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Intensive Care Medicine Apr 2020Constipation can be a significant problem in critically unwell patients, associated with detrimental outcomes. Opioids are thought to contribute to the mechanism of... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Constipation 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.
METHODS
The 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.
RESULTS
A 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).
CONCLUSION
We 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.
Topics: Adult; Analgesics, Opioid; Constipation; Critical Care; Humans; Naltrexone; Opioid-Induced Constipation; Quaternary Ammonium Compounds
PubMed: 32016532
DOI: 10.1007/s00134-019-05913-6 -
British Journal of Anaesthesia Jul 2011Recent introduction of new analgesics into the clinic is best described as a slow process with activity classified into two main areas: improving analgesic... (Review)
Review
Recent introduction of new analgesics into the clinic is best described as a slow process with activity classified into two main areas: improving analgesic efficacy/potency and reducing side-effect profile. This review article describes some of the recent advances with an emphasis on use in the acute setting. In this respect, opioids continue to be the mainstay (but not the only) analgesic and there have been important improvements in their clinical effect profile. For example, tapentadol has been introduced as a mixed opioid and norepinephrine uptake inhibitor which, unlike tramadol, does not require metabolic activation and does not suffer from isomer-dependent pharmacodynamics. Opioid antagonists have received much attention recently either used alone, methylnaltrexone (s.c) or alvimopan (p.o), or in combination, Targinact (oxycodone/naloxone), and appear to be effective in reducing opioid side-effects such as those in the gastrointestinal tract. Other agents where there has been recent development include the use of gabapentin, methylxanthines, and local anaesthetics. An interesting area of translation of basic research is in the inhibition of breakdown of endogenous opioids with opiorphin, targeting of the endocannabinoid system, and the use of ampakines to obtund opioid-induced side-effects. It is clear that there is still much work to be done, but the need for highly efficacious analgesics with good side-effect profile remains.
Topics: Analgesia; Analgesics; Analgesics, Non-Narcotic; Analgesics, Opioid; Chemistry, Pharmaceutical; Drug Delivery Systems; Drug Discovery; Humans
PubMed: 21624966
DOI: 10.1093/bja/aer126 -
The Journal of Supportive Oncology 2009Methylnaltrexone, a peripheral mu-opioid receptor antagonist with restricted ability to cross the blood-brain barrier, may relieve opioid-induced constipation (OIC)... (Randomized Controlled Trial)
Randomized Controlled Trial
Methylnaltrexone, a peripheral mu-opioid receptor antagonist with restricted ability to cross the blood-brain barrier, may relieve opioid-induced constipation (OIC) without reversing analgesia. A total of 154 patients with advanced illness and OIC enrolled in a double-blind, randomized, placebo-controlled trial, with optional open-label phases (up to 4 months) in hospice and palliative care centers during 2003-2005. They received a single subcutaneous injection of methylnaltrexone (0.15 mg/kg or 0.3 mg/kg) or placebo. Laxation response within 4 hours was 62% and 58% for methylnaltrexone 0.15 mg/kg and 0.3 mg/kg, respectively, compared with 14% for placebo (P < 0.0001; each dose vs placebo). Approximately half of the methylnaltrexone responders defecated within 30 minutes of dosing. Open-label phase response rates mirrored those for methylnaltrexone during the double-blind phase.There was no change in pain scores or evidence of central opioid withdrawal.The most common adverse events (AEs) were abdominal pain and flatulence.Three patients had serious AEs attributed to methylnaltrexone. Subcutaneous methylnaltrexone was efficacious in rapidly inducing laxation and was generally well tolerated in patients with advanced illness and OIC.
Topics: Adult; Aged; Aged, 80 and over; Analgesia; Analgesics, Opioid; Constipation; Critical Illness; Defecation; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Pain Measurement; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Treatment Outcome
PubMed: 19278178
DOI: No ID Found -
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 Consultant Pharmacist : the Journal... Mar 2009To review the chemistry, pharmacodynamics, pharmacokinetics, clinical efficacy, tolerability, indications, and dosing and administration of methylnaltrexone... (Review)
Review
OBJECTIVE
To review the chemistry, pharmacodynamics, pharmacokinetics, clinical efficacy, tolerability, indications, and dosing and administration of methylnaltrexone methobromide, the first approved peripherally selective opioid receptor-antagonist.
DATA SOURCE
MEDLINE/PUBMED and EMBASE searches (January 1966-February 2009) were conducted to identify pertinent English-language studies.
STUDY SELECTION AND DATA EXTRACTION
All studies evaluating any aspect of methylnaltrexone methobromide.
DATA SYNTHESIS
Subcutaneous methylnaltrexone methobromide is the first opioid receptor-antagonist to be approved for the treatment of opioid receptor-agonist-induced constipation (subset with advanced disease, receiving palliative care, with an inadequate response to laxative therapy). This agent lacks meaningful activity in the central nervous system and, hence, will not compromise centrally mediated analgesia or precipitate centrally mediated signs/symptoms of opioid receptor-agonist withdrawal. There are no published comparative trials with traditional pharmacologic/nonpharmacologic laxation regimens.
CONCLUSION
Methylnaltrexone methobromide is administered into the upper arm, abdomen, or thigh once every other day, with the frequency of dosing being increased, if needed, to a maximum of once daily. Recommended doses are 8 mg, 12 mg, or 0.15 mg/kg, depending on patient weight. For creatinine clearances less than 30 mL/min, the dose should be reduced by 50%. The average wholesale price is $83.33 for a 12 mg single-use vial (Medispan, accessed December 4, 2008). Clearly, parenteral agents are not as useful as oral agents and results of ongoing studies with new oral formulations of this product are eagerly awaited.
Topics: Animals; Clinical Trials as Topic; Drug Interactions; Humans; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds
PubMed: 19555136
DOI: 10.4140/tcp.n.2009.210 -
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 -
Pain Management Mar 2020To evaluate methylnaltrexone for opioid-induced constipation in patients with and without cancer. This analysis comprises two Phase III, multicenter, double-blind,... (Randomized Controlled Trial)
Randomized Controlled Trial
To evaluate methylnaltrexone for opioid-induced constipation in patients with and without cancer. This analysis comprises two Phase III, multicenter, double-blind, randomized studies of advanced-illness patients who received methylnaltrexone subcutaneous injection or placebo. Significantly more patients treated with methylnaltrexone than placebo experienced laxation within 4 (cancer = 55.5 vs 15.5%; noncancer = 55.6 vs 12.8%) and 24 (cancer = 64.7 vs 29.8%; noncancer = 64.4 vs 30.8%) h after the first dose (p < 0.01 vs placebo). Regardless of cancer status, methylnaltrexone reduced median time to laxation and improved constipation relief without impacting opioid analgesia or withdrawal symptoms. Methylnaltrexone provided significant improvements in opioid-induced constipation over placebo in advanced-illness patients with and without cancer. study 301: NCT00401362; study 302: NCT00402038.
Topics: Adult; Aged; Cancer Pain; Double-Blind Method; Female; Humans; Injections, Subcutaneous; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Narcotics; Opioid-Induced Constipation; Outcome Assessment, Health Care; Quaternary Ammonium Compounds
PubMed: 31951150
DOI: 10.2217/pmt-2019-0045 -
Current Opinion in Clinical Nutrition... Mar 2013Gastrointestinal dysmotility and dysfunction underlie our difficulties in providing adequate nutrition by the enteral route to our critically ill patients. (Review)
Review
PURPOSE OF REVIEW
Gastrointestinal dysmotility and dysfunction underlie our difficulties in providing adequate nutrition by the enteral route to our critically ill patients.
RECENT FINDINGS
Recent studies have quantified gastric emptying and nutrient absorption. Slow gastric emptying is common and probably mediated by cholecystokinin and reduced active ghrelin concentrations. The cause of impaired nutrient absorption is not yet fully understood but may be related to small intestinal blood flow and/or mucosal factors. The absorption of the different macronutrients may be affected in different ways both by critical illness and by therapies. A better understanding of this may optimize the design of nutrient formulations in the future. New treatment modalities for gastrointestinal dysfunction are being investigated and include small intestinal feeding, nonpharmacological options such as acupuncture, and drugs including novel motilin receptor agonists, and opioid antagonists.
SUMMARY
We are gradually developing a better understanding of how the gut works during critical illness, which has implications for optimizing the delivery of nutrition and thereby improving nutritional and clinical outcomes.
Topics: Cholecystokinin; Critical Illness; Enteral Nutrition; Evidence-Based Medicine; Gastric Emptying; Gastrointestinal Agents; Gastrointestinal Diseases; Ghrelin; Humans; Intestine, Small; Motilin; Naltrexone; Quaternary Ammonium Compounds; Randomized Controlled Trials as Topic
PubMed: 23334174
DOI: 10.1097/MCO.0b013e32835c1fa5 -
International Journal of Palliative... Apr 2015
Topics: Analgesics, Opioid; Constipation; Humans; Naltrexone; Quaternary Ammonium Compounds; Terminal Care
PubMed: 25901587
DOI: 10.12968/ijpn.2015.21.4.162 -
Current Opinion in Investigational... Apr 2002Progenics is developing methylnaltrexone (MNTX), an opioid antagonist licensed from UR Labs and the University of Chicago, for the potential treatment of the side... (Review)
Review
Progenics is developing methylnaltrexone (MNTX), an opioid antagonist licensed from UR Labs and the University of Chicago, for the potential treatment of the side effects of opioid pain therapy, such as constipation and post-operative bowel dysfunction. MNTX was discovered at the University of Chicago and subsequently licensed by UR Labs. In October 2001, Progenics entered into an agreement with UR Labs to obtain exclusive worldwide rights to the drug [423791]. MNTX is in phase II trials, with phase III studies expected to begin in 2002 [423791]. In October 2001, a double-blind, randomized, phase II study evaluating sc MNTX in cancer patients for the treatment of opioid-induced constipation was initiated at the University of Chicago Medical Center [423791]. In December 2001, the company stated that it was preparing to initiate phase IIb trials of the compound in opioid-induced constipation and post-operative bowel dysfunction [423791], [432507]. These trials were initiated in February 2002 [440995].
Topics: Analgesics, Opioid; Animals; Constipation; Humans; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Randomized Controlled Trials as Topic; Structure-Activity Relationship
PubMed: 12090733
DOI: No ID Found