Abstract: Two RCTs (123 participants), both using amitriptyline, met the pre-specified inclusion criteria. These studies provided mixed findings on the efficacy of amitriptyline for the treatment of abdominal pain-related FGIDs. The larger, publicly-funded study reported no statistically significant difference in efficacy between amitriptyline and placebo in 90 children and adolescents with FGIDs after 4 weeks of treatment. On intention-to-treat (ITT)- analysis, 59% of the children reported feeling better in the amitriptyline group compared with 53% in the placebo group (RR 1.12; 95% CI: 0.77 to 1.63; P = 0.54). The risk of bias for this study was rated as low. The second RCT enrolled 33 adolescents with irritable bowel syndrome. Patients receiving amitriptyline experienced greater improvements in the primary outcome, overall quality of life, at weeks 6, 10, and 13 compared with those on placebo (P= 0.019, 0.004, and 0.013, respectively). No effect estimates were calculated for the quality of life outcome because mean quality of life scores and standard deviations were not reported. For most secondary outcomes no statistically significant differences between amitriptyline and placebo could be detected. The risk of bias for this study was rated as unclear for most items. However, it was rated as high for other bias due to multiple testing. The results of this study should be interpreted with caution due to the small number of patients and multiple testing. The larger study reported mild adverse events including fatigue, rash and headache and dizziness. On ITT analysis, 4% of the amitriptyline group experienced at least one adverse event compared to 2% of the placebo group. There was no statistically significant difference in the proportion of patients who experienced at least one adverse event (RR 1.91; 95% CI 0.18 to 20.35; P = 0.59). The smaller study reported no adverse events. The methods of adverse effects assessment was poorly reported in both studies and no clear conclusions on the risks of harms of amitriptyline can be drawn. Clinicians must be aware that for the majority of antidepressant medications no evidence exists that supports their use for the treatment of abdominal pain-related FGIDs in children and adolescents. The existing randomised controlled evidence is limited to studies on amitriptyline and revealed no statistically significant differences between amitriptyline and placebo for most efficacy outcomes. Amitriptyline does not appear to provide any benefit for the treatment of FGIDs in children and adolescents. Studies in children with depressive disorders have shown that antidepressants can lead to substantial, sometimes life-threatening adverse effects. Until better evidence evolves, clinicians should weigh the potential benefits of antidepressant treatment against known risks of antidepressants in paediatric patients.

Plain-language summary: Abdominal pain-related functional gastrointestinal disorders (FGIDs) are common in childhood and adolescence. In most cases no medical reason for the pain can be found. Various drug treatment approaches for the different types of abdominal pain-related FGIDs exist. These drug treatments include: prokinetics and antisecretory agents for functional dyspepsia; pizotifen, propranolol, cyproheptadine or sumatriptane for abdominal migraine; and antispasmodic and antidiarrhoeal regimen for irritable bowel syndrome. Antidepressants have been shown to be effective in some studies of adults with functional gastrointestinal disorders. As a result young patients with similar complaints are sometimes treated with antidepressants. The purpose of this review was to examine the evidence assessing the advantages and disadvantages of such an approach. Only two studies met the inclusion criteria. Both of these studies were randomised controlled trials and assessed the effectiveness and safety of amitriptyline in children with FGIDs. Amitriptyline is a first generation antidepressant (tricyclic antidepressant). Amitriptyline is no longer an agent of first choice for the treatment of depressive disorders because of potentially serious side effects including overdose. Amitriptyline has not been approved for the treatment of functional abdominal pain in children or adolescents. The larger study (n = 90) showed no difference in the proportion of patients feeling better between the treatment - and the placebo (sugar pill) groups. Side effects were mild and included fatigue, rash and headache and dizziness.The authors of the other, much smaller study (n = 33) reported a significant improvement in overall quality of life and a reduction in pain for specific areas of the abdomen and certain follow up times. However, the results of this study should be interpreted with caution due to poor methodological quality and the small number of patients enrolled. Amitriptyline does not appear to provide any benefit for the treatment of FGIDs in children and adolescents. At present, the evidence for the treatment of children and adolescents with abdominal pain-related diseases with antidepressants does not support the use of antidepressant agents in this group of patients. We suggest considering alternative treatments that are supported by stronger evidence. There is need for larger, well-conducted trials with adequate patient relevant outcomes such as quality of life and pain relief to provide more information regarding this common condition.