Methylnaltrexone for Opioid-induced Constipation in Cancer Patients

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.

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