BACKGROUND: Naldemedine is an orally available peripherally acting μ-opioid receptor antagonist approved to treat opioid-induced constipation (OIC). It is contraindicated for patients with known or suspected gastrointestinal obstruction to protect against naldemedine-induced perforation. Here, we report a clinical case of suspected perforation of a diverticulum in the sigmoid colon associated with naldemedine.
METHODS: The patient was a 65-year-old man with a history of oral cancer who had been prescribed oxycodone (20 mg/day) for cancer pain. On day 0, the patient started naldemedine 0.2 mg once daily before bedtime for OIC. The dose of oxycodone was increased for pain control up to 60 mg/day. On day 35 of naldemedine treatment, the patient developed fever and abdominal pain, and his frequency of defecation had decreased. Initial laboratory results showed a C-reactive protein (CRP) level of 28.5 mg/dL and white blood cell (WBC) count of 13,500/µL. On day 37, the patient still had tenderness in his lower abdomen. Abdominal computed tomography revealed free air in the abdominal cavity suggesting an intestinal perforation. A Hartmann procedure was performed. Histopathological findings showed numerous diverticula in the sigmoid colon, some of which were perforated.
CONCLUSIONS: These results suggest that the effects of OIC may have compressed the intestinal tract, which was followed by naldemedine-activation of peristalsis, which led to the onset of intestinal perforation. In patients with pre-existing diverticular disease, we should monitor for increased WBC counts and CRP levels after the initiation of treatment with naldemedine, and consider performing appropriate tests early in the event of abdominal complaints.

UNASSIGNED: The use of opioids occasionally causes tinnitus. However, there is a paucity of data regarding the use of peripherally acting μ-opioid receptor antagonists for opioid-associated tinnitus in patients with cancer.
UNASSIGNED: A 74-year-old male with pancreatic cancer complained of abdominal pain. Two days after initiating oxycodone therapy, the patient experienced tinnitus during body movements. Although peripheral tinnitus disappeared after discontinuing oxycodone, it reappeared with hydromorphone or tapentadol administration.
UNASSIGNED: Drug cessation is a preferred intervention for drug-induced tinnitus; however, the cessation of opioids may not be feasible in patients with cancer who are already taking opioids.
UNASSIGNED: Based on the presumed mechanism of peripheral tinnitus, the use of peripherally acting μ-opioid receptor antagonists was planned, and 200 μg/day of naldemedine was prescribed for tinnitus relief.
UNASSIGNED: Tinnitus disappeared immediately after initiating naldemedine, and the pain was well-controlled. The effect was preserved after increasing or switching opioids.
UNASSIGNED: The use of peripherally acting μ-opioid receptor antagonists may be an option to treat opioid-associated tinnitus without compromising the analgesic effects.
UNASSIGNED: Further clinical data regarding the secondary effect of peripherally acting μ-opioid receptor antagonists on opioid-associated complications other than constipation are required.

OBJECTIVE: In this study, we aimed to evaluate the safety and effectiveness of naldemedine for treating opioid-induced constipation (OIC) in patients with advanced cancer, who are receiving palliative care, and particularly explored its early effects.
METHODS: Palliative care teams and inpatient palliative care units across 14 institutions in Japan were included in this multicenter, prospective, observational study. Patients who were newly prescribed a daily oral dose of 0.2 mg naldemedine were enrolled. The spontaneous bowel movement (SBM) within 24 h after the first dose of naldemedine was considered the primary outcome, whereas, the secondary outcomes included weekly changes in SBM frequency and adverse events.
RESULTS: A total of 204 patients were enrolled and 184 completed the 7-day study. The average age of the participants (103 males, 101 females) was 63 ± 14 years. The primary cancer was detected in the lungs (23.5%), gastrointestinal tract (13.7%), and urological organs (9.3%). A considerable proportion of patients (34.8%) had ECOG performance status of 3-4. Most patients were undergoing active cancer treatment, however, 40.7% of the patients were receiving the best supportive care. Within 24 h of the first naldemedine dose, 146 patients (71.6%, 95% CI: 65.4-77.8%) experienced SBMs. The weekly SBM counts increased in 62.7% of the participants. The major adverse events included diarrhea and abdominal pain, detected in 17.6% and 5.4% of the patients, respectively. However, no serious adverse events were observed.
CONCLUSIONS: Conclusively, naldemedine is effective and safe for OIC treatments in real-world palliative care settings.
BACKGROUND: UMIN000031381, registered 20/02/2018.

Introduction Naldemedine and magnesium oxide are common first-line early laxative medications used in the real-world scenario in Japan, for patients with cancer pain who receive opioid prescriptions, as per a nationwide hospital claims database study. However, the real-world prescription patterns and associated outcomes are unknown. Methods In this retrospective, cohort study using the Medical Data Vision (MDV) database (January 2018 to December 2020), data were collected from eligible patients (who had a long-term prescription of strong opioids, for >30 days) in Japan with naldemedine or magnesium oxide as the first-line laxative prescription, for a long-term opioid prescription for cancer pain with ≥6 months post-opioid observation period. A laxative prescription within three days after the opioid prescription date was termed an \"early\" prescription. The composite incidence of dose increase or addition/change of laxatives at three months after the start of the opioid prescription was the primary endpoint after adjusting baseline characteristics between the treatment arms by propensity score matching. Results After propensity score matching, 1717 and 544 patients who were prescribed naldemedine and magnesium oxide each were included in the early prescription and non-early prescription groups, respectively. Even after matching, the incidence of death was not adjusted enough and was significantly higher in the naldemedine arm than in the magnesium oxide arm in the non-early group but comparable in the early group. The incidence of addition, change, or dose increase was significantly higher in the naldemedine arm than in the magnesium oxide arm of the early prescription group (hazard ratio (95% confidence interval), 1.08 (1.00, 1.17); p=0.0402); the incidence was comparable between the arms of the non-early group. Conclusion These findings may provide valuable insights into real-world clinical treatment patterns and preliminary evidence for the selection of first-line medications to mitigate opioid-induced constipation in Japanese patients with cancer pain.

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.

BACKGROUND: Opioid-induced constipation (OIC) is a pervasive and distressing side effect of chronic opioid therapy in patients with cancer pain, significantly impacting their quality of life. Peripherally acting μ-opioid receptor antagonists (PAMORAS) were developed for treatment-resistant OIC but most studies were conducted with non-cancer patients.
OBJECTIVE: to discuss two oral formulations of PAMORAs, naldemedine and naloxegol, and to review available evidence of the effectiveness of these drugs for OIC in cancer patients.
METHODS: a comprehensive search to identify primary literature for either naldemedine or naloxegol for OIC in cancer patients.
RESULTS: Only three prospective randomized, double-blind, placebo-controlled clinical trials for naldemedine enrolling cancer patients were identified; the results of a subgroup analysis of two of those studies and two non-interventional post marketing surveillance studies of these trials are also reported here. For naloxegol, only two randomized controlled trials were identified; both were unsuccessful in enrolling sufficient patients. An additional four prospective non-interventional observational studies with naloxegol were found that enrolled cancer patients. There were significantly higher rates of responders in the PAMORA groups than in the placebo groups. The most common side effect for both PAMORAs was diarrhea.
CONCLUSIONS: All studies were industry-funded, and given that only three trials were randomized controlled studies, the overall quality of the studies was lacking.
CONCLUSIONS: Naldemedine or naloxegol appeared safe and useful in the treatment of OIC in cancer patients and may improve their quality of life. Larger-scale randomized placebo-controlled studies of PAMORAs in cancer patients would strengthen existing evidence.

OBJECTIVE: 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 4β-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.
CONCLUSIONS: 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.

BACKGROUND: 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.
OBJECTIVE: 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.
CONCLUSIONS: 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.

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.

Naldemedine is structurally designed to prevent passage across the blood-brain barrier (BBB), resulting in the attenuation of opioid-induced constipation without interfering with the analgesic effects of opioids. However, the influence of brain metastasis (BM), as one indicator of BBB disruption, on the analgesic effects of opioids in patients treated with naldemedine remains unclear. To examine whether the analgesic effects of opioids following naldemedine treatment are lower in patients with BM than in those without BM, we surveyed inpatients with lung and breast cancers treated with naldemedine at Fujita Health University Hospital between April 2017 and March 2022. Changes in the numeric rating scale (NRS) scores, morphine milligram equivalents (MMEs), and the number of rescues were assessed as analgesia-related outcomes during the first 7 days of naldemedine treatment in patients with or without BM, matched by the propensity score. In total, 172 patients were enrolled. After propensity-score matching, 30 patients with BM and 60 patients without BM were included in the analysis. Changes in NRS scores, MMEs, and the number of rescues did not differ between patients with and without BM. In the linear mixed-effects model, the coefficient of interaction between patients with or without BM and the days for each outcome was not statistically significant. BM does not influence the analgesic effect of opioids in patients with lung and breast cancers treated with naldemedine. Naldemedine may be useful for treating BM.