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Safety of oral methylnaltrexone for opioid-induced constipation in patients with chronic noncancer pain.

ABSTRACT: Purpose:Oral methylnaltrexone was shown to be effective in treating opioid-induced constipation (OIC) in patients with chronic noncancer pain in a Phase III randomized controlled trial. This report provides a detailed safety analysis from that study. Methods:Adults (n=803) with chronic noncancer pain for ?2 months and confirmed OIC while receiving opioid doses ?50 mg morphine equivalent per day for ?14 days were randomized 1:1:1:1 to oral methylnaltrexone (150, 300, or 450 mg) or placebo once daily for 4 weeks, followed by as-needed use for 8 weeks. Safety was evaluated by examining treatment-emergent adverse events (TEAEs), clinical laboratory parameters, vital signs, electrocardiography, rescue-laxative and opioid use, Objective Opioid Withdrawal Scale (OOWS) and Subjective Opioid Withdrawal Scale (SOWS), and pain-intensity scores. Results:TEAEs occurred at a similar incidence in the methylnaltrexone groups (59.0%) and placebo group (63.0%). The most common TEAEs with methylnaltrexone were abdominal pain (8.0% vs 8.5% with placebo), nausea (6.8% vs 9.0%), and diarrhea (6.0% vs 3.5%). Cardiac-related TEAEs occurred in 1.8% and 1.0% of patients, respectively, and no major adverse cardiovascular events were reported. No patient had a cluster of TEAEs associated with opioid withdrawal after excluding gastrointestinal TEAEs. Changes in laboratory parameters, vital signs, and electrocardiography were generally small and similar across treatment groups. Rescue-laxative use was more common with placebo than methylnaltrexone 450 mg (6.20% vs 4.27% of study days, P=0.024). Changes in opioid dose, OOWS and SOWS scores, and pain-intensity scores during treatment were minimal. Conclusion:Oral methylnaltrexone had a safety profile comparable with placebo in the treatment of OIC in patients with chronic noncancer pain, with no evidence of cardiac toxicity or opioid withdrawal.

SUBMITTER: Rauck RL

PROVIDER: S-EPMC6307492 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Safety of oral methylnaltrexone for opioid-induced constipation in patients with chronic noncancer pain.

Rauck Richard L RL Slatkin Neal E NE Stambler Nancy N Israel Robert J RJ

Journal of pain research 20181224

<h4>Purpose</h4>Oral methylnaltrexone was shown to be effective in treating opioid-induced constipation (OIC) in patients with chronic noncancer pain in a Phase III randomized controlled trial. This report provides a detailed safety analysis from that study.<h4>Methods</h4>Adults (n=803) with chronic noncancer pain for ≥2 months and confirmed OIC while receiving opioid doses ≥50 mg morphine equivalent per day for ≥14 days were randomized 1:1:1:1 to oral methylnaltrexone (150, 300, or 450 mg) or ...[more]

PMID: 30613162

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Project description:Purpose:An oral formulation of methylnaltrexone has been developed for treating opioid-induced constipation (OIC). This manuscript examines the impact of oral methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, on opioid analgesia. Methods:This Phase III, randomized, double-blind, placebo-controlled trial, evaluated changes in pain intensity scores (0= no pain to 10= worst possible pain) and opioid use in adults with chronic noncancer pain. Patients taking ?50 mg/day oral morphine equivalent dose (MED) for ?14 days before screening with less than three rescue-free bowel movements/week received oral methylnaltrexone 150 mg/day (n=201), 300 mg/day (n=201), 450 mg/day (n=200), or placebo (n=201) once daily for 4 weeks followed by 8 weeks of oral methylnaltrexone as needed. Results:The primary condition requiring opioid use was back pain (68.2% of 803 patients). Baseline pain intensity scores were similar among treatment groups (mean range, 6.2-6.4) and remained stable throughout the 4-week double-blind (mean range, 6.1-6.5) and 8-week as needed (mean range, 6.3-6.5) periods. Baseline mean MED was comparable between oral methylnaltrexone 150 mg (200.0 mg/day), methylnaltrexone 450 mg (218.0 mg/day), and placebo (209.7 mg/day), but was slightly higher in the oral methylnaltrexone 300-mg group (252.6 mg/day). Nonsignificant, minimal changes in mean MED were observed after 4 weeks of treatment (214.5-235.6 mg/day) and at the end of the as needed phase (202.3-234.9 mg/day). The percentage of patients who initiated new opioid medications during the 4-week, once-daily dosing period was generally similar among the oral methylnaltrexone 150-mg, 300-mg, and 450-mg groups (44.8%, 43.3%, and 35.0%, respectively), the oral methylnaltrexone combined group (41.0%), and the placebo group (39.8%). The most common newly initiated opioid medications during this once-daily period were oxycodone (oral methylnaltrexone groups combined, 14.6%; placebo, 12.4%) and morphine (oral methylnaltrexone combined, 10.1%; placebo, 7.0%). Conclusion:Oral methylnaltrexone does not elicit opioid withdrawal or interfere with opioid analgesia.

Project description:PurposeTo evaluate the safety and efficacy of oral methylnaltrexone for opioid-induced constipation (OIC).Patients and methodsThis was a post hoc analysis of patients receiving methadone in a randomized, double-blind, placebo-controlled, Phase 3 trial. The trial included adults with chronic noncancer pain for ≥2 months receiving opioid doses ≥50 mg/day of oral morphine equivalents for ≥14 days and with a history of OIC. Patients were assigned to oral methylnaltrexone (150, 300, or 450 mg) or placebo once daily (QD) for 4 weeks followed by 8 weeks as needed. Percentage of dosing days that resulted in a rescue-free bowel movement (RFBM) within 4 hours of dosing was assessed during QD dosing (primary efficacy endpoint). Other endpoints included percentage of responders (ie, ≥3 RFBMs/week, with an increase of ≥1 RFBM/week from baseline for ≥3 of the 4 weeks) during QD dosing and change in weekly number of RFBMs. Adverse events were assessed.ResultsConcomitant methadone was reported in 120 patients (oral methylnaltrexone: 150 mg [n=33], 300 mg [n=30], and 450 mg [n=31]; placebo [n=26]). Oral methylnaltrexone-treated patients had significant increases in mean percentage of dosing days with RFBMs within 4 hours of dosing during weeks 1-4 with 300 mg (33.6%; P<0.01) and 450 mg (38.2%; P<0.001) vs placebo; improvements with 150 mg (20.0%) vs placebo (15.1%) did not reach statistical significance. The percentage of responders was greater vs placebo, but not significant, for the higher doses during the QD period (150 mg [39.4%], 300 mg [60.0%], 450 mg [67.7%], and placebo [38.5%]). Change from baseline in the mean number of weekly RFBMs (weeks 1-4) was significantly greater with oral methylnaltrexone 450 mg vs placebo (least-squares mean difference vs placebo, 1.2; P=0.04); no significant differences were found for 300 or 150 mg. Oral methylnaltrexone was well tolerated at all doses; few patients discontinued treatment.ConclusionOral methylnaltrexone, particularly 450 mg, was efficacious and safe for treating OIC in these patients.

Project description:ObjectivesThis multicenter, phase 3 trial evaluated oral lubiprostone for constipation associated with non-methadone opioids in patients with chronic noncancer-related pain.MethodsAdults with opioid-induced constipation (OIC; <3 spontaneous bowel movements [SBMs] per week) were randomized 1:1 to double-blind lubiprostone 24??g or placebo twice daily for 12 weeks. The primary end point was the overall SBM response rate. Responders had at least moderate response (?1 SBM improvement over baseline frequency) in all treatment weeks with available observed data, as well as full response (?3 SBMs per week) for at least 9 of the 12 treatment weeks.ResultsIn total, 431 patients were randomized; 212 each received lubiprostone and placebo, and 7 were not treated. Overall, the SBM response rate was significantly higher for patients treated with lubiprostone vs. placebo (27.1 vs. 18.9%, respectively; P=0.030). Overall mean change from baseline in SBM frequency was significantly greater with lubiprostone vs. placebo (3.2 vs. 2.4, respectively; P=0.001). The median time to first SBM was significantly shorter with lubiprostone vs. placebo (23.5 vs. 37.7?h, respectively; P=0.004). Compared with placebo, the patients treated with lubiprostone exhibited significant improvements in straining (P=0.004), stool consistency (P<0.001), and constipation severity (P=0.010). No significant differences were observed in quality-of-life measures or the use of rescue medication; however, the percentage of patients who used rescue medication was consistently lower in the lubiprostone group than in the placebo group at months 1 (34.9 vs. 37.7%), 2 (23.4 vs. 26.6%), and 3 (20.5 vs. 22.0%). Adverse events (AEs) >5% were diarrhea, nausea, vomiting, and abdominal pain (lubiprostone: 11.3, 9.9, 4.2, and 7.1%, respectively; placebo, 3.8, 4.7, 5.2, and 0%, respectively). None of the serious AEs (lubiprostone, 3.3%; placebo, 2.8%) were related to lubiprostone.ConclusionsLubiprostone significantly improved symptoms of OIC and was well tolerated in patients with chronic noncancer pain.

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Safety of oral methylnaltrexone for opioid-induced constipation in patients with chronic noncancer pain.

Publications

Safety of oral methylnaltrexone for opioid-induced constipation in patients with chronic noncancer pain.

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