Methylnaltrexone Effectively Treats OIC in Advanced Illness While Maintaining Pain Control

Subcutaneous methylnaltrexone reduced rescue-free laxation time in advanced-illness while maintaining pain control while on opioid therapy.

Subcutaneous methylnaltrexone may reduce rescue-free laxation time in patients with advanced illness and opioid induced constipation (OIC), with or without active cancer. These results were published in the Journal of Pain Research.

Two previously published studies indicated that subcutaneous methylnaltrexone had a “robust efficacy” in treating opioid-induced constipation without impacting central analgesia or precipitating opioid withdrawal. However, no prospective studies have evaluated the efficacy and safety of either peripherally acting µ-opioid receptor antagonists (PAMORAs) or laxatives in treating opioid-induced constipation in people with cancer.

In the current post-hoc analysis, investigators evaluated data from 2 similarly designed, multidose multicenter, double-blind, randomized, placebo-controlled studies ( identifiers: NCT00402038 and NCT00672477) studies in order to characterize baseline demographics, efficacy, and safety endpoints in patients with and without cancer who were receiving opioids and were treated with either methylnaltrexone or placebo.

In the first study—Study 302—participants were randomly assigned 1:1 to receive either subcutaneous methylnaltrexone 0.15 mg/kg or placebo every other day for 2 weeks, with those who had <3 bowel movements by day 8 eligible for dose escalation to 0.30 mg/kg. In the second study—Study 4000—participants were randomly assigned 1:1 to receive subcutaneous methylnaltrexone or placebo based on body weight: 0.4 mL (8 mg) or placebo for body weight 38 kg to <62 kg and 0.5 mL (12 mg) or placebo for body weight ≥62 kg every other day with a maximum of 7 doses for 14 days.

All participants who completed the studies were eligible to enroll in the respective open-label extension trials ( identifiers: NCT01367613 and NCT00672139).

Investigators stratified patients by those with active cancer and those without. Efficacy endpoints included the proportion of patients with rescue-free laxation within 4 hours after ≥2 of the first 4 doses, the proportion of patients with rescue-free laxation within 4 hours of the first dose, the time to first rescue-free laxation assessed at 4 hours and 24 hours, the number of laxations within 24 hours after dosing by week, the proportion of patients with ≥3 rescue-free bowel movements per week in weeks 1 and 2, the proportion of patients using rescue laxatives, and pain scores.

A total of 178 patients received methylnaltrexone and 185 received placebo, with 65.2% and 61.6% of each group having cancer. Those with cancer were taking higher median daily doses or opioid morphine equivalents (methylnaltrexone, 180 mg/d; placebo, 188 mg/d) vs those without cancer (120 mg/d and 80 mg/d, respectively). Nearly all patients were using laxatives at baseline.

In those with and without cancer, methylnaltrexone induced significantly greater rescue-free laxation responses within 4 hours of the first treatment dose vs placebo; significant differences after ≥2 of the first 4 doses were also noted. The probability of having a rescue-free laxation within 4 and 24 hours of the first dose of medication was significantly higher in those who received methylnaltrexone in those with and without cancer.

Median time to laxation within 24 hours after the first medication dose was 0.96 and 22.63 hours in those with cancer who received methylnaltrexone and placebo, respectively, and 1.25 and >24 hours in those without cancer. These data, according to the researchers, indicate that “most cancer and noncancer patients who received methylnaltrexone and responded to treatment did so within the first hour.”

Mean weekly number of lavations within 24 hours of dosing were similar in methylnaltrexone-treated patients with and without cancer; by week 2, this number was higher in the methylnaltrexone group regardless of cancer status.

Smaller proportions of those treated with methylnaltrexone in either group required the use of rescue laxatives compared with the placebo groups, but these differences did not reach significance.

No significant changes in pain scores from baseline to day 7 were noted in either group.

Among those with cancer, pains scores were 3.6 at baseline and 2.9 at day 7, compared with 3.5 and 3.2 over the same time period in the placebo group. In the methylnaltrexone group, the worst pain scores were not significantly different from baseline to day 7 in those with or without cancer.

Among patients with cancer, the worst pain scores were 5.1 and 4.0 at baseline at day 7 8in the methylnaltrexone group and 5.2 and 4.3 in the placebo group. In those without cancer, worst pain scores were 5.6 and 4.7 for methylnaltrexone and 5.4 and 4.4 for placebo.

Slightly higher proportions of cancer patients experienced treatment-emergent adverse events regardless of treatment group. The most frequently occurring treatment-emergent adverse event in those with cancer who received methylnaltrexone or placebo included abdominal pain, disease progression, and nausea. Similar adverse events were reported in those without cancer.

Serious adverse events were more common in the methylnaltrexone group with cancer compared with those without cancer (17.2% vs 7.9%).

Study limitations include the short duration of the trials due to advanced patient illness and the knowledge that the 2 pooled studies were not initially designed to compared cancer vs noncancer outcomes.

“Treatment with methylnaltrexone resulted in significantly higher proportions of both cancer and noncancer patients with [opioid-induced constipation] achieving laxation responses within 4 hours of administration compared with placebo,” the researchers concluded. “These results…support the approval and use of [subcutaneous] methylnaltrexone for [opioid-induced constipation] in patients with active cancer taking opioids for cancer-related pain.”

Disclosure: This clinical trial was supported by Salix Pharmaceuticals. Please see the original reference for a full list of authors’ disclosures.


Chamberlain BH, Rhiner M, Slatkin NE, Stambler N, Israel RJ. Subcutaneous methylnaltrexone for treatment of opioid-induced constipation in cancer versus noncancer patients: An analysis of efficacy and safety variables from two studies. J Pain Res. 2021;14:2687-2697.