Management of Functional Abdominal Pain and Irritable Bowel Syndrome in Children and Adolescents

Eric Chiou; Samuel Nurko

Disclosures

Expert Rev Gastroenterol Hepatol. 2010;4(3):293-304. 

In This Article

Pharmacotherapy

Potential pharmacological treatments for FAP and IBS have been identified based on our emerging understanding of the interactions between the CNS, enteric nervous system and GI tract, also known as the 'brain–gut axis'.[48] A significant degree of abdominal pain in functional disorders is believed to be associated with abnormal perception of visceral sensations or alterations in motility. Targets for modulation have included smooth muscle cells of the GI tract, peripheral neurotransmitter receptors for various stimuli, interneurons of the spinal cord that transmit information bidirectionally and cortical areas responsible for the perception of pain.[48] Medications initially indicated for the treatment of depression, anxiety and seizures have also been adopted for the management of FGIDs because of their effects on both the CNS and peripheral nervous system.

Antidepressants

Antidepressants are among the most studied pharmacologic agents for FGIDs. Mechanisms of action are thought to include reduction of pain perception, improvement of mood and sleep patterns, as well as modulation of the GI tract, often through anticholinergic effects. A recent review of adult studies found that antidepressants, such as tricyclic antidepressants (TCAs) and selective serotonin-reuptake inhibitors (SSRIs), were beneficial for the treatment of FGIDs.[49] However, in the last few years, overall use of antidepressant medications in children and adolescents has been somewhat tempered by concerns for increased suicidal thoughts and/or behavior, especially after the US FDA issued formal 'black-box' warnings in 2004. A subsequent meta-analysis did not find evidence that these suicidal thoughts or behaviors led to an increased risk of suicide.[50]

Tricyclic antidepressants primarily act through noradrenergic and serotonergic pathways but also have antimuscarinic and antihistaminic properties. Anticholinergic effects on the GI tract in terms of slowing transit can be beneficial for patients with IBS characterized by diarrhea, but may worsen constipation. Additional side effects include the potential for inducing cardiac arrhythmias, so evaluation for prolonged QT syndrome with a baseline ECG is recommended by the American Heart Association.[51] Owing to sedative properties, TCAs should be given at bedtime. The usual starting dose is 0.2 mg/kg and is increased to a therapeutic dose of approximately 0.5 mg/kg.

Two recent pediatric trials studied the efficacy of amitriptyline, a tertiary amine TCA, for the treatment of IBS and FAP. Bahar et al. studied 33 adolescents newly diagnosed with IBS according to Rome II criteria and randomized them to 8 weeks of 10, 20 or 30 mg of amitriptyline (based on weight) versus placebo.[52] The primary outcome was improvement in overall IBS quality of life score, which was measured along with IBS symptoms after 4 and 8 weeks of treatment, as well as after a 3-week washout period. Compared with placebo, patients receiving amitriptyline were more likely to have an improvement in overall quality of life from baseline at all three time points (p = 0.019, 0.004 and 0.013, respectively). Baseline scores for patients in the amitriptyline group were significantly lower than the placebo group to begin with: 109.4 versus 127.5, respectively (p = 0.05). There was also an unusual negative placebo effect seen in the control group, which may have contributed to the statistically significant differences seen in comparisons between the two groups. Patients receiving amitriptyline were found to have inconsistent improvement of pain in some, but not all, areas of the abdomen and only at certain times of follow-up. There was no significant improvement in any other IBS-related symptoms.

In a multicenter study by Saps et al., 83 children diagnosed with IBS, FAP or functional dyspepsia according to Rome II criteria were randomized to 4 weeks of placebo or amitriptyline (10 or 20 mg daily depending on weight).[13] The primary outcome was overall response to treatment based on the child's report of pain relief and sense of improvement. A substantial proportion of patients in both groups reported feeling better, but there was no significant difference between patients receiving amitriptyline versus placebo (63 vs 57.5%, respectively). Patients in the amitriptyline group had reduced anxiety scores (p < 0.0001), but there was no difference in improvement in pain, disability, depression or somatization scores during the 4-week trial. Children who had more severe pain at baseline in both groups had worse outcomes (p = 0.0065). The authors postulated that the lack of significant findings may have been due to issues with insufficient statistical power, clinical heterogeneity of patients, relatively lower dosing of amitriptyline and shorter treatment duration (4 weeks), as well as the high placebo response observed.

Selective serotonin-reuptake inhibitors act by blocking uptake of 5-hydroxytryptamine (5-HT), increasing its concentration at presynaptic nerve endings. In addition to its CNS effects on mood and anxiety, SSRIs may also be beneficial for gastrointestinal complaints, since serotonin is an important neurotransmitter in the GI tract and greater than 80% of the body's stores are located in enterochromaffin cells of the gut.[48] The exact role of serotonin in the GI tract has not been fully elucidated, but it has been implicated in the modulation of colonic motility and visceral pain in the gut.

Well-controlled randomized pediatric trials on the use of SSRIs for either FAP or IBS are lacking. Campo et al. conducted a prospective, open-label, flexible-dose study of citalopram for children (aged 7–18 years old) with 'functional recurrent abdominal pain'.[53] In total, 25 patients were started on 10 mg of citalopram daily for the first week and increased to 20 mg daily for the second week. If no clinical response was obtained and the medication was well-tolerated it was increased to 40 mg daily in week 4. Four patients withdrew from the study prematurely, including one subject owing to reported visual side effects. At the end of 12 weeks of treatment, 84% of subjects were classified as responders on a global illness improvement scale. Improvements in abdominal pain, anxiety, depression, other somatic symptoms and function compared with baseline were also reported.[53] Although these findings are promising, they need to be confirmed with additional clinical trials. In a recent randomized placebo-controlled trial of citalopram for adult patients with IBS, there was no significant benefit after 8 weeks of treatment.[54]

Monoamine uptake inhibitors, such as duloxetine and venlafaxine, represent a newer group of antidepressant medications with effects on serotonergic and adrenergic pain inhibition systems. These medications have shown evidence of analgesia in patients with fibromyalgia and diabetic neuropathy, but there have been no studies on the treatment of pediatric FGIDs.[48]

Antispasmodics

Antispasmodic medications, such as peppermint oil and hyoscyamine, are thought to be helpful for FAP and IBS through their effects on decreasing smooth muscle spasms in the GI tract that may produce symptoms such as pain. In a recent meta-analysis, antispasmodics as a class were superior to placebo in the treatment of adults with IBS.[17] There was a significant amount of variability among included studies in terms of antispasmodic preparation, measured outcomes and overall methodological quality. Several agents included in the meta-analysis, such as otilonium, cimetropium and pinaverium, are not currently available in the USA.

The active ingredient in peppermint oil, menthol, is a cyclic monoterpene with calcium channel blockade properties believed to be active on ileal and colonic smooth muscle. Reported side effects include rectal burning, esophageal pain or heartburn and allergic reactions. To date, there has only been one pediatric study of antispasmodic medication for FGIDs. Kline et al. performed a small, randomized placebo-controlled trial of peppermint oil in 42 children with IBS.[55] Subjects in the peppermint oil group received either 187 or 374 mg three-times daily depending on their weight, while control subjects received placebo capsules containing peanut oil. At the end of the 2-week trial, 76% of the children receiving peppermint oil reported improvement on an IBS symptom severity scale compared with 19% in the placebo group (p < 0.001). However, there was no difference between groups in terms of heartburn, belching, stool pattern or stool consistency.[55]

Hyoscyamine and dicyclomine are both considered antispasmodics owing to their anticholinergic effects on smooth muscle. Hyoscyamine has occasionally been used in children on a short-term basis for gastrointestinal symptoms of pain, but long-term use has been associated with anticholinergic side effects such as dry mouth, urine retention, blurred vision, tachycardia, drowsiness and constipation. There have been no studies of either medication for pediatric FAP or IBS, but hyoscyamine was found to have consistent evidence of efficacy in an adult meta-analysis.[17]

Cyproheptadine

Cyproheptadine is a medication with multiple mechanisms, including antihistaminic, anticholinergic and antiserotonergic properties, as well as possible calcium channel blockade effects. It has been used in appetite stimulation and prevention of pain and vomiting in abdominal migraine and cyclic vomiting syndrome. Sadeghian et al. studied the use of cyproheptadine in 29 children and adolescents (aged 4.5–12 years) diagnosed with FAP in a 2-week, double-blind placebo-controlled trial. At the end of the study, 86% in the cyproheptadine group had improvement or resolution of abdominal pain compared with 35.7% in the placebo group (p = 0.003).[56] These results need to be confirmed with additional larger trials.

Acid Suppressants

Acid suppression agents, such as H2 blockers and proton pump inhibitors, are among the most common medications that are used in children with abdominal pain. Famotidine was studied by See et al. in a randomized, double-blind, placebo-controlled crossover trial of 25 children (aged 5–18 years) who met Apley's crieteria for RAP and reported symptoms of dyspepsia.[57] Children who met criteria for IBS were excluded. Patients received famotidine 0.5 mg/kg per dose twice daily for at least 14 days, although the total treatment length was variable depending on symptom response. On a subjective global assessment scale, more patients reported improvement on famotidine (68%) versus placebo (12%). However, there was no significant difference between famotidine and placebo on quantitative measures of symptom frequency and severity. There have been no controlled studies on the use of proton pump inhibitors for FAP or IBS.

Prokinetics

Prokinetic agents that stimulate gastrointestinal motility have been employed for patients with FGIDs, especially for conditions involving constipation or delayed gastric emptying, such as IBS and functional dyspepsia.[58] Tegaserod is a serotonin agonist that induces acceleration of small bowel and colonic transit through activation of 5-HT4 receptors in the enteric nervous system. When combined with polyethylene glycol (PEG) 3350, tegaserod was found to be more effective in alleviating abdominal pain and increasing the number of bowel movements in adolescents with constipation-predominant IBS compared with PEG 3350 alone.[59] However, owing to an increased rate of cardiovascular events in adults taking the medication, tegaserod was removed from the market in March 2007. Two other serotonin-based agents with actions upon the 5-HT3 receptor, alosetron and cilansetron, were also shown to be effective for adults with diarrhea-predominant IBS, but complications of severe constipation, ischemic colitis and perforations prompted withdrawal of these medications from the market in 2000.[60] Dopamine (D2) receptor antagonists, such as metoclopramide and domperidone, improve gastric motility, but their use in pediatric FAP and IBS is limited by concerns for side effects including extrapyramidal reactions, drowsiness, agitation, irritability and fatigue.[61] Erythromycin, an antibiotic with motilin receptor agonist properties in the stomach at doses of 1–2 mg/kg per dose may also be helpful for symptoms of pain or dyspepsia, but there are no pediatric data to support its routine use in FAP or IBS.[62]

Other Agents

Several agents have been studied for the treatment of conditions such as dyspepsia, constipation, diarrhea, abdominal migraine or small bowel bacterial overgrowth in conjunction with FAP or IBS. Lubiprostone is a member of a new class of bicyclic fatty acid derivatives known as prostones. Lubiprostone acts on type-2 chloride channels located on the apical side of gastrointestinal epithelial cells to promote electrolyte and fluid secretion into the small intestine and may also stimulate colonic motility. In two clinical trials of adults with constipation-predominant IBS, 17.9% of patients treated with lubiprostone reported improvement in IBS symptoms compared with 10.1% of those treated with placebo (p = 0.001).[63] A pediatric trial of lubiprostone for functional constipation has been completed, and preliminary data suggest that it was efficacious in the treatment of children with constipation.

Loperamide is an opioid-receptor agonist that slows colonic transit by acting on myenteric plexus receptors of the large intestine. Although loperamide is commonly used for treating diarrhea and urgency in patients with diarrhea-predominant IBS, adult studies have shown efficacy only against symptoms of diarrhea and not abdominal pain.[64] For patients with FAP or IBS associated with constipation, stool softeners and laxatives have been likewise employed. In the previously mentioned study of adolescents with constipation-predominant IBS conducted by Khoshoo et al., patients treated with PEG 3350 oral solution as sole therapy did have a significant increase in number of bowel movements, but no improvement in abdominal pain.[59]

Finally, bacterial fermentation of undigested carbohydrates in small bowel bacterial overgrowth has been suggested as a potential cause of IBS symptoms such as abnormal gas production and bloating. Treatment of bacterial overgrowth with antibiotics such as neomycin and rifaxamin has been found to be beneficial in adults with IBS.[65,66] Similar studies in children and adolescents are currently lacking.

Despite the wide range of potential pharmacologic options, the lack of good quality, well-controlled, pediatric trials prompted a recent Cochrane review to conclude that the "true efficacy of drugs for FGIDs in children remains to be elucidated".[67] A technical review endorsed by the American Academy of Pediatrics and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition similarly found limited evidence to justify the use of drugs or herbal preparations for chronic abdominal pain in children.[68] The use of low-dose antidepressants may be beneficial for a select group of patients, especially those with anxiety or other psychological comorbidities.

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