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Clinical evaluation of the efficacy of methylnaltrexone in resolving constipation induced by different opioid subtypes combined with laboratory analysis of immunomodulatory and antiangiogenic effects of methylnaltrexone.

ABSTRACT: Opioid-induced constipation (OIC) is one of the major symptoms in palliative care with a prevalence of 30-50%. Methylnaltrexone for the treatment of OIC is significantly more effective than placebo, but only in about fifty percent of the patients regardless of dose increase. Dose increases cause increased toxicity without additional efficacy, and are therefore not recommended. While methylnaltrexone is a ?-receptor antagonist, only a few opioids are solely ?-receptor agonists. Therefore, the response to methylnaltrexone may be determined by the receptor-profile of a specific opioid. In addition, methylnaltrexone may also affect the immune system and angiogenesis as was found in pre-clinical studies. Primary aim of this study is to determine differences in the efficacy of methylnaltrexone prescribed to resolve opioid induced constipation between three commonly used opioid subtypes: morphine sulphate, oxycodone and fentanyl. Secondary aim is to explore potential immunomodulatory and antiangiogenic effects of methylnaltrexone.In this multi-center, prospective, parallel group trial we will evaluate the efficacy of methylnaltrexone in resolving OIC occurring as a side effect of the most common opioid subtypes: morphine, oxycodone and fentanyl. In total 195 patients with OIC despite prophylactic laxatives will receive methylnaltrexone every other day up to fourteen days. Patients will report its effect in a laxation diary. Group allocation is based on the opioid type the patient is using. At the start and end of the study period patients complete the Bowel Function Index questionnaire. A subgroup of the patients will donate blood for analysis of immunomodulatory- and anti-angiogenic effects of methylnaltrexone.In this study we aim to determine the efficacy of methylnaltrexone per opioid subtype to reduce constipation. We expect that the outcome of this study will improve the clinical use of methylnaltraxone.This trial is registered at clinicaltrials.gov: NCT01955213 and in the Dutch trial register: NTR4272.

SUBMITTER: Neefjes EC

PROVIDER: S-EPMC4145161 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Clinical evaluation of the efficacy of methylnaltrexone in resolving constipation induced by different opioid subtypes combined with laboratory analysis of immunomodulatory and antiangiogenic effects of methylnaltrexone.

Neefjes Elisabeth Cw EC van der Vorst Maurice Jdl MJ Boddaert Manon Sa MS Zuurmond Wouter Wa WW van der Vliet Hans J HJ Beeker Aart A van den Berg Hendrik P HP van Groeningen Cornelis J CJ Vrijaldenhoven Suzan S Verheul Henk Mw HM

BMC palliative care 20140820

<h4>Background</h4>Opioid-induced constipation (OIC) is one of the major symptoms in palliative care with a prevalence of 30-50%. Methylnaltrexone for the treatment of OIC is significantly more effective than placebo, but only in about fifty percent of the patients regardless of dose increase. Dose increases cause increased toxicity without additional efficacy, and are therefore not recommended. While methylnaltrexone is a μ-receptor antagonist, only a few opioids are solely μ-receptor agonists. ...[more]

PMID: 25165428

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Project description:BackgroundMethylnaltrexone, a peripherally acting µ-opioid receptor antagonist approved for the treatment of opioid-induced constipation (OIC), has restricted diffusion across the blood-brain barrier (BBB) and has not been demonstrated to impact opioid-induced central analgesia. Age-related changes in BBB permeability may compromise methylnaltrexone's restricted diffusion and alter opioid-induced central analgesic effects.ObjectiveThis analysis evaluated whether opioid analgesia is compromised in older adults receiving methylnaltrexone for OIC.MethodsThe analysis included adults diagnosed with OIC who received opioids for pain management and who had a terminal illness or chronic nonmalignant pain. Data were pooled from four randomized, double-blind trials and stratified by age (< 65 years and ≥ 65 years). Endpoints included pain intensity scores, symptoms of opioid withdrawal, treatment-related adverse events (TRAEs), and rescue-free laxation (RFL) within 4 h of treatment.ResultsOverall, 1323 patients were < 65 years of age (n = 908, methylnaltrexone; n = 415, placebo) and 304 patients were ≥ 65 years of age (n = 171, methylnaltrexone; n = 133, placebo). Nonsignificant pain intensity score reductions were observed in all groups. In the older cohort, measures of opioid withdrawal did not show statistical differences from baseline in either the methylnaltrexone or placebo groups. The most frequently reported TRAEs were abdominal pain, flatulence, and nausea. Relative to the first dose, gastrointestinal TRAEs potentially related to opioid withdrawal declined with the second dose and were comparable with placebo, regardless of age. RFL response within 4 h of methylnaltrexone treatment increased significantly in both age cohorts relative to placebo.ConclusionsMethylnaltrexone use did not adversely affect pain control, opioid withdrawal effects, or AEs while providing effective RFL, regardless of age. These results suggest that age does not appear to influence the safety and efficacy of methylnaltrexone for OIC. Further research is needed to assess the impact of other factors that alter BBB permeability, such as dementia, stroke, or drug interactions, on the safety and efficacy of methylnaltrexone.Clinical trial registration numbersStudy 302, NCT00402038; study 3200K1-4000, NCT00672477; study 3200K1-3356, NCT00529087; study 3201, NCT01186770.

Project description:PurposeOpioid-induced constipation (OIC) is a common side effect of opioid therapy. Methylnaltrexone (MNTX) is a selective, peripherally acting μ-opioid receptor antagonist, with demonstrated efficacy in treating OIC. We pooled results from MNTX clinical trials to compare responses to an initial dose in patients with chronic cancer and noncancer pain.Patients and methodsThis post hoc analysis used pooled data from 3 randomized, placebo-controlled studies of MNTX in patients with advanced illness with OIC. Assessments included the proportions of patients achieving rescue-free laxation (RFL) within 4 and 24 hours of the first study drug dose, time to RFL, current and worst pain intensity, and adverse events, stratified by the presence/absence of cancer.ResultsA total of 355 patients with cancer (MNTX n = 198, placebo n = 157) and 163 without active cancer (MNTX n = 83; placebo n = 80) were included. More patients treated with MNTX compared with those who received placebo achieved an RFL within 4 (cancer: MNTX, 61.1% vs placebo,15.3%, p<0.0001; noncancer: MNTX, 62.2% vs placebo, 17.5%, p<0.0001) and 24 hours (cancer: MNTX, 71.2% vs placebo, 41.4%, p<0.0001; noncancer: MNTX, 74.4% vs placebo, 37.5%, p<0.0001) of the initial dose. Cumulative RFL response rates within 4 hours of the first, second, or third dose of study drug were also higher in MNTX-treated patients. The estimated time to RFL was shorter among those who received MNTX and similar in cancer and noncancer patients. Mean pain scores declined similarly in all groups. The most common adverse events in both cancer and noncancer patients were abdominal pain, flatulence, and nausea.ConclusionAfter the first dose, MNTX rapidly induced a laxation response in the majority of both cancer and noncancer patients with advanced illness. Opioid-induced analgesia was not compromised, and adverse events were primarily gastrointestinal in nature. Methylnaltrexone is a well-tolerated and effective treatment for OIC in both cancer and noncancer patients.

Project description:BackgroundOpioid-induced constipation (OIC) may increase the risk of fecal impaction and mortality in patients with advanced illness. Methylnaltrexone (MNTX) is efficacious for OIC.ObjectiveThe purpose of this analysis was to evaluate cumulative rescue-free laxation response with repeat MNTX dosing in patients with advanced illness who were refractory to current laxative regimens and to assess the influence, if any, of poor functional status on response to MNTX treatment.MethodsThis analysis included pooled data from patients with advanced illness and established OIC who were on a stable opioid regimen in a pivotal, randomized, placebo (PBO)-controlled clinical trial (study 302 [NCT00402038]) or a randomized, PBO-controlled Food and Drug Administration-required postmarketing study (study 4000 [NCT00672477]). Patients in study 302 received subcutaneous MNTX 0.15 mg/kg or PBO every other day, whereas those in study 4000 received MNTX 8 mg (body weight ≥38 to <62 kg), MNTX 12 mg (body weight ≥62 kg), or PBO every other day. Outcomes included cumulative rescue-free laxation rates at 4- and 24-hours postdose for the first 3 doses of study drug and time to rescue-free laxation. To assess if functional status influenced treatment outcomes, we performed a secondary analysis on the outcomes stratified by baseline World Health Organization/Eastern Cooperative Oncology Group performance status, pain scores, and safety.ResultsOne hundred eighty-five patients received PBO and 179 patients received MNTX. The median age was 66.0 years, 51.5% were women, 56.5% had a baseline World Health Organization/Eastern Cooperative Oncology Group performance status score >2, and 63.4% had a primary diagnosis of cancer. Cumulative rescue-free laxation rates were significantly higher with MNTX than PBO 4- and 24-hours after doses 1, 2, and 3 (P < 0.0001), and between-treatment comparisons remained significant (P < 0.0001) regardless of performance status. The estimated time to first rescue-free laxation was shorter for patients receiving MNTX versus PBO. No new safety signals were identified.ConclusionsRepeated use of MNTX represents a safe and effective treatment for OIC in patients with advanced illness regardless of baseline performance status. ClinicalTrials.gov identifier: NCT00672477. (Curr Ther Res Clin Exp. 2023; 84:XXX-XXX)© 2023 Elsevier HS Journals, Inc.

Project description:PurposeAn 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.MethodsThis 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.ResultsThe 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%).ConclusionOral methylnaltrexone does not elicit opioid withdrawal or interfere with opioid analgesia.

Project description:PurposeConstipation can be a significant problem in critically unwell patients, associated with detrimental outcomes. Opioids are thought to contribute to the mechanism of bowel dysfunction. We tested if methylnaltrexone, a pure peripheral mu-opioid receptor antagonist, could reverse opioid-induced constipation.MethodsThe MOTION trial is a multi-centre, double blind, randomised placebo-controlled trial to investigate whether methylnaltrexone alleviates opioid-induced constipation (OIC) in critical care patients. Eligibility criteria included adult ICU patients who were mechanically ventilated, receiving opioids and were constipated (had not opened bowels for a minimum 48 h) despite prior administration of regular laxatives as per local bowel management protocol. The primary outcome was time to significant rescue-free laxation. Secondary outcomes included gastric residual volume, tolerance of enteral feeds, requirement for rescue laxatives, requirement for prokinetics, average number of bowel movements per day, escalation of opioid dose due to antagonism/reversal of analgesia, incidence of ventilator-associated pneumonia, incidence of diarrhoea and Clostridium difficile infection and finally 28 day, ICU and hospital mortality.ResultsA total of 84 patients were enrolled and randomized (41 to methylnaltrexone and 43 to placebo). The baseline demographic characteristics of the two groups were generally well balanced. There was no significant difference in time to rescue-free laxation between the groups (Hazard ratio 1.42, 95% CI 0.82-2.46, p = 0.22). There were no significant differences in the majority of secondary outcomes, particularly days 1-3. However, during days 4-28, there were fewer median number of bowel movements per day in the methylnaltrexone group, (p = 0.01) and a greater incidence of diarrhoea in the placebo group (p = 0.02). There was a marked difference in mortality between the groups, with ten deaths in the methylnaltrexone group and two in the placebo group during days 4-28 (p = 0.007).ConclusionWe found no evidence to support the addition of methylnaltrexone to regular laxatives for the treatment of opioid-induced constipation in critically ill patients; however, the confidence interval was wide and a clinically important difference cannot be excluded.

Project description:PurposeWe evaluated the impact of baseline patient characteristics on safety and efficacy of methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, in patients with advanced illness with opioid-induced constipation (OIC).Patients and methodsThis analysis pooled data from 2 randomized, double-blind, placebo-controlled studies (study 302: NCT00402038; study 4000: NCT00672477) in patients with advanced illness, including cancer, and OIC. Patients were randomized to receive subcutaneous methylnaltrexone (study 302: 0.15 mg/kg; study 4000: 8 or 12 mg based on weight) or placebo every other day for 2 weeks. The proportions of patients achieving rescue-free laxation within 4 or 24 hours after the first dose of study drug were assessed in patient subgroups stratified by baseline age, Eastern Cooperative Oncology Group (ECOG) performance status, cancer status, laxative type, and opioid requirement. Treatment-emergent adverse events (TEAEs) were evaluated.ResultsOverall, 363 patients were included in this analysis (methylnaltrexone, 178; placebo, 185). Mean (SD) age was 66.3 (13.7) years and 48.5% were men overall. A significantly greater proportion of patients receiving methylnaltrexone versus placebo achieved rescue-free laxation within 4 hours (111/178 [62.4%] vs 31/185 [16.8%]; P<0.0001) and 24 hours (135/178 [75.8%] vs 81/185 [43.8%]; P<0.0001) of the first dose. These trends were consistent across all subgroups. Most patients experienced ≥1 TEAE in the overall population (methylnaltrexone, 82.1%; placebo, 76.2%), which remained consistent when stratified by baseline characteristics. More than half of TEAEs were gastrointestinal in nature. Abdominal pain was more common in patients receiving methylnaltrexone than placebo across baseline characteristic subgroups.ConclusionMethylnaltrexone treatment was superior to placebo in achieving rescue-free laxation within 4 and 24 hours after the first dose, irrespective of patients' cancer status, baseline ECOG performance status, or baseline opioid or laxative use. The methylnaltrexone safety profile remained consistent across baseline characteristic subgroups.

Dataset Information

Clinical evaluation of the efficacy of methylnaltrexone in resolving constipation induced by different opioid subtypes combined with laboratory analysis of immunomodulatory and antiangiogenic effects of methylnaltrexone.

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Clinical evaluation of the efficacy of methylnaltrexone in resolving constipation induced by different opioid subtypes combined with laboratory analysis of immunomodulatory and antiangiogenic effects of methylnaltrexone.

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