A. Characteristics and Epidemiology

1. IBS is a functional disorder with no structural or biochemical disease
2. About 12% of adults worldwide report symptoms consistent with IBS
3. Disease affects women 75%, men 25%
4. Increased incidence during adolescence; incidence peaks ages 20-30 (rare onset after 50)
5. At least 12 weeks within previous year with abdominal pain or discomfort that:
   1. Cannot be explained by structural or biochemical abnormalities
   2. Is relieved with defacation
   3. Its onset is associated with change in frequency or consistency of stools
6. Altered Bowel Habits
   1. Constipation ± diarrhea (25% of the time)
   2. Loose or mucus laden stools
   3. Sensation of incomplete evacuation
7. Four Variants of IBS Identified [16]
   1. Pain predominant
   2. Constipation predominant (cIBS)
   3. Diarrhea predominant (dIBS)
   4. Constipation alternating with diarrhea (mixed or mIBS)
8. Onset usually in adolescence / early adult
9. Associated Diseases
   1. Fibromyalgia / chronic fatigue syndrome
   2. Abnormal eating behavior
   3. Non-ulcer dyspepsia / functional gastritis [4]
   4. Chronic stress
   5. Physical / sexual abuse
   6. Migraines
   7. Personality and Anxiety Disorders
   8. Sleep disturbance
10. Absence of weight loss, fever, intestinal bleeding or other serious signs
11. Long term prognosis is good, with <10% of patients converting to organic disease

B. Etiology [13]

1. Pathogenesis is not well understood
2. At least four contributing factors / systems are involved
   1. Physiological systems: autonomic nervous system, neuroendocrine, and pain sensation
   2. Emotional: anxiety, depression
   3. Cognitive: illness behavior, coping styles
   4. Behavioral: environmental stresses
3. Alteration in bowel Autonomic Nervous System (ANS)
   1. Changes in ANS are thought to be initiated by central nervous system (CNS) changes
   2. CNS drives emotional motor system which affects neuroendocrine, ANS, and pain
   3. Syndrome has components of abnormal ANS, neuroendocrine, and pain control
   4. ANS controls intestinal motility and leads to tonic-clonic and spastic contractions
   5. Serotonin system likely involved
4. Pain Sensation
   1. Endogenous opiate receptors implicated
   2. Kappa class receptors subject of pharmacologic focus
   3. Visceral pain hypersensitivity is well documented
   4. Pain hypersensitivity particularly to intestinal (particularly rectal) distension
5. Small intestinal bacterial overgrowth may be significant in IBS [5]
   1. Can cause bloating, pain,
   2. Associated with elevated hydrogen excretion after lactulose seen in IBS
   3. Eradication of small intestinal bacterial overgrowth improves symptoms in 75% of IBS [6]

C. Other Functional Gastrointestinal Disorders [4]

1. Esophageal Disorders - symptoms with no signs, globus, chest pain syndromes
2. Functional Dyspepsia [4,17]
   1. Ulcer-like, dysmotility-like
   2. No structural lesions causing symptoms are found
   3. Believed to be due to abnormal upper GI function
3. Treatment for Functional Dyspepsia [4]
   1. Dietary modification - limited evidence to support therapeutic benefit
   2. Psychological therapy - improves quality of life, reduces physician visits
   3. Helicobacter pylori eradication - small but significant benefit (NNT = 14)
   4. Proton pump inhibitors - benefit over placebo with NNT 9-14
   5. Antidepressants / anxiolytics - probably most effective (>50% reduction)
   6. Prokinetic Agents - efficacy 2X of placebo (NNT >4)
   7. Metoclopramide - poorly documented efficacy but often used
   8. Droperidone - improves global symptoms as assessed by clinician
   9. Itopride (dopamine D2 antagonist with cholinesterase inhibition activity) used in Japan
   10. Itopride 100mg and 200mg po tid superior to placebo on improving symptoms [17]
   11. Multiple agents often used together with psychological therapy
4. Bowel Disorders - IBS, abdominal bloating, functional constipation and/or diarrhea
5. Functional Abdominal Pain
6. Biliary Disorders - gallbladder dysfunction, Sphincter of Oddi dysfunction
7. Anorectal Disroders - functional incontinence, anorectal pain, dyschezia
8. Likely involve dysfunction of the "emotional motor system"

D. Signs and Symptoms

1. Abdominal Pain, crampy
2. Abdominal Distension
3. Increase in flatulence or belching
4. Scybalous stools
5. Alternating constipation and diarrhea
   1. One usually predominates
   2. Constipation more common throughout course
   3. Diarrhea more common at presentation [3]
6. Nausea and/or Vomiting, heartburn in 25-50% of patients
7. Normal physical examination is critical for diagnosis
8. Absence of alarming symptoms

E. Laboratory

1. Normal complete blood count, differential, ESR
2. Stool negative for blood, pus or elevated fat content
3. Normal electrolytes, Ca2+ and Mg2+
4. <200gm stool per day
5. Stool Guaiac Test
   1. Must be done on all patients
   2. OB+ (occult blood) stool is unusual in IBS and should prompt a thorough evaluation
6. Minimal diagnostic evaluations are performed
7. Abnormal lactulose breeath tests (increased hydrogen/methane secretion) in ~85% [5,6]
8. However, must rule out organic disorders (differential diagnosis)
9. Diagnosis is made by ruling out organic disorders with symptoms consistent with IBS

F. Abdominal Radiograph

1. Not required for diagnosis
2. Normal haustra
3. May show mild to moderate fecal impaction
4. Gaseous distension

G. Differential Diagnosis

1. Neoplasm
2. Inflammatory Bowel Disease (IBD)
3. Vascular Insufficiency
4. Chronic Constipation Syndromes - drug induced, poor diet
5. Chronic Diarrheas - infectious, malabsorption, drugs, bacterial overgrowth
6. Lactase Deficiency
7. Gynecologic Disorders - especially endometriosis
8. Ruling out these organic causes causes is crucial

H. Treatment Overview [7,8,9]

1. Based on primary symptoms (pain, dIBS, cIBS, mIBS)
2. Psychological / non-pharmacological therapies are crticial components
3. Psychological Issues
   1. Acknowledge pain and discomfort; reassurance is critical
   2. Remain empathetic focusing on patient education (not adversarial)
   3. Treatment plan and goals should be set
   4. Consider having patient develop a diary
   5. Focus on major symptom to develop an initial treatment strategy
   6. Negotiate treatment - discuss with patient, limit setting
   7. Strongly avoid addictive medications
   8. Consider tricyclic antidepressants (TCA); caution with anticholinergic activity [11]
   9. Consdier selective serotonin reuptake inhibitor (SSRIs) [11]
   10. Note placebo responses in clinical trials range 20-50%
4. Pain Predominant
   1. Change in diet
   2. Anticholinergic agent
   3. Nitrate
   4. Tricyclic antidepressant (TCA)
   5. Lubiprostone (Amitiza®) for IBSc may reduce pain []
   6. Tegaserod (Zelnorm®) - now only available through special programs
   7. Possibly: SSRIs
   8. Nonsteroidal antiinflammatory agent (NSAID)
   9. Opiod - generally only for severe symptoms
   10. Tramadol (Ultram®) may be considered for pain as a last resort
5. Benzodiazapines
   1. Anxiety therapy short-term
   2. May Worsen constipation
6. Other Modalities
   1. Chinese herbal formulations appear to help some patients with IBS [7]
   2. Behavioral / Biofeedback / Psychological Therapy [3]
   3. Kappa-opiate receptor agonists for pain control are in development as well

I. Treatment of dIBS

1. Overview of Agents
   1. Loperamide (Imodium®) is effective - 4mg/d initially, 4-8mg/d in single divided dose
   2. Diphenoxylate 2.5mg plus atropine sulfate 0.025mg (Lomotil®)
   3. Cholestyramine - especially in patients with high cholesterol, 1 packet qd or bid
   4. Serotonin receptor type 3 (5-HT3) antagonists
2. Alosetron (Lotronex®) [12,13,15]
   1. Serotonin Receptor Type 3 Antagonist
   2. Approved only for women with dIBS
   3. Initiate therapy at 1mg po qd and gradually increase as tolerated
   4. Caution as this agent has been linked with colonic ischemia and severe constipation
3. Antispasmodic Agents [8]
   1. Primarily anticholinergic agents; all fairly similar
   2. Good for pain control but do not modify disease
   3. Belladona: 0.3-1.2mg po qid
   4. Dicyclomine (Bentyl®): 10--20mg po qid e Hyoscyanamine (Levsin®): 0.125-0.25mg po qid
   5. Clidinium bromide: 2.5-5.0mg qid
   6. Glycopyrrolate (Robinul®): 1-2mg po tid
   7. Hyoscyamine, atropine, pheobarbital (Donnatal®): 0.1mg, 0.02mg po prn to qid (sedative)
   8. Cimetroprium, otilonium, mebeverine not available in USA
   9. Other agents: diltiazem (Cardizem® and others), a calcium blocker, may be helpful
4. Nonabsorbed Antibiotic Rifaximin (Xifaxan®) [18]
   1. Gut selective antibotic with <0.4% sytemic absorption
   2. Eradicates bacterial overgrowth in ~70% and active against Clostridium difficile
   3. Dose 400mg po tid for 10 days reduced IBS symptoms (cIBS and dIBS) and bloating
   4. Suggests bacterial overgrowth contributes to symptoms of IBS

J. Treatment of cIBS [16]

1. Overview of Agents
   1. Change in diet with increased fiber
   2. Fiber Supplementation mainly for cIBS: Wheat or Oat Bran or Psyllium
   3. Osmotic laxatives - lactulose, polyethylene glycol
   4. Other laxative
   5. Lubiprostone (Amitiza®)
   6. 5HT-4 receptor agonists
   7. Eradication of small intestinal bacterial overgrowth with neomycin improved 75% [6]
2. Lubiprostone (Amitiza®) [9,10]
   1. Activates ClC2 (chloride) channels, increasing intestinal fluid secretion
   2. Fatty acid metabolite of prostaglandin E1
   3. Not absorbed; only acts on stomach and small intestine
   4. Only drug currently approved by FDA for general use in cIBS
   5. Dose is 8 micrograms (µg) bid
   6. Main side effects are nausea 8% and diarrhea 7%
   7. Dose for chronic constipation (idiopathic) is 24µg bid, associated with 29% nausea and 12% diarrhea
3. Tegaserod (Zelnorm®) [13,14]
   1. Prokinetic 5-HT4 partial agonist approved for cIBS
   2. Increases GI motility and reduces visceral (pain) sensation
   3. Dose is 6mg po bid before meals
   4. Main side effect is diarrhea; possible increase gallstones and ovarian cysts
   5. May slightly increase ischemic cardiovascular events (but not QTc) and its use should be restricted to women or others that have no responded to other agents
4. Other Prokinetic Agents
   1. Cisapride (5HT4 agonist) - withdrawn from market due to QTc prolongation / arrhythmias
   2. Bethanechol (Urocholine®) - especially in patients with atonic bladders
   3. Prokinetic agents may be effective in patients with constipation predominant IBS
   4. Overall these agents have shown little convincing efficacy in clinical studies [8]
5. Tricyclic Antidepressants [11]
   1. Mild (secondary amines) to moderately (tertiary amines) constipating
   2. "Depression" range doses often required
   3. Good for chronic pain, anxiety
   4. Begin with amitriptyline - 10-25mg/hr of sleep to 75mg qd maximum
   5. Alternatively consider desipramine - 50mg/hr of sleep, to 75mg qd maximum
   6. Nortriptyline 25-75 mg/d has less anticholinergic activity than amitriptyline
   7. Antidepressants increased response rates 4.2 fold for patients with IBS [11]

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5. Lin HC. 2004. JAMA. 292(7):852
6. PImentel M, Chow EJ, Lin HC. 2003. Am J Gastroenterol. 98(2):412
7. Bensoussan A, Talley NJ, Hing M, et al. 1998. JAMA. 280(18):1585
8. Jailwala J, Imperiale TF, Kronke K. 2000. Ann Intern Med. 133(2):136
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14. Tegaserod. 2002. Med Let. 44(1139):79
15. Alosetron Revisited. 2002. Med Let. 44(1136):67
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17. Holtmann G, Talley NJ, Liebregts T, et al. 2006. NEJM. 354(8):832
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