Gut Interactions with Brain and Environment in Children; First International Symposium on Pediatric Neurogastroenterology Capri, Italy, September 18-20, 1997
Pharmacotherapy aimed at affecting brain gut interactions can act at a variety of levels to improve gastrointestinal and global functioning. For all practical purposes, current treatments for functional gastrointestinal disorders are targeted with one of three actions in mind, although targeting in any one direction may actually have broader effects. These three actions are: modulation of gastrointestinal motility, reduction in visceral sensitivity, and alteration in perception or reporting of symptoms. The mechanism of beneficial effect of some of the most commonly used agents, such as tricyclic antidepressants (TCAs), is often unclear and may encompass all these actions.
MODULATION OF GASTROINTESTINAL MOTILITY
These agents have recognized effects on transit, but their effects on functional gastrointestinal disorders are limited. Clinical studies are largely restricted to cisapride and domperidone, and the primary motor target has been the upper gastrointestinal tract. Cisapride has prokinetic effects in the esophagus and colon that are not seen with domperidone, effects that are responsible for the benefits of cisapride in some patients with reflux disease or constipation. Of the typical functional gastrointestinal disorders, NUD has been the most studied. Both cisapride and domperidone have acute benefits in this syndrome, although evidence for sustained improvement may be greatest for domperidone. For both drugs, clinical improvement is not clearly correlated with change in gastric emptying, the presumed target function. Domperidone does not alter the threshold volume to pain with gastric distention (a measure of visceral sensitivity), but some benefit may be related to central blockade of chemoreceptor trigger zone, an important source of afferent input to the vomiting center, is found in this dopamine2 receptors in the area postrema of the medulla, a site external to the blood-brain barrier. The dopamine2 receptors in the area postrema of the medulla, a site external to the blood-brain barrier. The chemoreceptor trigger zone, an important source of afferent input to the vomiting center, is found in this region. Central antiemetic effects may help explain the symptomatic benefits of domperidone in NUD as well as in a host of other nausea/vomiting disorders in which it has been tried. The macrolide class of prokinetics is being exploited, but clinical information in functional disorders is unavailable.
The anticholinergics have been most studied and are mainstay treatments of many typical functional disorders despite limited evidence of efficacy. The drugs have been targeted at reducing abnormal or spastic motor contractions, although they also have effects on pain. Experiments using the esophagus as a model system have demonstrated that anticholinergic agents can increase significantly the threshold to pain with intraluminal balloon distention. In contrast, cholinergic stimulants will decrease the threshold. Thus, although traditionally considered motor-active agents, anticholinergic drugs may have benefit through effects on visceral sensitivity. Other studies in the esophagus demonstrate that nifedipine does not alter balloon-distention sensitivity, possibly explaining the failure of calcium-channel blockers in controlled clinical trials of functional chest pain syndromes. In contrast, calcium-channel blockers may have a role in irritable bowel syndrome (IBS), potentially by altering distention sensitivity of the rectum that is not observed in the esophagus.
REDUCTION IN VISCERAL SENSITIVITY
This is presently the area of greatest pharmaceutical investigation and development for functional gastrointestinal disorders. 5HT is relevant at both peripheral and central levels in the mediation of nociception. The 5HT3 receptor subtype is of particular interest, but the effects of antagonists (e.g., granisetron, ondansetron) have been variable in patients with functional gut disorders. Kappa opioid agonists (e.g., fedotozine) also have nociceptive suppressive effects and can increase the threshold to pain from rectal distention in IBS patients. A variety of other substances are currently under investigation. From a practical standpoint, clinicians can influence visceral sensitivity in several ways while awaiting drug development. Preventing undue luminal distention by decreasing meal size, avoiding gaseous foods, or even by using prokinetics may be of benefit. Eliminating sensitizing luminal factors (e.g., acid reflux events in chest pain syndromes, mucosal inflammation in patients with functional-like symptoms and concomitant inflammatory gut disorders) may also be beneficial. And use of available agents that are often targeted at other functions, such as antispasmodics and TCAs, may be of help. The TCAs decrease pain reporting in functional syndromes and have analgesic effects in other painful disorders. Preliminary reports of their direct effects on visceral sensitivity have yielded conflicting findings.
ALTERATION IN PERCEPTION OR REPORTING OF SYMPTOMS
Many patients with functional gastrointestinal disorders have concomitant psychiatric disturbances, particularly the anxiety and affective disorders. These psychiatric diagnoses are most common in the group of subjects seeking health care, suggesting that the emotional disturbance is altering the course of the gastrointestinal process -- either by directly accentuating the pathophysiological process or by altering the cognitive perception of the problem. There are little data to support that the psychiatric disturbances are simply secondary outcomes of the chronic gastrointestinal symptoms. As a mechanistic example, anxiety commonly leads to misinterpretation of symptom significance, even if the patient (or parent) has been told repeatedly that the process is innocent. Psychopharmacological treatment of active psychiatric disorders of at least moderate severity is likely to help through a variety of ways including improvement of global functioning and quality of life, important endpoints in management of functional disorders. Little well-developed data are available to support this. Treatment of active panic disorder reduced pain episodes in one study of patients with functional chest pain syndromes. Low-dose TCAs probably do not work primarily through this mechanism.
1. Bradette M, Pare P, Douville P, Morin A. Visceral perception in health and functional dyspepsia: crossover study of gastric distention with placebo and domperidone. Dig Dis Sci
2. Cannon RO, Quyyumi AA, Mincemoyer R, et al. Imipramine in patients with chest pain despite normal coronary angiograms. N Engl J Med
1994; 330: 1411-7.
3. Clouse RE, Alpers DH. The relationship of psychiatric disorder to gastrointestinal illness. Annu Rev Med
4. Clouse RE, Carney RM. The psychological profile of non-cardiac chest pain patients. Eur J Gastroenterol Hepatol
5. Clouse RE, Lustman PJ, Eckert TC, Ferney DM, Griffith LS. Low-dose trazodone for symptomatic patients with esophageal contraction abnormalities: a double-blind, placebo-controlled trial. Gastroenterology
6. Clouse RE, Lustman PJ, Geisman RA, Alpers DH. Antidepressant therapy in 138 patients with irritable bowel syndrome: a five-year clinical experience. Aliment Pharmacol Ther
7. Clouse RE. Antidepressants for functional gastrointestinal syndromes. Dig Dis Sci
8. Davis RH, Clench MH, Mathias JR. effects of domperidone in patients with chronic unexplained upper gastrointestinal symptoms: a double-blind, placebo-controlled study. Dig Dis Sci
9. Delvaux M, Louvel D, Schere B, Fraitag B, Frexinos J. The kagonist fedotozine increases thresholds of first sensation and pain perception to colonic distension in patients with irritable bowel syndrome. Gastroenterology
10. Egbrenike IG, Chaffee BJ. Antidepressants in the management of chronic pain syndromes. Pharmacotherapy
11. Gorard DA, Libby GW, Farthing MJ. Effect of a tricyclic antidepressant on small intestinal motility in health and diarrhea-predominant irritable bowel syndrome. Dig Dis Sci
12. Greenbaum DS, Mayle JE, Vanegeren LE, et al. Effects of desipramine on irritable bowel syndrome compared with atropine and placebo. Dig Dis Sci
13. Mayer EA, Raybould HE. Role of visceral afferenct mechanisms in functional bowel disorders. Gastroenterology
14. Prior A, Read NW. Reduction of rectal sensitivity and postprandial motility by granisetron, a 5HTC3 receptor antagonist, in patients with the irritable bowel syndrome. Aliment Pharmacol Ther
15. Wilmer A, Tack J, Coremans G, Janssens J, Vantrappen G. Effect of ondansetron, a 5HT3 receptor antagonist on perception of gastric distention and gastric compliance in healthy man. Gastroenterology