Efficacy of Acotiamide in Pediatric Patients with Functional Dyspepsia

Functional gastrointestinal disorders (FGIDs) present with chronic abdominal and gastrointestinal symptoms in the absence of an organic disease that explains the symptoms. In particular, functional dyspepsia (FD) is a disorder that chronically presents with symptoms in the upper abdomen, such as postprandial fullness, early satiation, epigastric pain, and burning [1, 2]. The prevalence of FD is 15–24% in adults and 3–27% in children [3, 4]. Although the pathophysiology of FD remains unclear, several factors may be involved. These include impaired gastric accommodation, delayed gastric emptying, visceral hypersensitivity, gastric acid, genetics, early life events, lifestyle, duodenal micro-inflammation, and prior infections [2]. Although FD is generally a non-life-threatening disorder, it significantly impairs health-related quality of life (QOL). Pediatric patients with FGIDs are more likely to miss school, spend additional time in bed requiring care, and have greater healthcare utilization, which also leads to parents missing more workdays [5]. Consequently, pediatric FGIDs not only negatively affect the child’s QOL but also place a considerable emotional and economic burden on their families. Poor growth and nutritional statuses are frequently observed in children with FGIDs [6]. These findings underscore the importance of early and appropriate interventions in pediatric FD. In 2013, acotiamide received its first regulatory approval for the treatment of FD in Japan. It exerts gastrokinetic activity by enhancing acetylcholine release, acting as an antagonist of M1 and M2 muscarinic receptors in the enteric nervous system, and inhibiting acetylcholinesterase activity [7]. Several trials have shown that acotiamide is effective for treating adult patients with FD. According to the guidelines revised by the Japanese Society of Gastroenterology (JSGE) in 2021, acotiamide is the first-line treatment along with acid inhibitors and rikkunshito [2]. However, its efficacy in children remains unclear. This study retrospectively reviewed the efficacy of acotiamide in children with FD at a single tertiary center.

This single-center retrospective study revealed that acotiamide improved symptoms in approximately 60% of pediatric patients with FD one month after initiation.

In a systematic review by Shrestha et al. [1], the improvement in symptoms of FD after treatment was higher in patients treated with acotiamide than placebo, although not statistically significant (odds ratio, 1.48; 95% confidence interval, 0.93–2.35). In phase II studies conducted in Japan and Europe, acotiamide exerted gastroprokinetic activity, and improved gastric emptying and accommodation, thereby confirming its beneficial effects in alleviating FD symptoms [11, 12]. A phase III trial involving adult Japanese patients reported that the improvement rate of PDS symptoms after 4 weeks was 34.8% in the placebo group and 52.2% in the acotiamide group, showing significantly higher improvement in the acotiamide group than in the placebo group [13]. In the present study, the improvement rate of FD symptoms was similar to that reported in previous studies in adults [13, 14]. Therefore, acotiamide may be an effective treatment option for pediatric patients with FD.

FD can be divided into two subtypes: EPS and PDS. The Rome IV criteria suggest treatment based on the subtypes of FD, with the first-line treatments being acid inhibitors for patients with EPS and prokinetics for patients with PDS [15]. In a systematic review of the efficacy of acotiamide in adult FD, it was found to be effective for overall FD and PDS; however, there was no significant difference between acotiamide and placebo in the case of EPS [2]. However, a phase II study also demonstrated some beneficial effects on EPS symptoms such as upper abdominal pain [16]. Consistent with this finding, a single-center retrospective study reported the efficacy of acotiamide for both PDS and EPS (78.0% vs. 70.0%) [14], whereas a recent multicenter prospective study similarly showed high efficacy (66.0% vs. 73.1%) [17]. Our study also demonstrates its efficacy in the treatment of EPS and overlap PDS-EPS. The wide range of responses observed in the FD group can be attributed to the diverse pharmacological effects of acotiamide. Previous studies in human and animal models have shown that beyond its local effects on bowel motility, acotiamide may indirectly alleviate dyspeptic symptoms through its influence on the brain-gut axis [18].

Notably, in the present study, the proportion of EPS was higher than that previously reported in FD studies [19, 20]. In adults, PDS occurs more frequently than EPS (PDS, 89% vs. EPS, 33%) [19]. In contrast, Légeret et al. [21] reported that 75.9% of pediatric patients were diagnosed with EPS. This suggests that the distribution of FD subtypes differs between children and adults. The differences in subtype proportions may reflect the varying effects of acotiamide in children and adults. Future studies should perform a detailed comparison of FD subtype distributions in pediatric and adult populations to better understand their impact on treatment outcomes.

In this study, acotiamide demonstrated efficacy in treating EPS and overlap PDS-EPS, although no statistically significant differences were observed between the subtypes. This may indicate that acotiamide is effective in pediatric FD, regardless of the subtype, or it could reflect limitations in statistical power owing to the small sample size and potential data bias. Future studies with larger cohorts and balanced subtype representations are needed to clarify whether the efficacy of acotiamide in pediatric FD varies by subtype and determine how these findings compare to those in the adult population.

Five patients with symptom duration of less than two months were excluded based on the Rome IV criteria. Symptom duration among the excluded patients ranged from 30 to 60 days. Previous retrospective studies in Japan have often defined symptom duration as exceeding one month [14, 17, 22, 23]. This is likely due to the accessibility of medical facilities under Japan’s National Health Insurance system, which enables relatively short intervals between symptom onset and hospital visits. Kinoshita et al. [23] reported that only 12.3% of adults with FD in Japan met the symptom duration criteria outlined in the Rome III guidelines. Therefore, the JSGE guidelines do not define “chronic symptoms” for a specific duration [2]. Kinoshita et al. [23] reported that among patients with FD, the intensity of symptoms and impairment in quality of life were similar regardless of symptom duration, including in patients with symptoms lasting less than one month. This finding suggests that the clinical relevance of dyspeptic symptoms may be independent of the duration. Furthermore, symptom duration was not associated with drug responsiveness [17], and no statistically significant correlation was observed between previous symptom duration and time to complete resolution after endoscopy [21]. In our study, acotiamide was effective in four of the five excluded cases. These findings suggest that acotiamide may be a viable treatment option for pediatric FD, even when symptom duration ranges from 4 to 8 weeks. However, it is essential to rule out organic causes such as infections, as outlined in the Rome IV diagnostic criteria.

It has been suggested that this improvement is maintained even after an acotiamide dose interruption. One adult study reported a recurrence-free rate of 51% one year after the cessation of acotiamide [3]. Even if FD symptoms relapse after dose interruption, they can be relieved by resuming acotiamide [24]. In the present study, seven of the 19 patients who showed efficacy discontinued acotiamide treatment and had no subsequent relapse of symptoms. In our department, if FD symptoms did not recur after the cessation of acotiamide treatment, the patient follow-up period tended to be shorter (ranging from one to six months). In the future, it will be necessary to observe the long-term outcomes in children.

In a systematic review by Xiao et al. [25], the incidence of adverse events did not significantly differ between the placebo and acotiamide groups. Acotiamide was well tolerated, with most adverse events reported in the included studies being mild or moderate. The incidence rates of overall, treatment-related, serious, or severe treatment-emergent adverse events were consistently low in previous trials [13, 16, 26]. In the present study, adverse events included abdominal pain in two of the 33 patients, but no other serious adverse events were observed. Acotiamide appears safe for pediatric patients with FD.

This study has several limitations. First, this was a retrospective study and the number of cases was small. A meta-analysis conducted by Moayyedi et al. [27] reported a strong placebo effect in patients with FD. A double-blind, controlled study is required to confirm the efficacy of acotiamide. Second, a quantitative evaluation of FD symptom improvement was not performed. Future prospective studies using self-administered questionnaires to evaluate symptom improvement are warranted: the overall treatment effectiveness approach for overall improvement, the Izumo scale [28] and GOS scale [29] for digestive symptoms, and the Short Form-Nepean Dyspepsia Index Questionnaire for QoL [30].

In summary, this retrospective study demonstrated the efficacy of acotiamide in pediatric patients with FD. Therefore, acotiamide could be a first-line therapy for children with FD.