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Anesthesiology Jan 2019Methylnaltrexone Reverses Chronic Opioid-induced Constipation: A Randomized, Controlled Trial. By Yuan CS, Foss JF, O'Connor M, Osinski J, Karrison T, Moss J, Roizen MF.... (Randomized Controlled Trial)
Randomized Controlled Trial
UNLABELLED
Methylnaltrexone Reverses Chronic Opioid-induced Constipation: A Randomized, Controlled Trial. By Yuan CS, Foss JF, O'Connor M, Osinski J, Karrison T, Moss J, Roizen MF. JAMA 2000; 130:142-8. Reprinted with permission.
CONTEXT
Constipation is the most common chronic adverse effect of opioid pain medications in patients who require long-term opioid administration, such as patients with advanced cancer, but conventional measures for ameliorating constipation often are insufficient.
OBJECTIVE
To evaluate the efficacy of methylnaltrexone, the first peripheral opioid receptor antagonist, in treating chronic methadone-induced constipation.
DESIGN
Double-blind, randomized, placebo-controlled trial conducted between May 1997 and December 1998.
SETTING
Clinical research center of a university hospital.
PARTICIPANTS
Twenty-two subjects (9 men and 13 women; mean [SD] age, 43.2 [5.5] years) enrolled in a methadone maintenance program and having methadone-induced constipation.
MAIN OUTCOME MEASURES
Laxation response, oral-cecal transit time, and central opioid withdrawal symptoms were compared between the 2 groups.
RESULTS
The 11 subjects in the placebo group showed no laxation response, and all 11 subjects in the intervention group had laxation response after intravenous methylnaltrexone administration (P<.001). The oral-cecal transit times at baseline for subjects in the methylnaltrexone and placebo groups averaged 132.3 and 126.8 minutes, respectively. The average (SD) change in the methylnaltrexone-treated group was -77.7 (37.2) minutes, significantly greater than the average change in the placebo group (-1.4 [12.0] minutes; P<.001). No opioid withdrawal was observed in any subject, and no significant adverse effects were reported by the subjects during the study.
CONCLUSIONS
Our data demonstrate that intravenous methylnaltrexone can induce laxation and reverse slowing of oral cecal-transit time in subjects taking high opioid dosages. Low-dosage methylnaltrexone may have clinical utility in managing opioid-induced constipation.
Topics: Adult; Analgesics, Opioid; Constipation; Double-Blind Method; Female; Humans; Male; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Treatment Outcome
PubMed: 30277930
DOI: 10.1097/ALN.0000000000002428 -
Neurogastroenterology and Motility Mar 2017Endogenous opioids (EO) acting on μ-opiod receptors in central and enteric nervous system (ENS) control gastrointestinal motility but it is still unclear whether EO in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Endogenous opioids (EO) acting on μ-opiod receptors in central and enteric nervous system (ENS) control gastrointestinal motility but it is still unclear whether EO in ENS may control esophageal function in man, thus we will study the effects of methylnaltrexone (MNTX), a peripherally selective, and naloxone (NA), a non-selective μ-opiod receptor antagonist, on esophageal motility in healthy subjects.
METHODS
Fifteen HV (6 M; 34.1 ± 0.6 years; BMI: 22.1 ± 0.1 kg/m ) underwent three esophageal high-resolution manometry impedance (HRiM) studies with 10 saline swallows administered every 30 minutes: drug was administered after 30 minutes (MNTX subcutaneously/NA or saline intravenously), a solid meal after 90 minutes; measurements continued for 120 minutes postprandially.
KEY RESULTS
Methylnaltrexone did not significantly decrease the upper esophageal sphincter (UES) percentage of relaxation preprandially (72.5 ± 5 vs 66.9 ± 4.6 and 73 ± 3.8%, ANOVA between placebo, MNTX and NA, P=NS) and postprandially (60 minutes: 68.2 ± 5.6 vs 61 ± 5.5 and 67.1 ± 5.6%; 120 minutes: 68 ± 5.9 vs 59.3 ± 5.2 and 67.7 ± 4.7%; ANOVA between placebo, MNTX and NA, P=NS). MNTX and NA did not significantly alter preprandial and postprandial LES resting pressures and integrated relaxation pressure (ANOVA between placebo, MNTX and NA, all P=NS). Peak front velocity and distal contractile integral were not altered pre- and postprandially by MNTX and NA (ANOVA between placebo, MNTX and NA, P=NS). Transient lower esophageal sphincter relaxations (TLESRs') number was not altered by MNTX and NA (ANOVA between placebo, MNTX and NA, all P=NS).
CONCLUSIONS AND INFERENCES
The peripheral selective and non-selective μ-opioid receptor antagonists MNTX and NA, respectively, do not alter TLESRs occurrence and esophageal peristalsis.
Topics: Adolescent; Adult; Cross-Over Studies; Esophageal Sphincter, Lower; Esophageal pH Monitoring; Female; Humans; Male; Naloxone; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Single-Blind Method; Young Adult
PubMed: 28110513
DOI: 10.1111/nmo.12938 -
Drugs & Aging Jun 2021Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist approved for the treatment of opioid-induced constipation (OIC), has restricted diffusion across... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Methylnaltrexone, 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.
OBJECTIVE
This analysis evaluated whether opioid analgesia is compromised in older adults receiving methylnaltrexone for OIC.
METHODS
The 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.
RESULTS
Overall, 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.
CONCLUSIONS
Methylnaltrexone 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 NUMBERS
Study 302, NCT00402038; study 3200K1-4000, NCT00672477; study 3200K1-3356, NCT00529087; study 3201, NCT01186770.
Topics: Age Factors; Aged; Analgesics, Opioid; Constipation; Humans; Naltrexone; Opioid-Induced Constipation; Quaternary Ammonium Compounds; Treatment Outcome
PubMed: 33788162
DOI: 10.1007/s40266-021-00850-w -
Cancer Aug 2015Mu opioids are among the most widely used drugs for patients with cancer with both acute and chronic pain as well as in the perioperative period. Several retrospective... (Review)
Review
Mu opioids are among the most widely used drugs for patients with cancer with both acute and chronic pain as well as in the perioperative period. Several retrospective studies have suggested that opioid use might promote tumor progression and as a result negatively impact survival in patients with advanced cancer; however, in the absence of appropriate prospective validation, any changes in recommendations for opioid use are not warranted. In this review, the authors present preclinical and clinical data that support their hypothesis that the mu opioid receptor is a potential target for cancer therapy because of its plausible role in tumor progression. The authors also propose the hypothesis that peripheral opioid antagonists such as methylnaltrexone, which reverses the peripheral effects of mu opioids but maintains centrally mediated analgesia and is approved by the US Food and Drug Administration for the treatment of opioid-induced constipation, can be used to target the mu opioid receptor.
Topics: Animals; Humans; Mice; Molecular Targeted Therapy; Naltrexone; Narcotic Antagonists; Neoplasms; Quaternary Ammonium Compounds; Receptors, Opioid, mu
PubMed: 26043235
DOI: 10.1002/cncr.29460 -
Journal of Pediatric Orthopedics Aug 2021Methylnaltrexone, a peripheral opioid antagonist, is used to decrease opioid-induced constipation; however, there is limited evidence for its use in children. The...
BACKGROUND
Methylnaltrexone, a peripheral opioid antagonist, is used to decrease opioid-induced constipation; however, there is limited evidence for its use in children. The primary objective of the study is to assess the efficacy of per os (PO) methylnaltrexone in inducing bowel movements (BMs) in patients with adolescent idiopathic scoliosis who underwent a posterior spinal fusion and instrumentation (PSFI). Secondary outcomes include hospital length of stay, postoperative pain scores, and postoperative opioid usage.
METHODS
Retrospective chart review identified all adolescent idiopathic scoliosis patients above 10 years of age who underwent PSFI with a minimum of 24 hours of postoperative opioid analgesia after the initiation of the new bowel regimen protocol. The bowel regimen included daily administration of PO methylnaltrexone starting on postoperative day 1 until BM is achieved. A case-matched cohort was obtained with patients who did not receive PO methylnaltrexone and otherwise had the same bowel function regimen. Case-matched controls were also matched for age, sex, body mass index, and curve severity. t Tests and Pearson χ2 tests were used for statistical analysis.
RESULTS
Fifty-two patients received oral methylnaltrexone (14±2.6 y) and 52 patients were included in the case-matched control group (14±2.1 y). The methylnaltrexone group had a significantly shorter hospital length of stay (3.09±0.66) compared with controls (3.69±0.80) (P<0.01). 59% (31 of 52) of the methylnaltrexone group had a BM by postoperative day postoperative day 2, compared with 30% (16 of 52) of the control group (P<0.01). In the methylnaltrexone group, 44% (23 of 52) of the patients required a Dulcolax (bisacodyl) suppository and 11% (6 of 52) required an enema, compared with 50% (26 of 52) and 33% (12 of 52) of the control group respectively (P=0.43 and 0.12). In addition, significantly less patients had abdominal distension during their postoperative stay in the methylnaltrexone group (17%, 9 of 52) compared with the control group (40%, 21 of 52) (P<0.01). There was no significant difference in self-reported average FACES pain score (P=0.39) or in opioid morphine equivalents required per hour (P=0.18).
CONCLUSIONS
Patients who received PO methylnaltrexone after PSFI had decreased length of stay and improved bowel function. Administration of methylnaltrexone did not increase maximum self-reported FACES pain values or opioid consumption compared with controls. The use of oral methylnaltrexone after PSFI reduces postoperative constipation, which has implications for reducing hospital length of stay and overall morbidity.
LEVEL OF EVIDENCE
Level III-retrospective comparative study.
PubMed: 34001807
DOI: 10.1097/BPO.0000000000001854 -
The American Journal of Medicine Sep 2018
Review
Topics: Analgesics, Opioid; Cancer Pain; Constipation; Enema; Gastrointestinal Agents; Gastrostomy; Humans; Laxatives; Morphinans; Naltrexone; Piperidines; Polyethylene Glycols; Practice Guidelines as Topic; Quaternary Ammonium Compounds
PubMed: 29621475
DOI: 10.1016/j.amjmed.2018.02.038 -
United European Gastroenterology Journal Oct 2018Chronic pain affects a large part of the global population, leading to an increase of opioid use. Opioid-induced constipation (OIC), a highly prevalent adverse effect of... (Review)
Review
Chronic pain affects a large part of the global population, leading to an increase of opioid use. Opioid-induced constipation (OIC), a highly prevalent adverse effect of opioid use, has a major impact on patients' quality of life. Thanks to the introduction of new drugs for chronic constipation, which can also be used in OIC, and the development of peripherally acting mu-opioid receptor blockers, specifically for use in OIC, therapeutic options have seen major development. This review summarises current and emerging treatment options for OIC based on an extensive bibliographical search. Efficacy data for laxatives, lubiprostone, prucalopride, linaclotide, oxycodone/naloxone combinations, methylnaltrexone, alvimopan, naloxegol, naldemedine, axelopran, and bevenopran in OIC are summarised.
PubMed: 30288274
DOI: 10.1177/2050640618796748 -
The Clinical Journal of Pain Feb 2019Opioid analgesics may be associated with chronic adverse effects, such as opioid-induced constipation (OIC). Available and emerging prescription medications for OIC in... (Review)
Review
OBJECTIVES
Opioid analgesics may be associated with chronic adverse effects, such as opioid-induced constipation (OIC). Available and emerging prescription medications for OIC in patients with chronic noncancer pain are described, including concerns and challenges associated with OIC management.
METHODS
Narrative review.
RESULTS
OIC is characterized by a change in bowel habits and defecation patterns that occurs when initiating opioid therapy and is associated with reduced bowel frequency, straining, sensation of incomplete evacuation, and/or patient distress related to bowel habits. Prescription medications are indicated when OIC persists despite conservative approaches (eg, increased fiber and fluid intake, exercise, over-the-counter laxatives and stool softeners). Phase 3 studies have demonstrated the efficacy of peripherally acting µ-opioid receptor antagonists (PAMORA; methylnaltrexone, naloxegol, naldemedine), and a chloride channel activator (lubiprostone) for improving OIC in patients with chronic noncancer pain. Although head-to-head studies are lacking, a meta-analysis demonstrated that μ-opioid receptor antagonists were more effective than placebo for the treatment of OIC. The most common adverse effects associated with prescription medications for OIC are gastrointestinal related (eg, nausea, diarrhea, abdominal pain, or distention), with most being mild or moderate in severity. Therapy currently in development for OIC includes the PAMORA axelopran.
DISCUSSION
Health care providers should be aware of this complication in patients receiving opioids and should monitor and address constipation-related symptoms to optimize pain management and improve patient quality of life.
Topics: Analgesics, Opioid; Chronic Pain; Constipation; Disease Management; Humans
PubMed: 30289777
DOI: 10.1097/AJP.0000000000000662 -
Expert Opinion on Pharmacotherapy Mar 2015Opioid-induced constipation (OIC) is one of the most frequent and burdening adverse events (AE) of opioid therapy. This systematic review aimed to evaluate efficacy and... (Review)
Review
INTRODUCTION
Opioid-induced constipation (OIC) is one of the most frequent and burdening adverse events (AE) of opioid therapy. This systematic review aimed to evaluate efficacy and safety of drugs in randomized controlled trials (RCTs) with adult OIC patients.
AREAS COVERED
Efficacy assessment focused on objective outcome measures (OOMs): bowel movement (BM) frequency, BM within 4 h and time to first BM. Twenty-one studies examining seven drugs were identified. Methylnaltrexone showed improvements in all three OOMs. RCTs in naloxone and alvimopan tended to be effective for BM frequency measures. Naloxegol (≥ 12.5 mg) improved all OOMs. Though effectiveness of lubiprostone was demonstrated for all OOMs, group differences were small to moderate. CB-5945 and prucalopride tended to increase BM frequency, especially for 0.1 mg twice daily and 4 mg daily, respectively. Besides nausea and diarrhea, abdominal pain was the most frequent AE for all drugs (risk ratio, range: 1.52 - 5.06) except for alvimopan. Treatment-related serious AEs were slightly higher for alvimopan (cardiac events) and prucalopride (severe abdominal pain, headache). Pain scores for placebo and intervention groups were similar for all drugs.
EXPERT OPINION
Finding a consensus definition and inclusion criteria for OIC plus a rational balance between efficacy and AEs of drugs remain future challenges.
Topics: Abdominal Pain; Analgesics, Opioid; Constipation; Diarrhea; Gastrointestinal Motility; Headache; Humans; Nausea; Pain; Randomized Controlled Trials as Topic
PubMed: 25539282
DOI: 10.1517/14656566.2015.995625 -
Journal of Pain and Symptom Management Apr 2024Constipation is a common problem among patients with cancer. By some accounts, about 60% of cancer patients experience constipation. There is limited empirical evidence... (Meta-Analysis)
Meta-Analysis Review
CONTEXT
Constipation is a common problem among patients with cancer. By some accounts, about 60% of cancer patients experience constipation. There is limited empirical evidence of the clinical effectiveness of pharmacologic agents in opioid-induced constipation in advanced diseases.
OBJECTIVES
We sought to quantitatively summarize the therapeutic effectiveness of the pharmacologic means of managing opioid-induced constipation.
METHODS
Randomized control trials (RCTs) identified from medical literature databases that reported quantitative measures of the effect of pharmacotherapeutic agents to treat opioid induced constipation in patients with cancers and other advanced illnesses were included in this study. A conventional random effects meta-analysis was conducted including >3 trials with the same exposure and outcome assessed, and a network-meta-analysis was conducted for all placebo-controlled trials.
RESULTS
Eighteen studies that examined the effect of various pharmacotherapeutic agents were included. The medications were Methylnatrexone (N = 5), Naldemedine (N = 5), other conventional agents (N = 4) and herbal medicines (N = 4). In conventional meta-analysis, methylnaltrexone increased the proportion achieving rescue-free laxation by 2.68 fold (95% CI: 1.34, 5.37; P = 0.0054) within 4 hours of the administration compared to placebo. In network meta-analysis, the pooled RR of the pharmacotherapeutic agents on rescue-free bowel movements as 2.26 (95% CI: 1.52, 3.36) for methylnaltrexone, 1.58 (95% CI: 0.94, 2.66) for naldemedine, and 0.74 (95% CI: 0.45, 1.23) for polyethylene glycol, compared to placebo.
CONCLUSION
Methylnatrexone and Naldemedine have currently shown promise in randomized trials concerning opioid-induced constipation in cancer and advanced illness. It is imperative that future research ascertain not just the relative therapeutic efficacy but also the cost-benefit analyses of these newer regimens with more commonly used and accessible laxatives.
Topics: Humans; Opioid-Induced Constipation; Narcotic Antagonists; Analgesics, Opioid; Naltrexone; Constipation; Laxatives; Neoplasms; Randomized Controlled Trials as Topic; Quaternary Ammonium Compounds
PubMed: 38092261
DOI: 10.1016/j.jpainsymman.2023.12.010