Portenoy, R.K., Thomas, J., Moehl Boatwright, M.L., Tran, D., Galasso, F.L., Stambler, N., . . . Israel, R.J. (2008). Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with advanced illness: A double-blind, randomized, parallel group, dose-ranging study. Journal of Pain and Symptom Management, 35, 458-468.

To assess the efficacy and safety of subcutaneous methylnaltrexone in patients with advanced illness and opioid-induced constipation (OIC), and to clarify whether a dose-response relationship could be identified.

Methylnaltrexone was administered in doses of 1 mg, 5 mg, or 12.5 mg subcutaneously; patients were randomized to those dose groups in a ratio of 1:1:1. After 22 patients, the dose range was extended to 20 mg; patients were randomized in a ratio of 1:1:3 to 1-mg, 12.5-mg, or 20-mg dose groups. Patients received study medication if they had no bowel movement for at least two days and had a score of 3 or higher on a 5-point scale assessing constipation-related distress. Patients receiving laxatives had to be on a stable regimen for at least four days and remain on regimen during the study.

During the first week of the study, subcutaneous injections were administered on days 1, 3, and 5. Following the first week of double-blind study, patients received the option for open-label study for a maximum of three weeks. The initial dose was 5 mg subcutaneously as often as every other day. The maximum dose was 15 mg in the first 22 patients and 20 mg for the remaining 11 patients. Dose could be increased or decreased by the investigator.

• The study reported on a sample of 33 adult men and women (39 screened) with advanced illness, including patients with cancer receiving palliative care and chronic opioid therapy for pain.
• Mean patient age was 61 years (range 20-87). 
• Mean body weight was 64 kg.
• Seventy-nine percent of patients were Caucasian.
• Eighty-five percent of patients had a primary diagnosis of cancer.
• Eighty-five percent of patients used laxatives at baseline, 33% used stool softeners or emollients, and 27% used osmotic agents. 
• Patients were included in the study if they were receiving opioids, were stable for two weeks, and remained stable for four weeks; had no bowel movements despite conventional laxative therapy; had a life expectancy of at least four weeks; and had stable vital signs.

Multi-center

This randomized controlled, parallel-group, repeated-dose, dose-ranging trial included a double-blind phase for one week followed by an open-labeled phase for a maximum of three weeks.

• The primary endpoint, laxation response, was a bowel movement within four hours of the initial dose.
• Subjective outcomes were obtained prior to each dose and approximately three hours postdose.
• Constipation severity and distress were graded on a five-point categorical scale.
• The Opioid Withdrawal Scale was a modified Himmelsbach scale.
• Patient satisfaction was assessed on a seven-point scale.
• The severity of opioid adverse events were graded on a four-point categorical scale.

Twenty-two patients completed the blinded phase, and 14 completed the open-label phase.

In the blinded phase, laxation occurred within four hours on day 1 for 1 of 10 patients (10%) in the 1-mg dose group, 3 of 7 patients (43%) in the 5-mg dose group, 6 of 10 patients (60%) in the 12.5-mg dose group, and 2 of 6 patients (33%) in the 20-mg dose group. On day 2, for all dose groups higher than 1 mg, 11 of 23 patients (48%) responded (p = 0.05). There was no dose-response relationship across the three highest doses compared to the 1-mg dose.

The median time to laxation was higher than 48 hours for the 1-mg dose group and 1.72, 0.48, and 6.75 hours in the 5-, 12.5-, and 20-mg dose groups, respectively. The median time to laxation was 1.26 hours for all patients dosed 5 mg or higher, and was statistically significant compared to the 1-mg group (p < 0.0003). The 1-mg dose group required laxative rescue approximately twice as often as other groups. There was no trend in worsening pain control over time.

In the open-label phase, the response rate was from 49% to 64% for patients in dose groups from 5 mg to 12.5 mg. Secondary outcomes were not evaluated because of the small sample size.

Methylnaltrexone doses of 5 mg or higher in patients with advanced illness relieved OIC without decreased analgesia or withdrawal symptoms.

• The sample size was small (fewer than 100 patients).
• The drop-out rate was high: 11 of 22 patients withdrew during the double-blind phase, 4 declined the open-label phase, and 4 withdrew from the open-label phase.