Methylnaltrexone Treatment for Opioid-Induced Constipation in Patients with and without Cancer: Effect of Initial Dose

Abstract

Purpose

Opioid-induced constipation (OIC) is a common side effect of opioid therapy. Methylnaltrexone (MNTX) is a selective, peripherally acting μ-opioid receptor antagonist, with demonstrated efficacy in treating OIC. We pooled results from MNTX clinical trials to compare responses to an initial dose in patients with chronic cancer and noncancer pain.

Patients and Methods

This post hoc analysis used pooled data from 3 randomized, placebo-controlled studies of MNTX in patients with advanced illness with OIC. Assessments included the proportions of patients achieving rescue-free laxation (RFL) within 4 and 24 hours of the first study drug dose, time to RFL, current and worst pain intensity, and adverse events, stratified by the presence/absence of cancer.

Results

A total of 355 patients with cancer (MNTX n = 198, placebo n = 157) and 163 without active cancer (MNTX n = 83; placebo n = 80) were included. More patients treated with MNTX compared with those who received placebo achieved an RFL within 4 (cancer: MNTX, 61.1% vs placebo,15.3%, p<0.0001; noncancer: MNTX, 62.2% vs placebo, 17.5%, p<0.0001) and 24 hours (cancer: MNTX, 71.2% vs placebo, 41.4%, p<0.0001; noncancer: MNTX, 74.4% vs placebo, 37.5%, p<0.0001) of the initial dose. Cumulative RFL response rates within 4 hours of the first, second, or third dose of study drug were also higher in MNTX-treated patients. The estimated time to RFL was shorter among those who received MNTX and similar in cancer and noncancer patients. Mean pain scores declined similarly in all groups. The most common adverse events in both cancer and noncancer patients were abdominal pain, flatulence, and nausea.

Conclusion

After the first dose, MNTX rapidly induced a laxation response in the majority of both cancer and noncancer patients with advanced illness. Opioid-induced analgesia was not compromised, and adverse events were primarily gastrointestinal in nature. Methylnaltrexone is a well-tolerated and effective treatment for OIC in both cancer and noncancer patients.

Keywords:

• peripheral mu-opioid receptor antagonist
• PAMORA
• chronic pain
• opioid

Abbreviations

BBB, blood–brain barrier; BM, bowel movements; CNS, central nervous system; GI, gastrointestinal; ITT, intent to treat; MNTX, methylnaltrexone; N/A, not available; OIC, opioid-induced constipation; PAMORA, peripherally acting μ-opioid receptor antagonist; PBO, placebo; RFL, rescue-free laxation; SBM, spontaneous bowel movement; SC, subcutaneous; SD, standard deviation; TEAE, treatment-emergent adverse event.

Data Sharing Statement

The datasets generated and/or analyzed during the current study are not publicly available at this time due to the proprietary nature of this information. Requests for additional information should be made to the corresponding author.

Ethics Approval and Informed Consent

Patients or their legally acceptable representative provided written informed consent to participate before any study-specific procedures were conducted. The specific ethical review boards that provided approval and oversight are listed below for each study.

Study 301

Human Investigative Committee, University of Virginia Health System, Charlottesville, Virginia, USA

University of Wisconsin Health Sciences IRB, VA Medical Center, Madison, Wisconsin, USA

Stanford University Institutional Review Board, Stanford University, Palo Alto, California, USA

University of Utah IRB, University of Utah Health Sciences Center, Salt Lake City, Utah, USA

Schulman Associates Institutional Review Board, Cincinnati, Ohio, USA

Beth Israel Medical Center Institutional Review Board, Beth Israel Medical Center, New York, New York, USA

University of Alabama at Birmingham IRB, University of Alabama at Birmingham, Alabama, USA

City of Hope IRB, City of Hope, Duarte, California, USA

San Diego Hospice IRB, San Diego Hospice, San Diego, California, USA

The University of Texas IRB, M.D. Anderson Cancer Center, Houston, Texas, USA

Hospice of North Central Florida IRB, Hospice of North Central Florida, Gainesville, Florida, USA

Geisinger IRB, Geisinger, Danville, Pennsylvania, USA

Humility of Mary Health Partners IRB, Humility of Mary Health Partners, Youngstown, Ohio, USA

Study 302

Schulman Associates Institutional Review Board, Cincinnati, Ohio, USA

Research Ethics Board, McGill University Health Centre, Montreal, Quebec, Canada

University of British Columbia, British Columbia Cancer Agency Research Ethics Board, Vancouver, British Columbia, Canada

San Diego Hospice IRB, San Diego Hospice, San Diego, California, USA

University of Utah Institutional Review Board, University of Utah Health Sciences Center, Salt Lake City, Utah, USA

Henry Ford Health System Institutional Review Board, Henry Ford Health System, Detroit, Michigan, USA

Human Subjects Protection Office, The Penn State University/Milton S Hershey Medical Center, Hershey, Pennsylvania

City of Hope IRB, City of Hope, Duarte, California, USA

Study 4000

Schulman Associates Institutional Review Board, Cincinnati, Ohio, USA

The University of Texas IRB, M.D. Anderson Cancer Center, Houston, Texas, USA

Division of Research Integrity & Compliance, Moffitt Cancer Center, Tampa, Florida, USA

Fox Chase Cancer Centre Institutional Review Board, Fox Chase Cancer Centre, Rockledge, Pennsylvania, USA

Regonala Etikprövningsnämnden i Linköping, Palliative Unit Vrinnevi Hospital, Linköping, Sweden

Ethics Committee CEIC. CSUB Ciutat Sanitaria Universitaria Bellvitge, Spain

Bellberry Limited, Dulwich, South Australia, Australia

Azienda Sanitaria Locale di Asti - ASL AT Sede, Asti, Italy

Comitato Etico Dell`Azienda Ospedaliera Guido Salvini di Garbagnate Milanese, Milan, Italy

Comitato Etico Indipendente Della Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

St Vincent’s Hospital Human Research Ethics Committee (HREC), St Vincent’s Hospital, Darlinghurst, New South Wales, Australia

Ethik-Kommission an der Medizinischen Fakultät Technischen Hochschule Aachen, University of Aachen, Aachen, Germany

Ethik-Kommission bei der Medizinischen Fakultät der Ludwig-Maximilians Universität München, Munich, Germany

The Peter Mac Ethics Committee, Peter MacCallum Cancer Center, East Melbourne, Victoria, Australia

CIUSSS Research Ethics Board, The Jewish General Hospital, Montreal, Quebec, Canada

Bannatyne Campus Research Ethics Board, University of Manitoba, Winnipeg, Manitoba, Canada

Ethics Committee Research Leuven, UZ Leuven, Leuven, Belgium

Comité de Protection des Personnes – Sud Est V, Centre Hospitalier Universitaire de Grenoble, Grenoble, France

Hamilton Health Sciences, Hamilton, Ontario, Canada

London – Central MREC, London, United Kingdom

CHUQ Research Ethics Committee, Centre Hospitalier Universitaire de Quebec, Quebec City, Quebec, Canada

Western Institutional Review Board, Olympia, Washington, USA

Comitê de ética em Pesquisa em seres Humanos da Fundação Antônio Prudente, A.C. Camargo Cancer Center, São Paulo, Brazil

University of Utah Institutional Review Board, University of Utah Health Sciences Center, Salt Lake City, Utah, USA

Alberta Cancer Research Ethics Committee, University of Alberta, Edmonton, Alberta, Canada

Comité Bioético para la Investigación Clínica, Mexico City, Mexico

VA New Jersey Healthcare System Institutional Review Board, VA New Jersey Healthcare System, East Orange, New Jersey, USA

Previous Presentations

Annual Assembly of the American Academy of Hospice and Palliative Medicine and Hospice and Palliative Nurses Association; March 13–16, 2019; Orlando, Florida.

Society of Hospital Medicine 2019; March 24–27, 2019; National Harbor, Maryland.

PAINWeek 2019; September 3–7, 2019; Las Vegas, Nevada.

Annual National Conference of the American Society for Pain Management Nursing; September 18–21, 2019; Portland, Oregon.

Disclosure

Dr Chamberlain has nothing to disclose. Dr Rhiner received funding from Wyeth Pharmaceuticals for the methylnaltrexone studies 301 and 302 referenced in this paper and reports grants from City of Hope, during the conduct of the study. Dr Slatkin is an employee of Salix Pharmaceuticals, a division of Bausch Health, US, LLC. Dr Stambler is a full-time employee of Progenics Pharmaceuticals, Inc., a subsidiary of Lantheus Holdings, Inc., and a shareholder of Lantheus Holdings, Inc. Dr Israel is an employee of Bausch Health US, LLC.

Additional information

Funding

This study was supported by Salix Pharmaceuticals, a division of Bausch Health US, LLC, Bridgewater, NJ, USA, which has licensed the rights to develop and commercialize Relistor^® from Progenics Pharmaceuticals, Inc., a wholly owned subsidiary of Lantheus Holdings, Inc., North Billerica, MA. Progenics Pharmaceuticals had a role in the study design, implementation of the study, and data collection. Salix had a role in the data collection, data analysis, and the decision to publish. Technical editorial and medical writing assistance was provided under the direction of the authors by Drayton Hammond, PharmD, Echelon Brand Communications, LLC, an OPEN Health company, Parsippany, NJ, USA. Funding for this support was provided by Salix Pharmaceuticals.