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F1000Research 2021Opioids prescribed for the management of chronic noncancer pain are associated with nausea, vomiting, and constipation. Methylnaltrexone, a peripherally acting...
Attrition of methylnaltrexone treatment-emergent adverse events in patients with chronic noncancer pain and opioid-induced constipation: a post hoc pooled analysis of two clinical trials.
Opioids prescribed for the management of chronic noncancer pain are associated with nausea, vomiting, and constipation. Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, has demonstrated robust efficacy and was well-tolerated in treating opioid-induced constipation without affecting central analgesia. Our objective was to assess changes in the frequency of treatment-emergent adverse events (TEAEs) after the first or second dose of methylnaltrexone or placebo. This post hoc analysis pooled data from two randomized, placebo-controlled clinical trials assessing methylnaltrexone for opioid-induced constipation in the outpatient setting. Patients received subcutaneous methylnaltrexone (12 mg once daily or 12 mg once every other day), oral methylnaltrexone (150, 300, or 450 mg daily), or placebo. TEAEs, opioid withdrawal symptoms, pain intensity, and rescue-free bowel movements (RFBMs) within 4 hours of the first dose (i.e., RFBM responders) were assessed. Associations between TEAE frequencies and RFBM response were also evaluated. The analysis included 1263 adult patients with chronic noncancer pain. TEAE rates declined from treatment day 1 to 2 (methylnaltrexone: 16.2%-5.3%; placebo: 6.6%-5.4%). Among methylnaltrexone-treated patients, significantly greater proportions of RFBM responders versus nonresponders reported gastrointestinal TEAEs on day 1. No associations between RFBM response and the frequency of TEAEs were observed in the placebo group. No meaningful changes in opioid withdrawal symptoms or pain intensity were observed. Early-onset TEAEs following methylnaltrexone treatment, particularly gastrointestinal TEAEs, are at least partially due to laxation. Methylnaltrexone treatment effectively relieves opioid-induced constipation without affecting the central analgesic effects of opioids.
PubMed: 34631030
DOI: 10.12688/f1000research.51073.2 -
BMJ Open Jul 2016Gastrointestinal dysmotility and constipation are common problems in intensive care patients. The majority of critical care patients are sedated with opioids to... (Randomized Controlled Trial)
Randomized Controlled Trial
Protocol for a randomised control trial of methylnaltrexone for the treatment of opioid-induced constipation and gastrointestinal stasis in intensive care patients (MOTION).
INTRODUCTION
Gastrointestinal dysmotility and constipation are common problems in intensive care patients. The majority of critical care patients are sedated with opioids to facilitate tolerance of endotracheal tubes and mechanical ventilation, which inhibit gastrointestinal motility and lead to adverse outcomes. Methylnaltrexone is a peripheral opioid antagonist that does not cross the blood-brain barrier and can reverse the peripheral side effects of opioids without affecting the desired central properties. This trial will investigate whether methylnaltrexone can reverse opioid-induced constipation and gastrointestinal dysmotility.
METHODS
This is a single-centre, multisite, double-blind, randomised, placebo-controlled trial. 84 patients will be recruited from 4 intensive care units (ICUs) within Imperial College Healthcare NHS Trust. Patients will receive intravenous methylnaltrexone or placebo on a daily basis if they are receiving opioid infusion to facilitate mechanical ventilation and have not opened their bowels for 48 hours. All patients will receive standard laxatives as per the clinical ICU bowel protocol prior to randomisation. The primary outcome of the trial will be time to significant rescue-free laxation following randomisation. Secondary outcomes will include tolerance of enteral feed, gastric residual volumes, incidence of pneumonia, blood stream and Clostridium difficile infection, and any reversal of central opioid effects.
ETHICS AND DISSEMINATION
The trial protocol, the patient/legal representative information sheets and consent forms have been reviewed and approved by the Harrow Research Ethics Committee (REC Reference 14/LO/2004). An independent Trial Steering Committee and Data Monitoring Committee are in place, with patient representation. On completion, the trial results will be published in peer-reviewed journals and presented at national and international scientific meetings.
TRIAL REGISTRATION NUMBER
2014-004687-37; Pre-results.
Topics: Adult; Analgesics, Opioid; Blood-Brain Barrier; Constipation; Critical Care; Female; Gastrointestinal Motility; Humans; Laxatives; Male; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds
PubMed: 27412108
DOI: 10.1136/bmjopen-2016-011750 -
Journal of Pain Research 2019Oral methylnaltrexone was shown to be effective in treating opioid-induced constipation (OIC) in patients with chronic noncancer pain in a Phase III randomized...
PURPOSE
Oral methylnaltrexone was shown to be effective in treating opioid-induced constipation (OIC) in patients with chronic noncancer pain in a Phase III randomized controlled trial. This report provides a detailed safety analysis from that study.
METHODS
Adults (n=803) with chronic noncancer pain for ≥2 months and confirmed OIC while receiving opioid doses ≥50 mg morphine equivalent per day for ≥14 days were randomized 1:1:1:1 to oral methylnaltrexone (150, 300, or 450 mg) or placebo once daily for 4 weeks, followed by as-needed use for 8 weeks. Safety was evaluated by examining treatment-emergent adverse events (TEAEs), clinical laboratory parameters, vital signs, electrocardiography, rescue-laxative and opioid use, Objective Opioid Withdrawal Scale (OOWS) and Subjective Opioid Withdrawal Scale (SOWS), and pain-intensity scores.
RESULTS
TEAEs occurred at a similar incidence in the methylnaltrexone groups (59.0%) and placebo group (63.0%). The most common TEAEs with methylnaltrexone were abdominal pain (8.0% vs 8.5% with placebo), nausea (6.8% vs 9.0%), and diarrhea (6.0% vs 3.5%). Cardiac-related TEAEs occurred in 1.8% and 1.0% of patients, respectively, and no major adverse cardiovascular events were reported. No patient had a cluster of TEAEs associated with opioid withdrawal after excluding gastrointestinal TEAEs. Changes in laboratory parameters, vital signs, and electrocardiography were generally small and similar across treatment groups. Rescue-laxative use was more common with placebo than methylnaltrexone 450 mg (6.20% vs 4.27% of study days, =0.024). Changes in opioid dose, OOWS and SOWS scores, and pain-intensity scores during treatment were minimal.
CONCLUSION
Oral methylnaltrexone had a safety profile comparable with placebo in the treatment of OIC in patients with chronic noncancer pain, with no evidence of cardiac toxicity or opioid withdrawal.
PubMed: 30613162
DOI: 10.2147/JPR.S170086 -
American Family Physician Jun 2009As death approaches, a gradual shift in emphasis from curative and life prolonging therapies toward palliative therapies can relieve significant medical burdens and...
As death approaches, a gradual shift in emphasis from curative and life prolonging therapies toward palliative therapies can relieve significant medical burdens and maintain a patient's dignity and comfort. Pain and dyspnea are treated based on severity, with stepped interventions, primarily opioids. Common adverse effects of opioids, such as constipation, must be treated proactively; other adverse effects, such as nausea and mental status changes, usually dissipate with time. Parenteral methylnaltrexone can be considered for intractable cases of opioid bowel dysfunction. Tumor-related bowel obstruction can be managed with corticosteroids and octreotide. Therapy for nausea and vomiting should be targeted to the underlying cause; low-dose haloperidol is often effective. Delirium should be prevented with normalization of environment or managed medically. Excessive respiratory secretions can be treated with reassurance and, if necessary, drying of secretions to prevent the phenomenon called the "death rattle." There is always something more that can be done for comfort, no matter how dire a situation appears to be. Good management of physical symptoms allows patients and loved ones the space to work out unfinished emotional, psychological, and spiritual issues, and, thereby, the opportunity to find affirmation at life's end.
Topics: Analgesics, Opioid; Antiemetics; Cathartics; Constipation; Continuity of Patient Care; Delirium; Dyspnea; Humans; Nausea; Pain; Palliative Care; Quality of Life; Respiratory Sounds; Terminal Care
PubMed: 19530636
DOI: No ID Found -
Psychopharmacology Jan 2015Methylnaltrexone bromide (MTNX) is a peripherally acting mu-opioid receptor antagonist, prescribed for the treatment of opioid-induced constipation in patients with... (Randomized Controlled Trial)
Randomized Controlled Trial
RATIONALE
Methylnaltrexone bromide (MTNX) is a peripherally acting mu-opioid receptor antagonist, prescribed for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care. Studies have used this drug to determine if other opioid-induced effects besides constipation are altered by MTNX in humans and have suggested, based on their results, that these other effects are altered by peripheral opioid actions.
OBJECTIVE
The primary objective of this report is to present results that provide indirect evidence that MTNX has centrally mediated effects, albeit slight, and secondarily to describe the effects of MTNX on psychopharmacological effects of morphine.
METHODS
In a crossover, randomized, placebo-controlled, double-blind study, 29 healthy volunteers received 0.45 mg/kg MTNX or saline subcutaneously, followed by saline intravenously. In three other conditions, 0.143 mg/kg of morphine sulfate administered intravenously was preceded by subcutaneous administration of 0, 0.225, or 0.45 mg/kg MTNX. Before and after drug administration, subjective and physiological measures, including pupil diameter, were assessed.
RESULTS
Two separate analyses confirmed that 0.45 mg/kg MTNX alone induced a slight degree of miosis, a centrally mediated opioid agonist effect. This dose had minimal subjective effects. MTNX at either or both the 0.225 and 0.45 mg/kg dose reduced some subjective effects of morphine without altering miosis.
CONCLUSIONS
We present indirect evidence that MTNX crosses the blood-brain barrier in humans. Therefore, whether the reductions in subjective effects of morphine by MTNX that were observed in past studies and in this study can be attributed to peripheral mechanisms is open to question.
Topics: Adult; Analgesics, Opioid; Cross-Over Studies; Double-Blind Method; Female; Healthy Volunteers; Heart Rate; Humans; Infusions, Intravenous; Male; Morphine; Naltrexone; Narcotic Antagonists; Pupil; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Treatment Outcome; Young Adult
PubMed: 24871705
DOI: 10.1007/s00213-014-3637-8 -
Journal of Pain and Symptom Management Jul 2002Opioid antagonists have well-established indications in the reversal of life-threatening opioid toxicity, but also hold considerable promise for other applications in... (Review)
Review
Opioid antagonists have well-established indications in the reversal of life-threatening opioid toxicity, but also hold considerable promise for other applications in palliative care practice, particularly management of opioid-related constipation. We briefly review current understanding of opioid receptors, focusing on their complex role in gastrointestinal physiology. We summarize the pharmacology, conventional indications, and clinical usage of three major groups of opioid antagonists, including a promising new peripherally acting agent, methylnaltrexone, which is not commercially available. We suggest an approach to administering opioid antagonists for reduction of life-threatening opioid toxicity in patients with pain. The literature on opioid-induced constipation and its treatment with opioid-antagonists is reviewed in detail. Finally, other potential uses of opioid antagonists in palliative care are described, especially strategies for reducing such opioid side effects as nausea and pruritus and for improving analgesia or reducing tolerance by concomitantly administrating both an opioid agonist and low dosages of an antagonist.
Topics: Constipation; Humans; Narcotic Antagonists; Narcotics; Palliative Care
PubMed: 12183097
DOI: 10.1016/s0885-3924(02)00424-4 -
Therapeutics and Clinical Risk... Mar 2010Constipation is a common symptom in palliative care patients which can generate considerable suffering. There is uncertainty about the choice of treatment options from...
Constipation is a common symptom in palliative care patients which can generate considerable suffering. There is uncertainty about the choice of treatment options from varying recommendations for management of constipation and a varying clinical practice in palliative care settings. The purpose of the review was to evaluate the current recommendations of therapy guidelines for the management of opioid-induced constipation in palliative care patients with a focus on methylnaltrexone bromide. Recent findings in the literature and related information on the opioid-induced gastrointestinal disorders in patients with advanced illness, as well as information on the opioid-antagonist methylnaltrexone, are discussed. Knowledge of the role of definitions, the causes of constipation and the pathophysiology of opioid-induced constipation must be given high priority in the treatment of patients receiving opioids. Diagnosis and therapy of constipation, therefore, should relate to findings in clinical investigation. Opioid-induced constipation and its adequate treatment is an important issue for patients with advanced illness and also poses therapeutic challenge for clinicians in daily routine. Methylnaltrexone bromide may represent an important therapeutic option for palliative care patients who are suffering from opioid-induced constipation with failure of conventional prophylactic oral laxative treatment.
PubMed: 20234787
DOI: 10.2147/tcrm.s4301 -
Alimentary Pharmacology & Therapeutics Oct 2010The short-term effects of methylnaltrexone (MNTX), a peripherally acting mu-opioid receptor antagonist, on gastrointestinal and colonic transit remain unclear. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The short-term effects of methylnaltrexone (MNTX), a peripherally acting mu-opioid receptor antagonist, on gastrointestinal and colonic transit remain unclear.
AIM
To compare the effects of placebo, codeine, subcutaneous (s.c.) MNTX and codeine with s.c. MNTX on gastrointestinal and colonic transit of solids in healthy humans.
METHODS
In a randomized, parallel-group, double-blind, placebo-controlled trial of 48 healthy volunteers, effects of 6 consecutive days of placebo [s.c. and p.o. (orally), n = 8], codeine (p.o. 30 mg q.d.s., n = 8), MNTX (s.c. 0.30 mg/kg, n = 16) and combined MNTX and codeine (same doses and routes, n = 16) on gastrointestinal and colonic transit were assessed. A validated scintigraphic method was used to measure transit during the last 48 h of treatment. Bowel function was estimated during treatment as well as 1 week preceding treatment using standard diaries. Analysis of covariance was used to assess treatment effects.
RESULTS
Codeine delayed colonic transit [geometric centre at 24 h (P = 0.04) and ascending colon t(1/2) (P = 0.02)] and reduced stool frequency (P = 0.002), but had no effect on stool form. MNTX did not affect transit, stool frequency or stool form, either alone or with codeine (P > 0.3). No drug interaction effects were detected (P > 0.15).
CONCLUSION
Methylnaltrexone does not alter gastrointestinal or colonic transit and does not reverse acute codeine-associated delayed gut transit in health.
Topics: Adolescent; Adult; Analgesics, Opioid; Codeine; Double-Blind Method; Drug Combinations; Female; Gastrointestinal Tract; Gastrointestinal Transit; Humans; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Young Adult
PubMed: 20839388
DOI: 10.1111/j.1365-2036.2010.04422.x -
Alimentary Pharmacology & Therapeutics Mar 2011The centrally acting mu-opioid receptor antagonist naloxone inhibits meal-induced gastric accommodation.
BACKGROUND
The centrally acting mu-opioid receptor antagonist naloxone inhibits meal-induced gastric accommodation.
AIM
To study the role of peripheral mu-opioid receptors in the regulation of gastric tone and food intake by comparing the effects of naloxone with the peripherally restricted mu-opioid receptor antagonist methylnaltrexone.
METHODS
Methylnaltrexone (12 mg s.c.), naloxone (20 μg/kg/h intravenous infusion after 0.4 mg bolus) and placebo were studied in 23 healthy volunteers. Gastric volume was recorded using an intragastric bag held at constant pressure connected to a barostat, with administration of a nutrient drink after 30 min. Pressure in the stomach was measured during intragastric nutrient drink infusion until the volunteers scored maximal satiation.
RESULTS
Methylnaltrexone inhibited significantly the volume increase after food intake as assessed with the barostat (P < 0.01). During nutrient drink infusion the intragastric pressure significantly decreased as compared with the preprandial pressure after placebo treatment. Both methylnaltrexone and naloxone significantly inhibited this intragastric pressure decrease (P < 0.001 and P < 0.05, respectively). Volunteers scored maximal satiation after 979 ± 96, 958 ± 84 and 1124 ± 107 mL nutrient drink infused (for naloxone, methylnaltrexone and placebo treatment, respectively; P < 0.05).
CONCLUSIONS
These results indicate that endogenous opioids mediate gastric accommodation and satiation via peripheral mu-opioid receptors. Effects were less pronounced after naloxone treatment, which indicates that centrally involved mu-opioid receptors mediate an opposing effect.
Topics: Adult; Analgesics, Opioid; Analysis of Variance; Eating; Female; Food; Humans; Male; Naloxone; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Satiation; Stomach
PubMed: 21198709
DOI: 10.1111/j.1365-2036.2010.04557.x -
Journal of Pain Research 2018An oral formulation of methylnaltrexone has been developed for treating opioid-induced constipation (OIC). This manuscript examines the impact of oral methylnaltrexone,...
PURPOSE
An oral formulation of methylnaltrexone has been developed for treating opioid-induced constipation (OIC). This manuscript examines the impact of oral methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, on opioid analgesia.
METHODS
This Phase III, randomized, double-blind, placebo-controlled trial, evaluated changes in pain intensity scores (0= no pain to 10= worst possible pain) and opioid use in adults with chronic noncancer pain. Patients taking ≥50 mg/day oral morphine equivalent dose (MED) for ≥14 days before screening with less than three rescue-free bowel movements/week received oral methylnaltrexone 150 mg/day (n=201), 300 mg/day (n=201), 450 mg/day (n=200), or placebo (n=201) once daily for 4 weeks followed by 8 weeks of oral methylnaltrexone as needed.
RESULTS
The primary condition requiring opioid use was back pain (68.2% of 803 patients). Baseline pain intensity scores were similar among treatment groups (mean range, 6.2-6.4) and remained stable throughout the 4-week double-blind (mean range, 6.1-6.5) and 8-week as needed (mean range, 6.3-6.5) periods. Baseline mean MED was comparable between oral methylnaltrexone 150 mg (200.0 mg/day), methylnaltrexone 450 mg (218.0 mg/day), and placebo (209.7 mg/day), but was slightly higher in the oral methylnaltrexone 300-mg group (252.6 mg/day). Nonsignificant, minimal changes in mean MED were observed after 4 weeks of treatment (214.5-235.6 mg/day) and at the end of the as needed phase (202.3-234.9 mg/day). The percentage of patients who initiated new opioid medications during the 4-week, once-daily dosing period was generally similar among the oral methylnaltrexone 150-mg, 300-mg, and 450-mg groups (44.8%, 43.3%, and 35.0%, respectively), the oral methylnaltrexone combined group (41.0%), and the placebo group (39.8%). The most common newly initiated opioid medications during this once-daily period were oxycodone (oral methylnaltrexone groups combined, 14.6%; placebo, 12.4%) and morphine (oral methylnaltrexone combined, 10.1%; placebo, 7.0%).
CONCLUSION
Oral methylnaltrexone does not elicit opioid withdrawal or interfere with opioid analgesia.
PubMed: 30147355
DOI: 10.2147/JPR.S160488