Slatkin, N., Thomas, J., Lipman, A.G., Wilson, G., Boatwright, M., Wellman, C., . . . Israel, R. (2009). Methylnaltrexone for treatment of opioid-induced constipation in advanced illness patients. Journal of Supportive Oncology, 7, 39-46.

To determine the safety and efficacy of subcutaneous (SC) methylnaltrexone in opioid-induced constipation (OIC).

Double-Blind Phase

Patients were randomized to a single dose of study drug or placebo administered SC.  Groups were 0.15 mg/kg, 0.3 mg/kg, or placebo. Patients were randomly assigned in a 1:1:1 ratio to each study group. Baseline laxative regimens could be continued. Rescue laxatives (laxatives administered on an as needed [PRN] basis) were allowed, except within four hours before or after dose administration.

Open-Label Phase

This phase was 28 days with 1 dose per 24 hours PRN. The initial dose of 0.15 mg/kg could be decreased to 0.075 mg/kg or increased to 0.3 mg/kg, based on response.

Protocol Extension

Patients completing the open-label phase could enter a three-month extension. The initial dose was the same as in the open-label phase, with dosing adjusted to 0.075 mg/kg, 0.15 mg/kg, or 0.3 mg/kg by investigator discretion.

• Of the 154 patients initially randomized, the median age was 66 years, 81.2% had a cancer diagnosis, more than 65% had World Health Organization (WHO) performance status of 3 or 4, and 95% had baseline laxative use.
• Patients were included in the study if they had advanced illness with a life expectancy of one to six months, were on a stable opioid regimen at least three days prior to study entry, had no significant laxation 48 hours prior, and had stable vital signs.
• Patients were excluded if they had previously used methylnaltrexone, naltrexone, or naloxone; process suggestive of gastrointestinal obstruction; or nonopioid constipation, diverticular disease, fecal impaction, acute abdomen, or peritoneal catheter.

Double-Blind Phase

• The age range was 21 to 100 years, with similar median ages across all groups.
• The sample comprised 54.5% men and 45.5% women, with a similar distribution across groups.
• Sixty-seven percent had a WHO performance status of 3 or higher.
• Oral morphine equivalents were 207 mg/day in the 0.15-mg/kg group, 188 mg/day in the 0.3 mg/kg group, and 150 mg/day in the placebo group.
• No significant differences existed in age, constipation distress, or mean pain score across study groups.
• At baseline, 95% used laxatives, 83% used stimulants, 56% used osmotic laxatives, and 27% used stool softener.

Open-Label Phase

• Of the 147 patients who elected the open-label phase, 72 completed the phase.
• Of the remaining 75 patients, 36 withdrew and 39 died.

Extension Phase

• Twenty-seven patients elected extension.
• Nine patients completed extension.

• Patients were recruited from hospice and palliative care settings.
• 17 treatment sites

This was a double-blind, randomized, placebo-controlled, single-dose study, followed by an open-label phase, and then an open-label extension phase.

Efficacy/Primary Outcomes

• Percent of patients who defecated within four hours of dose
• Twenty-four–hour rescue-free laxation rates
• Median time to rescue-free laxation
• Global Clinical Impression of Change (GCIC) scale (seven-point rating scale from “much worse” to “much better”)
• Improvement in stool consistency (patient report, 1 = very hard to 6 = watery)
• Constipation distress (five-point scale from 1= none to 5 = very much)

Secondary Outcomes

• Pain, as measured on a 10-point scale from 0 (none) to 10 (worst possible)
• Modified Himmelsbach opioid withdrawal scale (composite summed score for seven symptoms, each scored on a four-point scale from 1 = none to 4 = severe)
• National Cancer Institute common toxicity criteria, version 2
• WHO performance status

• In the methylnaltrexone 0.15 mg/kg group, 61.7% had laxation within four hours, 64.4% reported improvement in constipation distress, and 58.7% reported improvement in GCIC.
• In the methylnaltrexone 0.3 mg/kg group, 58.2% had laxation within four hours, 63.5% had improvement in constipation distress, and 58.8% had improvement in GCIC.
• In the placebo group, 13.5% had laxation within four hours, 34% had improvement in constipation distress, and 21.6% had improvement in GCIC.
• Comparisons between each methylnaltrexone group and placebo were significant (p < 0.00001).
• In the open-label phase (n = 72), laxation within four hours was experienced by 55.8% in weeks 1 and 2, 61.7% in weeks 3 and 4, and 63.7% at more than 8 weeks.
• Nineteen patients had AEs. Three patients in the open-label phase reported serious AEs.
• A few patients experienced abdominal pain and watery stool.
• No changes were observed in pain or symptoms of opioid withdrawal four hours after dosing.
• In the open-label phase, the 0.3 mg/kg dose was associated with more abdominal pain than the 0.15 mg/kg dose.

SC methylnaltrexone is effective in the treatment of OIC and generally is well tolerated. No relationship exists between dose and laxation response, suggesting the optimal dose is 0.15 mg/kg.

• Patients who responded to SC dosing often defecated soon after drug administration, with 50% responding within 30 minutes. Average time to defecation or timing in all respondents to the medication were not described.  Timing of response may be important for planning patient care related to toileting.
• Three patients were reported as having severe AEs. When they occurred in the open-label phase of study and what percentage of cases were affected was unclear. Investigators noted patients were frail and rapid reversal of constipation in such cases can be associated with AEs. Data for AEs in control and study groups were not provided.
• What impact continued laxative use had on the results was unclear. Many patients were on multiple types of laxatives, as well as the study drug.
• This study reported on patients with a short life expectancy and advanced disease; therefore, findings may not be applicable to other populations.