Functional gastrointestinal disorders (FGIDs) are a group of diseases presenting with a variety of chronic or recurrent gastrointestinal symptoms that cannot be explained properly by any other underlying disease (1). Childhood functional abdominal pain (FAP), currently referred to as FAP-not otherwise specified (FAP-NOS), is one of the common causes of frequent abdominal pain in the pediatric population (2,3). The total universal prevalence of FAP disorders among children is 13.5%, with a prevalence of 2%–4.4% for childhood FAP in different regions (3–6). Patients with childhood FAP may experience functional disabilities, anxiety, social phobia, psychosomatic complaints and depression, and display increased risk for other FGIDs (7–9). These children have a lower quality of life compared with their healthy peers or those with other chronic conditions such as migraine or asthma (8,10).
The exact pathophysiology of abdominal pain–related FGIDs (currently known as FAP disorders), including childhood FAP, is still unknown; however, abnormal brain-gut interactions, involvement of pain-related brain circuits, changes in the level of neurotransmitters in the central and peripheral levels, hypersensitivity of the gut to psychological and physiological stimulators, and abnormal contractions in parts of gastrointestinal tract have been proposed to be involved (1,11,12). Suggested treatment options for childhood FAP include psychological interventions, antidepressants, smooth muscle relaxants, probiotics, and specific diets (13–17). Pharmacological interventions have not been efficacious in controlling childhood FAP so far. In addition, psychological interventions, although efficient, are not favorable options for either physicians or families because of the limitations they impose (13,18). There is a lack of randomized clinical trials evaluating therapeutic options in children with abdominal pain–related FGIDs, including those with childhood FAP, and most of the suggested treatments are experimental or based on the results from the studies on adults (19,20). A recent report from a working team of the Rome foundation recommended the administration of azapirones (such as buspirone and tandospirone) as a combination therapy for adult patients suffering abdominal pain predominant–FGIDs that do not show enough improvements after tricyclic antidepressants or selective serotonin receptor inhibitors therapy (12). Azapirones, a group of neuromodulators targeting 5HT serotonin receptors, are also reported to be helpful in adults suffering functional dyspepsia (21,22). Researchers have shown the beneficial effects of tandospirone in improving abdominal pain in irritable bowel syndrome (IBS) and fundus relaxant effects of buspirone in this group (21,23). Moreover, some experimental studies have shown improvement of abdominal pain in animal models of FGIDs by buspirone administration and suggested that mechanisms led to symptom improvement may emulate in humans as well (24,25).
To the best of our knowledge, no study has investigated the efficacy of buspirone in abdominal pain–related FGIDs among children before (12,18). Because buspirone is a safe and well-tolerated medication in children and based on the mentioned evidences of abdominal pain alleviating effects in adults, we aimed to investigate the efficacy of this medication in childhood FAP in comparison to placebo for the first time.
MATERIAL AND METHODS
This randomized, double-blind, placebo-controlled trial was conducted from January to November 2018 at a large single outpatient private pediatrics gastroenterology referral clinic in Isfahan, Iran. The inclusion criteria were children aged 6–18 years with the diagnosis of childhood FAP according to the proposed diagnostic criteria by Rome III (26); not taking antibiotics, probiotics, or any psychiatric medications in the past 2 months; no history of symptom relief after 2 weeks of lactose-free diet; no positive result in the lactose respiratory test; no concomitant gastrointestinal or organic disorder; and not having weight or height below the 5 or over the 95 percentiles for the appropriate age and sex.
A group of patients had already been evaluated for organic diseases with different diagnostic tests before referral to the clinic. In those without adequate previous evaluations, we ordered the missing diagnostic tests as needed. These tests included complete blood count, erythrocyte sedimentation rate, electrolytes, glucose, blood urea nitrogen, creatinine, calcium, liver function tests, pancreatic enzymes, albumin, urinalysis, fecal occult blood, ova and parasite test (in stool), H. pylori antigen in stool, tissue transglutaminase antibody, H. pylori antibody, serum pregnancy test for postmenarche women, and/or electrocardiogram, and/or abdominopelvic ultrasonography. These diagnostic tests were the requirements to rule out all other possible organic causes and make an accurate diagnosis of childhood FAP as part of the Rome III criteria. Therefore, we did not consider it as a different inclusion criterion. We obtained written informed consents from parents and verbal assent from children.
At the power of 80% and a significance level of 0.05, 50 children were estimated to be needed in each group. The study was approved by the ethics committee of the Islamic Azad University of Najafabad (ID: 15010101951020, approval date: 18.08.2017) and was registered in the Iranian Registry of Clinical Trials (IRCT) before enrollment (ID: IRCT20140304016844N3).
After the initial enrollment and explaining the study procedure to participants and their parents, patients were randomized into intervention or control groups. Random numbers were generated by random allocation software in 4 blocks and medication bottles were coded by a pharmacist who was not aware of the study design. A random number was allocated to each patient at the time of enrollment. Then, based on the number, the associated medication bottle was handed to the patient. Each package included 30 tablets which allowed the study personnel to count the consumed tablets on the follow-up visit and check on treatment adherence. The additional tablets were discarded at the end of study. The physician, psychologist, statistical analyzer, and participants were all blinded regarding the randomization status. We asked participants to come back one week later to fill out the questionnaires, visit our pediatric gastroenterologist, and receive the first batch of their medication. The given medications were for 4 weeks, and at the end of this period, patients were assessed as the first follow-up. In the follow-up session, we asked the patients to complete the same questionnaires and the study gastroenterologist revisited the patients. We asked the patient to discontinue the medication after the first follow-up visit and invited them to come back for the second follow-up session 8 weeks later. Patients completed the same questionnaires in the second follow-up session as well and were seen by the study gastroenterologist.
The buspirone group received the medication with the appropriate dose adjusted for age as follows: 2.5 mg/d for the first week and then 5 mg/d for the following 3 weeks for participants <10 years; 5 mg/d for the first week and then twice a day for the 3 following weeks for those aged 10 to 15 years; and 5 mg/d for the first week, 2 times a day for the second week, and 3 times a day for the following 2 weeks for those aged 15–18 years. Buspirone 5 mg tablets (BUSPIRAX) were provided from the Tehran Darou pharmaceutical company (Tehran, Iran).
The placebo group received the medication with the same protocol to the buspirone group. The placebo was made by the faculty of pharmacy and pharmaceutical sciences of the Isfahan University of Medical Sciences in a similar shape, size, and color to the buspirone tablets. Buspirone and placebo were both placed in opaque bottles coded by a pharmacist earlier.
Compliance with the medication was assessed after 2 weeks of therapy through a telephone interview with the parents. Parents were asked to explain the usage method, for protocol comprehension recheck, and the number of remaining tablets. In addition, we repeated the questions regarding medication compliance in the first follow-up session and asked the participants to bring the remaining tablets, if there were any. The remaining tablets were counted by the study team members and the numbers were recorded.
We assessed the participants at baseline, first follow-up (after 4 weeks of therapy), and second follow-up (after 8 weeks of medication discontinuation). In each session, patients were evaluated regarding the level of abdominal pain, symptoms of depression, anxiety, somatization, and sleep disturbances. In addition, the study gastroenterologist assessed the disease severity and improvement. The comprehensive explanation of the questionnaires used in the study is available in Supplementary file 1, Supplementary Digital Content 1, http://links.lww.com/AJG/B463.
In summary, we assessed pain using the Wong-Baker FACES Pain Rating Scale (WBFPRS) (27), depression using the Children's Depression Inventory (CDI) (28), level of anxiety using the Revised Children's Manifest Anxiety Scale (RCMASTM) (29), and somatization using the Children's Somatization Inventory–Revised Form (CSI-24) (also known as the Children's Somatic Symptoms Inventory [CSSI]) (30,31). We also used the Clinical Global Impression Severity and Improvement scales (CGI-S, CGI-I) (32) and the Sleep Disturbances Scale for Children (SDSC) (33).
The primary outcome was treatment response, defined as at least 2 points reduction in WBFPRS in the first follow-up interview compared with the baseline score, or report of “no pain” in this time point. The secondary outcomes were changes in the scores of depression, anxiety, somatization, sleep disturbances, and physician-rated disease severity in the first follow-up interview compared with baseline. We used the validated Persian version of all the mentioned questionnaires if available. We also validated the unavailable questionnaires (RCMASTM and CSI-24) before the study initiation in a pilot study. Information regarding validation process and reliability is included in the Supplementary file 1, Supplementary Digital Content 1, http://links.lww.com/AJG/B463. We recorded the adverse events in each group using a checklist that included all possible adverse events of buspirone based on the previous reports. Adverse events were assessed after 2 weeks of using the medication through a phone call interview and during the first follow-up visit. If the child was experiencing severe adverse effects such as intractable vomiting, stupor, and allergic reactions, they were asked to discontinue the medication and bring the child to the clinic as soon as possible.
Based on the age range of the participant, they were not all able to read the questionnaires. Therefore, a single trained psychologist read the questions and possible answers for the child and marked the answers without any interpretations. Parents were also invited to be present in the interview sessions so that the child feels more comfortable.
Data were described using mean value ± SD or frequency (%). To compare interval variables between the groups, we used the independent t-test or the nonparametric equal where applicable. Categorical data were compared using the χ2 tests. Primary and secondary outcomes were assessed in each group using repeated measure analysis of variance, and per-protocol (PP) and intention-to-treat (ITT) analyses were both implemented during data analysis. To calculate the treatment response in the ITT analysis, we assumed that the scores have not changed in the missing follow-up sessions. Statistical analysis was carried out using the Statistical Package for Social Sciences software (SPSS, Chicago, IL; version 18), and a P value of less than 0.05 was considered as statistically significant.
We approached a total of 152 patients, 11 patients were not eligible for the study (5 patients had the history of antibiotic usage during past 2 months, 4 were on antidepressants, and 2 had concomitant reflux disorder) and 24 patients did not agree to participate. Hence, 117 patients were enrolled and randomly assigned to either the buspirone group or the placebo group (59 and 58 patients, respectively) (Figure 1). We lost 11 patients in each group by the first follow-up and 3 patients by the second follow up (2 in the placebo and 1 in the buspirone groups). Eventually, 47 patients in the buspirone group and 45 in the placebo group completed the study. Details regarding the reasons for leaving/withdrawing from the study are presented in the study diagram (Figure 1).
Table 1 presents the baseline characteristics of patients based on the ITT analysis. The mean age of patients in the buspirone and placebo groups were 7.61 ± 1.80 and 7.96 ± 1.79 years, respectively (P = 0.297). The reported mean pain scores were 3.54 ± 0.953 and 3.45 ± 1.062 in the buspirone and placebo groups, respectively (P = 0.615). We observed no statistically significant difference between the 2 groups in any of the categories at baseline.
Primary outcome measure
We observed improved pain scores in both groups after 4 weeks compared with the baseline scores (P < 0.001) (Table 2). The observed improvements were persistent after 8 weeks of medication discontinuation as well (P < 0.001) (Figure 2). We found no statistically significant difference in pain scores between the 2 groups at either week 4 or 12 of the study (P = 0.708 and P = 0.818, respectively) (Table 3). We also found no statistically significant differences in the amount of changes in the WBFPRS scores from baseline to week 4 and week 12, and from week 4 to week 12 between the 2 groups (P = 0.887, P = 0.498, and P = 0.634, respectively) (Table 4).
Based on the PP analysis, the treatment response rates in the buspirone and placebo groups were 58.3% and 59.6% at week 4 (P = 0.902) and 68.1% and 71.1% at week 12 (P = 0.753), respectively. The ITT analysis showed no significant differences between the 2 groups regarding the treatment response rate as well (47.5% for buspirone and 48.3% for placebo at week 4 [P = 0.929] and 54.2% for buspirone and 55.2% for placebo at week 12 [P = 0.919]).
Secondary outcome measures
Depressive symptoms were not improved statistically significant in either arms of the study after 4 weeks of intervention (P = 0.765 for the buspirone group and P = 1.00 for the placebo group). However, by the second follow-up, we observed improvements in both groups (P < 0.001 in the buspirone and P = 0.028 in the placebo groups) compared with the baseline scores (Table 2). Furthermore, anxiety symptoms, somatization, and clinical global impression severity scale were all improved at both follow-up assessments in both groups compared with the baseline scores (P < 0.01) (Table 2). Regarding sleep disturbances, both groups showed statistically significant improvements after 4 weeks of intervention (P = 0.004 in the buspirone and P = 0.007 in placebo groups). No statistically significant difference was observed at the second follow-up compared with the baseline score for SDSC in the buspirone group (P = 0.051); however, sleep disturbances in the placebo group improved at the second follow-up compared with baseline (P = 0.016).
Predictors of treatment response
According to Table 5, girls had 3.2 times more chance than boys to show favorable response to the treatment by week 12 of the study (odds ratio: 3.213; confidence interval [1.230–14.491]; P = 0.033), and this response did not depend on the type of used medication or any other sociodemographic factors or psychological status of the patient. We found no other predictor for treatment response at any time points.
Table 6 demonstrates the adverse events experienced by patients in each arms of the study. Overall, 48.28% of the cases in the buspirone group and 36.54% in the placebo group reported at least one occurrence of side effect by week 4 of the study. Drowsiness was the most reported complaint in the buspirone group, and headache was the most reported adverse event in the placebo group. There were no statistically significant differences between the study groups regarding the occurrence of side effects either at week 2 or week 4 of the study (P = 0.938 and P = 0.200, respectively). In both groups, patients experiencing adverse events reported persistence of these symptoms for almost 3–7 days of the treatment initiation. Only a 12-year-old boy in the buspirone group reported drowsiness persisting more than 2 weeks.
In the present study, we investigated the efficacy of buspirone compared with placebo in childhood FAP for the first time. We found a favorable effect of buspirone on pain and commonly associated psychological symptoms of childhood FAP, including depression, anxiety, somatization, and sleep disturbances. These positive effects were also present after 2 months of medication discontinuation in all the mentioned domains, except in sleep disturbances. However, buspirone was not superior to placebo in alleviating childhood FAP symptoms and associated consequences.
By 2 months of drug discontinuation, we expected the elimination of buspirone from the body based on its half-life; however, the positive effects were still present. These positive effects were persistent in the placebo group as well.
We speculate that by the reduction of abdominal pain episodes after the medication/placebo usage, children believed to be generally healthier and more able to live like their healthy peers. In addition, parents felt relieved. We speculate that these factors, along with the reduced need for medical services for abdominal pain and being able to be more functional, had improved patients' mental health. Hence, the positive psychological effects were still persistent after the medications were discontinued. Moreover, reduced depressive, anxiety and somatization symptoms, and better sleep quality could have contributed to the persistency of pain alleviation after medication discontinuation because these symptoms are known to highly affect the exacerbation and maintenance of pain in childhood FAP disorders (34). In addition, based on the previous studies, depression and poor sleep quality are associated with lower pain thresholds, and any improvement in these aspects also results in increased pain threshold and persistency of pain relief (35). Regarding depression, we observed improvement only after medication discontinuation in both groups. We think this has probably happened because depressive symptoms usually follow chronic pain and anxiety symptoms, although at last depressive symptoms per se would exacerbate both pain and anxiety symptoms (36,37). Hence, we speculate that it would take more time for depressive symptoms to be improved because these symptoms are consequences of anxiety and pain that should be resolved first.
Our findings are in concordance with the reports from other studies using tricyclic antidepressants and selective serotonin receptor inhibitors in pediatric FAP because 2 of the most important categories of neuromodulators.
In 2004, Campo et al. (38) conducted an open-label study on 25 functional recurrent abdominal pain pediatric patients and found a significant improvement in the symptoms after 12 weeks of citalopram therapy; however, they failed to include a placebo group for comparison. Similarly, Roohafza et al. implemented a placebo-controlled randomized study on citalopram therapy for 4 weeks for childhood FAP. They reported superiority of citalopram over placebo in improving self-reported pain and CGI-S scales via PP analyses after 8 weeks of medication discontinuation, with no statistically significant differences between study groups in other psychological symptoms after 4 or 12 weeks (39). In another multicentric study, Saps and colleagues compared the efficacy of the 4-week therapy with amitriptyline and placebo in 83 pediatric patients suffering irritable bowel syndrome, FAP, or functional dyspepsia. Although amitriptyline improved the symptoms, it showed no superiority over placebo (14).
The efficacy of placebo in improving pain and related psychological complaints in patients with childhood FAP reflects the important role of psychosocial factors in this disease and complexity of its pathophysiology. A meta-analysis on pediatric patients suffering abdominal pain–related FGIDs showed a response rate of 41% for placebo (40). In our experiment, the response rates to buspirone and placebo were 58.3% and 59.6% for the first follow-up and 68.1% and 71.1% for the second follow-up, respectively.
Regarding the side effects, most of the reported symptoms were present only during the first days of therapy. Only one patient (12-year-old boy) in the buspirone group reported drowsiness after 2 weeks which made him withdraw from the study. Moreover, 3 patients in the buspirone group reported myalgia (almost 5%). Data on buspirone adverse events in the pediatric population are very limited; however, it is reported that around 1% of the patients experience myalgia after buspirone usage. We could not find any convincing explanation for the higher myalgia presentation in our study.
It should be noted that although we used the Rome III criteria for patient recruitment, all our cases met the criteria for the FAP-NOS diagnosis suggested by Rome IV because Rome IV proposes a wider criteria. Based on Rome IV, the diagnosis of FAP-NOS can be proposed for a patient with concurrent organic disease, such as celiac disease (41). In addition, omitting the need for diagnostic tests to rule out all other inflammatory, anatomic, metabolic, or neoplastic causes in the Rome IV criteria may increase the chances for the possible presence of concurrent another organic disease. Hence, we used the Rome III criteria to be sure of the absence of any other underlying causes in our patients.
Our study was limited by the short follow-up duration and using low doses of buspirone. Some researchers have suggested that long-term efficacy of medications in the pediatric population with FGIDs is better to be evaluated after at least 6 months of follow-up (42). However, we decided to assess the patients in an earlier time point because of the limited evidences on the effect of neuromodulators on this age group. In addition, managing longer follow-ups was very challenging considering the sample size, the socioeconomic status of patients, and limited funds and resources. Regarding the buspirone dose, we used a low dose of buspirone in this study because this was the first trial of buspirone in childhood FAP, and the suggested dose for neuromodulators in FGIDs are usually much less than the indicated dose for psychiatric purposes. However, we believe the low dose of medication could be another possible reason for the similar therapeutic effects in the 2 groups. Factors such as percentage of female participants, physician-patient relationship, duration of the therapy, and dropout rates could also affect the response rate to placebo in the studies on the pediatric population with FGIDs (13). Here, we tried to eliminate these factors through randomization and blindness, as strengths of our study. The other limitations of our study were not using more detailed psychological questionnaires, especially for pain assessment, and absence of a questionnaire to assess the school performance.
Buspirone improves pain and associated psychological symptoms including depressive symptoms, anxiety, somatization, and sleep disturbances in children and young adolescents suffering childhood FAP. However, it does not show any superiority over placebo. These effects are persistent after 2 months of medication discontinuation, except for sleep disturbances. Further studies with higher doses of buspirone and longer follow-ups are recommended. For the better assessment of the proposed treatment, we also recommend future studies to use more detailed psychological questionnaires including the school performance questionnaire for children and anxiety and quality of life questionnaires for their parents.
CONFLICTS OF INTEREST
Guarantor of the article: Hossein Saneian, MD, and Omid Yaghini, MD.
Specific author contributions: H.S.: conceptualized the study, cooperated in designing the data collection instruments, visited the patients, supervised data collection, interpreted the results, critically reviewed the manuscript, and approved the final manuscript as submitted. O.Y.: conceptualized the study, cooperated in designing the data collection instruments, supervised the data collection, interpreted the results, critically reviewed the manuscript, and approved the final manuscript as submitted. S.B.: contributed in preparing study instruments, drafted the manuscript, and approved the final manuscript as submitted. N.B.: designed the study, conducted the study, collected the data, interpreted the data, drafted the manuscript, and approved the final manuscript as submitted. A.S.: contributed in the statistical analysis of the data, critically reviewed the manuscript, and approved the final manuscript as submitted.
Financial support: This study was funded by the vice chancellor for research and technology of the Isfahan University of Medical Sciences (grant number of 297097).
Potential competing interests: None to report.
Clinical Trial Registration Number: Iranian registry of clinical trials: IRCT20140304016844N3.
Ethical approval: This study was approved by the ethics committee of Islamic Azad University of Najafabad (approval code: 15010101951020).
WHAT IS KNOWN
- ✓ Pharmacological interventions have not been efficacious in the treatment of childhood functional abdominal pain.
- ✓ Neuromodulators are suggested to be efficacious based on the disease's pathophysiology and studies on adults.
WHAT IS NEW HERE
- ✓ Buspirone and placebo equally improve pain and associated psychological symptoms in childhood FAP.
- ✓ These effects are persistent after 2 months of medication discontinuation with both buspirone and placebo.
We would like to express our special thanks of gratitude to Dr Ali Gholamrezaei for his kind instructions and guidance in implementing this study, Dr Arash Najimi, Dr Maryam Agha Rashti and Dr Roya Riahi for their valuable guidance and supports for the statistical analysis of this project, and Dr Hamid Nasiri for his thoughtful instructions in validating the questionnaires. We deeply appreciate all the efforts by the personnel of Dr Saneian's private pediatric clinic for their cooperation in better implementation of this study. We also acknowledge the Islamic Azad University of Najafabad for the support and the Isfahan University of Medical Sciences for funding this project. At last we would like to thank the anonymous reviewers for their invaluable and insightful comments and suggestions on our manuscript that helped us to improve it.
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