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Advances in Therapy Jul 2021The prescribing and use of opioid analgesics is increasing in Italy owing to a profusion in the number and types of opioid analgesic products available, and the... (Review)
Review
The prescribing and use of opioid analgesics is increasing in Italy owing to a profusion in the number and types of opioid analgesic products available, and the increasing prevalence of conditions associated with severe pain, the latter being related to population aging. Herein we provide the expert opinion of an Italian multidisciplinary panel on the management of opioid-induced constipation (OIC) and bowel dysfunction. OIC and opioid-induced bowel dysfunction are well-recognised unwanted effects of treatment with opioid analgesics that can profoundly affect quality of life. OIC can be due to additional factors such as reduced mobility, a low-fibre diet, comorbidities, and concomitant medications. Fixed-dose combinations of opioids with mu (μ) opioid receptor antagonists, such as oxycodone/naloxone, have become available, but have limited utility in clinical practice because the individual components cannot be independently titrated, creating a risk of breakthrough pain as the dose is increased. A comprehensive prevention and management strategy for OIC should include interventions that aim to improve fibre and fluid intake, increase mobility or exercise, and restore bowel function without compromising pain control. Recommended first-line pharmacological treatment of OIC is with an osmotic laxative (preferably polyethylene glycol [macrogol]), or a stimulant laxative such as an anthraquinone. A second laxative with a complementary mechanism of action should be added in the event of an inadequate response. Second-line treatment with a peripherally acting μ opioid receptor antagonist (PAMORA), such as methylnaltrexone, naloxegol or naldemedine, should be considered in patients with OIC that has not responded to combination laxative treatment. Prokinetics or intestinal secretagogues, such as lubiprostone, may be appropriate in the third-line setting, but their use in OIC is off-label in Italy, and should therefore be restricted to settings such as specialist centres and clinical trials.
Topics: Analgesics, Opioid; Constipation; Expert Testimony; Humans; Italy; Narcotic Antagonists; Opioid-Induced Constipation; Quality of Life; Receptors, Opioid, mu
PubMed: 34086265
DOI: 10.1007/s12325-021-01766-y -
Drugs & Aging Jun 2021
PubMed: 33890230
DOI: 10.1007/s40266-021-00860-8 -
Cureus Apr 2021The present study discusses opioid-induced constipation (OIC) in advanced cancer patients, focusing on the OIC definition, pathophysiology, and treatment. OIC is any... (Review)
Review
The present study discusses opioid-induced constipation (OIC) in advanced cancer patients, focusing on the OIC definition, pathophysiology, and treatment. OIC is any change from baseline defecation patterns and bowel habits that developed after starting opioid therapy. The condition is characterized by bowel frequency reduction, worsening or development of straining, a sensation of incomplete defecation, or distress associated with bowel habits. OIC is common in advanced cancer patients, with a prevalence of approximately 51%-87% in patients taking opioids for pain management. Patients are likely to experience severe distress, work productivity reduction, poor quality of life, and increased healthcare utilization. OIC has a complex pathophysiology that involves propulsive and peristalsis impairment, intestinal mucosal secretion inhibition, intestinal fluid absorption enhancement, and anal sphincters function impairment. The Rome III criteria are used to assess and diagnose clinical OIC and can also be diagnosed through the Patient Assessment of Constipation (PAC) measures, including the symptom survey (PAC-SYM) and quality of life survey (PAC-QOL). Non-pharmacological treatment of OIC involves lifestyle habits and dietary adjustments, although these interventions might be insufficient to manage the condition. Pharmacological treatments involve the use of traditional laxatives and newer agents like peripherally acting mu-opioid receptor agonists (PAMORAs), including naldemedine, naloxegol, and methylnaltrexone. More novel treatments for OIC that target the pathophysiology are still needed and should be studied carefully for safety and efficacy.
PubMed: 33850679
DOI: 10.7759/cureus.14386 -
Drugs & Aging Jun 2021Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist approved for the treatment of opioid-induced constipation (OIC), has restricted diffusion across... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist approved for the treatment of opioid-induced constipation (OIC), has restricted diffusion across the blood-brain barrier (BBB) and has not been demonstrated to impact opioid-induced central analgesia. Age-related changes in BBB permeability may compromise methylnaltrexone's restricted diffusion and alter opioid-induced central analgesic effects.
OBJECTIVE
This analysis evaluated whether opioid analgesia is compromised in older adults receiving methylnaltrexone for OIC.
METHODS
The analysis included adults diagnosed with OIC who received opioids for pain management and who had a terminal illness or chronic nonmalignant pain. Data were pooled from four randomized, double-blind trials and stratified by age (< 65 years and ≥ 65 years). Endpoints included pain intensity scores, symptoms of opioid withdrawal, treatment-related adverse events (TRAEs), and rescue-free laxation (RFL) within 4 h of treatment.
RESULTS
Overall, 1323 patients were < 65 years of age (n = 908, methylnaltrexone; n = 415, placebo) and 304 patients were ≥ 65 years of age (n = 171, methylnaltrexone; n = 133, placebo). Nonsignificant pain intensity score reductions were observed in all groups. In the older cohort, measures of opioid withdrawal did not show statistical differences from baseline in either the methylnaltrexone or placebo groups. The most frequently reported TRAEs were abdominal pain, flatulence, and nausea. Relative to the first dose, gastrointestinal TRAEs potentially related to opioid withdrawal declined with the second dose and were comparable with placebo, regardless of age. RFL response within 4 h of methylnaltrexone treatment increased significantly in both age cohorts relative to placebo.
CONCLUSIONS
Methylnaltrexone use did not adversely affect pain control, opioid withdrawal effects, or AEs while providing effective RFL, regardless of age. These results suggest that age does not appear to influence the safety and efficacy of methylnaltrexone for OIC. Further research is needed to assess the impact of other factors that alter BBB permeability, such as dementia, stroke, or drug interactions, on the safety and efficacy of methylnaltrexone.
CLINICAL TRIAL REGISTRATION NUMBERS
Study 302, NCT00402038; study 3200K1-4000, NCT00672477; study 3200K1-3356, NCT00529087; study 3201, NCT01186770.
Topics: Age Factors; Aged; Analgesics, Opioid; Constipation; Humans; Naltrexone; Opioid-Induced Constipation; Quaternary Ammonium Compounds; Treatment Outcome
PubMed: 33788162
DOI: 10.1007/s40266-021-00850-w -
Supportive Care in Cancer : Official... Sep 2021Peripherally acting μ-opioid receptor antagonists such as methylnaltrexone (MNTX, Relistor) are indicated for the treatment of opioid-induced constipation (OIC). The... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Peripherally acting μ-opioid receptor antagonists such as methylnaltrexone (MNTX, Relistor) are indicated for the treatment of opioid-induced constipation (OIC). The structural properties unique to MNTX restrict it from traversing the blood-brain barrier (BBB); however, the BBB may become more permeable in patients with brain metastases. We investigated whether the presence of brain metastases in cancer patients compromises the central effects of opioids among patients receiving MNTX for OIC.
METHODS
This post hoc analysis of pooled data from 3 randomized, placebo-controlled trials included cancer patients with OIC who received MNTX or placebo. Endpoints included changes from baseline in pain scores, rescue-free laxation (RFL) within 4 or 24 h of the first dose, and treatment-emergent adverse events (TEAEs), including those potentially related to opioid withdrawal symptoms.
RESULTS
Among 356 cancer patients in the pooled population, 47 (MNTX n = 27; placebo n = 20) had brain metastases and 309 (MNTX n = 172; placebo n = 137) did not have brain metastases. No significant differences in current pain, worst pain, or change in pain scores from baseline were observed between patients treated with MNTX or placebo. Among patients with brain metastases, a significantly greater proportion of patients who received MNTX versus placebo achieved an RFL within 4 h after the first dose (70.4% vs 15.0%, respectively, p = 0.0002). TEAEs were similar between treatment groups and were generally gastrointestinal in nature and not related to opioid withdrawal.
CONCLUSION
Focal disruptions of the BBB caused by brain metastases did not appear to alter central nervous system penetrance of MNTX.
Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Brain Neoplasms; Central Nervous System; Constipation; Double-Blind Method; Female; Humans; Male; Middle Aged; Naltrexone; Quaternary Ammonium Compounds
PubMed: 33629189
DOI: 10.1007/s00520-021-06070-7 -
Pain and Therapy Jun 2021Opioid-induced constipation (OIC) is a distressing side effect during opioid analgesia and is mainly mediated by gastrointestinal μ-opioid receptors. Methylnaltrexone,... (Review)
Review
INTRODUCTION
Opioid-induced constipation (OIC) is a distressing side effect during opioid analgesia and is mainly mediated by gastrointestinal μ-opioid receptors. Methylnaltrexone, a peripheral μ-opioid receptor antagonist with restricted ability to cross the blood-brain barrier, may alleviate OIC without reversing analgesia. We performed a meta-analysis to assess the efficacy and safety of methylnaltrexone for the treatment of OIC.
METHODS
This meta-analysis was registered in PROSPERO (CRD42020187290). We searched PubMed, Embase, and Cochrane Library for randomized controlled trials that compared methylnaltrexone with placebo for the treatment of OIC. Relative risks (RR) and 95% confidence interval (CI) were pooled using a random-effects model. We used the GRADE approach to assess the certainty of the evidence.
RESULTS
Eight trials with 2034 participants were included. Compared with placebo, methylnaltrexone significantly increased rescue-free bowel movement (RFBM) within 4 h after the first dose (eight trials; 1833 participants; RR 3.74, 95% CI 3.02-4.62; high-certainty evidence), RFBM within 24 h after the first dose (two trials; 614 participants; RR 1.98, 95% CI 1.52-2.58; moderate-certainty evidence), and RFBM ≥ 3 times per week (three trials; 1,396 participants; RR 1.33, 95% CI 1.17-1.52; moderate-certainty evidence) and decreased need to take rescue laxatives (three trials; 807 participants; RR 0.73, 95% CI 0.63-0.85; moderate-certainty evidence). For safety outcomes, there was no difference in any adverse events between the two groups (eight trials; 2034 participants; RR 1.11, 95% CI 0.99-1.23; moderate-certainty evidence), including diarrhea, nausea, vomiting, and flatulence; but for the most commonly reported adverse events, the abdominal pain was higher in methylnaltrexone group than that in placebo group (six trials; 1813 participants; RR 2.30, 95% CI 1.29-4.08; moderate-certainty evidence).
CONCLUSION
Methylnaltrexone is an effective and safe drug for the treatment of OIC, but the safety of abdominal pain should be considered.
PubMed: 33575953
DOI: 10.1007/s40122-021-00237-0 -
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 -
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 -
Psychopharmacology Bulletin Jul 2020Opioid medications are a pillar of acute and chronic analgesia, though their use is often accompanied by side-effects, such as opioid-induced constipation.... (Review)
Review
PURPOSE OF REVIEW
Opioid medications are a pillar of acute and chronic analgesia, though their use is often accompanied by side-effects, such as opioid-induced constipation. Unfortunately, tolerance rarely develops to this untoward side effect. This review presents the background, evidence, and indications for the use of Naldemedine (Brand name Symproic 0.2 mg tablets) to treat opioid-induced constipation.
RECENT FINDINGS
Opioids are often used for the treatment of acute and chronic analgesia. Outside of the central effect they exert, they also interact with peripheral receptors, resulting in opioid-induced constipation, the commonest of side effects of chronic opioid usage. Complications include colonic distention, ileus, perforation, and can progress to other serious bowel complications, which can result in hospitalization and fatal events.For the most part, laxatives and other anti-constipation therapies are often inefficient and require intervention directed at the root cause, such as peripheral mu receptor agonists, including methylnaltrexone, naloxegol, and naldemedine. Naldemedine is the most recent to gain FDA approval of the group.An antagonist of Mu, Kappa, and Delta peripheral receptors, Naldemedine, is the only drug to counteract all three receptor classes. It was shown to be both safe and effective when compared with placebo. No data exists to compare its efficacy to that of other members of the group.
SUMMARY
Opioids are frequently used in the management of acute and chronic pain. The most common of the side effects is opioid-induced constipation, secondary to the peripheral activity of opioids. Naldemedine is an FDA-approved, once-daily oral tablet that counteracts this side effect by antagonizing mu, kappa, and delta-opioid receptors and has been shown to be safe and effective. Further investigation including head-to-head clinical trials are required to evaluate the relative efficacy of naldemedine compare with other peripheral opiate receptor antagonists.
Topics: Analgesics, Opioid; Constipation; Humans; Naltrexone; Narcotic Antagonists; Opioid-Induced Constipation
PubMed: 32733114
DOI: No ID Found -
The Clinical Journal of Pain Sep 2020The objective of this study was to provide an overview of opioid-induced constipation (OIC) and its influence on disease burden and quality of life (QOL). (Review)
Review
Opioid-induced Constipation: A Review of Health-related Quality of Life, Patient Burden, Practical Clinical Considerations, and the Impact of Peripherally Acting μ-Opioid Receptor Antagonists.
OBJECTIVE
The objective of this study was to provide an overview of opioid-induced constipation (OIC) and its influence on disease burden and quality of life (QOL).
METHODS
This is a narrative review.
RESULTS
For many patients, opioid-related side effects, the most common being OIC, have the potential to significantly impair patients' QOL. Patients with OIC often experience substantial overall burden (ie, increases in anxiety and depression, impairments in activities of daily living, low self-esteem, feelings of embarrassment) and economic burden (ie, higher health care costs, more frequent doctor visits, increased out-of-pocket medication costs), which often causes patients to modify or discontinue opioid treatment despite the analgesic benefits. OIC occurs when opioids bind to peripheral μ-opioid receptors in the gastrointestinal tract. Currently, 4 Food and Drug Administration (FDA)-approved medications are available for OIC, 3 of which are peripherally acting µ-opioid receptor antagonists (PAMORAs). PAMORAs block µ-opioid receptors in the gastrointestinal tract without affecting the central analgesic effects of the opioid and thus provide a targeted approach to OIC management. Two PAMORAs, naldemedine and methylnaltrexone, have shown significant improvements in QOL based on the Patient Assessment of Constipation Symptoms questionnaire relative to placebo. Along with pharmacologic management for OIC, health care providers should institute comprehensive communication strategies with patients to ensure OIC is effectively recognized and managed.
DISCUSSION
OIC has both physical and psychological impacts on patients. PAMORAs provide effective relief of OIC while also improving QOL. To augment the pharmacologic management of OIC, proactive counseling approaches between physicians and patients may help relieve some of the patient burden associated with OIC and lead to improved outcomes.
Topics: Activities of Daily Living; Analgesics, Opioid; Humans; Narcotic Antagonists; Opioid-Induced Constipation; Quality of Life
PubMed: 32554978
DOI: 10.1097/AJP.0000000000000852