See “Commentary on ‘Psychotropic Medications for Pediatric Functional Gastrointestinal Disorders’” by Sipe on page 279.
During the past 2 decades, pediatric gastroenterologists have been using psychotropic medications for off-label indications, despite the absence of randomized clinical trials (RCTs). Pediatric gastroenterologists learned about psychotropic medicines from adult gastroenterology RCTs. Adult data, however, do not assess the risk of long-term effects of psychotropic medicine on the developmental aspects of the central nervous system (CNS) or the enteric nervous system. The possibility of adverse neurodevelopmental alterations caused by psychotropic medications is a reason for caution in treating children.
The Pediatric Research Equity Act of 2007 mandated that the pharmaceutical industry perform pediatric trials for safety and efficacy after a new drug is approved (1). A minority of psychotropic drugs has been studied in children, and safety data remain inadequate. Psychotropic drugs used for gastrointestinal symptoms in pediatric patients will be off-label for the foreseeable future. The purpose of the present article was to review psychotropic medicines used for gastrointestinal symptoms, and to consider evidence for their safety and efficacy in children. On many psychotropic drug labels, there is a warning about suicidal thoughts and actions in adolescents. Suicide risk may be related to depressed individuals responding to antidepressants with new energy to carry out suicidal thoughts (2,3).
Functional gastrointestinal disorders (FGIDs) are common in the general population, but only a minority seeks symptom relief from a pediatric gastroenterologist. The decision to consult with a gastroenterologist is based on the family's concern about disease and/or concern about disability associated with functional symptoms. The disability associated with functional symptoms is most often related to a maladaptive coping style and overt or covert mental health issues such as learning disabilities, anxiety, or depression. In adolescents, FGIDs associated with school absence are most often related to the patient's perception of his or her own social or academic incompetence. Patients who are disabled (ie, cannot attend school or cannot eat) by functional symptoms may benefit from a biopsychosocial, combined mind–body approach. Conversely, in adolescents with a functional disorder and disability, a focus isolated to either mind or body alone is less likely to work. Most pediatric gastroenterologists do not collaborate routinely with psychiatrists or other mental health professionals, and may find the present article useful as a practical guidance.
Before prescribing psychotropic drugs or psychological interventions, the clinician must address inaccurate beliefs or expectations of patients and their parents. Some children and their families express skepticism about the role for psychotropic medications for physical symptoms (Fig. 1). Moreover, children and families do not want to be labeled as having mental health problems, and fear stigmatizing from the use of a psychotropic drug. Discussion among parents and patients may change their minds about the differences between the medical and biopsychosocial models of practice, the role of CNS arousal in disabling chronic symptoms, evidence of efficacy using psychotropic drugs for functional symptoms and associated disability, and factors known to predict absence of symptom improvement, such as refusal to accept psychosocial influences as a factor in disability and refusal to engage with a mental health professional (4–6). The prescriber must provide information about adverse effects and a rationale that is consistent with patient's interests, and must dispel the unspoken fears. It is important to reassure children and their families that properly prescribed psychotropic drugs do not alter patients’ minds or give rise to addiction, and they do reduce pain by working on pain centers in the brain. It is helpful to emphasize that the doses used by pediatric gastroenterologists are lower than those used by psychiatrists, and drugs’ effects do not last afters drugs are discontinued. This discussion requires documentation in the medical record and a time-based billing code.
INDICATIONS FOR USING PSYCHOTROPIC DRUGS IN PEDIATRIC GASTROENTEROLOGY
Pediatric gastroenterologists should familiarize themselves with the first tier of choices for various FGIDs (Fig. 2). Amitriptyline is on the first tier because it has been an accepted treatment for functional abdominal pain despite its frequent undesirable adverse effects and cardiac risk associated with overdose. Gabapentin is on the first tier because of its favorable adverse effect profile despite less than optimal efficacy. Mirtazapine is on the first tier because of its excellent efficacy and favorable adverse effect profile. Neurogastroenterologists should be comfortable with both the first and second tiers. For combination therapy with second-generation antipsychotics (SGAs), it may be advisable to collaborate with a child psychiatrist. The choice of psychotropic medications (Table 1) depends on the type of FGID, and various tiers can be applied depending on the clinical scenario. It will also be useful for practicing pediatric gastroenterologists to understand the sites of action for various psychotropic drugs on the brain–gut axis (Fig. 3).
Chronic Abdominal Pain
Chronic abdominal pain is the most common chief complaint at pediatric gastroenterology clinics. Chronic pain is often caused by a sensitization of visceral afferent nerves to pressure (hyperalgesia), and amplification of pain messages in CNS arousal systems (secondary hyperalgesia). Chronic visceral pain is a CNS disorder, characterized by altered pain pathways and structural changes (7–11). Brain and gut are connected by efferent and afferent nerves, each modulating the other, providing a rationale for the use of psychotropic drugs for the treatment for chronic gastrointestinal symptoms (Fig. 3). Moreover, recent evidence from brain imaging demonstrated changes in cortical thickness and white matter pathways associated with chronic pain (12). CNS sensory amplification of peripheral pain and nausea is a feature of chronic pain physiology. Finally, it may be that the disability associated with FGIDs is related to a child's prediction error, or catastrophization, that is, the child believes that the symptoms are severe and hopeless, can only worsen, and that they cannot cope (13). Catastrophization further activates autonomic arousal. Similarly, an external locus of control, the belief that the suffering can be reduced only from outside sources, interferes with coping and further amplifies arousal.
Many children experience chronic abdominal pain that is not severe enough to affect activities. Treatment of choice for chronic, bothersome functional abdominal pain is usually pharmacological (Table 1), and the most common treatment has been amitriptyline (14,15), followed by gabapentin and clonidine (discussed in detail below). Although evidence exists about how food, infection, inflammation, permeability, and the gut microbiome contribute to triggering symptoms, pain or nausea associated with FGIDs responds to treatments targeting the CNS. Hypnosis (16,17), cognitive behavioral therapy (CBT) (18–20), and Celexa (21) trials in children were more successful than cisapride, tegaserod, famotidine (22), or rifaximin (23,24) for irritable bowel syndrome (IBS). Hypnosis and cognitive behavioral strategies, however, are not helpful with young nonverbal or preverbal children.
Amitriptyline is used to treat chronic neuropathic pain and to prevent migraine headache in all age groups except infants and toddlers. At the low doses used for chronic pain (<1 mg · kg−1 · day−1), there have been no reports of death or serious adverse effects such as cardiac arrhythmias. Studies using amitriptyline to treat visceral pain in infants and toddlers showed promise (25), and pain is believed to be a contributor to some children with chronic food refusal (26). An adult RCT comparing a tricyclic antidepressant (TCA) with CBT showed that drugs and CBT were equivalent in short-term relief of chronic pain from IBS, and both were better than time spent on IBS education (27). Psychotherapy and hypnosis have the advantage of effects that last long after the treatment period compared with drug effects that last only as long as treatment continues. Drugs, however, have the advantage of not requiring a psychotherapist.
Pain-associated disability syndrome (PADS) describes when chronic functional abdominal pain (or another symptom, eg, nausea or rumination) causes disabilities such as school absenteeism or food refusal for ≥2 months in the absence of organic disease (28,29). PADS occurs in preteens and adolescents. Treatment requires a multidisciplinary team approach that must include the family. When the family does not accept the diagnosis or challenges the treatment, management fails. When the child, family, and team of professionals are in sync, treatment succeeds.
When a preteen or teen complains of constant nausea or dyspepsia, there is a high probability that the cause is unrecognized (or recognized) anxiety. Several psychotropic drugs reduce the nonspecific CNS arousal that results in chronic, continuous nausea (Table 2). Bedtime amitriptyline, mirtazapine, or twice-daily buspirone may eliminate anxiety-associated nausea. Selective serotonin reuptake inhibitors (SSRIs) have transient but bothersome gastrointestinal adverse effects that may preclude their use for anxiety-associated nausea.
Cyclic Vomiting Syndrome (CVS)
Psychotropic drugs are used to prevent acute episodes of CVS, and to treat an acute episode. Amitriptyline reduces the number of acute attacks in 80% of affected children, and the highest prevention rate of the drugs used for prophylaxis and dosing should be <1 mg · kg−1 · day−1 (maximum 50 mg/day). Recently, mirtazapine seemed an effective prophylaxis for CVS (30).
The goal of treatment for acute CVS is to relieve suffering, which is accomplished with long-acting intravenous benzodiazepines (BZDs) titrated to restful sleep in most patients. For families who opt to stay at home, repeated doses of rectal diazepam (approximately 50% bioavailable) are the best option. The goal at home is restful sleep until vomiting episodes cease to exist.
Prevention of Medical Posttraumatic Stress Disorder (PTSD)
Hospitalization may be associated with increased arousal and distress. Hospitalization for medical illness is a trigger for PTSD, especially when perceived as a life-threatening problem or acute, severe pain. Procedures and treatments ordered by well-meaning clinicians may precipitate medical PTSD when patient comfort is not a priority. Placement of a nasogastric tube or an intravenous catheter by a novice and without sedation is an example of an unnecessary pain experience. Oral or nasal midazolam and an experienced clinician help the child to cope with unavoidable trauma. There are development-dependent signs and symptoms for childhood PTSD, and evidence-based trauma-focused treatment is indicated for those who remain greatly distressed or impaired (13).
Comorbid Psychological Symptoms
Comorbid psychological distress is associated with disability from pain-predominant FGIDs (29). Psychological distress, in turn, is related to maladaptive coping styles (31). Catastrophization, a belief that the pain can only get worse and that the patient is helpless against pain, may be at the root of anxiety symptoms. These can be treated with CBT to change the maladaptive thinking or with drugs to treat symptoms.
Sleep disorders affect a majority of children with stomachache. Promptly correcting a sleep problem is a way to gain a therapeutic alliance with a patient experiencing insomnia and chronic pain. Although most drugs and psychotherapy may take weeks to achieve maximal effect, sleep can be treated from the initial visit. When patients’ fatigue resolves after restful sleep, they are more likely to accept other suggestions. There is no consensus about which drug to use. Over-the-counter melatonin is the safest of drugs used to initiate sleep. If it does not sustain sleep, after night waking a patient may repeat the dose of melatonin. Amitriptyline regulates sleep and treats chronic pain and diarrhea. Trazadone is used to promote sleep, but there are no RCTs to support its use. Mirtazapine 7.5 mg induces sleep because antihistaminic effects are prominent at the low dose. The α2-adrenergic agonist clonidine helps disordered sleep. The antihistamine diphenhydramine is prescribed for sleep more than any other drug, but there is evidence of frequent paradoxical excitation, next-day fatigue, drowsiness, and impaired cognition, and tolerance develops quickly to antihistamines (32). Antihistamines are a poor choice for regulating sleep.
CLASSES OF PSYCHOTROPIC DRUGS FOR PEDIATRIC FGIDS
Amitriptyline is an antidepressant with sedative and complex antinociceptive effects (Table 2). It inhibits the membrane pump mechanism responsible for uptake of norepinephrine and serotonin, and inhibits 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 (33).
In RCTs among children with functional abdominal pain, both amitriptyline and placebo were associated with an excellent therapeutic response (14,15). In doses that are a small fraction of the doses required for depression, amitriptyline reduced chronic pain. For chronic gastrointestinal pain or constant nausea, a single daily bedtime dose is standard. Amitriptyline has the greatest anticholinergic and antihistaminergic effects among the TCAs, inducing sleep and reducing diarrhea in diarrhea-predominant irritable bowel syndrome (34). It prevents attacks in patients with CVS (35), abdominal migraine, and migraine headaches (36). Other tricyclics may be less sedating and less constipating, including imipramine, doxepin, nortriptyline, desipramine, and clomipramine (37), all of which have been shown to be effective for reducing chronic pain in rats. Doxepin has the best anxiolytic effects of the tricyclics; for patients with anxiety-associated symptoms, doxepin may be a better choice than amitriptyline. Doxepin and nortriptyline are sold as liquids suitable for children who cannot swallow tablets. Liquid amitriptyline and the other tricyclics require preparation at a compounding pharmacy.
Amitriptyline's anticholinergic and antihistaminic effects result in adverse effects such as dry mouth, constipation, urinary retention, and sedation. Weight gain is common, because amitriptyline improves postprandial pain, nausea, and early satiety (37). Less common adverse effects include muscle stiffness, nausea, nervousness, dizziness, blurred vision, urinary retention, and insomnia. Rare adverse effects include tinnitus, hypotension, mania, psychosis, heart block, arrhythmias, lip and mouth ulcers, extrapyramidal symptoms, depression, and hepatotoxicity. Amitriptyline can also cause dizziness, peripheral numbness, and tingling and reduce seizure threshold. Medications including SSRIs, clonidine, fluconazole, erythromycin, terfenadine, carbamazepine, and phenothiazines compete with amitriptyline for metabolism.
The usual dose of amitriptyline for chronic functional abdominal pain is 1 mg · kg−1 · day−1 up to a maximum of 50 mg/day. It should be taken 1 or 2 hours before bedtime to promote restful sleep. To avoid oversedation, the first-week dose should be one-fourth of the final dose. Each week the dose can be increased by one-fourth of the final dose. If the child responds at a smaller dose than 1 mg/kg, dose escalation should stop, so the child receives the lowest effective dose to minimize dose-dependent adverse effects. Treatment duration for chronic pain or nausea is usually until the symptom disappears plus 6 months. Abrupt cessation of amitriptyline is associated with nightmares (37). Sleep disturbances are avoided by incremental dose reduction for several weeks, in steps similar to dose escalation at the start of treatment.
Is an Electrocardiogram (EKG) Necessary Before Starting or for Monitoring During Treatment With Amitriptyline?
Amitryptyline overdose is associated with serious cardiac arrhythmias and death. On the contrary, at doses <1 mg · kg−1 · day−1 used to treat chronic pain and nausea, there have been no reports of death or cardiac arrhythmias in >60 years. An EKG 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 corrected QT interval prolongation or a history of heart disease, or in children requiring a dose of >50 mg/day. 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 (38). EKGs, however, picked up cases of true prolonged corrected QT interval and Wolff-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 a mode of therapy (Table 1).
Meta-analysis of RTCs in adults suggested that SSRIs were equivalent to TCAs in symptom relief in IBS, followed by larger studies showing usefulness of SSRIs in IBS (39). In children there was a single RCT showing citalopram superior to placebo in IBS (21). Some clinicians obtain an EKG assessing corrected QT interval before initiating citalopram doses >20 mg daily. There appears to be an increased risk of cardiac arrhythmias at doses >40 mg daily. SSRIs may be used in combination with TCAs in teens and adolescents, for example, amitriptyline at bedtime to treat pain and facilitate sleep, with nonsedating fluoxetine for anxiety and/or depression in the morning. SSRIs compete with TCAs in degradation pathways, so using them simultaneously may increase serum concentrations of both. Gastrointestinal adverse effects such as diarrhea, nausea, and constipation are common but usually transient with all of the SSRIs. Gastrointestinal adverse effects may be minimized by beginning treatment at low doses. Responses to each SSRI may differ in the same patient, so that clinicians should not feel limited to 1 SSRI. It may benefit patients who find 1 SSRI intolerable or ineffective after 1 month to switch to another SSRI, mirtazapine, or buspirone.
Short-acting BZDs (eg, midazolam, diazepam) are used for sedation and amnesia for minor procedures such as nasogastric tube placement, changing gastrostomy appliances, and in outpatient surgeries (40). There is no role for short-acting BZDs for chronic abdominal pain or nausea. Intravenous long-acting BZDs may be effective for inducing sleep and so relieve suffering in an acute CVS episode. There is only anecdotal evidence that these agents may have beneficial effects in patients with IBS with anxiety disorders. Occasionally clonazepam 0.25 to 0.5 mg bid may be helpful for anxiety relief for 1 or 2 weeks, when waiting for an SSRI to take effect. The addiction potential, worsening of associated depression, and poor safety profile of BZDs make them unattractive. Chronic BZD use is associated with drug tolerance and drug dependency.
Serotonin-Norepinephrine Reuptake Inhibitors
Duloxetine, venlafaxine, and milnacipran are drugs that increase synaptic serotonin and norepinephrine. All are Food and Drug Administration (FDA) approved for treating adults with fibromyalgia, and there is anecdotal evidence for improvement in symptoms with other chronic pain disorders. No RTCs have investigated serotonin-norepinephrine reuptake inhibitors for FGIDs.
Gabapentin is an anticonvulsant often used to treat neuropathic pain. It works on voltage-sensitive calcium channels to reduce excessive neuronal activity and neurotransmitter release. In postmarketing assessments it appeared to improve chronic pain in about one-third of those taking it (41). It relieved chronic irritability in nonverbal children, perhaps by reducing pain or dysphoria (42). For infants and toddlers treated with 10 mg · kg−1 · dose−1 BID or TID, adverse effects are uncommon. Adverse effects include dry mouth, nausea, tiredness, clumsiness, or dizziness. Serious adverse effects are rare. In anecdotes, it improved early satiety in infants after cardiac surgery and in infantile colic. Infants and toddlers with presumed dysphagia or dyspepsia after unusual pain experiences are treated with 10 mg · kg−1 · dose−1 bid and advanced to tid if there are no adverse effects. There are no long-term safety data concerning the effects of gabapentin on brain development.
Clonidine is an α-agonist used in patients with abdominal pain (43). In adults, clonidine improved diarrhea-predominant IBS (44). It reduces gastrointestinal symptoms from narcotic withdrawal. Common adverse effects include dry mouth, drowsiness, dizziness, and tiredness. Because of clonidine's antihypertensive properties, we recommend checking blood pressure at each clinic visit and at any time new symptoms associated with hypotension occur. Clonidine is available as patch (0.1–0.3 mg) and is convenient for use in children (Table 2).
SGAs are powerful drugs usually reserved for treating psychosis. In low doses, however, an SGA may be a useful adjunct to induce and maintain sleep and reduce severe anxiety. Quetiapine is an antipsychotic with complex effects related to dopamine, α2-adrenergic, and serotonin antagonism. It appears to reduce risk of suicide in agitated depression. In nonverbal developmentally delayed children who appear to be in great distress, risperidone may be effective in calming both patient and family (45). Usually low doses (0.2–0.5 mg per dose twice daily) suffice. Metabolic and neurological adverse effects occur in children treated with SGAs. The risk of weight gain, increased body mass index, and abnormal lipid levels is greatest with olanzapine, followed by clozapine and quetiapine. The risk of neurological adverse effects including dysphoria and extrapyramidal symptoms is greatest with risperidone, followed by olanzapine and aripiprazole (46).
There is no role for opiates in the treatment of chronic pain or nausea. Opiates may be necessary to relieve pain during acute episodes of abdominal migraine. Codeine is a cause for constipation and sphincter of Oddi malfunction–induced pancreatitis (47).
Buspirone is an anxiolytic used alone or in combination with SSRIs or TCAs. It acts via non-BZD γ-aminobutyric acid receptors. It has a strong affinity for serotonin receptors (5-HT1 and 5-HT2) and a moderate affinity for dopamine-2 receptors (D-2). In adults the anxiolytic buspirone reduced symptoms of dyspepsia presumably by improving receptive relaxation of the stomach and through CNS effects (48). Buspirone may improve symptoms, or augment therapy with antidepressants in adolescents (49). It was effective in children and adolescents with anxiety disorder (50).
Mirtazapine is a noradrenergic and specific serotonergic antidepressant. Structurally, it is classified as a tetracyclic antidepressant. In adolescents, mirtazapine helped chronic vomiting by reducing nausea, early satiety, and postprandial fullness (30). It is effective for children with social phobia (51) and for reducing panic attacks. It is a good choice for chronic nausea because it has only a few drug interactions (unlike amitriptyline). At a 7.5-mg dose, mirtazapine's antihistamine effects dominate the adverse effect profile, and it is sedating. It is taken at bedtime to improve sleep. At 15 and 30 mg, mirtazapine is less sedating because at doses higher than 7.5 mg, α2-adrenergic presynaptic receptor blockade leads to increased norepinephrine neurotransmission. Weight gain is a common adverse effect.
Melatonin (N-acetyl-5-methoxytryptamine) is an endogenous hormone secreted from the pineal gland that plays a role in the regulation of circadian rhythms. Exogenous melatonin taken at bedtime can initiate, but not maintain, sleep. There is a great deal of evidence that melatonin is safe and effective in a majority of children, in doses between 3 and 10 mg, 1 or 2 hours before bedtime (52).
Phenothiazines were a mainstay of treatment for acute, severe vomiting in the past. Newer drugs are safer, and have a better adverse effect profile. For cyclic vomiting episodes and familial dysautonomia vomiting crises, long-acting BZDs (intravenous lorazepam or rectal diazepam) are a better choice than phenothiazines, including prochlorperazine and promethazine.
Patients with difficult-to-manage FGIDs may benefit from treatment with >1 drug. Examples may include amitriptyline at bedtime to treat chronic pain and facilitate sleep, and an SSRI in the morning. For anxious children with dyspepsia, there is a rationale for buspirone in the morning and mirtazapine at bedtime. For children with PADS, a first step of improving sleep with amitriptyline or mirtazapine changes the patient's outlook from one of hopelessness to one of accepting the possibility of positive outcomes. CBT takes weeks before it is effective, whereas some drugs have a more rapid onset, especially for inducing restorative sleep. Augmentation may include 2 different antidepressants, antidepressant plus atypical antipsychotic, or antidepressant and gabapentin. For example, when amitriptyline 50 mg or mirtazapine 7.5 mg qhs is ineffective, sleep may be restored by adding quetiapine 50 mg, and increasing by 50 mg per night (maximum 300 mg) until the desired response is achieved.
Most pediatric gastroenterologists believe that it is sometimes necessary to prescribe drugs for indications that have not been FDA approved for children. Careful communication with the patient and caregivers is essential for ethical and medicolegal reasons. An ideal physician–patient–family conversation is the key to put a great deal of these medicolegal issues to rest. A good example of such communication may be, “Amitriptyline is in a class of medicine called anti-depressants, but we are not using amitriptyline for depression in your case. A small dose of amitriptyline has been used for over 30 years for chronic pain. Because it is classified as an anti-depressant, the FDA warns us that it may cause a depressed person to think about or even try suicide. If you ever had any such thoughts, you can’t take this. If you develop suicidal ideations being on this medication, stop taking the medicine, tell your parents about your thoughts, and notify me. Amitriptyline has a number of side effects. Two common ones are sleepiness and constipation. Because it will make you sleepy, we only give it before bedtime. If you get constipated you may need to take some over the counter stool softeners. If you take amitriptyline every day for several months but forget to take it one night, you may wake up with an upsetting dream. If you do wake with a nightmare, then get up, take your amitriptyline, watch TV or read something for 30 minutes, then go back to bed. If you get new symptoms that bother you, please contact me immediately by calling my office or via the email address on my business card.”
The prescribing pediatric gastroenterologist must negotiate a treatment plan involving psychotropic medications with the patient and caregivers, and communicate by telephone or e-mail in the initial days and weeks to assess compliance. Descriptions of individual drugs in the present review are too brief to provide accurate guidance to someone who is not already familiar with them. It is our hope that the information in the present review will provide a stimulus for the practicing pediatric gastroenterologists to seek out and engage mental health collaborators in their own communities to better serve children with significant FGIDs.
The authors thank Andrew Williams, MD, for critical review of the manuscript.
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