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Oral methylnaltrexone does not negatively impact analgesia in patients with opioid-induced constipation and chronic noncancer pain.

ABSTRACT: 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.

SUBMITTER: Webster LR

PROVIDER: S-EPMC6095122 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Oral methylnaltrexone does not negatively impact analgesia in patients with opioid-induced constipation and chronic noncancer pain.

Webster Lynn R LR Israel Robert J RJ

Journal of pain research 20180813

<h4>Purpose</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 30147355

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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 μg 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.

Project description:PurposeTo evaluate the efficacy and safety of subcutaneous (SC) methylnaltrexone for opioid-induced constipation (OIC) in patients with and without active cancer.Patients and methodsWe analyzed two randomized, double-blind, placebo-controlled, Phase 3/4 trials (NCT00402038, NCT00672477). Patients received SC methylnaltrexone (study 302, 0.15 mg/kg; study 4000, 8 mg or 12 mg based on body weight) or placebo every other day for 2 weeks. Patients were stratified by cancer status. Primary efficacy endpoints included proportion of patients achieving rescue-free laxation (RFL); secondary endpoints included time to RFL, pain intensity scores, and safety/tolerability. Trial results were evaluated separately.ResultsThe safety population (patients receiving ≥1 study drug dose) included 364 patients (study 302, n=134; study 4000, n=230). Study 302 had 78 patients with active cancer (methylnaltrexone, n=37; placebo, n=41) and 56 without cancer (methylnaltrexone, n=26; placebo, n=30); study 4000 had 152 patients with active cancer (methylnaltrexone, n=79; placebo, n=73) and 78 without cancer (methylnaltrexone, n=37; placebo, n=41). A significantly greater proportion of patients treated with methylnaltrexone achieved a laxation response within 4 hours after at least 2 of the first 4 doses versus placebo, dosed by body weight (cancer, 54.1% [methylnaltrexone] vs 7.3% [placebo], P<0.0001; noncancer, 48.0% vs 10.0%; P<0.005) or given as a weight-adjusted fixed dose (cancer, 59.5% vs 6.8%; noncancer, 70.3% vs 14.6%; P<0.0001 each). With fixed-dose methylnaltrexone, average time to RFL for patients with and without cancer was <1 hour of the first dose; with methylnaltrexone dosed by body weight, the first RFL occurred in <4 and <7 hours of treatment in patients with and without cancer, respectively. No significant differences were found in pain scores. SC methylnaltrexone was well tolerated at all doses in all patient cohorts.ConclusionSC methylnaltrexone was efficacious in inducing rapid RFL and safe among patients with and without active cancer suffering from OIC.

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Oral methylnaltrexone does not negatively impact analgesia in patients with opioid-induced constipation and chronic noncancer pain.

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Oral methylnaltrexone does not negatively impact analgesia in patients with opioid-induced constipation and chronic noncancer pain.

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