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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 -
Current Treatment Options in Oncology Jul 2022Constipation is one of the most frequent problems in cancer patients, and its etiology is multifactorial. It leads to decreased quality of life and impedes optimal pain... (Review)
Review
Constipation is one of the most frequent problems in cancer patients, and its etiology is multifactorial. It leads to decreased quality of life and impedes optimal pain treatment. Despite the high prevalence, constipation is frequently underdiagnosed mainly because of lack of validated diagnostic criteria or widely accepted definition of constipation in cancer patients. All cancer patients should be evaluated regularly for constipation, and concomitant causes and risk factors were assessed. Opioids are responsible for a much of the secondary constipation in cancer patients. The management of constipation in cancer patients should be multifaceted, addressing dietary and behavioral issues and optimizing pharmacological interventions. Prevention of opioid-induced constipation (OIC) is pivotal, as treatment is often unsatisfactory or inefficient. Dietary and behavioral interventions should be considered. Non-pharmacological measures include hydration and nutrition, ensuring privacy during defecation, using a commode or footstool, and the availability of a caregiver. Abdominal massage may be of value. Traditional laxatives are recommended in prevention but not in the treatment of OIC. Peripherally acting mu-opioid receptor antagonists (PAMORA) appear the first choice in the treatment and an alternative to laxatives in some recent clinical practice guidelines in preventing OIC. Naldemedine, naloxegol, and methylnaltrexone are supported by quality evidence for OIC management. Naloxone or naltrexone, taken orally in combined formulations with opioids, may be valuable in preventing or reducing OIC symptoms.
Topics: Analgesics, Opioid; Constipation; Humans; Laxatives; Neoplasms; Opioid-Induced Constipation; Quality of Life
PubMed: 35441979
DOI: 10.1007/s11864-022-00976-y -
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 -
Advances in Therapy Jul 2021The prescribing and use of opioid analgesics is increasing in Italy owing to a profusion in the number and types of opioid analgesic products available, and the... (Review)
Review
The prescribing and use of opioid analgesics is increasing in Italy owing to a profusion in the number and types of opioid analgesic products available, and the increasing prevalence of conditions associated with severe pain, the latter being related to population aging. Herein we provide the expert opinion of an Italian multidisciplinary panel on the management of opioid-induced constipation (OIC) and bowel dysfunction. OIC and opioid-induced bowel dysfunction are well-recognised unwanted effects of treatment with opioid analgesics that can profoundly affect quality of life. OIC can be due to additional factors such as reduced mobility, a low-fibre diet, comorbidities, and concomitant medications. Fixed-dose combinations of opioids with mu (μ) opioid receptor antagonists, such as oxycodone/naloxone, have become available, but have limited utility in clinical practice because the individual components cannot be independently titrated, creating a risk of breakthrough pain as the dose is increased. A comprehensive prevention and management strategy for OIC should include interventions that aim to improve fibre and fluid intake, increase mobility or exercise, and restore bowel function without compromising pain control. Recommended first-line pharmacological treatment of OIC is with an osmotic laxative (preferably polyethylene glycol [macrogol]), or a stimulant laxative such as an anthraquinone. A second laxative with a complementary mechanism of action should be added in the event of an inadequate response. Second-line treatment with a peripherally acting μ opioid receptor antagonist (PAMORA), such as methylnaltrexone, naloxegol or naldemedine, should be considered in patients with OIC that has not responded to combination laxative treatment. Prokinetics or intestinal secretagogues, such as lubiprostone, may be appropriate in the third-line setting, but their use in OIC is off-label in Italy, and should therefore be restricted to settings such as specialist centres and clinical trials.
Topics: Analgesics, Opioid; Constipation; Expert Testimony; Humans; Italy; Narcotic Antagonists; Opioid-Induced Constipation; Quality of Life; Receptors, Opioid, mu
PubMed: 34086265
DOI: 10.1007/s12325-021-01766-y -
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 -
Hospital Pharmacy Nov 2016Each month, subscribers to receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to...
Each month, subscribers to receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of publishes selected reviews in this column. For more information about , contact Wolters Kluwer customer service at 866-397-3433. The November 2016 monograph topics are apaziquone, crisaborole, irinotecan liposome, plecanatide, and telotristat. The Safety MUE is on methylnaltrexone PO.
PubMed: 27928191
DOI: 10.1310/hpj5110-847 -
The Medical Letter on Drugs and... Dec 2022
Topics: Humans; Analgesics, Opioid; Pain; Oxycodone; Morphine
PubMed: 36541938
DOI: No ID Found -
Journal of the American Heart... Jan 2019Background Morphine administration is a strong predictor of delayed onset of action of orally administered ticagrelor in patients with ST-segment-elevation myocardial... (Randomized Controlled Trial)
Randomized Controlled Trial
Background Morphine administration is a strong predictor of delayed onset of action of orally administered ticagrelor in patients with ST-segment-elevation myocardial infarction, likely because of impaired gastrointestinal motility. The aim of this study was to evaluate whether the peripheral opioid antagonist methylnaltrexone could improve pharmacodynamics and pharmacokinetics of orally administered ticagrelor in patients with ST-segment-elevation myocardial infarction receiving morphine. Methods and Results The MOVEMENT (Methylnaltrexone to Improve Platelet Inhibition of Ticagrelor in Morphine-Treated Patients With ST-Segment Elevation Myocardial Infarction) trial was a multicenter, prospective, randomized, controlled trial in patients with ST-segment-elevation myocardial infarction treated with morphine and ticagrelor. Upon arrival to the catheterization laboratory, patients were randomized to a blinded intravenous injection of either methylnaltrexone (8 or 12 mg according to weight) or 0.9% sodium chloride. The proportion of patients with high on-treatment platelet reactivity and plasma concentrations of ticagrelor and AR -C124910XX were assessed at baseline (arrival in the catheterization laboratory) and 1 and 2 hours later. A total of 82 patients received either methylnaltrexone (n=43) or placebo (n=39). Median (interquartile range) time from ticagrelor administration to randomization was 41 (31-50) versus 45.5 (37-60) minutes ( P=0.16). Intravenous methylnaltrexone administration did not significantly affect prevalence of high on-treatment platelet reactivity at 2 hours after inclusion, the primary end point, when compared with placebo (54% versus 51%, P=0.84). Plasma concentrations of ticagrelor and its active metabolite, the prespecified secondary end points, did not differ significantly between the groups over time. There was no significant difference in patient self-estimated pain between the groups. Conclusions Methylnaltrexone did not significantly improve platelet reactivity or plasma concentrations of orally administered ticagrelor in patients with ST-segment-elevation myocardial infarction receiving morphine. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 02942550.
Topics: Administration, Oral; Aged; Analgesics, Opioid; Blood Platelets; Cardiac Catheterization; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Injections, Intravenous; Male; Middle Aged; Morphine; Naloxone; Platelet Aggregation Inhibitors; Platelet Function Tests; Prospective Studies; Quaternary Ammonium Compounds; ST Elevation Myocardial Infarction; Single-Blind Method; Ticagrelor; Treatment Outcome
PubMed: 30636504
DOI: 10.1161/JAHA.118.010152