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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 -
Neurogastroenterology and Motility May 2018Opioid-induced constipation (OIC) is a major side effect of opioid use. Centrally acting antagonists result in opioid withdrawal or worsening of pain and lead to use of... (Review)
Review
BACKGROUND
Opioid-induced constipation (OIC) is a major side effect of opioid use. Centrally acting antagonists result in opioid withdrawal or worsening of pain and lead to use of peripherally acting mu-opioid receptor antagonists (PAMORAs). The required doses of the PAMORAs, methylnaltrexone and naloxegol, in the treatment of OIC are well established in chronic opioid users. OIC may occur after short duration of opioid treatment; the required doses of naloxone, naltrexone, and PAMORAs in opioid-naïve subjects (with no opioid use for at least 3 months) are unclear. The aim of this review was to evaluate the PAMORA dose required for opioid-naïve subjects to achieve similar beneficial effects on symptoms or valid surrogates to those observed in chronic opioid users.
METHODS
A PubMed search of μ-opioid antagonists to counter μ-opioid effects included terms: naloxone, naltrexone, methylnaltrexone, alvimopan, and naloxegol, as well as OIC and colonic transit.
KEY RESULTS
The approved dose of methylnaltrexone in chronic opioid users, 0.3 mg/kg subcutaneous (SQ), did not affect motility in opioid-naïve subjects. Trials investigating the required dose of alvimopan showed 0.5-1 mg dose was efficacious in treating OIC; a 10-fold higher dose (12 mg) of alvimopan is needed to block effects of codeine on small bowel and colonic transit in opioid-naïve subjects compared to chronic opioid users. Opioid-naïve users need 125 mg of naloxegol to reverse the effects of opioids on transit; this is in contrast to the 12.5 to 25 mg needed to treat OIC in chronic opioid users.
CONCLUSIONS & INFERENCES
Opioid-naïve subjects require a higher dose of PAMORA than chronic opioid users to achieve μ-opioid antagonist effect.
Topics: Analgesics, Opioid; Constipation; Dose-Response Relationship, Drug; Gastrointestinal Agents; Humans; Morphinans; Narcotic Antagonists; Pain; Piperidines; Polyethylene Glycols; Receptors, Opioid, mu; Treatment Outcome
PubMed: 29119706
DOI: 10.1111/nmo.13250 -
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 -
BMJ Supportive & Palliative Care Sep 2020Opioid-induced constipation (OIC) is common and can significantly affect quality of life. Naloxegol and methylnaltrexone are peripherally acting µ-opioid receptor...
Opioid-induced constipation (OIC) is common and can significantly affect quality of life. Naloxegol and methylnaltrexone are peripherally acting µ-opioid receptor antagonists (PAMORAs) which are effective for the management of OIC. We report on a case in the palliative care setting where a patient with established OIC had an inadequate response to naloxegol but an effective and immediate response to methylnaltrexone at the dose recommended for her weight. This is the first reported case of two PAMORAs used concomitantly.
Topics: Analgesics, Opioid; Female; Humans; Middle Aged; Morphinans; Naltrexone; Narcotic Antagonists; Opioid-Induced Constipation; Palliative Care; Polyethylene Glycols; Quality of Life; Quaternary Ammonium Compounds
PubMed: 32709705
DOI: 10.1136/bmjspcare-2019-002172 -
Journal of Palliative Medicine Jul 2015Opioid-induced constipation (OIC) is common among children and adolescents and young adults (AYA) with progressive incurable cancer. Although methylnaltrexone is a...
BACKGROUND
Opioid-induced constipation (OIC) is common among children and adolescents and young adults (AYA) with progressive incurable cancer. Although methylnaltrexone is a successful treatment for OIC in adult cancer patients, no case series has established its safety and efficacy in pediatric cancer patients.
OBJECTIVES
The aim of the study was to describe the safety and efficacy of methylnaltrexone use for OIC in children and AYA with progressive incurable cancer at the end of life in the inpatient and outpatient settings.
METHODS
We conducted a retrospective review of medical records of children and AYA with progressive incurable cancer who received methylnaltrexone at our institution from May 2008 to June 2013. Pharmacy data were reviewed for each patient and a chart review was performed for documentation of laxation and side effects.
RESULTS
Of the 9 patients (age range: 17 months to 21 years) with progressive incurable cancer who developed OIC, 7 (78%) had laxation after methylnaltrexone administration (0.15 mg/kg/dose). Of these 7 patients, 5 (71%) had laxation with the first dose, and 5 (71%) who responded had a continued response to repeated doses. The longest a patient regularly received methylnaltrexone was 9 months. Of 5 patients with intraabdominal disease, 4 (80%) had laxation. There were no negative side effects in any of the patients. Also, there was no increase in pain either qualitatively or by pain score.
CONCLUSIONS
Methylnaltrexone appears to be safe and efficacious in treating OIC in children and AYA with progressive incurable cancer. Methylnaltrexone was tolerated in both the inpatient and outpatient settings and with repeated dosing.
Topics: Adolescent; Analgesics, Opioid; Child; Child, Preschool; Constipation; Double-Blind Method; Female; Humans; Infant; Male; Medical Audit; Naltrexone; Narcotic Antagonists; Neoplasms; Quaternary Ammonium Compounds; Retrospective Studies; Terminally Ill; Young Adult
PubMed: 25927665
DOI: 10.1089/jpm.2014.0364 -
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 -
The Journal of Pediatric Pharmacology... 2023Critically ill pediatric patients commonly experience opioid-induced dysmotility. Methylnaltrexone, a subcutaneously administered, peripherally acting mu-opioid receptor...
OBJECTIVE
Critically ill pediatric patients commonly experience opioid-induced dysmotility. Methylnaltrexone, a subcutaneously administered, peripherally acting mu-opioid receptor antagonist, is a compelling adjunct to enteral laxatives in patients with opioid-induced dysmotility. Data for methylnaltrexone use in critically ill pediatric patients are limited. The purpose of this study was to determine the effectiveness and safety of methylnaltrexone for opioid-induced dysmotility in critically ill infants and children.
METHODS
Patients younger than 18 years who received subcutaneous methylnaltrexone from January 1, 2013, through September 15, 2020, in the pediatric intensive care units at an academic institution were included in this retrospective analysis. Outcomes included incidence of bowel movement, enteral nutrition feeding volume, and adverse drug events.
RESULTS
Twenty-four patients, median age 3.5 years (IQR, 0.58-11.1), received 72 methylnaltrexone doses. The median dose was 0.15 mg/kg (IQR, 0.15-0.15). Patients were receiving a mean ± SD of 7.5 ± 4.5 mg/kg/day of oral morphine milligram equivalents (MMEs) at methylnaltrexone administration and received opioids for median 13 days (IQR, 8.8-21) prior to methylnaltrexone administration. A bowel movement occurred within 4 hours following 43 (60%) administrations and within 24 hours following 58 (81%) administrations. Enteral nutrition volume increased by 81% (p = 0.002) following administration. Three patients had emesis and 2 received anti-nausea medication. No significant changes in sedation or pain scores were observed. Withdrawal scores and daily oral MMEs decreased following administration (p = 0.008 and p = 0.002, respectively).
CONCLUSIONS
Methylnaltrexone may be an effective treatment for opioid-induced dysmotility in critically ill pediatric patients with low risk of adverse effects.
PubMed: 37139255
DOI: 10.5863/1551-6776-28.2.136 -
Journal of Pharmacy Practice Oct 2019Nationally, the prescription of opioids for acute and chronic pain is increasing. As opioid use continues to expand and become of increased concern for health-care... (Review)
Review
Nationally, the prescription of opioids for acute and chronic pain is increasing. As opioid use continues to expand and become of increased concern for health-care practitioners, so do the adverse effects and long-term management of those effects. Opioid-induced constipation (OIC) presents a unique challenge because tolerance does not develop to this particular adverse effect, making chronic pain management a delicate balance between relieving pain and preventing long-term adverse effects such as constipation and dependence. Several agents have been developed for the treatment of OIC in patients with chronic noncancer pain on the basis of short-term studies of 12 weeks or less. However, chronic pain management often extends beyond this 12-week boundary, resulting in health-care professionals questioning the safety and efficacy of continued treatment with OIC agents. This review evaluates available literature on long-term treatment of OIC in patients with chronic noncancer pain with lubiprostone, naloxegol, and methylnaltrexone as well as preliminary results of the recently completed naldemedine long-term trial, COMPOSE-3.
Topics: Analgesics, Opioid; Chloride Channel Agonists; Chronic Pain; Humans; Long-Term Care; Narcotic Antagonists; Opioid-Induced Constipation; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 29207909
DOI: 10.1177/0897190017745395 -
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 Medicine (Malden, Mass.) Dec 2015Aims of this consensus panel were to determine (1) an optimal symptom-based method for assessing opioid-induced constipation in clinical practice and (2) a threshold of... (Review)
Review
OBJECTIVE
Aims of this consensus panel were to determine (1) an optimal symptom-based method for assessing opioid-induced constipation in clinical practice and (2) a threshold of symptom severity to prompt consideration of prescription therapy.
METHODS
A multidisciplinary panel of 10 experts with extensive knowledge/experience with opioid-associated adverse events convened to discuss the literature on assessment methods used for opioid-induced constipation and reach consensus on each objective using the nominal group technique.
RESULTS
Five validated assessment tools were evaluated: the Patient Assessment of Constipation-Symptoms (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL), Stool Symptom Screener (SSS), Bowel Function Index (BFI), and Bowel Function Diary (BF-Diary). The 3-item BFI and 4-item SSS, both clinician administered, are the shortest tools. In published trials, the BFI and 12-item PAC-SYM are most commonly used. The 11-item BF-Diary is highly relevant in opioid-induced constipation and was developed and validated in accordance with US Food and Drug Administration guidelines. However, the panel believes that the complex scoring for this tool and the SSS, PAC-SYM, and 28-item PAC-QOL may be unfeasible for clinical practice. The BFI is psychometrically validated and responsive to changes in symptom severity; scores range from 0 to 100, with higher scores indicating greater severity and scores >28.8 points indicating constipation.
CONCLUSIONS
The BFI is a simple assessment tool with a validated threshold of clinically significant constipation. Prescription treatments for opioid-induced constipation should be considered for patients who have a BFI score of ≥30 points and an inadequate response to first-line interventions.
Topics: Analgesics, Opioid; Constipation; Drug Administration Schedule; Drug Prescriptions; Humans; Practice Guidelines as Topic; Surveys and Questionnaires; United States
PubMed: 26582720
DOI: 10.1111/pme.12937