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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 -
Journal of Cellular Physiology Nov 2021The Mu-opioid receptor (MOR) has been implicated in tumorigenesis and metastasis. Methylnaltrexone (MNTX), an antagonist of MOR, has shown to inhibit tumor growth and...
The Mu-opioid receptor (MOR) has been implicated in tumorigenesis and metastasis. Methylnaltrexone (MNTX), an antagonist of MOR, has shown to inhibit tumor growth and metastasis in lung cancer cell lines. The effect of MNTX on other cell lines such as head and neck squamous cell carcinoma (HNSCC) has not been investigated. We measured the expression and activity of the receptor in different HNSCC cell lines. Then, we evaluated the impact of modulating the expression MOR and the effect of MNTX on the proliferation, clonogenic activity, invasion, and migration of two HNSCC (FaDu and MDA686Tu) cell lines expressing MOR and one cell line (UMSCC47) not expressing the receptor. We also evaluated the impact of MNTX on tumor growth and metastasis formation in vivo. Activation of the receptor with [d-Ala2,N-Me-Phe4, Gly5-ol] (DAMGO) caused a significant reduction in cyclic adenosine monophosphate levels in FaDu cells. Knockdown of MOR inhibited in vitro aggressive cell behaviors on FaDu and MDA686Tu cells and correlated with a reduction in markers of epithelial-mesenchymal transition. In vitro studies showed that MNTX strongly inhibited the proliferation, clonogenic activity, invasion, and migration of FaDu and MDA686Tu cells but has no effect on UMSCC47 cells. In vivo experiments demonstrated that MNTX suppresses tumor growth in HNSCC cell tumor-bearing mice. Our studies indicate that MOR could be considered as a therapeutic target to treat HNSCC.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Head and Neck Neoplasms; Humans; Male; Mice, Inbred C57BL; Mice, Nude; Naltrexone; Narcotic Antagonists; Neoplasm Invasiveness; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Tumor Burden; Xenograft Model Antitumor Assays; Mice
PubMed: 34038587
DOI: 10.1002/jcp.30421 -
Journal of Pediatric Orthopedics Aug 2021Methylnaltrexone, a peripheral opioid antagonist, is used to decrease opioid-induced constipation; however, there is limited evidence for its use in children. The...
BACKGROUND
Methylnaltrexone, a peripheral opioid antagonist, is used to decrease opioid-induced constipation; however, there is limited evidence for its use in children. The primary objective of the study is to assess the efficacy of per os (PO) methylnaltrexone in inducing bowel movements (BMs) in patients with adolescent idiopathic scoliosis who underwent a posterior spinal fusion and instrumentation (PSFI). Secondary outcomes include hospital length of stay, postoperative pain scores, and postoperative opioid usage.
METHODS
Retrospective chart review identified all adolescent idiopathic scoliosis patients above 10 years of age who underwent PSFI with a minimum of 24 hours of postoperative opioid analgesia after the initiation of the new bowel regimen protocol. The bowel regimen included daily administration of PO methylnaltrexone starting on postoperative day 1 until BM is achieved. A case-matched cohort was obtained with patients who did not receive PO methylnaltrexone and otherwise had the same bowel function regimen. Case-matched controls were also matched for age, sex, body mass index, and curve severity. t Tests and Pearson χ2 tests were used for statistical analysis.
RESULTS
Fifty-two patients received oral methylnaltrexone (14±2.6 y) and 52 patients were included in the case-matched control group (14±2.1 y). The methylnaltrexone group had a significantly shorter hospital length of stay (3.09±0.66) compared with controls (3.69±0.80) (P<0.01). 59% (31 of 52) of the methylnaltrexone group had a BM by postoperative day postoperative day 2, compared with 30% (16 of 52) of the control group (P<0.01). In the methylnaltrexone group, 44% (23 of 52) of the patients required a Dulcolax (bisacodyl) suppository and 11% (6 of 52) required an enema, compared with 50% (26 of 52) and 33% (12 of 52) of the control group respectively (P=0.43 and 0.12). In addition, significantly less patients had abdominal distension during their postoperative stay in the methylnaltrexone group (17%, 9 of 52) compared with the control group (40%, 21 of 52) (P<0.01). There was no significant difference in self-reported average FACES pain score (P=0.39) or in opioid morphine equivalents required per hour (P=0.18).
CONCLUSIONS
Patients who received PO methylnaltrexone after PSFI had decreased length of stay and improved bowel function. Administration of methylnaltrexone did not increase maximum self-reported FACES pain values or opioid consumption compared with controls. The use of oral methylnaltrexone after PSFI reduces postoperative constipation, which has implications for reducing hospital length of stay and overall morbidity.
LEVEL OF EVIDENCE
Level III-retrospective comparative study.
PubMed: 34001807
DOI: 10.1097/BPO.0000000000001854 -
Drugs & Aging Jun 2021
PubMed: 33890230
DOI: 10.1007/s40266-021-00860-8 -
Journal of Palliative Medicine Aug 2021Opioid-induced constipation (OIC) remains the most common adverse event associated with opioid use. Treatment with more novel and costly agents (such as peripheral...
Opioid-induced constipation (OIC) remains the most common adverse event associated with opioid use. Treatment with more novel and costly agents (such as peripheral μ-opioid receptor antagonists [PAMORAs]) may be indicated in patients with laxative-refractory OIC. Three PAMORAs are U.S. Food and Drug Administration approved for managing OIC-methylnaltrexone (FDA approved in 2008), naloxegol (in 2014), and naldemedine (in 2017). These drugs are indicated only in limited scenarios. Their contemporary patterns of use and burden of spending remain unknown. To evaluate the trends in use and expenditures for the three PAMORAs approved for treating OIC. Retrospective cross-sectional study using the 2014-2018 Medicare Part D Prescription Drug Event data and the 2018 Part D Prescriber Public Use File. Prescribers and beneficiaries using PAMORAs. The annual spending, number of beneficiaries, number of claims, and spending per beneficiary and claim for each PAMORA. The distribution by prescriber specialty using PAMORA. From 2014 to 2018, aggregate spending on PAMORAs increased, from $13.6 to $150.9 million, and use increased, from 4221 to 72,592 beneficiaries. After FDA approval in 2014, naloxegol overtook methylnaltrexone in the number of users in 2015 and spending in 2016. In 2018, 6989 unique prescribers used any PAMORA. Among them, the most common specialties/professions were family practice (20.2%), internal medicine (18.0%), and nurse practitioner (15.4%). Our findings-significant and increasing expenditure on PAMORAs, and broad use across specialties-serve as a call for defining and implementing appropriate use of PAMORAs.
Topics: Aged; Analgesics, Opioid; Constipation; Cross-Sectional Studies; Humans; Medicare; Narcotic Antagonists; Opioid-Induced Constipation; Receptors, Opioid, mu; Retrospective Studies; United States
PubMed: 33872062
DOI: 10.1089/jpm.2021.0021 -
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