Efficacy and safety of naldemedine for opioid-induced constipation in older patients with cancer: a retrospective study.

BACKGROUND: Opioids are pain relievers that are often associated with opioid-induced constipation (OIC) that worsens with age. We performed a multicenter, retrospective analysis on the efficacy and safety of naldemedine, an opioid receptor antagonist, in treating OIC in patients with cancer (age >75 years). METHODS: The electronic medical records of cancer patients who received naldemedine at 10 Japanese institutions between 7 June 2017 and August 31, 2019, were retrieved. Patients aged ≥75 years who were treated with naldemedine for the first time and hospitalized for at least 7 days before and after initiating naldemedine therapy were included in this analysis. RESULTS: Sixty patients were observed for at least 7 days before and after starting naldemedine. The response rate was 68.3%, and the frequency of bowel movements increased significantly after naldemedine administration in the overall population ( P  < 0.0001) and among those who defecated <3 times/week before naldemedine administration ( P  < 0.0001). Diarrhea was the most frequent adverse event in all grades, observed in 45% of patients, of which 92.6% were Grade 1 or 2. Grade 4 or higher adverse events, including death, were not observed. CONCLUSION: Naldemedine exhibits significant efficacy and safety in OIC treatment in older patients with cancer.

Pharmacological prevention and treatment of opioid-induced constipation in cancer patients: A systematic review and meta-analysis.

BACKGROUND: Cancer-related pain often requires opioid treatment with opioid-induced constipation (OIC) as its most frequent gastrointestinal side-effect. Both for prevention and treatment of OIC osmotic (e.g. polyethylene glycol) and stimulant (e.g. bisacodyl) laxatives are widely used. Newer drugs such as the peripherally acting µ-opioid receptor antagonists (PAMORAs) and naloxone in a fixed combination with oxycodone have become available for the management of OIC. This systematic review and meta-analysis aims to give an overview of the scientific evidence on pharmacological strategies for the prevention and treatment of OIC in cancer patients. METHODS: A systematic search in PubMed, Embase, Web of Science and the Cochrane Library was completed from inception up to 22 October 2022. Randomized and non-randomized studies were systematically selected. Bowel function and adverse drug events were assessed. RESULTS: Twenty trials (prevention: five RCTs and three cohort studies; treatment: ten RCTs and two comparative cohort studies) were included in the review. Regarding the prevention of OIC, three RCTs compared laxatives with other laxatives, finding no clear differences in effectivity of the laxatives used. One cohort study showed a significant benefit of magnesium oxide compared with no laxative. One RCT found a significant benefit for the PAMORA naldemedine compared with magnesium oxide. Preventive use of oxycodone/naloxone did not show a significant difference in two out of three other studies compared to oxycodone or fentanyl. A meta-analysis was not possible. Regarding the treatment of OIC, two RCTs compared laxatives, of which one RCT found that polyethylene glycol was significantly more effective than sennosides. Seven studies compared an opioid antagonist (naloxone, methylnaltrexone or naldemedine) with placebo and three studies compared different dosages of opioid antagonists. These studies with opioid antagonists were used for the meta-analysis. Oxycodone/naloxone showed a significant improvement in Bowel Function Index compared to oxycodone with laxatives (MD -13.68; 95 % CI -18.38 to -8.98; I2 = 58 %). Adverse drug event rates were similar amongst both groups, except for nausea in favour of oxycodone/naloxone (RR 0.51; 95 % CI 0.31-0.83; I2 = 0 %). Naldemedine (NAL) and methylnaltrexone (MNTX) demonstrated significantly higher response rates compared to placebo (NAL: RR 2.07, 95 % CI 1.64-2.61, I2 = 0 %; MNTX: RR 3.83, 95 % CI 2.81-5.22, I2 = 0 %). With regard to adverse events, abdominal pain was more present in treatment with methylnaltrexone and diarrhea was significantly more present in treatment with naldemedine. Different dosages of methylnaltrexone were not significantly different with regard to both efficacy and adverse drug event rates. CONCLUSIONS: Magnesium oxide and naldemedine are most likely effective for prevention of OIC in cancer patients. Naloxone in a fixed combination with oxycodone, naldemedine and methylnaltrexone effectively treat OIC in cancer patients with acceptable adverse events. However, their effect has not been compared to standard (osmotic and stimulant) laxatives. More studies comparing standard laxatives with each other and with opioid antagonists are necessary before recommendations for clinical practice can be made.

Impacts of genetic polymorphisms and cancer cachexia on naldemedine pharmacokinetics and bowel movements in patients receiving opioid analgesics.

BACKGROUND/OBJECTIVES: Clinical responses to naldemedine vary between individuals with advanced cancer. This is a prospective, single-center, observational study aimed to evaluate the influence of genetic polymorphisms and cachexia status on plasma naldemedine and clinical responses. METHODS: Forty-eight patients being treated with naldemedine for opioid-induced constipation under treatment of cancer pain were enrolled. Plasma naldemedine concentrations were determined on the fourth day or later after administration of naldemedine, and the associations with genotypes, cachexia status, and clinical responses were assessed. RESULTS: Cancer patients exhibited a large variation in the plasma naldemedine concentrations, and it was correlated with serum total protein level. Patients who were homozygous CYP3A5*3 had a higher plasma concentration of naldemedine than those with the *1 allele. ABCB1 genotypes tested in this study were not associated with plasma naldemedine. A negative correlation was observed between the plasma naldemedine concentration and 4ß-hydroxycholesterol level. The plasma naldemedine concentration was lower in patients with refractory cachexia than in those with precachexia and cachexia. While serum levels of interleukin-6 (IL-6) and acute-phase proteins were higher in patients with refractory cachexia, they were not associated with plasma naldemedine. A higher plasma concentration of naldemedine, CYP3A5*3/*3, and an earlier naldemedine administration after starting opioid analgesics were related to improvement of bowel movements. CONCLUSION: Plasma naldemedine increased under deficient activity of CYP3A5 in cancer patients. Cachectic patients with a higher serum IL-6 had a lower plasma naldemedine. Plasma naldemedine, related to CYP3A5 genotype, and the initiation timing of naldemedine were associated with improved bowel movements.

The P2Y1 receptor in the colonic myenteric plexus of rats and its correlation with opioid-induced constipation.

This study was designed to explore the expression changes of P2Y1 receptors in the distal colonic myenteric layer of rats. An opioid induced constipation(OIC) rat model was generated by intraperitoneal (i.p) injection of loperamide. At 7 days post-treatment, the model rats were assessed by calculating the fecal water content and the gastrointestinal transit ratio. The immunofluorescence (IF)-based histochemical study was used to observe the distribution of P2Y1 receptors in the distal colonic myenteric plexus. Western blotting (WB) was performed to evaluate the expression changes of P2Y1 proteins in the myenteric layer, and the electrophysiological approaches were carried out to determine the regulatory roles of P2Y1 receptors on distal colonic motor function. IF showed that P2Y1 receptors are co-expressed MOR in the enteric nerve cells of the distal colonic myenteric plexus. Moreover, the WB revealed that the protein levels of P2Y1 were significantly decreased in the distal colonic myenteric layer of OIC rats. In vitro tension experiments exhibited that the P2Y1 receptor antagonist MRS2500 enhanced the spontaneous contraction amplitude, adding EM2 and ß-FNA did not have any effect on MRS2500. Therefore, P2Y1 receptor expression could be associated with the occurrence of OIC in this rat model and the regulation of colonic motility by MOR may be related to the release of purine neurotransmitters such as ATP in the colonic nervous system.

Naldemedine is associated with earlier defecation in critically ill patients with opioid-induced constipation: A retrospective, single-center cohort study.

INTRODUCTION: There are few reports describing the association of naldemedine with defecation in critically ill patients with opioid-induced constipation. The purpose of this study was to determine whether naldemedine is associated with earlier defecation in critically ill patients with opioid-induced constipation. METHODS: In this retrospective cohort study, patients admitted to the Intensive Care Unit (ICU) without defecation for 48 hours while receiving opioids were eligible for enrollment. The primary endpoint was the time of the first defecation within 96 hours after inclusion. Secondary endpoints included presence of diarrhea, duration of mechanical ventilation, ICU length of stay, ICU mortality, and in-hospital mortality. The Cox proportional hazard regression analysis with time-dependent covariates was used to evaluate the association naldemedine with earlier defecation. RESULTS: A total of 875 patients were enrolled and were divided into 63 patients treated with naldemedine and 812 patients not treated. Defecation was observed in 58.7% of the naldemedine group and 48.8% of the no-naldemedine group during the study (p = 0.150). The naldemedine group had statistically significantly prolonged duration of mechanical ventilation (8.7 days vs 5.5 days, p < 0.001) and ICU length of stay (11.8 days vs 9.2 days, p = 0.001) compared to the no-naldemedine group. However, the administration of naldemedine was significantly associated with earlier defecation [hazard ratio:2.53; 95% confidence interval: 1.71-3.75, p < 0.001]. CONCLUSION: The present study shows that naldemedine is associated with earlier defecation in critically ill patients with opioid-induced constipation.

The Management of Opioid-Induced Constipation in Cancer and Advanced Illness: A Meta-Analysis.

CONTEXT: Constipation is a common problem among patients with cancer. By some accounts, about 60% of cancer patients experience constipation. There is limited empirical evidence of the clinical effectiveness of pharmacologic agents in opioid-induced constipation in advanced diseases. OBJECTIVES: We sought to quantitatively summarize the therapeutic effectiveness of the pharmacologic means of managing opioid-induced constipation. METHODS: Randomized control trials (RCTs) identified from medical literature databases that reported quantitative measures of the effect of pharmacotherapeutic agents to treat opioid induced constipation in patients with cancers and other advanced illnesses were included in this study. A conventional random effects meta-analysis was conducted including >3 trials with the same exposure and outcome assessed, and a network-meta-analysis was conducted for all placebo-controlled trials. RESULTS: Eighteen studies that examined the effect of various pharmacotherapeutic agents were included. The medications were Methylnatrexone (N = 5), Naldemedine (N = 5), other conventional agents (N = 4) and herbal medicines (N = 4). In conventional meta-analysis, methylnaltrexone increased the proportion achieving rescue-free laxation by 2.68 fold (95% CI: 1.34, 5.37; P = 0.0054) within 4 hours of the administration compared to placebo. In network meta-analysis, the pooled RR of the pharmacotherapeutic agents on rescue-free bowel movements as 2.26 (95% CI: 1.52, 3.36) for methylnaltrexone, 1.58 (95% CI: 0.94, 2.66) for naldemedine, and 0.74 (95% CI: 0.45, 1.23) for polyethylene glycol, compared to placebo. CONCLUSION: Methylnatrexone and Naldemedine have currently shown promise in randomized trials concerning opioid-induced constipation in cancer and advanced illness. It is imperative that future research ascertain not just the relative therapeutic efficacy but also the cost-benefit analyses of these newer regimens with more commonly used and accessible laxatives.

The safety and efficacy of methylnaltrexone in pediatric oncology patients: A single center experience.

INTRODUCTION: Peripherally acting µ-opioid receptor antagonists (PAMORAs) are used in the treatment of opioid induced constipation without impacting the actions of opioid analgesics. Subcutaneous methylnaltrexone was one of the first PAMORAs approved in April 2008 for the treatment of opioid induced constipation in adult patients. The safety and effectiveness of methylnaltrexone has not been established in pediatric patients. In this study, the use of subcutaneous methylnaltrexone in pediatric patients is analyzed and reviewed. The primary outcome is occurrence of a bowel movement within 24 h after methylnaltrexone (MNTX) administration and the number of bowel movements following treatment with methylnaltrexone. Secondary outcomes include safety in this patient cohort. METHODS: This is a retrospective study of 79 pediatric patients with opioid induced constipation. Patients were administered methylnaltrexone during their inpatient stay. Data on bowel activity after methylnaltrexone was obtained from the hospital information system. RESULTS: Out of the 79 patients who received methylnaltrexone, there were seven patients from whom data could not be analyzed. Of the 72 patients whose data was available, 38% (N = 27) were documented as having a bowel movement, 62% (N = 45) did not have a bowel movement. Reported adverse events were minimal with nausea (N = 3), vomiting (N = 1), and flatulence (N = 6). CONCLUSION: Methylnaltrexone appears safe in the pediatric population and produces bowel movements in more than a third of pediatric patients. It is a feasible and safe option for opioid induced constipation in pediatric patients.

Metabolites 13,14-Dihydro-15-keto-PGE2 Participates in Bifidobacterium animalis F1-7 to Alleviate Opioid-Induced Constipation by 5-HT Pathway.

SCOPE: People suffer from constipation caused by many factors, including constipation (Opioid-Induced Constipation, OIC) during analgesic treatment. Microorganisms may be a potent solution to this problem, but the mechanism is still unclear. METHODS AND RESULTS: Based on models in vivo and in vitro, the potential mechanism involving Bifidobacterium animalis F1-7 (B. animalis F1-7), screened in the previous studies, is explored through non-targeted metabonomics, electrophysiological experiment and molecular level docking. The results showed that B. animalis F1-7 effectively alleviates OIC and promotes the expression of chromogranin A (CGA) and 5-hydroxytryptamine (5-HT). The metabolite 13,14-dihydro-15-keto-PGE2 related to B. animalis F1-7 is found, which has a potential improvement effect on OIC at 20 mg kg BW-1 in vivo. At 30 ng mL-1 it effectively stimulates secretion of CGA/5-HT (408.95 ± 1.18 ng mL-1 ) by PC-12 cells and changes the membrane potential potassium ion current without affecting the sodium ion current in vitro. It upregulates the target of free fatty acid receptor-4 protein(FFAR4/ß-actin, 0.81 ± 0.02). CONCLUSION: The results demonstrate that metabolite 13,14-dihydro-15-keto-PGE2 participated in B. animalis F1-7 to alleviate OIC via the 5-HT pathway.

Incidence of opioid-induced constipation in the pediatric intensive care unit: A descriptive cohort study.

BACKGROUND: Opioid-induced constipation (OIC) is a well-known phenomenon, although there is limited literature evaluating the incidence of OIC in children admitted to the pediatric intensive care unit (PICU). The primary aim of this study was to determine the incidence of OIC in the PICU and to determine if it is associated with a higher rate of morbidities or prolonged length of stay (LOS). METHODS: We conducted a single-center retrospective chart review from July 1, 2014, to June 30, 2015, in our PICU. We included all patients aged ≤18 years with a PICU stay of ≥96 h who received opioids during their admission. Data were collected on the frequency of bowel movements and characteristics of opioid administration. Demographic and clinical data were obtained from Virtual Pediatric Systems, LLC. RESULTS: Of the 94 patients who met the study criteria, 39.4% developed constipation. These patients tended to be older (P = 0.06) and were noted to weigh more (P = 0.03). There was no significant difference in the total or median daily doses, duration of opioid treatment, or mode of administration. Constipation rates did not differ by the severity of illness. There was a higher incidence of constipation in the patients who were admitted for neurological issues or after trauma or abdominal surgery (P = 0.002). Patients with constipation had a longer LOS than patients without constipation, but the difference was not statistically significant. CONCLUSION: These results indicate that opioid use is not the sole risk factor for constipation in the PICU setting.

Insights into the Current and Possible Future Use of Opioid Antagonists in Relation to Opioid-Induced Constipation and Dysbiosis.

Opioid receptor agonists, particularly those that activate µ-opioid receptors (MORs), are essential analgesic agents for acute or chronic mild to severe pain treatment. However, their use has raised concerns including, among others, intestinal dysbiosis. In addition, growing data on constipation-evoked intestinal dysbiosis have been reported. Opioid-induced constipation (OIC) creates an obstacle to continuing treatment with opioid analgesics. When non-opioid therapies fail to overcome the OIC, opioid antagonists with peripheral, fast first-pass metabolism, and gastrointestinal localized effects remain the drug of choice for OIC, which are discussed here. At first glance, their use seems to only be restricted to constipation, however, recent data on OIC-related dysbiosis and its contribution to the appearance of several opioid side effects has garnered a great of attention from researchers. Peripheral MORs have also been considered as a future target for opioid analgesics with limited central side effects. The properties of MOR antagonists counteracting OIC, and with limited influence on central and possibly peripheral MOR-mediated antinociception, will be highlighted. A new concept is also proposed for developing gut-selective MOR antagonists to treat or restore OIC while keeping peripheral antinociception unaffected. The impact of opioid antagonists on OIC in relation to changes in the gut microbiome is included.

A Retrospective Observational Study of Factors Affecting the Efficacy of Concurrent Prescription of Naldemedine for Opioid-Induced Constipation Caused by Oxycodone Tablets.

Naldemedine is indicated for the treatment of opioid-induced constipation (OIC), but reports on its efficacy in preventing OIC are few. Therefore, we retrospectively investigated factors affecting the efficacy of concurrent prescription of naldemedine on OIC. Outpatients with cancer who were started on oxycodone 10 mg/d were included in the study. The eligible patients were classified by their physicians into the following three groups: Group A used regular laxatives before the introduction of oxycodone and initiated naldemedine treatment simultaneously with oxycodone administration, Group B did not take laxatives before the introduction of oxycodone and started naldemedine simultaneously with oxycodone administration, and Group C had been administering regular laxatives before the introduction of oxycodone and were not prescribed naldemedine simultaneously with oxycodone treatment. The Support Team Assessment Schedule Japanese edition score for constipation, frequency of defecation, Bristol Stool Form Scale, sense of incomplete rectal evacuation, and development or worsening of straining to pass bowel movements were compared among the three groups before and after oxycodone administration. In Group B, there was significant worsening of the four parameters except for the sense of incomplete rectal evacuation, whereas Groups A and C did not present any changes. In logistic regression analysis, body weight ≥51.8 kg was a factor significantly decreasing the preventive effect of naldemedine on OIC, and regular use of laxatives was a factor significantly increasing the preventive effect of naldemedine on OIC. Thus, the initiation of naldemedine should be considered depending on the body weight and regular laxative use.

Overcoming barriers to opioid-induced constipation management in cancer patients.

PURPOSE: Opioid-induced constipation (OIC) is a common adverse effect of opioid therapy. We aim to identify the main barriers hindering clinical recommendations implementation and propose consensus solutions to improve OIC control in cancer patients. METHODS: Following collaborative and prioritization techniques, a scientific committee generated statements addressing possible barriers to optimal OIC management (related to patients, health providers and health care system), and potential interventions to overcome these barriers. An expert panel of 36 oncologists assessed the statements to reach a consensus. RESULTS: The survey consisted of 70 statements. Consensus was reached on 12/45 items related to barriers (26.6%) and on 19/25 items about corrective interventions (76%). The panel considered that patients are unaware of the existence of a specific OIC treatment, and their information sources are highly variable and unreliable. Regarding health providers, the panel considered that the oncologists prioritize symptoms such as diarrhea, pain, anxiety, or other treatment toxicities, over constipation. Work overload and bureaucratic requirements were the main barriers related to health care system. Regarding potential interventions, best-rated proposals included specific training programs development for primary care physicians and nurses, and multiplatform informative resources development for patients and caregivers, including precisely written instructions about OIC recognition and management. Oncologists assessed positively measures aiming to improve coordination between primary care physicians and oncologists, and nursing consultations implementation. The panel considered useful the OIC treatment algorithms simplification. CONCLUSIONS: The expert panel identified the main barriers to optimal OIC management and suggested some feasible approaches to overcome these barriers.

Peripherally-active mu-opioid receptor antagonists for constipation in critically ill patients receiving opioids: A case-series and a systematic review and meta-analysis of the literature.

BACKGROUND: Constipation is frequent in critically ill patients, and potentially related to adverse outcomes. Peripherally-active mu-opioid receptor antagonists (PAMORAs) are approved for opioid-induced constipation, but information on their efficacy and safety in critically ill patients is limited. We present a single-center, retrospective, case-series of the use of naldemedine for opioid-associated constipation, and we systematically reviewed the use of PAMORAs in critically ill patients. METHODS: Case-series included consecutive mechanically-ventilated patients; constipation was defined as absence of bowel movements for >3 days. Naldemedine was administered after failure of the local laxation protocol. Systematic review: PubMed was searched for studies of PAMORAs to treat opioid-induced constipation in adult critically ill patients. PRIMARY OUTCOMES: time to laxation, and number of patients laxating at the shortest follow-up. SECONDARY OUTCOMES: gastric residual volumes and adverse events. KEY RESULTS: A total of 13 patients were included in the case-series; the most common diagnosis was COVID-19 ARDS. Patients had their first bowel movement 1 [0;2] day after naldemedine. Daily gastric residual volume was 725 [405;1805] before vs. 250 [45;1090] mL after naldemedine, p = 0.0078. Systematic review identified nine studies (two RCTs, one prospective case-series, three retrospective case-series and three case-reports). Outcomes were similar between groups, with a trend toward a lower gastric residual volume in PAMORAs group. CONCLUSIONS & INFERENCES: In a highly-selected case-series of patients with refractory, opioid-associated constipation, naldemedine was safe and associated to reduced gastric residuals and promoting laxation. In the systematic review and meta-analysis, the use of PAMORAs (mainly methylnaltrexone) was safe and associated with a reduced intolerance to enteral feeding but no difference in the time to laxation.

Recommendations for the management of opioid-induced constipation - how to improve usability in clinical practice.

INTRODUCTION: Opioid-induced constipation remains undertreated despite effective and safe treatment options exists. Previous guidelines have only been partially effective in improving management, possibly due to their complexity, and studies suggest that a simple setup of concise and behaviorally-orientated steps improves usability. AREAS COVERED: This article introduces the concept of opioid-induced constipation and provides an overview of existing guidelines in this field. We also propose simplified recommendations for managing opioid-induced constipation, derived from a synthesis of current guidelines and the principles of optimal guideline design theory. EXPERT OPINION: Despite standard treatment with laxatives and fluid intake in patients with opioid-induced constipation, escalation of treatment is often needed where µ-opioid receptor antagonists or newer medications such as lubiprostone, linaclotide, or prucalopride are used. Previous guidelines have not been used sufficiently and thus management of the condition is often insufficient. We therefore propose simplified recommendations to management, which we believe can come into broader use. It was validated in primary care for credibility, clarity, relevance, usability, and overall benefit. We believe that this initiative can lead to better management of the substantial proportion of patients suffering from side effects of opioids.

Prevalence and Burden of Illness of Rome IV Chronic Idiopathic Constipation, Opioid-Induced Constipation, and Opioid-Exacerbated Constipation in the United States.

INTRODUCTION: Chronic idiopathic constipation (CIC) and opioid-induced constipation (OIC) are disorders that negatively affect quality of life. We sought to assess the prevalence, symptom severity, and medication use among people with Rome IV CIC, OIC, and opioid-exacerbated constipation (OEC) using a nationally representative data set with nearly 89,000 people in the United States. METHODS: From May 3, 2020, to June 24, 2020, we recruited a representative sample of people in the United States ≥ 18 years to complete an online national health survey. The survey guided participants through the Rome IV CIC and OIC questionnaires, Patient-Reported Outcome Measurement Information System gastrointestinal scales (percentile 0-100; higher = more severe), and medication questions. Individuals with OEC were identified by asking those with OIC whether they experienced constipation before starting an opioid and whether their symptoms worsened afterward. RESULTS: Among the 88,607 participants, 5,334 (6.0%) had Rome IV CIC, and 1,548 (1.7%) and 335 (0.4%) had Rome IV OIC and OEC, respectively. When compared with people with CIC (Patient-Reported Outcome Measurement Information System score, 53.9 ± 26.5; reference), those with OIC (62.7 ± 28.0; adjusted P < 0.001) and OEC (61.1 ± 25.8, adjusted P = 0.048) had more severe constipation symptoms. People with OIC (odds ratio 2.72, 95% confidence interval 2.04-3.62) and OEC (odds ratio 3.52, 95% confidence interval 2.22-5.59) were also more likely to be taking a prescription medication for their constipation vs those with CIC. DISCUSSION: In this nationwide US survey, we found that Rome IV CIC is common (6.0%) while Rome IV OIC (1.7%) and OEC (0.4%) are less prevalent. Individuals with OIC and OEC have a higher burden of illness with respect to symptom severity and prescription constipation medication use.

Efficacy and safety of naldemedine treatment for opioid-induced constipation in gastrointestinal cancer: a retrospective analysis.

BACKGROUND: Gastrointestinal cancers are one of the most common cancer cases worldwide. Cancer treatment is multidisciplinary, which includes opioid pain management. Opioid analgesics cause opioid-induced constipation (OIC) with the onset of effect. Naldemedine, a peripheral opioid receptor antagonist, is an OIC-modifying agent, but no focused efficacy and safety analysis has been conducted for its use in gastrointestinal cancers. METHODS: We retrospectively evaluated patients with gastrointestinal cancer treated with naldemedine at ten institutions in Japan from June 2017 to August 2019. Patients with gastrointestinal cancer who initiated treatment with opioids during hospitalization and were treated with naldemedine for the first time were included in the study. The gastrointestinal cancer types included were esophageal, gastric, small bowel, and colorectal cancers. We assessed the defecation frequency before and after the initiation of naldemedine use. Responders were defined as patients who defecated three or more times/week, with an increase from the baseline of one or more bowel movements/week over seven days after starting naldemedine. RESULTS: Thirty-three patients were observed for one week before and after starting naldemedine. Twenty-one patients had an increase in defecation frequency of at least three times per week or at least once per week above the baseline. The response rate was 63.6% [95% confidence interval (CI): 46.6-77.9%]. The median number of bowel movements for a week before and after the initiation of naldemedine treatment was 3 (range, 0-13) and 7 (range, 1-39), respectively, in the overall population (n=33), with a significant increase in defecation frequency following naldemedine administration (Wilcoxon signed rank test, P<0.005). Diarrhea was the predominant gastrointestinal symptom, with 13 (39.4%) patients experiencing grade 1 and none experiencing grade 3 or grade 4 adverse events. The frequency of other grade 1 adverse events was low abdominal pain in two patients, nausea in two patients, and anorexia in one patient, without any grade 2-4 adverse events. CONCLUSIONS: The results of the study suggest that naldemedine is effective and safe in clinical practice for gastrointestinal cancer treatment.

Efficacy and Safety of Naldemedine Administration for Opioid-Induced Constipation in Cancer Patients with Poor Performance Status.

Background: Constipation is a concern among patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 3 and 4. Objectives: To assess naldemedine's efficacy and safety in cancer patients on opioids with poor PS. Design: Multicenter, retrospective study. Setting/Subjects: Japanese cancer patients with ECOG performance status 3 or 4 who received naldemedine. Measurements: Frequency of defecations before/after naldemedine use. Responders were patients whose defecation frequency increased to ≥3 times/week, from baseline ≥1 defecations/week over seven days after naldemedine administration. Results: Seventy-one patients were analyzed; 66.1% were responders (95% confidence interval: 54.5%-76.1%). Defecation frequency increased significantly after naldemedine in the overall population (6 vs. 2, p < 0.0001) and among those who defecated <3 times/week before naldemedine (4.5 vs. 1, p < 0.0001). Diarrhea (38.0%) of all grades was the most common adverse event; 23 (85.2%) events were classified as Grade 1 or 2. Conclusion: Naldemedine is effective and safe among cancer patients with poor PS.

A Retrospective Study of the Efficacy and Safety of Naldemedine for Treatment of Opioid-Induced Constipation in Patients with Hepatobiliary Pancreatic Cancer.

Background and Objectives: Opioid analgesics, which are used for cancer-related pain management, cause opioid-induced constipation (OIC). Naldemedine, a peripheral opioid receptor antagonist, is an OIC-modifying agent, but no focused efficacy and safety analysis has been conducted for its use in hepatobiliary pancreatic cancers. We performed a multi-institutional study on the efficacy and safety of naldemedine in patients with hepatobiliary pancreatic cancer using opioids in clinical practice. Materials and Methods: We retrospectively evaluated patients with hepatobiliary pancreatic cancer (including liver, biliary tract, and pancreatic cancers) treated with opioids and naldemedine during hospitalization at ten institutions in Japan from June 2017 to August 2019. We assessed the frequency of bowel movements before and after the initiation of naldemedine therapy. Responders were defined as patients who defecated ≥3 times/week, with an increase from a baseline of ≥1 defecations/week over seven days after the initiation of naldemedine administration. Results: Thirty-four patients were observed for one week before and one week after starting naldemedine. The frequency of bowel movements increased by one over the baseline frequency or to at least thrice per week in 21 patients. The response rate was 61.7% (95% confidence interval: 45.4-78.0%). The median number of weekly bowel movements before and after naldemedine treatment was 2 (range: 0-9) and 6 (range: 1-17), respectively, in the overall population (n = 34); the increase in the number of bowel movements following naldemedine administration was statistically significant (Wilcoxon signed-rank test, p < 0.0001). Diarrhea was the predominant gastrointestinal symptom, and 10 (29.4%) patients experienced grade 1, grade 2, or grade 3 adverse events. The only other adverse event included fatigue in one patient; grade 2-4 adverse events were absent. Conclusions: Naldemedine is effective, and its use may be safe in clinical practice for patients with hepatobiliary pancreatic cancer receiving opioid analgesics.

Magnesium hydroxide versus macrogol/electrolytes in the prevention of opioid-induced constipation in incurable cancer patients: study protocol for an open-label, randomized controlled trial (the OMAMA study).

BACKGROUND: Opioid-induced constipation (OIC) is a common symptom in cancer patients treated with opioids with a prevalence of up to 59%. International guidelines recommend standard laxatives such as macrogol/electrolytes and magnesium hydroxide to prevent OIC, although evidence from randomized controlled trials is largely lacking. The aim of our study is to compare magnesium hydroxide with macrogol /electrolytes in the prevention of OIC in patients with incurable cancer and to compare side-effects, tolerability and cost-effectiveness. METHODS: Our study is an open-label, randomized, multicenter study to examine if magnesium hydroxide is non-inferior to macrogol/electrolytes in the prevention of OIC. In total, 330 patients with incurable cancer, starting with opioids for pain management, will be randomized to treatment with either macrogol/electrolytes or magnesium hydroxide. The primary outcome measure is the proportion of patients with a score of < 30 on the Bowel Function Index (BFI), measured on day 14. The Rome IV criteria for constipation, side effects of and satisfaction with laxatives, pain scores, quality of life (using the EQ-5D-5L), daily use of laxatives and escape medication, and cost-effectiveness will also be assessed. DISCUSSION: In this study we aim to examine if magnesium hydroxide is non-inferior to macrogol/electrolytes in the prevention of OIC. The outcome of our study will contribute to prevention of OIC and scientific evidence of guidelines on (opioid-induced) constipation. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov: NCT05216328 and in the Dutch trial register: NTR80508. EudraCT number 2022-000408-36.

[Survey of Prophylactic Administration of Naldemedine for Opioid-induced Constipation].

Opioid-induced constipation (OIC), an adverse event that occurs due to opioid analgesics, reportedly causes poor quality of life and adherence to opioid analgesics in patients. Therefore, this issue must be addressed appropriately. Naldemedine (NAL), a peripherally-acting µ-opioid receptor antagonist, is currently recommended for treating OIC when other laxatives are ineffective, but there have been no clinical reports of NAL being used prophylactically for OIC. Therefore, we conducted a retrospective survey of hospitalized patients who received NAL as prophylaxis for OIC with strong opioid analgesics to clarify the reality of this situation and to consider points to be taken into account in its clinical implementation. In this study, 61.7% of the subjects had an Eastern Cooperative Oncology Group performance status score of 3 or higher. The rate of addition of new laxatives and increased laxatives during seven days of NAL prophylaxis was 46.8%, and the rate of diarrhea was 6.1%. This study suggests that patients initiated with strong opioid analgesics during hospitalization often presented with poor performance status, and it is important to pay attention to constipation even under NAL prophylaxis. However, the incidence of diarrhea was low, and the safety of NAL prophylaxis was considered to be good.