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Drug Design, Development and Therapy 2015Opioid-induced bowel dysfunction (OIBD) comprises gastrointestinal (GI) symptoms, including dry mouth, nausea, vomiting, gastric stasis, bloating, abdominal pain, and... (Review)
Review
Opioid-induced bowel dysfunction (OIBD) comprises gastrointestinal (GI) symptoms, including dry mouth, nausea, vomiting, gastric stasis, bloating, abdominal pain, and opioid-induced constipation, which significantly impair patients' quality of life and may lead to undertreatment of pain. Traditional laxatives are often prescribed for OIBD symptoms, although they display limited efficacy and exert adverse effects. Other strategies include prokinetics and change of opioids or their administration route. However, these approaches do not address underlying causes of OIBD associated with opioid effects on mostly peripheral opioid receptors located in the GI tract. Targeted management of OIBD comprises purely peripherally acting opioid receptor antagonists and a combination of opioid receptor agonist and antagonist. Methylnaltrexone induces laxation in 50%-60% of patients with advanced diseases and OIBD who do not respond to traditional oral laxatives without inducing opioid withdrawal symptoms with similar response (45%-50%) after an oral administration of naloxegol. A combination of prolonged-release oxycodone with prolonged-release naloxone (OXN) in one tablet (a ratio of 2:1) provides analgesia with limited negative effect on the bowel function, as oxycodone displays high oral bioavailability and naloxone demonstrates local antagonist effect on opioid receptors in the GI tract and is totally inactivated in the liver. OXN in daily doses of up to 80 mg/40 mg provides equally effective analgesia with improved bowel function compared to oxycodone administered alone in patients with chronic non-malignant and cancer-related pain. OIBD is a common complication of long-term opioid therapy and may lead to quality of life deterioration and undertreatment of pain. Thus, a complex assessment and management that addresses underlying causes and patomechanisms of OIBD is recommended. Newer strategies comprise methylnaltrexone or OXN administration in the management of OIBD, and OXN may be also considered as a preventive measure of OIBD development in patients who require opioid administration.
Topics: Analgesics, Opioid; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Narcotic Antagonists
PubMed: 25931815
DOI: 10.2147/DDDT.S32684 -
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 -
Canadian Journal of Surgery. Journal... Apr 2009The duration of postoperative ileus following abdominal surgery is quite variable, and prolonged postoperative ileus is an iatrogenic phenomenon with important influence... (Review)
Review
The duration of postoperative ileus following abdominal surgery is quite variable, and prolonged postoperative ileus is an iatrogenic phenomenon with important influence on patient morbidity, hospital costs and length of stay in hospital. Adequate treatment for prolonged postoperative ileus is important to improve patient morbidity and clinical efficiency. Both clinical and pharmacological management strategies have improved rapidly over the last decade, and appropriate and timely management using multimodal techniques should be used for optimal care. In this review, we define postoperative ileus, describe the pathogenesis and briefly discuss clinical management before detailing potential pharmacologic management options.
Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Anti-Inflammatory Agents, Non-Steroidal; Bisacodyl; Cathartics; Cisapride; Dihydroergotamine; Humans; Ileus; Inflammation; Naltrexone; Neostigmine; Parasympathomimetics; Piperidines; Postoperative Complications; Propranolol; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Serotonin Receptor Agonists
PubMed: 19399212
DOI: No ID Found -
Journal of Gastrointestinal Surgery :... Jan 2021Postoperative ileus (POI) and constipation are common secondary effects of opioids and carry significant clinical and economic impacts. μ-Opioid receptors mediate... (Review)
Review
Postoperative ileus (POI) and constipation are common secondary effects of opioids and carry significant clinical and economic impacts. μ-Opioid receptors mediate opioid analgesia in the central nervous system (CNS) and gastrointestinal-related effects in the periphery. Peripherally acting μ-opioid receptor antagonists (PAMORAs) block the peripheral effects of opioids in the gastrointestinal tract, while maintaining opioid analgesia in the CNS. While most are not approved for POI or postoperative opioid-induced constipation (OIC), PAMORAs have a potential role in these settings via their selective effects on the μ-opioid receptor. This review will discuss recent clinical trials evaluating the safety and efficacy of PAMORAs, with a focus on alvimopan (Entereg) and methylnaltrexone (Relistor) in patients with POI or postoperative OIC. We will characterize potential factors that may have impacted the efficacy observed in phase 3 trials and discuss future directions for the management and treatment of POI.
Topics: Analgesics, Opioid; Constipation; Humans; Ileus; Narcotic Antagonists; Postoperative Complications
PubMed: 32779081
DOI: 10.1007/s11605-020-04671-x -
Journal of Neurogastroenterology and... Apr 2024Daily use of opioid analgesics has significantly increased in recent years due to an increasing prevalence of conditions associated with chronic pain. Opioid-induced... (Review)
Review
Daily use of opioid analgesics has significantly increased in recent years due to an increasing prevalence of conditions associated with chronic pain. Opioid-induced constipation (OIC) is one of the most common, under-recognized, and under-treated side effects of opioid analgesics. OIC significantly reduces the quality of life by causing psychological distress, lowering work productivity, and increasing access to healthcare facilities. The economic and social burden of OIC led to the development of precise strategies for daily clinical practice. Key aspects are the prevention of constipation through adequate water intake and fiber support, avoidance of sedentariness, and early recognition and treatment of cofactors that could worsen constipation. Recommended first-line therapy includes osmotic (preferably polyethylene glycol) and stimulant laxatives. Peripherally acting μ-opioid receptor antagonists, such as methylnaltrexone, naloxegol, or naldemedine, should be used in patients that have not responded to the first-line treatments. The bowel functional index is the main tool for assessing the severity of OIC and for monitoring the response. The paper discusses the recent literature on the pathophysiology, clinical evaluation, and management of OIC and provides a pragmatic approach for its assessment and treatment.
PubMed: 38576366
DOI: 10.5056/jnm23144 -
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 -
Drugs & Aging Aug 2016Constipation is a common and often debilitating condition in the elderly, which may be caused by underlying disease conditions, structural abnormalities in the bowel,... (Review)
Review
Constipation is a common and often debilitating condition in the elderly, which may be caused by underlying disease conditions, structural abnormalities in the bowel, and a variety of medications such as anticholinergics, antidepressants, and opiates. In this review, we focus on opioid-induced constipation (OIC), which is often underrecognized and undertreated in the elderly. When opioid therapy is initiated, healthcare providers are encouraged to evaluate risk factors for the development of constipation as part of a thorough patient history. To this end, the patient assessment should include the use of validated instruments, such as the Bristol Stool Scale and Bowel Function Index, to confirm the diagnosis and provide a basis for evaluating treatment outcomes. Healthcare providers should use a stepwise approach to the treatment of OIC in the elderly. Conventional laxatives are a first-line option and considered well tolerated with short-term use as needed; however, evidence is lacking to support their effectiveness in OIC. Moreover, because of the risk of adverse events and other considerations, such as chewing difficulties and swallowing disorders, conventional oral laxatives may be inappropriate for the treatment of OIC in the elderly. Thus, the availability of new pharmacologic agents such as the peripherally acting µ-opioid receptor antagonists methylnaltrexone and naloxegol, which target the underlying causes of OIC, and the secretagogue lubiprostone may provide more effective treatment options for elderly patients with OIC.
Topics: Aged; Analgesics, Opioid; Constipation; Health Personnel; Humans; Laxatives; Naltrexone; Narcotic Antagonists; Pain; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Treatment Outcome
PubMed: 27417446
DOI: 10.1007/s40266-016-0381-2 -
Gastroenterology & Hepatology Jan 2013
Review
PubMed: 24707236
DOI: No ID Found -
The Cochrane Database of Systematic... Jan 2011Constipation is common in palliative care; it can generate considerable suffering due to the unpleasant physical symptoms. In the first Cochrane Review on effectiveness... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Constipation is common in palliative care; it can generate considerable suffering due to the unpleasant physical symptoms. In the first Cochrane Review on effectiveness of laxatives for the management of constipation in palliative care patients, published in 2006, no conclusions could be drawn because of the limited number of evaluations. This article describes the first update of this review.
OBJECTIVES
To determine the effectiveness of laxatives or methylnaltrexone for the management of constipation in palliative care patients.
SEARCH STRATEGY
We searched databases including MEDLINE and CENTRAL (The Cochrane Library) in 2005 and in the update to August 2010.
SELECTION CRITERIA
Randomised controlled trials (RCTs) evaluating laxatives for constipation in palliative care patients. In the update we also included RCTs on subcutaneous methylnaltrexone; an opioid-receptor antagonist that is now licensed for the treatment of opioid-induced constipation in palliative care when response to usual laxative therapy is insufficient.
DATA COLLECTION AND ANALYSIS
Two authors assessed trial quality and extracted data. The appropriateness of combining data from the studies depended upon clinical and outcome measure homogeneity.
MAIN RESULTS
We included seven studies involving 616 participants; all under-reported methodological features. In four studies the laxatives lactulose, senna, co-danthramer, misrakasneham, and magnesium hydroxide with liquid paraffin were evaluated. In three methylnaltrexone.In studies comparing the different laxatives evidence was inconclusive. Evidence on subcutaneous methylnaltrexone was clearer; in combined analysis (287 participants) methylnaltrexone, in comparison with a placebo, significantly induced laxation at 4 hours (odds ratio 6.95; 95% confidence interval 3.83 to 12.61). In combined analyses there was no difference in the proportion experiencing side effects, although participants on methylnaltrexone suffered more flatulence and dizziness. No evidence of opioid withdrawal was found. In one study severe adverse events, commonly abdominal pain, were reported that were possibly related to methylnaltrexone. A serious adverse event considered to be related to the methylnaltrexone also occurred; this involved a participant having severe diarrhoea, subsequent dehydration and cardiovascular collapse.
AUTHORS' CONCLUSIONS
The 2010 update found evidence on laxatives for management of constipation remains limited due to insufficient RCTs. However, the conclusions of this update have changed since the original review publication in that it now includes evidence on methylnaltrexone. Here it found that subcutaneous methylnaltrexone is effective in inducing laxation in palliative care patients with opioid-induced constipation and where conventional laxatives have failed. However, the safety of this product is not fully evaluated. Large, rigorous, independent trials are needed.
Topics: Analgesics, Opioid; Anthraquinones; Cathartics; Constipation; Humans; Lactulose; Magnesium Hydroxide; Naltrexone; Palliative Care; Paraffin; Quaternary Ammonium Compounds; Randomized Controlled Trials as Topic; Senna Extract
PubMed: 21249653
DOI: 10.1002/14651858.CD003448.pub3 -
Clinical Interventions in Aging Aug 2010Constipation disproportionately affects older adults, with a prevalences of 50% in community-dwelling elderly and 74% in nursing-home residents. Loss of mobility,... (Review)
Review
Constipation disproportionately affects older adults, with a prevalences of 50% in community-dwelling elderly and 74% in nursing-home residents. Loss of mobility, medications, underlying diseases, impaired anorectal sensation, and ignoring calls to defecate are as important as dyssynergic defecation or irritable bowel syndrome in causing constipation. Detailed medical history on medications and co-morbid problems, and meticulous digital rectal examination may help identify causes of constipation. Likewise, blood tests and colonoscopy may identify organic causes such as colon cancer. Physiological tests such as colonic transit study with radio-opaque markers or wireless motility capsule, anorectal manometry, and balloon expulsion tests can identify disorders of colonic and anorectal function. However, in the elderly, there is usually more than one mechanism, requiring an individualized but multifactorial treatment approach. The management of constipation continues to evolve. Although osmotic laxatives such as polyethylene glycol remain mainstay, several new agents that target different mechanisms appear promising such as chloride-channel activator (lubiprostone), guanylate cyclase agonist (linaclotide), 5HT(4) agonist (prucalopride), and peripherally acting mu-opioid receptor antagonists (alvimopan and methylnaltrexone) for opioid-induced constipation. Biofeedback therapy is efficacious for treating dyssynergic defecation and fecal impaction with soiling. However, data on efficacy and safety of drugs in elderly are limited and urgently needed.
Topics: Aged; Aging; Constipation; Geriatrics; Humans; Palliative Care
PubMed: 20711435
DOI: 10.2147/cia.s8100