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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 -
American Journal of Health-system... May 2023Peripherally acting μ-opioid receptor antagonists (PAMORAs) are indicated to treat laxative-refractory opioid-induced constipation (OIC). While several PAMORAs exist,...
PURPOSE
Peripherally acting μ-opioid receptor antagonists (PAMORAs) are indicated to treat laxative-refractory opioid-induced constipation (OIC). While several PAMORAs exist, no head-to-head comparative data are available. This study evaluated the efficacy, safety, and cost of oral naloxegol vs subcutaneous methylnaltrexone for OIC in the hospital.
METHODS
In this multicenter retrospective chart review, patients who received oral naloxegol or subcutaneous methylnaltrexone as an inpatient were included if they were at least 18 years old, were still admitted to the hospital 48 hours after the first PAMORA dose, and either had an outpatient opioid prescription or received at least 30 morphine milligram equivalents in the 24 hours before the first PAMORA dose. The primary outcome was achievement of a bowel movement (BM) within 48 hours of the first dose. Secondary outcomes included a BM in 24 hours, time to the first BM, antimotility agent use, PAMORA cost per patient, and use of a second PAMORA due to failure of the first agent.
RESULTS
A total of 330 patients were included with 2:1 allocation (220 patients receiving methylnaltrexone vs 110 patients receiving naloxegol). Baseline characteristics were similar between the groups, except for body mass index and weight. Naloxegol met a prespecified noninferiority margin of 15% in production of a BM within 48 hours (risk difference, -4.6%; 90% confidence interval, -13.6% to 4.5%; P = 0.028). Achievement of a BM within 24 hours and time to first BM were also noninferior. Antimotility agent use was higher with naloxegol, naloxegol cost $193.16 less per patient, and 2 patients switched from naloxegol to methylnaltrexone.
CONCLUSION
Oral naloxegol may be an effective, cost-efficient alternative to subcutaneous methylnaltrexone for treatment of OIC in the hospital setting.
Topics: Humans; Adolescent; Analgesics, Opioid; Opioid-Induced Constipation; Retrospective Studies; Constipation; Narcotic Antagonists; Hospitals
PubMed: 36440903
DOI: 10.1093/ajhp/zxac356 -
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 -
Alimentary Pharmacology & Therapeutics Jul 2020When opioid-induced constipation is treated with centrally acting opioid antagonists, there may be opioid withdrawal or aggravation of pain due to inhibition of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
When opioid-induced constipation is treated with centrally acting opioid antagonists, there may be opioid withdrawal or aggravation of pain due to inhibition of μ-opioid analgesia. This led to the development of peripherally acting μ-opioid receptor antagonists (PAMORAs).
AIM
To evaluate the efficacy of available PAMORAs and other approved or experimental treatments for relieving constipation in patients with opioid-induced constipation, based on a systematic review and meta-analysis of published studies.
METHODS
A search of MEDLINE, EMBASE and EBM Reviews Cochrane Central Register of Controlled Trials was completed in July 2019 for randomised trials compared to placebo. FDA approved doses or highest studied dose was evaluated. Efficacy was based on diverse endpoints, including continuous variables (the bowel function index, number of spontaneous bowel movements and stool consistency based on Bristol Stool Form Scale), or responder analysis (combination of >3 spontaneous bowel movements or complete spontaneous bowel movements plus 1 spontaneous bowel movement or complete spontaneous bowel movements, respectively, over baseline [so-called FDA endpoints]). Adverse effects evaluated included central opioid withdrawal, serious adverse events, abdominal pain and diarrhoea.
RESULTS
We included 35 trials at low risk of bias enrolling 13 566 patients. All PAMORAs demonstrated efficacy on diverse patient response endpoints. There was greater efficacy with approved doses of the PAMORAs (methylnaltrexone, naloxegol and naldemidine), with lower efficacy or lower efficacy and greater adverse effects with combination oxycodone with naloxone, lubiprostone and linaclotide.
CONCLUSIONS
Therapeutic response in opioid-induced constipation is best achieved with the PAMORAs, methylnaltrexone, naloxegol and naldemidine, which are associated with low risk of serious adverse events.
Topics: Analgesics, Opioid; Constipation; Humans; Laxatives; Narcotic Antagonists; Randomized Controlled Trials as Topic; Receptors, Opioid, mu; Treatment Outcome
PubMed: 32462777
DOI: 10.1111/apt.15791 -
Journal of Pain Research 2021Methylnaltrexone inhibits opioid-induced constipation (OIC) by binding to peripheral µ-opioid receptors without impacting central opioid receptor mediated analgesia....
Subcutaneous Methylnaltrexone for Treatment of Opioid-Induced Constipation in Cancer versus Noncancer Patients: An Analysis of Efficacy and Safety Variables from Two Studies.
PURPOSE
Methylnaltrexone inhibits opioid-induced constipation (OIC) by binding to peripheral µ-opioid receptors without impacting central opioid receptor mediated analgesia. This analysis compared methylnaltrexone efficacy and safety among advanced illness patients with and without active cancer and OIC.
PATIENTS AND METHODS
This post hoc analysis included two multicenter, randomized, double-blind, placebo-controlled studies in adults with advanced illness and OIC who received subcutaneous methylnaltrexone. Efficacy endpoints included the proportion of patients achieving rescue-free laxation (RFL), time to RFL, weekly laxations within 24 hours after dosing, rescue laxative use, and pain scores. Adverse events were monitored for safety.
RESULTS
After pooling, 178 patients received methylnaltrexone (n = 116 with cancer) and 185 received placebo (n = 114 with cancer). Median baseline daily opioid morphine equivalents (mg/d) were higher in cancer (methylnaltrexone: 180; placebo: 188) versus noncancer patients (methylnaltrexone: 120; placebo: 80). The proportions of patients achieving RFL within 4 hours after ≥2 of the first 4 doses were significantly greater with methylnaltrexone (cancer: 56.9%; noncancer: 58.1%) versus placebo (cancer: 5.3%; noncancer: 11.3%; < 0.0001). The median time to laxation within 24 hours after the first methylnaltrexone dose was significantly shorter in cancer and noncancer patients versus placebo (cancer: 0.96 vs 22.53 hours, < 0.0001; noncancer: 1.25 vs >24 hours, = 0.0002). The mean number of weekly laxations within 24 hours after dosing by week 2 was significantly higher in methylnaltrexone- vs placebo-treated cancer and noncancer patients (cancer: 7.9 vs 4.9, < 0.0001; noncancer: 8.4 vs 5.0, < 0.0001). Methylnaltrexone reduced rescue laxative use without impacting pain scores. Consistent with previous data, methylnaltrexone was well tolerated in cancer and noncancer patients, and the AE profile did not suggest symptoms of opioid withdrawal.
CONCLUSION
Methylnaltrexone reduced RFL time in advanced-illness patients with and without active cancer, while maintaining pain control with opioid treatment despite higher baseline opioid use among cancer patients.
PubMed: 34512008
DOI: 10.2147/JPR.S312731 -
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 -
Oncology Nursing Forum Nov 2020A systematic review and meta-analysis was conducted to inform the development of national clinical practice guidelines on the management of cancer constipation. (Meta-Analysis)
Meta-Analysis
PROBLEM IDENTIFICATION
A systematic review and meta-analysis was conducted to inform the development of national clinical practice guidelines on the management of cancer constipation.
LITERATURE SEARCH
PubMed®, Wiley Cochrane Library, and CINAHL® were searched for studies published from May 2009 to May 2019.
DATA EVALUATION
Two investigators independently reviewed and extracted data from eligible studies. The Cochrane Collaboration risk-of-bias tool was used, and the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used to assess the certainty of the evidence.
SYNTHESIS
For patients with cancer and opioid-induced constipation, moderate benefit was found for osmotic or stimulant laxatives; small benefit was found for methylnaltrexone, naldemedine, and electroacupuncture. For patients with cancer and non-opioid-related constipation, moderate benefit was found for naloxegol, prucalopride, lubiprostone, and linaclotide; trivial benefit was found for acupuncture.
IMPLICATIONS FOR PRACTICE
Effective strategies for managing opioid-induced and non-opioid-related constipation in patients with cancer include lifestyle, pharmacologic, and complementary approaches.
SUPPLEMENTAL MATERIAL CAN BE FOUND AT&NBSP;HTTPS
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Topics: Analgesics, Opioid; Constipation; Gastrointestinal Agents; Humans; Neoplasms
PubMed: 33063777
DOI: 10.1188/20.ONF.E211-E224 -
Journal of Medicinal Chemistry Nov 2019Genetic variants in the hepatic uptake transporter OCT1, observed in 9% of Europeans and white Americans, are known to affect pharmacokinetics and efficacy of tramadol,...
Genetic variants in the hepatic uptake transporter OCT1, observed in 9% of Europeans and white Americans, are known to affect pharmacokinetics and efficacy of tramadol, morphine, and codeine. Here, we report further opioids to be substrates and inhibitors of OCT1. Methylnaltrexone, hydromorphone, oxymorphone, and meptazinol were identified as OCT1 substrates. Methylnaltrexone is the strongest OCT1 substrate currently reported. It showed 86-fold higher accumulation in OCT1-overexpressing cells compared to control cells. We observed substantial differences in the inhibitory potency among structurally highly similar morphinan opioids (IC ranged from 6.4 μM for dextrorphan to 2 mM for oxycodone). The ether linkage of C4-C5 in the morphinan ring leads to a strong reduction of inhibitory potency. In conclusion, although polyspecific, OCT1 possesses a strong selectivity for its ligands. In contrast to methylnaltrexone and hydromorphone, oxycodone and hydrocodone do not interact with OCT1 and may be safer for use in individuals with genetic OCT1 deficiency.
Topics: Analgesics, Opioid; HEK293 Cells; Humans; Inhibitory Concentration 50; Models, Molecular; Organic Cation Transporter 1; Permeability; Protein Conformation
PubMed: 31597043
DOI: 10.1021/acs.jmedchem.9b01301 -
Journal of Neuroscience Research Jan 2022Opioids are effective analgesics in the management of severe pain. However, tolerance, leading to dose escalation and adverse effects are significant limiting factors in...
Opioids are effective analgesics in the management of severe pain. However, tolerance, leading to dose escalation and adverse effects are significant limiting factors in their use. The role of peripheral opioid receptors in analgesia has been discussed especially under inflammatory conditions. The results from pharmacological and conditional knockout studies together do not provide a clear picture of the contribution of peripheral opioid receptors on antinociceptive tolerance and this needs to be evaluated. Therefore, we studied whether the peripherally restricted opioid receptor antagonist, methylnaltrexone (MNTX), could prevent morphine tolerance without attenuating the antinociceptive effect of morphine. Male Sprague-Dawley rats were treated for 7 days with increasing subcutaneous doses of morphine (5-30 mg/kg) and were coadministered saline, MNTX (0.5 or 2 mg/kg), or naltrexone (NTX; 2 mg/kg). Nociception was assessed with tail-flick, hotplate, and von Frey tests. Morphine, MNTX, and NTX concentrations in the plasma, brain, and spinal cord were measured by liquid chromatography-tandem mass spectrometry. In acute coadministration, NTX, but not MNTX, abolished the acute antinociceptive effects of morphine in all nociceptive tests. The antinociceptive tolerance after repeated morphine administration was also prevented by NTX but not by MNTX. MNTX penetrated to the spinal cord and the brain to some extent after repeated administration. The results do not support the use of MNTX for preventing opioid tolerance and also suggest that morphine tolerance is mediated by central rather than peripheral opioid receptors in the rat.
Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Tolerance; Male; Morphine; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Opioid, mu
PubMed: 32459013
DOI: 10.1002/jnr.24638