methylnaltrexone and Substance-Withdrawal-Syndrome

Opioid-induced bowel dysfunction (OIBD) is characterised by constipation, incomplete evacuation, bloating, and gastric reflux. It is one of the major adverse events (AEs) of treatment for pain in cancer and palliative care, resulting in increased morbidity and reduced quality of life. This review is a partial update of a 2008 review, and critiques as previous update (2018) trials only for people with cancer and people receiving palliative care.. To assess for OIBD in people with cancer and people receiving palliative care the effectiveness and safety of mu-opioid antagonists (MOAs) versus different doses of MOAs, alternative pharmacological/non-pharmacological interventions, placebo, or no treatment.. We searched CENTRAL, MEDLINE, Embase, CINAHL, and Web of Science (December 2021), clinical trial registries and regulatory websites. We sought contact with MOA manufacturers for further data.. Randomised controlled trials (RCTs) assessing the effectiveness and safety of MOAs for OIBD in people with cancer and people at a palliative stage irrespective of the type of terminal disease.. Two review authors assessed risk of bias and extracted data. The appropriateness of combining data from the trials depended upon sufficient homogeneity across trials. Our primary outcomes were laxation response, effect on analgesia, and AEs. We assessed the certainty of evidence using GRADE and created summary of findings tables.. We included 10 studies (two new trials) randomising in-total 1343 adults with cancer irrespective of stage, or at palliative care stage of any disease. The MOAs were oral naldemedine and naloxone (alone or in combination with oxycodone), and subcutaneous methylnaltrexone. The trials compared MOAs with placebo, MOAs at different doses, or in combination with other drugs. Two trials of naldemedine and three of naloxone with oxycodone were in people with cancer irrespective of disease stage. The trial on naloxone alone was in people with advanced cancer. Four trials on methylnaltrexone were in palliative care where most participants had advanced cancer. All trials were vulnerable to biases; most commonly, blinding of the outcome assessor was not reported.  Oral naldemedine versus placebo Risk (i.e. chance) of spontaneous laxations in the medium term (over two weeks) for naldemedine was over threefold greater risk ratio (RR) 2.00, 95% confidence interval (CI) 1.59 to 2.52, 2 trials, 418 participants, I² = 0%. Number needed to treat for an additional beneficial outcome (NNTB) 3, 95% CI 3 to 4; moderate-certainty evidence). Earlier risk of spontaneous laxations and patient assessment of bowel change was not reported. Very low-certainty evidence showed naldemedine had little to no effect on opioid withdrawal symptoms. There was little to no difference in the risk of serious (non-fatal) AEs (RR 3.34, 95% CI 0.85 to 13.15: low-certainty evidence). Over double the risk of AEs (non-serious) reported with naldemedine (moderate-certainty evidence). Low-dose oral naldemedine versus higher dose Risk of spontaneous laxations was lower for the lower dose (medium term, 0.1 mg versus 0.4 mg: RR 0.69, 95% CI 0.53 to 0.89, 1 trial, 111 participants (low-certainty evidence)). Earlier risk of spontaneous laxations and patient assessment of bowel change not reported. Low-certainty evidence showed little to no difference on opioid withdrawal symptoms (0.1 mg versus 0.4 mg mean difference (MD) -0.30, 95% CI -0.85 to 0.25), and occurrences of serious AEs (0.1 mg versus 0.4 mg RR 0.25, 95% CI 0.03 to 2.17). Low-certainty evidence showed little to no difference on non-serious AEs. Oral naloxone versus placebo Risk of spontaneous laxations and AEs not reported. Little to no difference in pain intensity (very low-certainty evidence). Full data not given. The trial reported that no serious AEs occurred. Oral naloxone + oxycodone versus oxycodone Risk of spontaneous laxations within 24 h. This update's findings for naldemedine and naloxone with oxycodone have been strengthened with two new trials, but conclusions have not changed. Moderate-certainty evidence for oral naldemedine on risk of spontaneous laxations and non-serious AEs suggests in people with cancer that naldemedine may improve bowel function over two weeks and increase the risk of AEs. There was low-certainty evidence on serious AEs. Moderate-certainty evidence for methylnaltrexone on spontaneous laxations over two weeks suggests subcutaneous methylnaltrexone may improve bowel function in people receiving palliative care, but certainty of evidence for AEs was low. More trials are needed, more evaluation of AEs, outcomes patients rate as important, and in children.

Topics: Adult; Analgesics, Opioid; Child; Humans; Naloxone; Naltrexone; Narcotic Antagonists; Neoplasms; Opioid-Induced Constipation; Oxycodone; Palliative Care; Quaternary Ammonium Compounds; Substance Withdrawal Syndrome

Methylnaltrexone is a methylated form of the mu-opioid antagonist naltrexone that blocks peripheral effects of opioids without affecting centrally mediated analgesia. The authors conducted a 3-month open-label extension trial of methylnaltrexone in patients with advanced illness and opioid-induced constipation (OIC). Following completion of a 2-week double-blind (DB) trial, 82 patients with OIC who did not respond to laxatives received subcutaneous (SC) methylnaltrexone as needed for up to 3 months. Patients received 0.15 mg/kg as a first dose, adjusted to 0.3 mg/kg or 0.075 mg/kg as needed (maximum of one dose per 24 hours). Mean laxation response (rescue-free bowel movement within 4 hours) rates (DB phase, months 1, 2, 3 open-label phase) were 45.3%, 45.5%, 57.7%, and 57.3%, respectively, for patients treated with DB methylnaltrexone and 10.8%, 48.3%, 47.6%, and 52.1%, respectively, for patients treated with DB placebo. Median time to laxation among responders was 45 minutes (range 0-4 hours) for all doses. Approximately 50% of patients reported improvement in constipation distress. Patient and investigator global clinical impression of change scores also improved. There were minimal changes in pain scores and opioid withdrawal symptoms. Adverse events included abdominal pain and nausea, mostly mild or moderate in severity. SC methylnaltrexone administered PRN (as needed) for up to 3 months continued to rapidly induce laxation in advanced illness patients with OIC.

Topics: Aged; Aged, 80 and over; Analgesics, Opioid; Constipation; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Injections, Subcutaneous; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Substance Withdrawal Syndrome; Time Factors; Treatment Outcome

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.. To evaluate the efficacy of methylnaltrexone, the first peripheral opioid receptor antagonist, in treating chronic methadone-induced constipation.. Double-blind, randomized, placebo-controlled trial conducted between May 1997 and December 1998.. Clinical research center of a university hospital.. 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.. Laxation response, oral-cecal transit time, and central opioid withdrawal symptoms were compared between the 2 groups.. 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.. 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; Gastrointestinal Transit; Humans; Male; Methadone; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Statistics, Nonparametric; Substance Withdrawal Syndrome

Topics: Abdominal Pain; Adult; Analgesics, Opioid; Anorexia; Chronic Disease; Diabetes Mellitus, Type 1; Drug Administration Schedule; Endoscopy, Gastrointestinal; Gastroparesis; Humans; Hypertension; Kidney Failure, Chronic; Male; Naltrexone; Narcotic Antagonists; Nausea; Neuralgia; Quaternary Ammonium Compounds; Substance Withdrawal Syndrome; Treatment Outcome; Vomiting

Rats implanted for 5 days with a morphine pellet were dosed once with naltrexone (subcutaneous, s.c.) or methylnaltrexone (intraventricular, i.c.v.). Then the rats were observed for several somatic signs of precipitated withdrawal and tested for aversion to the place of the withdrawal. The two antagonist treatments produced different withdrawal syndromes, but both were associated with a place aversion which followed a simple monophasic function of the dose of antagonist. More importantly, there was an absence of any overall relation between individual withdrawal signs (jumping, writhing, shaking, diarrhea, and weight loss) and the aversive effect seen. It was concluded, therefore, that the motivational impact of opiate abstinence is not always addressed in conventional models of withdrawal.

Topics: Animals; Avoidance Learning; Behavior, Animal; Body Weight; Dose-Response Relationship, Drug; Drug Implants; Male; Morphine; Motivation; Naltrexone; Quaternary Ammonium Compounds; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome

Diarrhea is a common manifestation of withdrawal from opiates in dependent subjects. This study examined the possibility that this diarrhea results in part from alterations in intestinal fluid transport. Isolated loops of jejunum, ileum and colon were created in morphine-dependent and nondependent rats implanted s.c. with morphine or lactose pellets, respectively. The administration of naltrexone (1 mg/kg s.c.) or its quaternary analog methylnaltrexone (0.01-3 mg/kg i.v.), which does not readily cross the blood-brain barrier, produced a dose-related reduction in fluid absorption from the jejunum and colon of dependent animals only. Similar effects were observed after the i.c.v. injection of quaternary naltrexone (1.0-10 microgram/rat). Both narcotic antagonists, given by any route, produced no change in ileal absorption. Pretreatment with hexamethonium (10 mg/kg i.v.) or atropine (4 mg/kg i.v.) attenuated the antiabsorptive effects of quaternary naltrexone on the jejunum. Serosal addition of naltrexone (10 microM) had no effect on Na or Cl fluxes, short-circuit current or tissue conductance across isolated segments of intestinal mucosa from dependent and nondependent rats. These results indicate that precipitated opiate withdrawal is associated with decreases in jejunal and colonic fluid absorption mediated at sites within both the central nervous system and periphery. Moreover, these effects are not a consequence of a direct opiate action on enterocytes.

Topics: Animals; Atropine; Biological Transport; Diarrhea; Gastrointestinal Motility; Hexamethonium Compounds; Humans; Intestinal Absorption; Male; Morphine; Morphine Dependence; Naltrexone; Quaternary Ammonium Compounds; Rats; Rats, Inbred Lew; Substance Withdrawal Syndrome; Water-Electrolyte Balance