The serotonin (5HT)-1 and H-1 histamine receptor antagonist cyproheptadine is used as a first-line drug by many practitioners due to its favorable side effect profile (Table 45.2). 5HT-1 blockade may improve gastric accommodation, thus improving dyspeptic symptoms and providing more room for a larger meal. In toddlers with poor weight gain cyproheptadine is used to stimulate appetite [8]. At 0.25–0.5 mg/kg/day in two or three divided doses it appears to increase voluntary oral intake in more half those treated for about 3 weeks. Tolerance to appetite stimulation appears after roughly 3 weeks, so when it is used as an appetite stimulant cyproheptadine is cycled: 3 weeks on then 3 weeks off. Cyproheptadine prevents cyclic vomiting syndrome and abdominal migraine in the doses described above [9]. NASPGHAN guidelines suggest trying cyproheptadine before amitriptyline in children <5 years of age because of cyproheptadine’s safety and side effect profile when compared to amitriptyline. Also, cyproheptadine is available as a liquid, but amitriptyline must be compounded to liquid form for children unable or unwilling to swallow pills. Cyproheptadine may improve symptoms in children with dyspepsia [10] and other functional abdominal pain disorders [11].

Amitriptyline and other tricyclic antidepressants (TCAs ) have complex anti-nociceptive effects. They inhibit the membrane pump mechanism responsible for uptake of norepinephrine and serotonin, increasing adrenergic and serotonergic activities. Tricyclics inhibit muscarinic cholinergic binding. Amitriptyline’s pain-relieving properties are likely to be mediated, in part, by recruitment of the endogenous opioid system acting through delta opioid receptors [12]. One theory is that tricyclics begin a process leading to decreased corticotropin releasing factor secretion, thus reducing autonomic arousal. Low dose tricyclic antidepressants have been used for chronic pain for decades. An adult RCT comparing a TCA to cognitive behavioral therapy showed that desipramine and CBT were equivalent in short-term relief of chronic pain from IBS, and both were better than time spent on IBS education [13]. Another adult RCT compared amitriptyline, escitalopram, and placebo for functional dyspepsia [14]. Amitriptyline was most effective for epigastric pain-type dyspepsia. Escitalopram was no better than placebo. Amitriptyline is used to treat chronic neuropathic pain. In RCTs among children with functional abdominal pain, amitriptyline and placebo were both associated with an excellent therapeutic response [15, 16]. In doses that are a small fraction of the doses required for depression, amitriptyline was shown to reduce chronic pain. Amitriptyline was part of a multidisciplinary approach to treat chronic pain in tube fed, medically fragile infants and toddlers, resulting in subjects moving to oral feeding [17, 18]. For chronic gastrointestinal pain or constant nausea a single daily bedtime dose is standard. Amitriptyline has the greatest anticholinergic and anti-histaminergic effects among the TCAs, inducing sleep and reducing diarrhea in diarrhea-predominant IBS [19]. Other TCAs including imipramine, doxepin, nortriptyline, desipramine, and clomipramine may be less sedating and less constipating, and all reduce chronic pain in rats. Doxepin has the best anxiolytic effects of the TCAs, and is sedating, so for patients with anxiety-associated symptoms, doxepin may be a better choice than amitriptyline. Nortriptyline is the least sedating, least constipating of the TCAs. Doxepin and nortriptyline are sold as liquids suitable for children who cannot swallow tablets. Liquid amitriptyline and the other TCAs require preparation at a compounding pharmacy.

Amitriptyline’s anticholinergic and antihistaminic properties result in side effects such as dry mouth, constipation, urinary retention, and sedation. Weight gain is common, because amitriptyline improves postprandial pain, nausea, and early satiety [20]. Less common side effects include muscle stiffness, nausea, nervousness, dizziness, blurred vision, urinary retention, and insomnia. Rare side effects include tinnitus, hypotension, mania, psychosis, heart block, arrhythmias, lip and mouth ulcers, extra pyramidal symptoms, depression, and hepatotoxicity [20]. TCAs can also cause dizziness, peripheral numbness, and tingling and reduce seizure threshold. Medications including serotonin reuptake inhibitors (SSRIs ), clonidine, fluconazole, erythromycin, terfenadine, carbamazepine, and phenothiazines compete with amitriptyline for metabolism.

In the author’s experience, the usual amitriptyline dose for chronic functional abdominal pain is 1 mg/kg/day up to 50 mg/day. It should be taken an hour or two before bedtime to promote restful sleep. To avoid over-sedation, the first week dose should be 10 mg in patients >50 kg, or one-third to one-fourth of the final dose. Each week the dose can be increased by the starting dose. If the patient responds at a lower dose than 1 mg/kg escalating doses stop, so that the patient receives the lowest effective dose to minimize dose-dependent side effects. Treatment duration for chronic pain or nausea is usually until the symptom disappears plus 6 months, or perhaps until the end of the school year. Pain reduction may take several weeks or even months. Immediate pain reduction likely represents a placebo effect. On the other hand, amitriptyline may improve sleep disturbances from the first doses. Abrupt cessation of amitriptyline is associated with nightmares. Sleep disturbances are avoided by incremental dose reduction over several weeks, in steps similar to dose escalation at the start of treatment.

Amitriptyline in doses similar to those for abdominal pain prevents attacks in patients with cyclic vomiting syndrome [9], abdominal migraine, and migraine headaches [21]. Amitriptyline reduces the number of acute CVS attacks in 80 % of affected children, the highest prevention rate of the drugs used for prophylaxis.

In contrast to the routine use of amitriptyline in adults and older children, there is a lack of anything but retrospective, uncontrolled data on the use of amitriptyline in infants and toddlers. Although studies using amitriptyline to treat visceral pain in infants and toddlers showed promise [17] and pain is believed to be a contributor to some children with chronic food refusal [18], one small RCT showed no effect of 1 mg/kg/day amitriptyline in the transition from tube to oral feeding [22]. In that study serial electrocardiograms over 24 weeks revealed no changes in heart rate, P-R interval, QRS duration, or QTc interval.

In the author’s experience, amitriptyline frequently resolves long-term fecal incontinence following successful surgery for Hirschsprung’s disease .

Amitriptyline overdose is associated with serious cardiac arrhythmias and death. On the other hand, at doses 1 mg/kg/day used to treat chronic pain and nausea, there have been no reports of death or cardiac arrhythmias in over 60 years. In the author’s opinion, an electrocardiogram before starting a TCA is unnecessary in otherwise healthy children and adolescents, but may be advisable in those with a personal or family history of QTc prolongation or a history of heart disease. In a risk-prevention study involving 760 children with functional abdominal pain, the risk of true prolonged QT interval was no greater than that of the normal population [23, 24]. However, electrocardiograms picked up cases of prolonged QTc interval and Wolf–Parkinson–White syndrome in unsuspected children and the drug was avoided in those children. If there are cardiac safety issues, it is advisable to choose a different psychotropic medication or mode of therapy.

Serotonin-receptor inhibitors (SSRIs ) increase the extracellular level of serotonin by limiting its reabsorption into the presynaptic cell, increasing the level of serotonin in the synaptic cleft available to bind to the postsynaptic receptor. SSRIs have weak affinity for the norepinephrine and dopamine transporters, and weak anticholinergic effects. Because they have efficacy equal to the tricyclics, but fewer side effects at doses that treat depression, and safer with overdose, SSRIs are first-line drugs for depression and anxiety. SSRIs include fluoxetine (Prozac), citalopram (Celexa), escitalopram (Lexapro), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft).