain in advanced disease, but adverse effects can affect the quality of life. Opioid-induced bowel dysfunction can lead to refractory constipation. Methylnaltrexone bromide is a peripherally acting mu antagonist and is indicated for the treatment of opioid-induced constipation in patients with advanced illness, when response to standard laxative therapy has been inefficacious. This pharmacology update will review the etiology, pathophysiology, and treatment of opioid-induced constipation, focused on methylnaltrexone as a novel treatment for refractory cases.
Topics: Analgesics, Opioid; Constipation; Defecation; Humans; Naltrexone; Narcotic Antagonists; Pain, Intractable; Palliative Care; Quality of Life; Quaternary Ammonium Compounds
PubMed: 20801917
DOI: 10.1177/1049909110373507 -
Expert Opinion on Drug Metabolism &... Feb 2011Opioid-induced constipation is a major side effect of the use of opioid pain medications in a palliative care population. At present, the only approved treatment for... (Review)
Review
INTRODUCTION
Opioid-induced constipation is a major side effect of the use of opioid pain medications in a palliative care population. At present, the only approved treatment for opioid-induced constipation is methylnaltrexone bromide subcutaneous injection. Methylnaltrexone is a peripherally restricted opioid antagonist with μ-opioid receptor selectivity that can reduce opioid activity in peripheral organs such as the gastrointestinal tract while sparing the pain relief afforded by the pain medications.
AREAS COVERED
This article addresses the pharmacokinetics of parenterally administered methylnaltrexone, including the studies in humans that form the basis for our understanding, and information on the disposition, metabolism and elimination of the drug. From this review, the reader will gain an understanding of the body's handling of methylnaltrexone following intravenous or subcutaneous administration.
EXPERT OPINION
Studies conducted to date indicate that methylnaltrexone has high bioavailability after subcutaneous administration at therapeutic dose levels, a terminal half-life of ∼ 8 - 9 h, minimal metabolism, elimination involving renal and non-renal routes, and a limited potential for drug-drug interactions. Combined with high efficacy and good tolerability, the predictable pharmacokinetic behavior of methylnaltrexone facilitates its successful utilization in clinical practice for the treatment of opioid-induced constipation in patients with advanced medical illness.
Topics: Clinical Trials as Topic; Constipation; Humans; Injections, Intravenous; Injections, Subcutaneous; Naltrexone; Narcotic Antagonists; Palliative Care; Quaternary Ammonium Compounds
PubMed: 21222554
DOI: 10.1517/17425255.2011.549824 -
Postgraduate Medicine 2016Constipation is a common adverse effect in patients requiring long-term opioid therapy for pain control. Methylnaltrexone, a quaternary peripheral mu-opioid receptor... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Constipation is a common adverse effect in patients requiring long-term opioid therapy for pain control. Methylnaltrexone, a quaternary peripheral mu-opioid receptor antagonist, is an effective treatment of opioid induced constipation (OIC) without affecting centrally mediated analgesia. Our objective was to conduct a review and meta-analysis to evaluate the efficacy of methylnaltrexone for treatment of OIC, as well as to provide a clinical discussion regarding newly developed alternatives and provide the current treatment algorithm utilized at our institution.
METHODS
We performed a systematic review and meta-analysis of randomized control trials using Cochrane Collaboration Databases and MEDLINE from 2007-present. Literature related to methylnaltrexone, opioids, opioid receptors, opioid antagonists, opioid-induced constipation were reviewed. A meta-analysis was completed with the primary outcome of rescue-free bowel movement (RFBM) within four hours of administration. All pooled analyses were based on random-effects models.
RESULTS
1239 patients were analyzed; 599 received methylnaltrexone and 640 received placebo. With a 95% CI calculated, the true risk difference is between 0.267 and 0.385, demonstrating a statistically significant difference in RFBM between treatment and placebo groups (p < 0.0001). Both the 0.15 mg/kg, 0.30 mg/kg doses every other day, and 12 mg/day dose were found to have increased risk of RFBM compared to placebo.
CONCLUSION
Results support the use of methylnaltrexone. Furthermore, the use of methylnaltrexone to induce laxation may decrease use of health care resources, increase work productivity, and improve cost utilization. New treatments have been made available; however, controlled clinical studies are needed to demonstrate long-term efficacy, safety and cost-effectiveness. Possible limitations of this study include the relatively small number of randomized, placebo-controlled trials investigating the efficacy of methylnaltrexone versus placebo. There is also the possibility of publication bias, which may lead to overestimating the efficacy of methylnaltrexone in treating OIC.
Topics: Analgesics, Opioid; Chronic Pain; Constipation; Humans; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Treatment Outcome
PubMed: 26839023
DOI: 10.1080/00325481.2016.1149017