Randomized, Double‐Blind Trial of Oral Methylnaltrexone for the Treatment of Opioid‐Induced Constipation in Patients with Chronic Noncancer Pain

Abstract

Background: Subcutaneous methylnaltrexone, a peripherally acting l-opioid receptor antagonist, improves opioid-induced constipation (OIC) in patients with chronic noncancer pain. An oral methylnaltrexone formulation has been developed. Methods: In this phase 3, double-blind trial, adults with chronic noncancer pain receiving opioid doses of ≥ 50 mg/ day oral morphine equivalents with OIC were randomly assigned to oral methylnaltrexone (150, 300, or 450 mg) or placebo once daily (QD) for 4 weeks followed by as-needed dosing for 8 weeks. Patients who had ≥ 3 rescue-free bowel movements (RFBMs)/week, with an increase of ≥ 1 RFBM/ week from baseline for ≥ 3 of 4 weeks during the QD period, were responders. Results: Overall, 803 patients were included in the analyses. A significantly greater percentage of patients had an increase in mean percentage of dosing days resulting in an RFBM within 4 hours of dosing during weeks 1 through 4 (QD period; primary endpoint) with methylnaltrexone (300 mg/ day [24.6%; P = 0.002] and 450 mg/day [27.4%; P < 0.0001]) vs. placebo (18.2%). The percentage of responders (49.3% for 300 mg [P = 0.03] and 51.5% for 450 mg [P = 0.005] vs. 38.3% with placebo) and change from baseline in mean number of weekly RFBMs (difference vs. placebo, 0.5 for 300 mg [P = 0.03] and 0.5 for 450 mg [P = 0.02]) was significantly greater with methylnaltrexone 300 and 450 mg/day vs. placebo during the QD period. All dosages of oral methylnaltrexone were well tolerated. Conclusions: Oral methylnaltrexone was efficacious and well tolerated for OIC in patients with chronic noncancer pain, particularly the 450-mg dose. &

The Efficacy of Peripheral Opioid Antagonists in Opioid-Induced Constipation and Postoperative Ileus

“…17,33,34 The selected dose for studies with subcutaneous methylnaltrexone was 12 mg in 2 studies, 31,32 8 or 12 mg in 1 study, 17 0.15 mg/kg in 1 study, 34 0.15 or 0.3 mg/kg in 1 study, 33 and up to 0.365 mg/kg in the study that used intravenous methylnaltrexone. 35 The single study of oral methylnaltrexone included doses of 150, 300, and 450 mg. 18 The primary outcome was positive in all 7 studies. In 5 studies, the primary outcome was achievement of an SBM within 4 hours of receiving the study drug.…”

“…Although this end point was greater in both 300-and 450-mg groups, it was lower than the response rate for the subcutaneous formulation. 18 The 450-mg dose had the highest efficacy without increasing adverse events. Study quality was moderate for 2 studies, 17,18 low for 3 studies, 32-34 and very low for 2 studies.…”

“…30 There were 7 studies on methylnaltrexone for OIC. 17,18,[31][32][33][34][35] Four studies included patients with noncancer pain only, 18,31,32,35 whereas the other 3 enrolled patients with both cancer and noncancer pain. 17,33,34 The selected dose for studies with subcutaneous methylnaltrexone was 12 mg in 2 studies, 31,32 8 or 12 mg in 1 study, 17 0.15 mg/kg in 1 study, 34 0.15 or 0.3 mg/kg in 1 study, 33 and up to 0.365 mg/kg in the study that used intravenous methylnaltrexone.…”

“…17,[31][32][33][34] For oral methylnaltrexone, pain scores did not change from baseline. 18 In the remaining study, pain and opioid use were not assessed, but patients reported no change in subjective withdrawal symptoms. 35 In the largest study by Michna et al, 32 rescue laxatives were used by 61.7% of the placebo group versus 38.7% in the daily-dosing group and 41.7% in the everyother-day dosing group.…”

“…15 The most recent addition to the PAM-OR antagonists, naloxegol, has been in clinical use since its approval in 2014 as "an opioid antagonist indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic noncancer pain." 16 Several randomized trials involving PAM-OR antagonists have recently been published 17,18 ; in addition, previous reviews have focused solely on a single agent 19,20 or either OIC 21 or POI 7 but not both. Therefore, an update that discusses strengths and limitations of the evidence is warranted.…”