title: Phase II trial of subcutaneous methylnaltrexone in the treatment of severe opioid-induced constipation (OIC) in cancer patients: an exploratory study.
abstract: BACKGROUND
  Methylnaltrexone is a peripherally acting mu-opioid receptor antagonist that has been shown to relieve severe opioid-induced constipation (OIC) in patients with advanced disease receiving palliative care. Its efficacy remains unknown in cancer patients who are not terminally ill. The primary aim of this study was to evaluate the efficacy of methylnaltrexone over 48 h in cancer patients who were not terminally ill.
  
  
  METHODS
  In this single-dose phase II trial, cancer patients with a prognosis of ≥3 months and OIC with <3 laxations during the preceding week were eligible. The primary endpoint was a rescue-free laxation ≤4 h after a single dose of methylnaltrexone. Friedman's two-way analysis of variance was conducted for the number of laxations, pain and withdrawal scales, and laxation- and constipation-related symptoms. Univariate/bivariate Cox proportional hazard models for laxation times were employed.
  
  
  RESULTS
  Twelve patients received methylnaltrexone. Eleven patients had an ECOG performance status of 1 or 2. Four (33.3 %) and 5 (41.7 %) patients had rescue-free laxation within 4 and 24 h, respectively, and 10 (83.3 %) had laxation within 48 h (p = 0.006). Difficulty passing a stool improved significantly over 48 h (p = 0.029). The bivariate Cox models revealed that a shorter time to laxation was associated with a higher baseline morphine equivalent daily dose (hazard ratio, 1.02 per 1 mg; p = 0.018) and a smaller number of laxations in the preceding week (hazard ratio, 0.13 per one laxation; p = 0.035). Patients tolerated methylnaltrexone well without opioid withdrawal.
  
  
  CONCLUSIONS
  Methylnaltrexone may relieve severe OIC in cancer patients who are not terminally ill. A larger prospective study is justified in this population. (NCT01004393, https://clinicaltrials.gov/show/NCT01004393 ).
authors.affiliation: Palliative Care Team, Seirei Mikatahara General Hospital, 3453, Mikatahara-cho, Kita-ku, Hamamatsu, Shizuoka, 433-8558, Japan. masanori.mori@sis.seirei.or.jp.
authors.forename: Masanori
authors.initials: M
authors.lastname: Mori
authors.affiliation: Division of Hematology/Oncology, Massachusetts General Hospital, Center for Cancer Care at Exeter Hospital, 5 Alumni Drive, Exeter, NH, 03833, USA.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Wilmot Cancer Center, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY, 14642, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Medical Biostatistics, University of Vermont College of Medicine, 27 Hills Building, 105 Carrigan Drive, Burlington, VT, 05405, USA.
authors.forename: Takamaru
authors.initials: T
authors.lastname: Ashikaga
authors.affiliation: Division of Hematology and Oncology, University of Vermont Cancer Center, Given E-214-UVM363, 89 Beaumont Avenue, Burlington, VT, 05405, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Ades
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid / Q000009:adverse effects*; D003248:Constipation / Q000139:chemically induced / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000627:therapeutic use*; D009367:Neoplasm Staging; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy; D011379:Prognosis; D000644:Quaternary Ammonium Compounds / Q000627:therapeutic use
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D000644:Quaternary Ammonium Compounds; C032257:methylnaltrexone; D009271:Naltrexone
keywords: Cancer; Methylnaltrexone; Opioid-induced constipation; Phase II trial