Volume 22, Issue 07

July 1, 2008

The following is an abstracted summary, not a verbatim transcript, of the lectures/discussions on this audio program. If, after reviewing the summary, you would like to hear the contents and earn CME/CE credit, simply use your browser's back button to return to the order page and add this program to your cart. You will receive by mail the one-hour audiocassette or audio CD, a hard copy of the written summary (including a 10-question test), and a CME/CE response form. Gastroenterology Program InfoAccreditation InfoCultural & Linguistic Competency Resources

Introductory remarks: speaker in favor of moving away from symptom-based therapy and towards hypothesis-based approach to treatment; proposed hypotheses for irritable bowel syndrome (IBS)—brain-gut axis; serotonin-driven (linked to dysmotility); acute gastroenteritis; bacterial overgrowth

Postinfectious IBS: patient goes from normal to altered bowel function as result of food poisoning; 3 recent meta-analyses found that 10% of patients who get food poisoning develop IBS; risk factors—female sex (women twice as likely to develop IBS after food poisoning); more severe, protracted course of food poisoning; younger adults appear more susceptible; patients who have vomiting (but no diarrhea) during food poisoning less likely to develop IBS (patients who have nausea and vomiting more likely to develop nonulcer dyspepsia); psychologic disposition of patient (eg, stress, anxiety) at time of food poisoning

Breath testing in patients with IBS: used to identify bacterial overgrowth as contributing factor; glucose substrate—penetrates only 2 to 3 ft into small bowel; positive test definite indication of bacterial overgrowth; however, glucose breath test [GBT] misses overgrowth in lower bowel; lactulose substrate—traverses entire digestive tract; however, in cases of rapid intestinal transit, pattern of gas production seen on lactulose breath test [LBT] may result in false- positive finding; LBT can be used to determine outcome of treatment; incidence of bacterial overgrowth in IBS— because GBT underestimates overgrowth and LBT overestimates it, incidence between 30% and 84%; culture data— substantiate breath-test data; show IBS patients have elevated bacterial counts in upper small bowel

Neomycin treatment of IBS: in double-blind controlled trial, patients with IBS given neomycin or placebo; neomycin effective in some patients (but not often); key findings—patients experience greatest improvement in symptoms when neomycin normalizes LBT; type of gas seen on LBT associated with IBS subgroup (methane production had 100% association with constipation-predominant IBS [CIBS]); now looking at role of methane in CIBS and in chronic constipation; neomycin better than placebo only in those patients who had methane production on LBT

Motility component of bacterial overgrowth: cleaning wave of gut (migrating motor complex; phase III of interdigestive motility) normally occurs every 90 min when not eating; if cleaning waves deficient or absent, person will develop bacterial overgrowth (in studies, these waves occur up to 68% less frequently in patients with IBS who have bacterial overgrowth)

Efficacy of erythromycin and tegaserod: in study by speaker et al, patients given no additional medication after being successfully treated for bacterial overgrowth had recurrence of symptoms at 58 days; patients given erythromycin after initial antibiotic therapy had recurrence at 138 days; patients given tegaserod went almost 12 mo before recurrence; findings demonstrate necessity of stimulating gut cleaning waves to sustain patient’s improvement (and avoid frequent use of antibiotics)

Rifaximin: in 2000 study by DiStefano et al, rifaximin proved 70% effective in treating bacterial overgrowth; currently, 200 mg tid approved by Food and Drug Administration (FDA) for treatment of traveler’s diarrhea; not yet approved for IBS; approved dose not effective against bacterial overgrowth (need ≥400 mg tid)

Probiotics: in published studies, none of lactobacillus-based probiotics met primary end point of global improvement of IBS symptoms; only organism showing efficacy so far Bifidobacterium infantis (in randomized double-blind placebo- controlled trial, patients received 1 x 1010 colony forming units [cfu]/day of Lactobacillus salivarius or B infantis in malted milk preparation, or placebo; only B infantis proved more effective than placebo; in another trial, freeze-dried encapsulated form of B infantis administered in doses of 1 x 106 , 1 x 108 , or 1 x 1010 cfu/mL for 4 wk; only 1 x 108 cfu dosage effective in relieving symptoms of IBS, and only in wk 4 of trial); number of studies looking at prokinectic action of probiotics (some appear to have prokinetic action similar to that of tegaserod)

Prokinetics: tegaserod (prokinetic agent) and alosetron (antikinetic agent) removed from market (alosetron for association with ischemic colitis; tegaserod for association with adverse cardiovascular events)

Lubiprostone (Amitiza): initially approved for management of idiopathic chronic constipation; chloride channel activator; multiple studies under way to determine efficacy in patients with CIBS; submitted for FDA approval for treatment of CIBS

Postinfectious model of IBS: speaker describes study in which rats randomized to placebo or colonization with Campylobacter; appears that acute gastroenteritis somehow affects small bowel (perhaps causes dysmotility or lack of cleaning waves); known that food poisoning releases neurotoxins; patients who have hydrogen production on LBT go on to develop diarrhea-predominant (DIBS) or mixed IBS, while those with methane production develop CIBS; stress known to play role in IBS (reduces cleaning waves; precipitates bacterial overgrowth in rat small bowel); found that one toxin (neurotoxin) common to all organisms that cause IBS (speaker conducting study with strain of Campylobacter that lacks this toxin; lack of bacterial overgrowth with this strain would suggest this toxin responsible; if this can be established, may be possible to prevent IBS through immunization)

BEHAVIORAL THERAPIES FOR FUNCTIONAL GI DISORDERS —Douglas A. Drossman, MD, Professor of Medicine and Psychiatry, University of North Carolina School of Medicine, and Co-Director, UNC Center for Functional GI and Motility Disorders, Chapel Hill

Evidence for Efficacy of Behavioral Treatments

Patients have high prevalence of psychosocial comorbidities: data over last 25 yr show patients with IBS have higher incidence of axis I psychiatric diagnoses than those with organic gastrointestinal (GI) disorders or normal patients (psychiatric comorbidities primarily anxiety, affective, and somatization disorders)

Altered cognitions: maladaptive patterns of thinking; include catastrophizing, GI-specific anxiety, health anxiety, and selective attention

Patients with IBS have enhanced gut reactivity to stress: speaker presents data from study in which acute physical and psychologic stress reduced rectal perception and pain thresholds in patients with IBS, but not in normal controls

Symptom severity relates to degree of psychologic disturbance: more severe IBS (greater symptom severity) associated with much higher scores on variety of psychologic measures, and with more days in bed, more physician visits, and more hospital admissions

Cognitive bias increases symptom behaviors: data show that the more patient catastrophizes, or the more he or she feels unable to decrease or control symptoms, the more likely patient will have poor outcome over next year; history of abuse and lower educational level also predictive

Brain-gut physiology: visceral hypersensitivity, lower sensation thresholds, and cytokine activation insufficient to explain differences in pain reports in patients with more severe and milder IBS; no one-to-one correlation between degree of bowel sensitivity and severity of pain

Hypothalamic-pituitary-adrenal (HPA) axis: increased cytokine activity in IBS and other functional GI disorders linked to HPA axis; involved in stress and inflammation; chronic inflammation associated with abnormalities in behavior and appetite; dysregulation of HPA axis in IBS, fibromyalgia, and chronic fatigue syndrome leads to abnormal stress response, increased reactivity, possibly failure to suppress inflammation, and increased inflammation and response to stress; when corticotropin-releasing hormone (CRH) given to patients with IBS, motor response enhanced over that of controls, and blocking CRH reduces this response; future treatments for IBS could be agents that suppress enhanced reactivity to stress

Anterior mid-cingulate cortex (MCC): processes physical and psychologic pain; activation associated with greater pain reports; study data—when rectum distended to produce pain, MCC activated in patients with IBS, while other areas activated in normal controls; ability of brain to turn down visceral signals impaired and upregulated in IBS and may be linked to psychologic stress; recent study found greater activation of this area and deactivation of “good” areas of brain in patients with IBS and history of sexual abuse

Clinical trials show improvement: in 10-yr-old review of trials of psychologic treatment, 10 of 13 studies found patients showed improvement; advantage of psychologic treatment that patients continue to do well after finishing course of therapy, because they adopt new methods to help deal with symptoms as they occur

Psychologic Treatments

Cognitive behavioral therapy: addresses thoughts, behaviors, and responses that result from patient’s experiences; can be associated with relaxation and stress management; helps patient to recognize relationship between beliefs and symptoms (involves reframing maladaptive thoughts so patient no longer interprets his or her condition as threatening)

Supporting data: CBT vs education and desipramine vs placebo for moderate to severe functional bowel disorders— CBT significantly more effective than education in all patient populations, except those with depression; patient’s satisfaction score (rating of overall global improvement) significantly better with CBT and desipramine, but difference in pain scores marginal (suggesting major improvement in medial limbic area of brain, where patients interpret pain as less noxious)

Psychodynamic interpersonal therapy: focuses on looking at relationships with others that might contribute to worsening symptoms; supporting data—in study comparing psychotherapy and selective serotonin reuptake inhibitor (SSRI) to usual treatment, also not much difference in pain scores; however, psychotherapy and SSRI significantly better in improving health-related quality of life; cost of psychotherapy slightly more during treatment period, but during year of follow-up, significant reduction in health care costs

Hypnotherapy: goal to take patient’s negative thinking and move it into visualization, increasing suggestibility and refocusing so that pain eliminated; brain imaging and motility studies show hypnotherapy extremely effective in treating dyspepsia as well as IBS

Psychologic treatment: refer if patient—has moderate to severe symptoms; sees relation of stress to symptoms; practices maladaptive coping; is motivated toward treatment; predictors of treatment response—confidence in treatment success; perceived sense of control over symptoms; good relationship with therapist; benefits—high response rate (70%); benefit to, patients not responding to medical treatment; additive to, and possibly synergistic with, medical treatments; no side effects; continued benefits for years after treatment ends; reduced health care costs; targets—maladaptive beliefs (eg, “I think I’m dying of cancer”); overactive stress response; maladaptive psychologic adjustments (eg, feelings of shame and guilt in abuse victims); maladaptive behaviors; limitations—requires patient motivation; patient must— understand process of psychologic intervention; accept illness and intervention without stigma; be willing to engage in frequent visits and home exercises; be willing to pay for treatment if necessary (reimbursement problematic; speaker uses “incident to” billing method); requirements—trained therapist experienced in working with patients with functional GI disorders; usually requires ongoing medical care

Combining antidepressants and psychologic treatment: antidepressants improve pain, vegetative signs and feelings of hopelessness, and increase motivation for psychologic treatments; psychologic treatments improve coping and cognitive function, address effects of trauma, and increase adherence to medication; brain imaging suggests that— antidepressants may have “bottom up” effects that act on limbic area of brain (cingulate cortex; insula) to activate vegetative signs and improve pain; psychologic treatments have more anterior and superior effects and act on prefrontal cortex to improve executive function (apparent synergism of drugs and psychologic therapy); clinical trials show benefit of combination treatment

Question and Answer

Is there a particular combination of antidepressants speaker has found most effective and best tolerated? for pain, consider tricyclic antidepressants, which have norepinephrine effects, and serotonin-norepinephrine reuptake inhibitors; for anxiety, SSRIs; lower doses advantage of combination therapy (all serious side effects associated with higher doses); speaker uses low dose (20 mg) of SSRI with 25 to 50 mg of tricyclic agent to try to get combined benefit; augmentation treatment with buspirone (has bowel-relaxing effects) or bupropion (eg, Wellbutrin) helpful; speaker has just submitted paper on quetiapine (Seroquel; atypical antipsychotic) in severe refractory patients who have not responded to antidepressants

Suggested Reading
Di Stefano M et al: Rifaximin versus chlortetracycline in the short-term treatment of small intestinal bacterial overgrowth. Aliment Pharmacol Ther 14:551, 2000; Dorn SD et al: Increased colonic pain sensitivity in irritable bowel syndrome is the result of an increased tendency to report pain rather than increased neurosensory sensitivity. Gut 56:1202, 2007; Drossman DA: Psychosocial factors and the disorders of GI function: what is the link? Am J Gastroenterol 99:358, 2004; Drossman DA: Treatment for bacterial overgrowth in the irritable bowel syndrome. Ann Intern Med 145:626, 2006; Drossman DA et al: Cognitive-behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders. Gastroenterology 125:19, 2003; Drossman DA et al: What determines severity among patients with painful functional bowel disorders? Am J Gastroenterol 95:974, 2000; Fass R et al: Evidence- and consensus-based practice guidelines for the diagnosis of irritable bowel syndrome. Arch Intern Med 161:2081, 2001; Fukudo S et al: Can modulating corticotropin releasing hormone receptors alter visceral sensitivity? Gut 55:146, 2006; Johanson JF et al: Clinical trial: phase 2 study of lubiprostone for irritable bowel syndrome with constipation. Aliment Pharmacol Ther 27:685, 2008; Levy RL et al: Psychosocial aspects of the functional gastrointestinal disorders. Gastroenterology 130:1447, 2006; McFarland LV, Dublin S: Meta-analysis of probiotics for the treatment of irritable bowel syndrome. World J Gastroenterol 14:2650, 2008; Murray CD et al: Effect of acute physical and psychological stress on gut autonomic innervation in irritable bowel syndrome. Gastroenterology 127:1695, 2004; Palsson OS, Drossman DA: Psychiatric and psychological dysfunction in irritable bowel syndrome and the role of psychological treatments. Gastroenterol Clin North Am 34:281, 2005; Pimentel M et al: A new rat model links two contemporary theories in irritable bowel syndrome. Dig Dis Sci 53:982, 2008; Pimentel M et al: Neomycin improves constipation- predominant irritable bowel syndrome in a fashion that is dependent on the presence of methane gas: subanalysis of a double-blind randomized controlled study. Dig Dis Sci 51:1297, 2006; Pimentel M et al: Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. a double-blind, randomized, placebo-controlled study. Am J Gastroenterol 98:412, 2003; Pimentel M et al: The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med 145:557, 2006; Ringel Y et al: Effect of abuse history on pain reports and brain responses to aversive visceral stimulation: an FMRI study. Gastroenterology 134:396, 2008; Ringel Y et al: Regional brain activation in response to rectal distension in patients with irritable bowel syndrome and the effect of a history of abuse. Dig Dis Sci 48:1774, 2003; Ringel Y et al: Sexual and physical abuse are not associated with rectal hypersensitivity in patients with irritable bowel syndrome. Gut 53:838, 2004; Ringel-Kulka T, Ringel Y: Probiotics in irritable bowel syndrome: has the time arrived? Gastroenterology 132:813,2007; Sagami Y et al: Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with irritable bowel syndrome. Gut 53:958, 2004; Scarpellini E et al: High dosage rifaximin for the treatment of small intestinal bacterial overgrowth. Aliment Pharmacol Ther 25:781, 2007; Whorwell PJ: Hypnotherapy for irritable bowel syndrome: The response of colonic and noncolonic symptoms. J Psychosom Res 64:621, 2008; Whorwell PJ et al: Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol 101:1581, 2006.

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