Methylnaltrexone for Opioid-induced Constipation in Cancer Patients

Phase 2

Completed

Conditions: Neoplasms
Opioid-Related Disorders
Constipation

Interventions: Drug: Methylnaltrexone bromide

Registration Number: NCT01004393

Lead Sponsor: University of Vermont

Brief Summary: The purpose of this study is to evaluate the efficacy of methylnaltrexone in relieving opioid-induced constipation in cancer patients at various stages of disease.

Detailed Description: Pain is one of the most common and important symptoms of cancer, often requiring opioid analgesics for control. However constipation is one of the most frequent and debilitating side effects of opioids, occurring in 40%-70% of patients being treated for chronic pain. Although laxatives are commonly used to manage opioid-induced constipation, these agents are not always effective or satisfactory. Methylnaltrexone bromide is a peripherally acting antagonist of the mu-opioid receptor. As a quaternary amine, the ability of methylnaltrexone to cross the blood-brain barrier is limited. This allows methylnaltrexone to function as a peripherally-acting antagonist in the gastrointestinal tract without impacting opioid-mediated analgesic effects in the central nervous system. The efficacy and safety of methylnaltrexone in treating opioid-induced constipation in patients with advanced disease receiving palliative care has been demonstrated. However the efficacy of this agent has not been evaluated in more active patients who are earlier in their disease course. The present study will evaluate the efficacy and safety of methylnaltrexone for the relief of severe opioid-induced constipation in this population and will attempt to identify factors predictive of methylnaltrexone response.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 12

Inclusion Criteria

Histologically or cytologically confirmed neoplasm
18 years of age or older
Have received opioids for analgesia for at least 2 weeks and been on a stable regimen of opioids and laxatives for 3 or more days before study entry
Fewer than three laxation during the preceding week and no laxation within 24 hours before study entry, or no laxation within 48 hours before study entry
Life expectancy of at least 6 months
World Health Organization Performance Status 0-3
Women of childbearing potential must have a negative pregnancy test
Breastfeeding should be discontinued prior to study entry
Ability to understand and the willingness to sign a written informed consent document.
Laboratory values within a week of study entry:

Absolute neutrophil count > 1,500/microliter Hemoglobin > 7 g/dL Platelet count > 100,000/microliter Calculated calcium < 10.5 mg/dL Calculated creatinine clearance > 30 mg.min Alanine aminotransferase < 3 x upper limit of normal (ULN) Aspartate aminotransferase < 3 x ULN Alkaline phosphatase < 2.5 x ULN Bilirubin < 1.5 x ULN

Exclusion Criteria

Constipation not primarily caused by opioids, such as mechanical gastrointestinal obstruction or ongoing vinca alkaloid administration
Indwelling peritoneal catheter
Clinically active diverticular disease
Fecal impaction
Acute surgical abdomen
Fecal ostomy
Peritoneal carcinomatosis
Known hypersensitivity to methylnaltrexone, naltrexone, or naloxone
Administration of any investigational drug or experimental product within the previous 30 days
Initiation of a new bowel regimen or prokinetic agents within a week of study entry

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Methylnaltrexone bromide	Methylnaltrexone bromide	A single dose of methylnaltrexone will be administered subcutaneously to eligible subjects based on weight at the study entry. Since we will include subjects at all stages of cancer management, administering this study drug is considered experimental. We will use the dose approved by FDA, i.e., 0.15 mg/kg (round dose up to nearest 0.1 mL of volume) for weight less than 38 kg or greater than 114 kg; 8 mg (0.4 mL) for weight 38 kg to less than 62 kg; and 12 mg (0.6 mL) for weight 62 kg to 114 kg.

Primary Outcome Measures

Name	Time	Method
Rescue-free Laxation After Administration of Subcutaneous Methylnaltrexone	4 hours after the dose of subcutaneous methylnaltrexone

Secondary Outcome Measures

Name	Time	Method
Laxation After Administration of Subcutaneous Methylnaltrexone	24 and 48 hours after the dose of subcutaneous methylnaltrexone
Time to Laxation After Administration of Subcutaneous Methylnaltrexone	48 hours after the dose of subcutaneous methylnaltrexone
Overall Pain Scores (0-10; 0=no Pain, 10=Worst Pain) After Administration of Subcutaneous Methylnaltrexone	48 hours after the dose of subcutaneous methylnaltrexone
Symptoms of Opioid Withdrawal (Modified Himmelsbach Withdrawal Scales (Ranging 7-28 in Total; 1=None - 4=Severe for 7 Items)) After Administration of Subcutaneous Methylnaltrexone	48 hours after the dose of subcutaneous methylnaltrexone
Bowel Movement Assessment (Frequency, Consistency and Difficulty) After Administration of Subcutaneous Methylnaltrexone	48 hours after the dose of subcutaneous methylnaltrexone
Constipation Assessment (Severity and Distress) After Administration of Subcutaneous Methylnaltrexone	48 hours after the dose of subcutaneous methylnaltrexone
Patient Satisfaction With the Study Medication After Administration of Subcutaneous Methylnaltrexone	48 hours after the dose of subcutaneous methylnaltrexone