Pharmacology

Pharmacological interventions for functional gastrointestinal disorders (FGIDs) are based on an evolving understanding of bidirectional brain–gut interactions, the “brain-gut axis.” Functional abdominal pain (FAP) and irritable bowel syndrome (IBS) are considered states of dysregulation within the enteric and the central nervous systems, resulting in alterations in sensation, motility, and possibly, immune system function. Brain–gut interactions may tonically or phasically up- or downregulate visceral afferent sensitivity, homeostatic reflexes, and ultimately conscious pain perception (1,2). Therefore, the targets of pharmacotherapy are within the entire pain transmission system, from the peripheral receptors in the gut responding to distension and chemical, osmotic, and thermal stimulation, through the dorsal horn and interneurons of the spinal cord, and ultimately to the levels of conscious perception in the cortex. By definition, visceral sensation is both sensory discriminative and affective motivational. Therefore, visceral pain may be attenuated by neuropathic pain medications, including agents used for nerve pain and mood disorders, as well as novel compounds in development. Such medications include sedatives and anxiolytics, antidepressants, serotonin and 5HT-3 receptor antagonists, somatostatin receptor agonists, and antiseizure agents. As for most pediatric treatment modalities, published controlled trials are rare. There are 3 reported studies in children with FAP for peripheral, non-neuropathic agents and 1 study for behavioral therapy. Evidence of efficacy is documented to be greater than placebo for famotidine for functional dyspepsia, pizotifen for abdominal migraine, peppermint oil for IBS, and behavioral interventions for FAP (3–6). Abdominal pain is associated with visceral hypersensitivity and abnormal perception of visceral sensations. Control subjects and patients with functional dyspepsia localize rectal pain during barostat examination to the S3 dermatome, but patients with FAP and IBS localize pain to aberrant dermatomal sites and have a decreased rectal sensory threshold (7). Such findings in children are similar to adult studies of visceral sensitivity in patients with FGIDs (8). Although the majority of research in the treatment of FGIDs in children has focused on the overall success of cognitive-behavioral therapies, there is an evolving literature regarding the use of pharmacology for receptors along the brain–gut axis. A brief review of some current studies follows. SEDATIVES AND ANXIOLYTICS In patients with abdominal pain and comorbid psychological symptoms, these agents are a logical choice because they modulate overlapping central nervous system circuits involved in emotion, autonomic stress responses, and pain. There is no significant evidence per clinical trials that these agents are effective, and there are numerous clinical reports of limiting adverse effects, such as sedation and addiction, especially prominent in chronic conditions (8). As an example, buspirone, a 5HT1A agonist and anxiolytic drug, effects colonic motility and stress responses in an animal model, decreases dyspepsia in some functional dyspepsia patients, but has no effect on bowel and sensory symptoms in human control subjects (9–11). ANTIDEPRESSANTS Of all of the medications available for the treatment of FAP, these agents have been studied the longest (12) and are most familiar to clinicians. They have both central and peripheral nervous system actions appropriate for patients with FGIDs, such as anticholinergic effects, gastrointestinal transit slowing, fundic relaxation, sleep restoration, potential treatment of comorbid depression, and analgesia due to receptor binding throughout the pain transmission system. In addition, there is a detailed literature of their use in multiple chronic pain disorders, including nerve-injury pain, fibromyalgia, and headache (12,13). Tricyclic antidepressants (secondary and tertiary amines), serotonin reuptake inhibitors (SSRIs; eg, citalopram), and monoamine uptake inhibitors (eg, duloxitene, velafaxine), show improvement of functional GI symptoms in patients with FGIDs in published reports. However, the design and analysis of the studies are variable. In 1 adult randomized placebo-controlled trial of patients with IBS without comorbid depression, subjects treated with an SSRI reported significant decreased abdominal pain and bloating and increased overall well-being (14). In an open-label 12-week flexible dose pediatric study (subjects 7–18 years old), 84% of patients with FAP reported improved function with decreased pain, depression, anxiety, and other somatic complaints (15). Newer monoamine uptake inhibitors affect descending serotonergic and adrenergic pain inhibition systems and show some evidence of analgesia in patients with fibromyalgia and diabetic neuropathy (16,17). Amitriptyline is best studied in pediatric patients with migraine but without placebo-controlled evidence. Open-label studies support efficacy greater than propranolol and cyproheptadine in 50% to 60% of children (18). In 1 pediatric study, 80% of children showed a >50% improvement in symptoms with titration of drug of 0.25 to 1 mg · kg−1 · day−1 over 8 to 10 weeks (19). Nortriptyline is reported in some studies to have an increased risk for cardiac arrhythmias. SSRIs have not been adequately studied in the pediatric population. With prescribing these agents to children and adolescents, it is recommended to provide appropriate information regarding depression and suicidal ideation for patients and families. A Web site with data updated by the American Pediatric Association and American Academy of Child and Adolescent Psychiatry is ParentsMedGuide.org. The site notes “The FDA [Food and Drug Administration] reported an increase in spontaneous reports of suicidal thoughts and/or behavior among children receiving medication, but there is no evidence that these suicidal thoughts or behaviors lead to an increased risk of suicide” (20). ANTISEIZURE MEDICATIONS Although there are no specific trials involving antiseizure agents for pediatric FGIDs, these medications have been increasingly used, off-label, for neuropathic pain conditions, such as migraine and neuralgia, in children. There is a significant adult literature for their efficacy in diabetic neuralgia, postherpetic neuralgia, and migraines and safety and efficacy data for their use in pediatric seizure disorders. Generically, they depress abnormal neuronal discharges and raise the inappropriately lowered threshold of sensitized neurons, such as those also present in states of visceral hyperalgesia. Much of the pediatric experience is with these agents for seizure management. Their use as analgesics is extrapolated from adult experience. The first-generation agents, such as phenytoin and carbamazepine, are associated with serious adverse effects and require regular blood level monitoring. The second-generation medications, such as gabapentin, lamotrigine, topiramate, zonisamide, levetiracetam, and pregabalin, may not require laboratory monitoring, have fewer sedation or cognitive effects, and less overall adverse effects. Caution is advised with their use because the pediatric experience with these agents is limited and the true incidence of serious side effect profile is not fully known. SEROTONIN AND 5HT-3 RECEPTOR ANTAGONISTS Serotonin (5HT) receptors are attractive candidates for pharmacotherapy in FGIDs because greater than 80% of serotonin is stored in the enterochromaffin cells of the gut. With mechanical or chemical stimulation or experimental stress, serotonin acts in a paracrine fashion on its receptors on intrinsic and afferent (vagal and spinal) nerve terminals. Two 5HT-3 compounds studied in adults, alosteron and cilansteron, have shown efficacy in patients with diarrhea-predominant IBS, but complications of severe constipation, ischemic colitis, and perforations have prompted FDA restrictions. A 5HT-4 antagonist, tegaserod, is in limited use (21–23). SOMATOSTATIN RECEPTOR AGONISTS (SSTs) Somatostatin receptor agonists (SSTs) have been available for the past 30 years as antisecretory agents. Recently, broader use has been considered because SST receptors are localized in both the GI tract and the central nervous system, with SST2 receptors located on spinal afferents, superficial dorsal horn spinal neurons, and within the locus ceruleus. Octreotide, a nonselective SST2, SST3, and SST5 receptor agonist, has analgesic efficacy in FGIDs, but has limited clinical use due to its parenteral formulation, inhibition of gallbladder emptying, and receptor desensitization with chronic use (24). CANDIDATE MEDICATIONS IN DEVELOPMENT Neurokinin (NK) receptor antagonists, potentially binding to NK1R (SP), NK2R (NKA), and NK3R (NKB) within the autonomic, enteric, and central nervous systems, have effect on intestinal motility, secretion, and visceral sensitivity in states of chronic pain and central sensitization. Corticotropin-releasing factor (CRF) receptor antagonists which bind to CRF 1 and 2 receptors have been shown to modulate the effect of stress on GI function. Other potential modulators of peripheral and central visceral hyperalgesia include α-adrenergic agonists (clonidine), cholecystokinin antagonists, N-methyl-D-aspartic acidantagonists (ketamine), and transient receptor potential ion channel antagonist of the vanilloid type.