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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 -
The Annals of Pharmacotherapy Jul 2023Opioid-induced constipation (OIC) may occur in up to 81% of critically ill patients and can lead to many complications. Opioid antagonists are a reasonable approach and...
BACKGROUND
Opioid-induced constipation (OIC) may occur in up to 81% of critically ill patients and can lead to many complications. Opioid antagonists are a reasonable approach and may be used for managing OIC.
OBJECTIVE
The purpose of this study was to assess the efficacy of enteral naloxone (NLX) versus subcutaneous methylnaltrexone (MNTX) for the management of OIC in critically ill patients.
METHODS
A retrospective analysis was conducted on adult patients who received NLX or MNTX and a continuous opioid infusion for at least 48 hours. The primary end point was time to resolution of constipation, defined as hours to first bowel movement (BM) after the first dose of an opioid antagonist. Reversal of analgesia was assessed by comparing the total number of morphine milligram equivalents (MME) 24 hours preopioid and postopioid antagonist administration. Univariate and multivariate analyses were conducted to assess treatment response within 48 hours.
RESULTS
Baseline characteristics were similar between patients receiving NTX (n = 89) and MNTX (n = 71). However, the time to the first BM with NLX was 18 hours compared with 41 hours with MNTX ( = 0.004). There was no difference in MME requirements 24 hours pre/post NLX or MNTX administration. Naloxone administration was identified as a statistically significant predictor of BM within 48 hours (odds ratio [OR] = 2.68 [1.33-5.38]).
CONCLUSION AND RELEVANCE
The time to first BM was shorter with enteral NLX. Both NLX and MNTX appear to be effective for the management of OIC without causing reversal of analgesia. Future controlled, prospective trials comparing these agents are warranted.
Topics: Adult; Humans; Naloxone; Analgesics, Opioid; Opioid-Induced Constipation; Critical Illness; Retrospective Studies; Prospective Studies; Constipation; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Pain
PubMed: 36314271
DOI: 10.1177/10600280221132851 -
The Annals of Pharmacotherapy Jul 2024Constipation impacts 58% to 83% of critically ill patients and is associated with increased time on mechanical ventilation, delirium, and increased length of stay (LOS)... (Comparative Study)
Comparative Study
BACKGROUND
Constipation impacts 58% to 83% of critically ill patients and is associated with increased time on mechanical ventilation, delirium, and increased length of stay (LOS) in the intensive care unit (ICU).
OBJECTIVE
The purpose of this study was to evaluate the efficacy of enteral naloxegol (NGL) versus subcutaneous methylnaltrexone (MNTX) for the management of opioid-induced constipation (OIC) in critically ill patients.
METHODS
A retrospective analysis was conducted on adult patients admitted to the ICU who received a parenteral opioid infusion for at least 4 hours and experienced no bowel movement (BM) within the 48-hour period preceding the administration of NGL or MNTX. The primary outcome was time to first BM from the start of NGL or MNTX therapy. Secondary outcomes included number of BMs 72 hours following NGL or MNTX administration, ICU LOS, and cost-effectiveness.
RESULTS
After exclusion criteria were applied, 110 and 51 patients were included in the NGL and MNTX groups, respectively. With a 10% noninferiority margin, NGL was noninferior to MNTX (Wald statistic = 1.67; = 0.047). Median time to first BM was 23.7 hours for NGL and 18.3 hours for MNTX patients. Median LOS was 14 days (NGL) and 12 days (MNTX), and the average number of BMs in 72 hours was 3.9 for NGL and 3.8 for MNTX. Using wholesale acquisition cost (WAC), the cost per BM for NGL and MNTX was $21.74 and $170.00, respectively.
CONCLUSION AND RELEVANCE
This study determined that NGL and MNTX had similar time to BM. NGL appears to be a safe and effective alternative with cost-saving potential in treating OIC in critically ill patients.
Topics: Humans; Male; Naltrexone; Female; Critical Illness; Middle Aged; Retrospective Studies; Polyethylene Glycols; Narcotic Antagonists; Quaternary Ammonium Compounds; Morphinans; Analgesics, Opioid; Aged; Opioid-Induced Constipation; Adult; Length of Stay; Intensive Care Units; Constipation
PubMed: 37881915
DOI: 10.1177/10600280231205023 -
The American Journal of Gastroenterology Jun 2024Opioids used to manage severe pain in acute pancreatitis might exacerbate the disease through effects on gastrointestinal and immune functions. Methylnaltrexone, a...
OBJECTIVES
Opioids used to manage severe pain in acute pancreatitis might exacerbate the disease through effects on gastrointestinal and immune functions. Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, may counteract these effects without changing analgesia.
METHODS
This double-blind, randomized, placebo-controlled trial included adult patients with acute pancreatitis and systemic inflammatory response syndrome at four Danish centers. Participants were randomized to receive five days of continuous intravenous methylnaltrexone (0.15mg/kg/day) or placebo added to the standard of care. The primary endpoint was the Pancreatitis Activity Scoring System score after 48 hours of treatment. Main secondary outcomes included pain scores, opioid use, disease severity, and mortality.
RESULTS
In total, 105 patients (54% males) were randomized to methylnaltrexone (n=51) or placebo (n=54). After 48 hours, the Pancreatitis Activity Scoring System score was 134.3 points in the methylnaltrexone group and 130.5 points in the placebo group (difference, 3.8 [95% CI, -40.1 to 47.6]; P=0.87). At 48 hours, we found no differences between groups in pain severity (0.0 [95% CI, -0.8 to 0.9]; P=0.94), pain interference (-0.3 [95% CI, -1.4 to 0.8]; P=0.55), and morphine equivalent doses (6.5 mg [95% CI, -2.1 to 15.2]; P=0.14). Methylnaltrexone also did not affect the risk of severe disease (8% [95% CI, -11 to 28]; P=0.38) and mortality (6% [95% CI, -1 to 12]; P=0.11). The medication was well-tolerated.
CONCLUSIONS
Methylnaltrexone treatment did not achieve superiority over placebo for reducing the severity of acute pancreatitis.
PubMed: 38916223
DOI: 10.14309/ajg.0000000000002904 -
The American Journal of Gastroenterology Jun 2024Opioid receptors are found throughout the gastrointestinal tract, including the large intestine. Many patients treated with opioids experience opioid-induced...
Opioid receptors are found throughout the gastrointestinal tract, including the large intestine. Many patients treated with opioids experience opioid-induced constipation. Laxatives are not effective in most patients, and in those who do initially respond, the efficacy of laxatives generally diminishes over time. Additionally, opioid-induced constipation does not spontaneously resolve for most patients. However, complications of opioids extend far beyond simply slowing gastrointestinal transit. Opioid use can affect intestinal permeability through a variety of mechanisms. Toll-like receptors (TLRs) are a crucial component of innate immunity and are tightly regulated within the gut epithelium. Pathologic µ-opioid receptor and TLR signaling, resulting from chronic opioid exposure, disrupts intestinal permeability leading to potentially harmful bacterial translocation, elevated levels of bacterial toxins, immune activation, and increased cytokine production. Peripherally active µ-opioid receptor antagonists, including methylnaltrexone, are effective at treating opioid-induced constipation. Benefits extend beyond simply blocking the µ-opioid receptor; these agents also act to ameliorate opioid-induced disrupted intestinal permeability. In this review we briefly describe the physiology of the gastrointestinal epithelial border and discuss the impact of opioids on gastrointestinal function. Finally, we consider the use of peripherally active µ-opioid receptor antagonists to treat disrupted intestinal permeability resulting from opioid use and discuss the potential for improved morbidity and mortality in patients treated with methylnaltrexone for opioid-induced bowel disorders.
PubMed: 38870087
DOI: 10.14309/ajg.0000000000002887 -
Palliative Medicine Reports 2024In addition to the more well-known adverse effects of opioids, such as constipation, mounting evidence supports underlying immunosuppressive effects as well.
BACKGROUND
In addition to the more well-known adverse effects of opioids, such as constipation, mounting evidence supports underlying immunosuppressive effects as well.
METHODS
In this study, we provide a narrative review of preclinical and clinical evidence of opioid suppression of the immune system as well as possible considerations for therapies.
RESULTS
and animal studies have shown clear effects of opioids on inflammatory cytokine expression, immune cell activity, and pathogen susceptibility. Observational data in humans have so far supported preclinical findings, with multiple reports of increased rates of infections in various settings of opioid use. However, the extent to which this risk is due to the impact of opioids on the immune system compared with other risk factors associated with opioid use remains uncertain. Considering the data showing immunosuppression and increased risk of infection with opioid use, measures are needed to mitigate this risk in patients who require ongoing treatment with opioids. In preclinical studies, administration of opioid receptor antagonists blocked the immunomodulatory effects of opioids.
CONCLUSIONS
As selective antagonists of peripheral opioid receptors, peripherally acting mu-opioid receptor (MOR) antagonists may be able to protect against immune impairment while still allowing for opioid analgesia. Future research is warranted to further investigate the relationship between opioids and infection risk as well as the potential application of peripherally acting MOR antagonists to counteract these risks.
PubMed: 38435086
DOI: 10.1089/pmr.2023.0049