Manabe, Noriaki

ABSTRACT Background Opioids are indicated for pain that occurs with cancer and other disorders that become more prevalent with aging. The most prevalent and persistent adverse effect of opioid therapy is opioid‐induced constipation (OIC). OIC impairs patient quality of life (QoL) and leads to suboptimal pain management due to medication non‐adherence. Unlike other adverse effects, OIC persists and is not associated with pharmacological tolerance, necessitating long‐term management. Objectives The objective of this study is to evaluate current clinical strategies for OIC by comparing recommendations from American, European, and Japanese clinical guidelines. We reviewed the clinical evidence for the peripherally acting μ‐opioid receptor antagonist (PAMORA) naldemedine (the only PAMORA approved in Japan) and the rationale for early intervention in OIC. Methods The clinical guidelines and recent clinical trial data, including the COMPOSE program (phase III clinical trials of naldemedine for OIC in patients with chronic non‐cancer pain), were reviewed to establish an evidence‐based framework for the management of chronic cancer and non‐cancer pain. Results Conventional laxatives frequently provide inadequate relief as they address secondary symptoms rather than the underlying receptor‐mediated cause. PAMORAs (including naldemedine, methyl naltrexone, and naloxegol) antagonize gastrointestinal opioid receptors without compromising central analgesia. Early initiation of PAMORAs stabilizes bowel function and reduces the incidence of treatment‐related diarrhea that occurs when using conventional laxatives to treat OIC. Conclusion The 2023 Japanese guidelines advocate the proactive use of the PAMORA naldemedine as a primary treatment option. This mechanism‐based early intervention model offers a promising framework for optimizing QoL and implementing effective analgesia in an aging global population.

Objective High rectal sensory thresholds (RSTs) are associated with chronic constipation (CC), especially in older patients. Bile acids (BAs) affect the RSTs of healthy individuals. Here, we aimed to investigate the effects of the BA transporter inhibitor elobixibat in patients with CC aged ≥60 years. Design We prospectively compared the RSTs of 17 patients with CC aged ≥60 years with those of 9 healthy individuals of the same age range. We next performed a prospective, randomised, parallel-group, double-blind, placebo-controlled clinical trial of 17 patients with CC who administered elobixibat or placebo daily for 1 week. Using barostat methodology, their first constant sensation volume (FCSV), defaecatory desire volume (DDV), and maximum tolerable volume (MTV) thresholds; their rectal compliance; and their faecal BA concentrations were measured before and after treatment. Results There were no significant differences in the RSTs of healthy individuals and patients with CC, but all of these tended to be higher in the latter group. Elobixibat increased the desire to defaecate, significantly reduced the threshold for FCSV (p=0.0018), and tended to reduce the threshold for DDV (p=0.0899) versus placebo. However, there were no differences in the MTV or rectal compliance of the two groups. The total faecal BA concentration increased, and particularly that of secondary BAs in the elobixibat group. Elobixibat was most efficacious in participants with a longer duration of CC and a history of treatment for CC. Conclusion Elobixibat reduces the RSTs of patients with CC aged ≥60 years, which may be important for its therapeutic effects. Trial registration number jRCTs061200030.

Daikenchuto (TU-100) is a traditional Japanese (Kampo) medicine used to treat postoperative ileus. TU-100 dose dependently increases gastrointestinal (GI) motility by modulating cholinergic and serotonergic mechanisms in animal studies. The aim of this study was to evaluate the effects of orally administered TU-100 on GI and colonic transit and bowel function in healthy humans. In a randomized, parallel-group, double-blind, placebo-controlled, dose-response study, 60 healthy subjects were randomly assigned to placebo or TU-100 2.5 g or 5 g tid ingested immediately before meals for 5 consecutive days. We measured GI and colonic transit by validated scintigraphy and stool frequency and consistency by daily diaries of bowel function. There were overall treatment effects on colonic filling at 6 h without any significant differences between each dose of TU-100 and placebo. There tended to be overall treatment effects on ascending colon (AC) emptying half-time; the TU-100 (7.5 g/day) treatment significantly accelerated AC emptying compared with placebo. There were numerically higher values of GC24 (which reflect overall colonic transit) with both doses of TU-100, but these changes were not statistically significant. There were no significant overall treatment effects on gastric emptying or stool frequency and consistency. One subject, who received 7.5 g/day of TU-100, had elevated creatine phosphokinase following the study. TU-100 (7.5 g/day) significantly accelerated AC emptying. Further randomized controlled trials in patients with functional constipation or irritable bowel syndrome with constipation are warranted to evaluate the clinical efficacy of TU-100 in these disorders.