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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 -
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 -
The Nurse Practitioner Mar 2009
Topics: Analgesics, Opioid; Constipation; Humans; Injections, Subcutaneous; Naltrexone; Narcotic Antagonists; Quality of Life; Quaternary Ammonium Compounds
PubMed: 19240629
DOI: 10.1097/01.NPR.0000346585.18786.65 -
Schmerz (Berlin, Germany) Oct 2009Chronic pain patients using opioids frequently suffer from constipation which compromises well-being. Such an opioid-induced gastro-intestinal complication can occur... (Review)
Review
Chronic pain patients using opioids frequently suffer from constipation which compromises well-being. Such an opioid-induced gastro-intestinal complication can occur regularly in patients in palliative care as well as in analgesic sedated intensive care patients or during prolonged perioperative pain therapy. Discomfort and distress in the affected patients can be so severely pronounced that they would rather suffer from the pain than from the side effect of constipation. Conventional therapy can be insufficient in providing satisfactory relief of constipation, mostly because this opioid-induced bowel hypomotility can be laxative-resistant. Moreover, constipation does not decrease during the course of therapy as do other side effects. It is well known that opioid-induced constipation is mediated via activation of micro-opioid receptors in the gastrointestinal tract. Selective peripheral micro-receptor antagonists (such as methylnaltrexone, Relistor) can effectively treat opioid-induced constipation. An interference with central analgesia does not occur as the molecules cannot pass the blood-brain barrier due to their charged states. A reduction of opioid therapy or the development of withdrawal symptoms can be avoided. Studies have shown that methylnaltrexone is not only safe and efficient for chronically constipated palliative care patients but offers promising therapeutic options for further patient collectives.
Topics: Analgesics, Opioid; Clinical Trials as Topic; Constipation; Critical Care; Humans; Naltrexone; Narcotic Antagonists; Palliative Care; Quaternary Ammonium Compounds
PubMed: 19690895
DOI: 10.1007/s00482-009-0824-3 -
The American Surgeon Mar 2022Postoperative ileus (POI) is a surgical complication resulting in increased morbidity and length of stay (LOS). Usual care for POI includes bowel rest and gastric...
BACKGROUND
Postoperative ileus (POI) is a surgical complication resulting in increased morbidity and length of stay (LOS). Usual care for POI includes bowel rest and gastric decompression. It has been questioned if methylnaltrexone (MNTX), a peripheral opioid antagonist, could be used as treatment for POI. The purpose of this study was to determine if MNTX is effective and safe for POI treatment.
METHODS
This single-center, retrospective cohort study included patients ⩾ 18 years with a POI. Patients with acute colonic pseudo-obstruction, small bowel obstruction, and gastrointestinal malignancy were excluded. The intervention was MNTX administration. The primary outcome was time to ileus resolution. Secondary outcomes included LOS, duration of nasogastric tube, total parenteral nutrition requirement, and incidence of gastrointestinal perforations.
RESULTS
110 patients were included in the analysis; 28 received MNTX. Time to ileus resolution was 9.9 days for the MNTX group and 11.4 days for the control group ( = .38). Duration of gastric decompression was 4.6 days for the MNTX group and 4.2 days for the control group ( = .71). Length of stay was 19.9 days for the MNTX group and 19.7 days for the control group ( = .96). The percentage of TPN requirement was 17.9% in the MNTX group and 22.0% in the control group ( = .65). No gastrointestinal perforations were observed in either group.
CONCLUSION
For the treatment of POI, MNTX did not significantly reduce time to resolution of ileus, LOS, duration of gastric decompression, or TPN requirements. However, no gastrointestinal perforations were seen, indicating that MNTX may be safely used in these patients.
Topics: Female; Humans; Ileus; Intestinal Perforation; Intubation, Gastrointestinal; Length of Stay; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Parenteral Nutrition; Postoperative Complications; Quaternary Ammonium Compounds; Retrospective Studies; Time Factors; Treatment Outcome
PubMed: 34645328
DOI: 10.1177/00031348211048825 -
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 Lancet. Oncology Apr 2002
Topics: Administration, Oral; Analgesics, Opioid; Clinical Trials, Phase II as Topic; Constipation; Humans; Methadone; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds
PubMed: 12067677
DOI: 10.1016/s1470-2045(02)00706-4 -
Clinical and Experimental... 2008Constipation is a significant problem related to opioid medications used to manage pain. This review attempts to outline the latest findings related to the therapeutic...
Constipation is a significant problem related to opioid medications used to manage pain. This review attempts to outline the latest findings related to the therapeutic usefulness of a μ opioid receptor antagonist, methylnaltrexone in the treatment of opioid-induced constipation. The review highlights methylnaltrexone bromide (Relistor™; Progenics/Wyeth) a quaternary derivative of naltrexone, which was recently approved in the United States, Europe and Canada. The Food and Drug Administration in the United States approved a subcutaneous injection for the treatment of opioid bowel dysfunction in patients with advanced illness who are receiving palliative care and when laxative therapy has been insufficient. Methylnaltrexone is a peripherally restricted, μ opioid receptor antagonist that accelerates oral-cecal transit in patients with opioid-induced constipation without reversing the analgesic effects of morphine or inducing symptoms of opioid withdrawal. An analysis of the mechanism of action and the potential benefits of using methylnaltrexone is based on data from published basic research and recent clinical studies.
PubMed: 21677823
DOI: 10.2147/ceg.s3889 -
Neuropharmacology Mar 2021Antagonism of peripheral opioid receptors by methylnaltrexone (MNTX) was recently proposed as a potential mechanism to attenuate the development of opioid analgesic...
BACKGROUND
Antagonism of peripheral opioid receptors by methylnaltrexone (MNTX) was recently proposed as a potential mechanism to attenuate the development of opioid analgesic tolerance based on experiments conducted in mice. However, reports indicate that MNTX is demethylated to naltrexone (NTX) in mice, and NTX may subsequently cross the blood-brain barrier to antagonize centrally-mediated opioid effects. The goal of this study was to determine whether MNTX alters centrally-mediated behaviors elicited by the opioid analgesics, morphine and oxycodone, and to quantify concentrations of MNTX and NTX in blood and brain following their administration in mice.
METHODS
Combinations of MNTX and morphine were tested under acute and chronic conditions in thermal nociceptive assays. Effects of MNTX and NTX pretreatment were assessed in an oxycodone discrimination operant procedure. Blood and brain concentrations of these antagonists were quantified after their administration using liquid chromatography-mass spectrometry.
RESULTS
MNTX dose-dependently attenuated acute and chronic morphine antinociception. MNTX and NTX dose-dependently antagonized the discriminative stimulus effects of oxycodone. MNTX and NTX were detected in both blood and brain after administration of MNTX, confirming its demethylation and demonstrating that MNTX itself can cross the blood-brain barrier.
CONCLUSIONS
These results provide converging behavioral and analytical evidence that MNTX administration in mice attenuates centrally-mediated effects produced by opioid analgesics and results in functional concentrations of MNTX and NTX in blood and brain. Collectively, these findings indicate that MNTX cannot be administered systemically in mice for making inferences that its effects are peripherally restricted.
Topics: Analgesics, Opioid; Animals; Blood-Brain Barrier; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred C57BL; Morphine; Naltrexone; Narcotic Antagonists; Oxycodone; Pain Measurement; Quaternary Ammonium Compounds
PubMed: 33316279
DOI: 10.1016/j.neuropharm.2020.108437 -
Pediatric Blood & Cancer Oct 2013Pediatric oncology patients can experience opioid-induced constipation, which may not respond to laxative treatment. Methylnaltrexone is an opioid receptor antagonist... (Clinical Trial)
Clinical Trial
BACKGROUND
Pediatric oncology patients can experience opioid-induced constipation, which may not respond to laxative treatment. Methylnaltrexone is an opioid receptor antagonist that can reverse opioid-induced constipation without affecting analgesia. Published literature on the use of methylnaltrexone in children is very limited. This retrospective review describes the effectiveness and safety of methylnaltrexone for opioid-induced constipation in pediatric oncology patients.
PROCEDURE
A retrospective review of health records was conducted for pediatric oncology in-patients who were prescribed methylnaltrexone between May 2008 and September 2012 at The Hospital for Sick Children. Demographic, clinical, efficacy, and safety data were collected, including; opioid, laxative, and methylnatrexone dosing and frequency.
RESULTS
Fifteen patients (median age: 14 years, range: 4-17 years) received methylnaltrexone; 12 received a single dose while three received multiple doses. At the time of methylnaltrexone administration, patients were receiving a median oral morphine dose equivalent of 5.7 mg/kg/day (range: 1.5-29.2 mg/kg/day) and had not had any bowel movements for several days despite treatment with multiple laxatives. Methylnaltrexone was given at a mean dose of 0.15 ± 0.02 mg/kg/dose (range: 3-12 mg/dose) as a subcutaneous injection. After 14 of 19 doses administered, patients had a bowel movement within 4 hours. Three patients had documented mild gastrointestinal upset following methylnaltrexone administration. None reported a reduction of pain control or opioid withdrawal symptoms.
CONCLUSION
This case series suggests that methylnaltrexone is safe and may be effective when given subcutaneously as a 0.15 mg/kg single dose to pediatric oncology patients with opioid-induced constipation.
Topics: Adolescent; Analgesics, Opioid; Child; Child, Preschool; Constipation; Female; Humans; Male; Naltrexone; Narcotic Antagonists; Neoplasms; Pain; Quaternary Ammonium Compounds; Retrospective Studies
PubMed: 23766091
DOI: 10.1002/pbc.24615