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Neurogastroenterology and Motility Dec 2023Constipation is frequent in critically ill patients, and potentially related to adverse outcomes. Peripherally-active mu-opioid receptor antagonists (PAMORAs) are... (Meta-Analysis)
Meta-Analysis
Peripherally-active mu-opioid receptor antagonists for constipation in critically ill patients receiving opioids: A case-series and a systematic review and meta-analysis of the literature.
BACKGROUND
Constipation is frequent in critically ill patients, and potentially related to adverse outcomes. Peripherally-active mu-opioid receptor antagonists (PAMORAs) are approved for opioid-induced constipation, but information on their efficacy and safety in critically ill patients is limited. We present a single-center, retrospective, case-series of the use of naldemedine for opioid-associated constipation, and we systematically reviewed the use of PAMORAs in critically ill patients.
METHODS
Case-series included consecutive mechanically-ventilated patients; constipation was defined as absence of bowel movements for >3 days. Naldemedine was administered after failure of the local laxation protocol. Systematic review: PubMed was searched for studies of PAMORAs to treat opioid-induced constipation in adult critically ill patients.
PRIMARY OUTCOMES
time to laxation, and number of patients laxating at the shortest follow-up.
SECONDARY OUTCOMES
gastric residual volumes and adverse events.
KEY RESULTS
A total of 13 patients were included in the case-series; the most common diagnosis was COVID-19 ARDS. Patients had their first bowel movement 1 [0;2] day after naldemedine. Daily gastric residual volume was 725 [405;1805] before vs. 250 [45;1090] mL after naldemedine, p = 0.0078. Systematic review identified nine studies (two RCTs, one prospective case-series, three retrospective case-series and three case-reports). Outcomes were similar between groups, with a trend toward a lower gastric residual volume in PAMORAs group.
CONCLUSIONS & INFERENCES
In a highly-selected case-series of patients with refractory, opioid-associated constipation, naldemedine was safe and associated to reduced gastric residuals and promoting laxation. In the systematic review and meta-analysis, the use of PAMORAs (mainly methylnaltrexone) was safe and associated with a reduced intolerance to enteral feeding but no difference in the time to laxation.
Topics: Adult; Humans; Narcotic Antagonists; Analgesics, Opioid; Constipation; Opioid-Induced Constipation; Retrospective Studies; Critical Illness; Naltrexone; Laxatives
PubMed: 37869768
DOI: 10.1111/nmo.14694 -
Journal of Pain Research 2023Opioid-induced constipation (OIC) is a common side effect of opioid therapy. Methylnaltrexone (MNTX) is a selective, peripherally acting μ-opioid receptor antagonist,... (Clinical Trial)
Clinical Trial
PURPOSE
Opioid-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 METHODS
This 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.
RESULTS
A 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%, <0.0001; noncancer: MNTX, 62.2% vs placebo, 17.5%, <0.0001) and 24 hours (cancer: MNTX, 71.2% vs placebo, 41.4%, <0.0001; noncancer: MNTX, 74.4% vs placebo, 37.5%, <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.
CONCLUSION
After 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.
PubMed: 37533563
DOI: 10.2147/JPR.S405825 -
Molecular Pain May 2023Activation of neurons and glial cells in the dorsal root ganglion is one of the key mechanisms for the development of hyperalgesia. The aim of the present study was to...
Activation of neurons and glial cells in the dorsal root ganglion is one of the key mechanisms for the development of hyperalgesia. The aim of the present study was to examine the role of neuroglial activity in the development of opioid-induced hyperalgesia. Male rats were treated with morphine daily for 3 days. The resultant phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in the dorsal root ganglion was analyzed by immunohistochemistry and Western blotting. Pain hypersensitivity was analyzed using behavioral studies. The amount of cytokine expression in the dorsal root ganglion was also analyzed. Repeated morphine treatment induced hyperalgesia and marked induction of phosphorylated ERK1/2 in the neurons and satellite glial cells on day 3. An opioid receptor antagonist, toll like receptor-4 inhibitor, MAP/ERK kinase (MEK) inhibitor and gap junction inhibitor inhibited morphine-induced hyperalgesia and ERK1/2 phosphorylation. Morphine treatment induced alteration of cytokine expression, which was inhibited by the opioid receptor antagonist, toll like receptor-4 inhibitor, MEK inhibitor and gap junction inhibitor. Dexamethasone inhibited morphine-induced hyperalgesia and ERK1/2 phosphorylation after morphine treatment. The peripherally restricted opioid receptor antagonist, methylnaltrexone, inhibited hyperalgesia and ERK1/2 phosphorylation. Morphine activates ERK1/2 in neurons and satellite glial cells in the dorsal root ganglion via the opioid receptor and toll like receptor-4. ERK1/2 phosphorylation is gap junction-dependent and is associated with the alteration of cytokine expression. Inhibition of neuroinflammation by activation of neurons and glia might be a promising target to prevent opioid-induced hyperalgesia.
PubMed: 37254240
DOI: 10.1177/17448069231181973 -
The Journal of Pediatric Pharmacology... 2023Critically ill pediatric patients commonly experience opioid-induced dysmotility. Methylnaltrexone, a subcutaneously administered, peripherally acting mu-opioid receptor...
OBJECTIVE
Critically ill pediatric patients commonly experience opioid-induced dysmotility. Methylnaltrexone, a subcutaneously administered, peripherally acting mu-opioid receptor antagonist, is a compelling adjunct to enteral laxatives in patients with opioid-induced dysmotility. Data for methylnaltrexone use in critically ill pediatric patients are limited. The purpose of this study was to determine the effectiveness and safety of methylnaltrexone for opioid-induced dysmotility in critically ill infants and children.
METHODS
Patients younger than 18 years who received subcutaneous methylnaltrexone from January 1, 2013, through September 15, 2020, in the pediatric intensive care units at an academic institution were included in this retrospective analysis. Outcomes included incidence of bowel movement, enteral nutrition feeding volume, and adverse drug events.
RESULTS
Twenty-four patients, median age 3.5 years (IQR, 0.58-11.1), received 72 methylnaltrexone doses. The median dose was 0.15 mg/kg (IQR, 0.15-0.15). Patients were receiving a mean ± SD of 7.5 ± 4.5 mg/kg/day of oral morphine milligram equivalents (MMEs) at methylnaltrexone administration and received opioids for median 13 days (IQR, 8.8-21) prior to methylnaltrexone administration. A bowel movement occurred within 4 hours following 43 (60%) administrations and within 24 hours following 58 (81%) administrations. Enteral nutrition volume increased by 81% (p = 0.002) following administration. Three patients had emesis and 2 received anti-nausea medication. No significant changes in sedation or pain scores were observed. Withdrawal scores and daily oral MMEs decreased following administration (p = 0.008 and p = 0.002, respectively).
CONCLUSIONS
Methylnaltrexone may be an effective treatment for opioid-induced dysmotility in critically ill pediatric patients with low risk of adverse effects.
PubMed: 37139255
DOI: 10.5863/1551-6776-28.2.136 -
Journal of the American Association For... May 2023Opioids are an integral component of pain management for nonhuman primates. These potent analgesics also adverse gastrointestinal (GI) effects that include constipation,...
Opioids are an integral component of pain management for nonhuman primates. These potent analgesics also adverse gastrointestinal (GI) effects that include constipation, bloating, and delayed gastric emptying. Methylnaltrexone bromide (MNTX) is a selective, peripherally acting μ- and κ-opioid receptor antagonist that can be used to mitigate the GI effects associated with opioid administration. Unlike naltrexone, a similar drug in this class, MNTX possesses an N-methyl-quaternary amine group that prevents it from crossing the blood brain barrier. This blockage allows inhibition of peripheral GI opioid receptors without affecting opioid-mediated analgesia in the central nervous system. We conducted a pharmacokinetic analysis of MNTX in serum and CSF of 6 healthy juvenile male rhesus macaques after subcutaneous administration of a 0.15-mg/kg dose. We hypothesized that the macaques would demonstrate a T of 0.5 h, similar to that of humans, and that no MNTX would be detected in the CSF. This treatment resulted in a peak serum concentration of 114 ± 44 ng/mL at 0.25 ± 0.00 h; peak CSF at concentrations were 0.34 ± 0.07 ng/mL at the T. These data show that subcutaneous administration of MNTX to rhesus macaques may block peripheral adverse effects of opioids without interfering with their central analgesic effects.
Topics: Humans; Male; Animals; Naltrexone; Macaca mulatta; Narcotic Antagonists; Analgesics, Opioid; Quaternary Ammonium Compounds
PubMed: 37080736
DOI: 10.30802/AALAS-JAALAS-22-000111 -
Journal of Oncology Pharmacy Practice :... Jan 2024Peripherally acting -opioid receptor antagonists (PAMORAs) are used in the treatment of opioid induced constipation without impacting the actions of opioid analgesics....
INTRODUCTION
Peripherally acting -opioid receptor antagonists (PAMORAs) are used in the treatment of opioid induced constipation without impacting the actions of opioid analgesics. Subcutaneous methylnaltrexone was one of the first PAMORAs approved in April 2008 for the treatment of opioid induced constipation in adult patients. The safety and effectiveness of methylnaltrexone has not been established in pediatric patients. In this study, the use of subcutaneous methylnaltrexone in pediatric patients is analyzed and reviewed. The primary outcome is occurrence of a bowel movement within 24 h after methylnaltrexone (MNTX) administration and the number of bowel movements following treatment with methylnaltrexone. Secondary outcomes include safety in this patient cohort.
METHODS
This is a retrospective study of 79 pediatric patients with opioid induced constipation. Patients were administered methylnaltrexone during their inpatient stay. Data on bowel activity after methylnaltrexone was obtained from the hospital information system.
RESULTS
Out of the 79 patients who received methylnaltrexone, there were seven patients from whom data could not be analyzed. Of the 72 patients whose data was available, 38% ( = 27) were documented as having a bowel movement, 62% ( = 45) did not have a bowel movement. Reported adverse events were minimal with nausea ( = 3), vomiting (= 1), and flatulence ( = 6).
CONCLUSION
Methylnaltrexone appears safe in the pediatric population and produces bowel movements in more than a third of pediatric patients. It is a feasible and safe option for opioid induced constipation in pediatric patients.
Topics: Adult; Humans; Child; Analgesics, Opioid; Opioid-Induced Constipation; Retrospective Studies; Constipation; Narcotic Antagonists; Neoplasms; Quaternary Ammonium Compounds; Naltrexone
PubMed: 36946143
DOI: 10.1177/10781552231163540 -
Current Therapeutic Research, Clinical... 2023Opioid-induced constipation (OIC) may increase the risk of fecal impaction and mortality in patients with advanced illness. Methylnaltrexone (MNTX) is efficacious for...
BACKGROUND
Opioid-induced constipation (OIC) may increase the risk of fecal impaction and mortality in patients with advanced illness. Methylnaltrexone (MNTX) is efficacious for OIC.
OBJECTIVE
The 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.
METHODS
This 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.
RESULTS
One 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 ( < 0.0001), and between-treatment comparisons remained significant ( < 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.
CONCLUSIONS
Repeated 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. (. 2023; 84:XXX-XXX)© 2023 Elsevier HS Journals, Inc.
PubMed: 36875317
DOI: 10.1016/j.curtheres.2023.100694 -
Journal of Pain Research 2023To evaluate the efficacy and safety of subcutaneous (SC) methylnaltrexone for opioid-induced constipation (OIC) in patients with and without active cancer.
Subcutaneous Methylnaltrexone as Treatment for Opioid-Induced Constipation in Patients with Advanced Cancer and Noncancer Illnesses: A Post Hoc Analysis of Two Clinical Trials.
PURPOSE
To evaluate the efficacy and safety of subcutaneous (SC) methylnaltrexone for opioid-induced constipation (OIC) in patients with and without active cancer.
PATIENTS AND METHODS
We 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.
RESULTS
The 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], <0.0001; noncancer, 48.0% vs 10.0%; <0.005) or given as a weight-adjusted fixed dose (cancer, 59.5% vs 6.8%; noncancer, 70.3% vs 14.6%; <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.
CONCLUSION
SC methylnaltrexone was efficacious in inducing rapid RFL and safe among patients with and without active cancer suffering from OIC.
PubMed: 36798078
DOI: 10.2147/JPR.S366460 -
The American Journal of Hospice &... Oct 2023Methylnaltrexone is a peripherally-acting mu-opioid receptor antagonist studied in both cancer and non-cancer patients with opioid-induced constipation (OIC), but...
Methylnaltrexone is a peripherally-acting mu-opioid receptor antagonist studied in both cancer and non-cancer patients with opioid-induced constipation (OIC), but mostly in the outpatient setting. For adult hospitalized cancer patients with OIC, its effectiveness is unknown. Objectives: Describe the efficacy of methylnaltrexone for OIC in the inpatient setting, defined as bowel movement (BM) within 24 hours of methylnaltrexone administration. We performed a single-center, retrospective chart review of all hospitalized, adult patients with a cancer diagnosis who received methylnaltrexone from the palliative care team between January 1st, 2012 and July 1st, 2019. We identified 194 patients. The mean age was 59, 50.5% were male and 88% were white. 192 patients (98%) received the 8 mg dose subcutaneously. The median oral morphine equivalent (OME) was 135 mg (IQR 70-354 mg). 45% (95% confidence interval, 38-53%) had a BM within 24 hours. Higher OME was correlated with successful BM, with a response in 93% (86/92) of patients receiving ≥150 OME and 2% (2/102) of patients receiving <150 OME ( < .0001). Prior laxative use did not predict response at 24 hours whether these were osmotic laxatives (40.7% vs 47.1%, = .52), stimulant laxatives (45.7% vs 45.2%, > .99), or stool softeners (44.7% vs 46.1%, = .89). Methylnaltrexone has a high response rate when used as treatment for OIC in hospitalized adult cancer patients, especially for patients taking ≥150 OME.
Topics: Adult; Humans; Male; Female; Analgesics, Opioid; Laxatives; Retrospective Studies; Constipation; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Neoplasms; Morphine
PubMed: 36565253
DOI: 10.1177/10499091221147903