Efficacy and Safety of Methylnaltrexone for Opioid-Induced Constipation in Patients With Chronic Noncancer Pain: A Placebo Crossover Analysis

Abstract

Background and objectives: In patients with chronic noncancer pain, subcutaneous methylnaltrexone for opioid-induced constipation (OIC) was examined in a randomized controlled trial (RCT) followed by an open-label extension (OLE). This study examined the reproducibility of RCT findings by analyzing data from placebo-treated patients who crossed over to methylnaltrexone.

Methods: Adults with less than 3 weekly rescue-free bowel movements (RFBMs), taking 50 mg or more of an oral morphine equivalent per day, were randomized to receive methylnaltrexone 12 mg or placebo for 4 weeks, followed by open-label methylnaltrexone 12 mg as needed for 8 weeks.

Results: A total of 134 placebo-treated patients (median morphine equivalent dose, 150 mg/d; mean of 1.1 RFBM per week) crossed over to methylnaltrexone in OLE. During the RCT, 9.7% of placebo-treated patients experienced an RFBM within 4 hours of first dose and 9.0% of all placebo injections resulted in an RFBM within 4 hours compared with 45.9% and 34.5%, respectively, with methylnaltrexone treatment in the OLE. When expressed as percentage of patients experiencing 3 or more RFBMs per week and a 1-RFBM increase over baseline, weekly values ranged from 35% to 40% during placebo treatment; at week 5 of OLE methylnaltrexone, this percentage increased to more than 70% and remained relatively stable throughout the OLE. The most common adverse events during methylnaltrexone treatment were abdominal pain (9.7% vs 1.5% for placebo) and nausea (5.2% vs 6.7%).

Conclusions: Findings during placebo treatment further establish the profile of OIC and support that little or no gastrointestinal tolerance develops across time. Findings under open-label conditions established the reproducibility and durability of methylnaltrexone for OIC.

FIGURE 1

Patient disposition. AE indicates adverse event; OLE, open-label extension; prn, as needed; qd, once a day; qod, every other day; RCT, randomized controlled trial.

FIGURE 2

Rescue-free bowel movement (RFBM) within 4 hours of administration of the first dose of randomized controlled trial (RCT) placebo or open-label extension (OLE) methylnaltrexone (MNTX) (A) and percentage of injections that resulted in any RFBM within 4 hours of administration of either RCT placebo or OLE MNTX (B).

FIGURE 3

Percentage of patients with both a weekly number of rescue-free bowel movements (RFBMs) of 3 or more and an increase of 1 or more RFBMs from baseline by week (A); average weekly number of RFBMs by week (B); and percentage of weekly injections resulting in an RFBM within 4 hours of dose administration by week (C). *Statistically significant difference versus placebo (P < 0.05) during the randomized controlled trial (RCT). MNTX indicates methylnaltrexone; OLE, open-label extension; prn, as needed; qd, once a day; qod, every other day.