Treatment options in Irritable Treatment options in Irritable Bowel SyndromeBowel Syndrome

Phillis Ling MPH, DOPhillis Ling MPH, DO

Definition and epidemiologyDefinition and epidemiology

• Revised Rome III diagnostic criteria Revised Rome III diagnostic criteria include the following:include the following:

Recurrent abd pain or discomfort at Recurrent abd pain or discomfort at least 3 days per month in the last 3 least 3 days per month in the last 3 months associated with 2 or more months associated with 2 or more

of the following:of the following:

-improvement with defecation-improvement with defecation

-Onset associated with a change in -Onset associated with a change in stool frequencystool frequency

-Onset associated with a change in -Onset associated with a change in stool formstool form

Most important step in the diagnosis is Most important step in the diagnosis is to listen, review symptoms in detail to listen, review symptoms in detail recognizing the key feature being the recognizing the key feature being the presence of abdominal pain or presence of abdominal pain or discomfort associated with bowel discomfort associated with bowel dysfunctiondysfunction

-this separates IBS from functional -this separates IBS from functional constipation and functional diarrheaconstipation and functional diarrhea

• IBS affects up to 10%-20% of IBS affects up to 10%-20% of adolescents and adults.adolescents and adults.

• Prevalence in women of 14.5% Prevalence in women of 14.5% compared to 7.7% of men with a 2:1 compared to 7.7% of men with a 2:1 (F:M) ratio(F:M) ratio

• 40% to 60% of referrals to outpatient 40% to 60% of referrals to outpatient gastroenterology clinics.gastroenterology clinics.

PathophysiologyPathophysiology

• Visceral hypersensitivityVisceral hypersensitivity

• Abnormal gut motilityAbnormal gut motility

• Genetics ( 2 fold increase in IBS in Genetics ( 2 fold increase in IBS in monozygotic twins, having a parent monozygotic twins, having a parent with IBS is an independent and with IBS is an independent and stronger predictor of IBS than having stronger predictor of IBS than having a twin with disease)a twin with disease)

• Psychosocial factors: heightened Psychosocial factors: heightened pain sensitivity to visceral pain sensitivity to visceral stimulation of the brain-gut axisstimulation of the brain-gut axis

- Fibromyalgia( 49%pts have IBS), - Fibromyalgia( 49%pts have IBS), chronic fatigue syndrome (51%), chronic fatigue syndrome (51%), chronic pelvic pain (50%), TMJ chronic pelvic pain (50%), TMJ syndrome (64%)syndrome (64%)

• Post –infectious causesPost –infectious causes

• Luminal irritation: small bowel Luminal irritation: small bowel bacterial overgrowth (SIBO), gas, ?bacterial overgrowth (SIBO), gas, ?food allergyfood allergy

Symptoms and treatmentSymptoms and treatment

• Dietary triggers: caffeine,excess fatty foods, sorbitol, Dietary triggers: caffeine,excess fatty foods, sorbitol, glucose, fructose, lactose, beans, uncooked broccoli, glucose, fructose, lactose, beans, uncooked broccoli, cabbage, cauliflower, carbonated drinks, certain spicescabbage, cauliflower, carbonated drinks, certain spices

• Dietary fiber: soluble (starches) vs insoluble (tough Dietary fiber: soluble (starches) vs insoluble (tough skin, peel seeds, pods)skin, peel seeds, pods)

- soluble fiber is fermented in the proximal colon results soluble fiber is fermented in the proximal colon results in increased stool viscosityin increased stool viscosity

- Insoluble fiber binds water but more resistant to Insoluble fiber binds water but more resistant to fermentation; increases stool bulk, decreases colonic fermentation; increases stool bulk, decreases colonic transit time but can cause bloating, diarrhea, abd pain.transit time but can cause bloating, diarrhea, abd pain.

AGA recommends 20-35g/day AGA recommends 20-35g/day fiber;typical diet contains 11-13g/dayfiber;typical diet contains 11-13g/day

- Bulking agents include - Bulking agents include metamucil,benefiber, citrucel,konsyl metamucil,benefiber, citrucel,konsyl are considered soluble fiber, may be are considered soluble fiber, may be beneficialbeneficial

-metamucil –psyllium seed (ispaghula -metamucil –psyllium seed (ispaghula seed) 4/5RCTS improve ease of stool seed) 4/5RCTS improve ease of stool passage but no change in painpassage but no change in pain

• Antispasmodics (hyoscyamine, Antispasmodics (hyoscyamine, didydoline, glycopyrrolate) didydoline, glycopyrrolate)

-Relax gut smooth muscle ; best -Relax gut smooth muscle ; best given 30-60 minutes before meals if given 30-60 minutes before meals if related to eatingrelated to eating

-insufficient data for -insufficient data for recommendationrecommendation

AntidiarrhealAntidiarrheal

Loperamide (IBS-D) opioid agonist inhibits Loperamide (IBS-D) opioid agonist inhibits

intestinal secretion and peristalsis, slows intestinal secretion and peristalsis, slows intestinal transit, allow absorption of fluid and intestinal transit, allow absorption of fluid and electrolyteselectrolytes

• Minimal analgesiaMinimal analgesia• Longer duration of action than diphenoxylate, Longer duration of action than diphenoxylate,

less abuse potential, no anticholinergic agent less abuse potential, no anticholinergic agent added (eg atropine) added (eg atropine)

• Generally safe and effective for treatment of Generally safe and effective for treatment of diarrhea but needs monitoring in chronic patients diarrhea but needs monitoring in chronic patients to avoid megacolonto avoid megacolon

• Tricyclic antidepressants (TCAs)Tricyclic antidepressants (TCAs)

1.1. Better than placebo at relieving global Better than placebo at relieving global symptoms and abd painsymptoms and abd pain

2.2. Used at a lower dose than in treating Used at a lower dose than in treating depression and anxiety depression and anxiety (eg: nortryptiline 10mg daily, (eg: nortryptiline 10mg daily, desipramine 50mg daily, amitryptiline desipramine 50mg daily, amitryptiline 10-25mg daily)10-25mg daily)

• Secondary agents (nortryptiline, Secondary agents (nortryptiline, desipramine) preferred over tertiary desipramine) preferred over tertiary agents (amitriptyline, imipramine) agents (amitriptyline, imipramine) due to more favorable side effect due to more favorable side effect profileprofile

• No evidence one more effective than No evidence one more effective than anotheranother

• Selective serotonin reuptake Selective serotonin reuptake inhibitor (SSRI)inhibitor (SSRI)

1.1. May have beneficial effects on May have beneficial effects on general well-beinggeneral well-being

2.2. No evidence one agent is better No evidence one agent is better than anotherthan another

• Serotonin-norepinephrine reuptake Serotonin-norepinephrine reuptake inhibitor (SNRI) such as duloxetine inhibitor (SNRI) such as duloxetine and venlafaxineand venlafaxine

1.1. Effective in reducing pain in chronic Effective in reducing pain in chronic pain such as fibromyalgia butpain such as fibromyalgia but

2.2. Data from RCT of their role in IBS Data from RCT of their role in IBS lackinglacking

Serotonin (5hydroxytryptamine, 5HT) seems Serotonin (5hydroxytryptamine, 5HT) seems to be the most important neurotransmitter in to be the most important neurotransmitter in the enteric nervous system in gut the enteric nervous system in gut sensitizationsensitization

Serotonin receptor modulating drugs:Serotonin receptor modulating drugs:

Alosetron 5 HT3 receptor antagonist -used in Alosetron 5 HT3 receptor antagonist -used in IBS-D by antagonizing the release of IBS-D by antagonizing the release of serotonin to mucosal stimulation that results serotonin to mucosal stimulation that results in increased intestinal secretion, motility and in increased intestinal secretion, motility and sensationsensation

AlosetronAlosetron

• Introduced in spring 2000;Introduced in spring 2000; Placebo-controlled RCT at 1mg po bid for 12 Placebo-controlled RCT at 1mg po bid for 12

weeksweeks1.1. Improved symptoms overallImproved symptoms overall2.2. Efficacy in women with IBS-D based on phase 2 Efficacy in women with IBS-D based on phase 2

trialstrials3.3. Complications from ileus, fecal impaction, Complications from ileus, fecal impaction,

ischemic colitis (latter prev 0.15% vs 0.06% in ischemic colitis (latter prev 0.15% vs 0.06% in placebo group)placebo group)

4.4. Reintroduced with strict guidelines in 2002 for Reintroduced with strict guidelines in 2002 for IBS-D women with at least 6 months of symptoms IBS-D women with at least 6 months of symptoms not responsive to conventional treatmentnot responsive to conventional treatment

Tegaserod (initially approved in July 2002)Tegaserod (initially approved in July 2002) Used in IBS-C by stimulating 5 HT4 Used in IBS-C by stimulating 5 HT4

receptors to increase gastric emptying, receptors to increase gastric emptying, small bowel and colonic motilitysmall bowel and colonic motility

- 0.11% (13/11600 pts) increased cv - 0.11% (13/11600 pts) increased cv events vs 0.01% ( 1/7031pts) events vs 0.01% ( 1/7031pts)

- Reintroduced July 2007: restricted access - Reintroduced July 2007: restricted access for use in women 18 to 54 years with for use in women 18 to 54 years with IBS-C or CC with unsatisfactory response IBS-C or CC with unsatisfactory response to other treatmentto other treatment

• Alosetron and Tegaserod – Grade A Alosetron and Tegaserod – Grade A AGA recommendationsAGA recommendations

-evidence based on a minimum of 2 -evidence based on a minimum of 2 RCTs, p value <0.05; adequate RCTs, p value <0.05; adequate sample size and appropriate sample size and appropriate methodsmethods

• Chloride channel activators (Lubiprostone)Chloride channel activators (Lubiprostone) - acts on epithelial cells to increase intestinal fluid - acts on epithelial cells to increase intestinal fluid

to promote spontaneous bowel movementsto promote spontaneous bowel movements1.1. Drossman et al ( Gastro 2007) showed Drossman et al ( Gastro 2007) showed

proportion of pts with symptom relief was proportion of pts with symptom relief was significantly higher at dose of 8mcg po bid significantly higher at dose of 8mcg po bid compared to placebo, in two 12 week phase 3 compared to placebo, in two 12 week phase 3 placebo-controlled randomized double blind placebo-controlled randomized double blind trialstrials

2.2. FDA approved at 24mcg po bid for CCFDA approved at 24mcg po bid for CC

Antibiotics and ProbioticsAntibiotics and Probiotics

Postinfectious (PI IBS) causes first suggested in the 1960s. Postinfectious (PI IBS) causes first suggested in the 1960s. • 90 % of people recover spontaneously following a bout of 90 % of people recover spontaneously following a bout of

enteritisenteritis• 10 % develop PI IBS10 % develop PI IBS• Overall incidence of 4% to 36% of new onset IBS after an Overall incidence of 4% to 36% of new onset IBS after an

acute enteritis. acute enteritis. • Symptoms can persist for years (6years)Symptoms can persist for years (6years)• Risk factors: Women, patients with anxiety, depression, Risk factors: Women, patients with anxiety, depression,

severe or prolonged symptoms of gastroenteritis, absence severe or prolonged symptoms of gastroenteritis, absence of vomiting. of vomiting.

• Salmonella infection results in the highest incidence Salmonella infection results in the highest incidence approx 10%; other pathogens include Campylobacter, E approx 10%; other pathogens include Campylobacter, E Coli, Giardia, ShigellaColi, Giardia, Shigella

• Mucosal inflammation develops as a Mucosal inflammation develops as a response to initial bacterial infectionresponse to initial bacterial infection

• Low-grade inflammation is an Low-grade inflammation is an abnormal reaction to the normal flora abnormal reaction to the normal flora or response to changes in the or response to changes in the intrinsic floraintrinsic flora

• Rifaximin –luminal nonabsorbable Rifaximin –luminal nonabsorbable (<0.4%) antibiotic(<0.4%) antibiotic

• No clinically relevant antimicrobial No clinically relevant antimicrobial resistance resistance

• ? Prevent traveler’s diarrhea to ? Prevent traveler’s diarrhea to reduce new-onset IBS symptoms reduce new-onset IBS symptoms being assessed.being assessed.

• Hypothesis that symptoms of IBS may Hypothesis that symptoms of IBS may result from abnormal fermentation assoc result from abnormal fermentation assoc with small intestinal bowel overgrowth with small intestinal bowel overgrowth (SIBO)(SIBO)

• Prevalence by lactulose breath test of 65 Prevalence by lactulose breath test of 65 % to 84% in IBS patients% to 84% in IBS patients

• Rifaximin relieved global symptoms up to Rifaximin relieved global symptoms up to 10 weeks after discontinuation of therapy 10 weeks after discontinuation of therapy (Pimental et al)(Pimental et al)

• Improve gas/bloating at lower dose Improve gas/bloating at lower dose • Need more studyNeed more study

Other antibioticsOther antibiotics

• NeomycinNeomycin

-oral aminoglycoside that is -oral aminoglycoside that is systemically absorbedsystemically absorbed

-neomycin 1g/day for 10 days -neomycin 1g/day for 10 days improved IBS scores compared to improved IBS scores compared to placebo (N=111, p<0.05)placebo (N=111, p<0.05)

• Normalization of LBT with neomycin leads Normalization of LBT with neomycin leads to decrease in IBS symptoms to decrease in IBS symptoms

• Subanalysis on IBS –C pts(n=39) 20 Subanalysis on IBS –C pts(n=39) 20 received placebo and 19 received received placebo and 19 received neomycin;global improvement seen, neomycin;global improvement seen, constipation improvedconstipation improved

• Methane producers receiving neomycin Methane producers receiving neomycin showed significantly improved showed significantly improved constipation (p<0.05)constipation (p<0.05)

• Definition of probiotics: live organisms Definition of probiotics: live organisms that, when ingested in adequate that, when ingested in adequate amounts, exert a health benefit on amounts, exert a health benefit on the hostthe host

• ?inhibit visceral perception of pain?inhibit visceral perception of pain

• normalize epithelial barrier functionnormalize epithelial barrier function

• Reduce inflammation (reduce IL10/IL Reduce inflammation (reduce IL10/IL 12 ratio)12 ratio)

• One controlled pilot study of 77pts with IBS One controlled pilot study of 77pts with IBS randomized to lactobacillus salivarius, randomized to lactobacillus salivarius, Bifidobacterium infantis or placebo for eight Bifidobacterium infantis or placebo for eight weeks (O’ Mahony 2005)weeks (O’ Mahony 2005)

-those treated with Bifidobacterium showed -those treated with Bifidobacterium showed greater reduction of symptoms throughout 8 greater reduction of symptoms throughout 8 week treatment period and some of the 4 week week treatment period and some of the 4 week washout period washout period

• Efficacy of B. infantis further studied Efficacy of B. infantis further studied in 362 women with IBS of any in 362 women with IBS of any subtype (Whorwell, 2006)subtype (Whorwell, 2006)

• 1X10 8 cfu/ml more effective1X10 8 cfu/ml more effective

• Bifidobacterium infantis 35624 formulation Bifidobacterium infantis 35624 formulation showed statistical improvement in IBS showed statistical improvement in IBS symptomssymptoms

• VSL#3 study inconclusiveVSL#3 study inconclusive

• At least 15 RCTs thus farAt least 15 RCTs thus far

• Occasional reports of endocarditis and Occasional reports of endocarditis and abscesses receiving probiotics usually abscesses receiving probiotics usually been secondary superinfections rather been secondary superinfections rather than primarythan primary

• PEG 3350 ( Grade A AGA PEG 3350 ( Grade A AGA recommendation)recommendation)

- Nonabsorbable nonmetabolized osmotic Nonabsorbable nonmetabolized osmotic agentagent

- Recent six month study suggested that Recent six month study suggested that PEG 3350 is effective over this period PEG 3350 is effective over this period compared to placebo (52% vs compared to placebo (52% vs 11%,P<0.001)11%,P<0.001)

- Concerns over long-term efficacyConcerns over long-term efficacy

Other agents in Other agents in developmentdevelopment

• Cilansetron similar to alosetron, a Cilansetron similar to alosetron, a 5HT3 antagonist for abd 5HT3 antagonist for abd pain/discomfortpain/discomfort

• Renzapride-a full 5-HT4 receptor Renzapride-a full 5-HT4 receptor agonist /5-HT 3 antagonist for IBS-Cagonist /5-HT 3 antagonist for IBS-C

RenzaprideRenzapride

• Pilot study in 17pts with IBS –Pilot study in 17pts with IBS –C ;received placebo, renzapride 2mg C ;received placebo, renzapride 2mg po qd and renzapride 2mg po bid for po qd and renzapride 2mg po bid for 28 days28 days

1.1. Improvement at 2mg po bid Improvement at 2mg po bid 2.2. Reduced abd pain, improved stool Reduced abd pain, improved stool

consistency, increased number of consistency, increased number of pain-free dayspain-free days

3.3. Well –tolerated by ptsWell –tolerated by pts

• Linaclotide-agonist of human Linaclotide-agonist of human guanylate cyclase for IBS-C (phase 2)guanylate cyclase for IBS-C (phase 2)

• Clonidine 0.1mg po bid alpha 2 Clonidine 0.1mg po bid alpha 2 agonist (phase 2/3) for IBS-Dagonist (phase 2/3) for IBS-D

• Fedotizine, asimadoline- peripheral Fedotizine, asimadoline- peripheral opioid agonists (phase 2)opioid agonists (phase 2)

• Alvimopan opioid antagonistAlvimopan opioid antagonist

• Dextofisopam-benzodiazepine receptor Dextofisopam-benzodiazepine receptor agonist (phase 2) for IBS-D and IBS-mixedagonist (phase 2) for IBS-D and IBS-mixed

• AT1-7505 5HT4 receptor agonist similar to AT1-7505 5HT4 receptor agonist similar to cisapridecisapride

• GW876008 CRF antagonist (phase 2) for GW876008 CRF antagonist (phase 2) for IBS-DIBS-D

• Pindolol- beta blocker and 5HT antagonist Pindolol- beta blocker and 5HT antagonist (phase 2)(phase 2)

Additional therapyAdditional therapy

• Cognitive –behavioral therapy Cognitive –behavioral therapy

1.1. Cognitive-Change thinking patterns Cognitive-Change thinking patterns underlying somatizationunderlying somatization

2.2. Behavioral-modify behavior through Behavioral-modify behavior through relaxation, contingency ( reward healthy relaxation, contingency ( reward healthy behavior) and assertion trainingbehavior) and assertion training

• Hypnotherapy –improve symptoms, QOL Hypnotherapy –improve symptoms, QOL

• Metanalysis of 17 RCTs of cog tx, Metanalysis of 17 RCTs of cog tx, beh tx,or both ( including beh tx,or both ( including hypnotherapy ) for IBS compared to hypnotherapy ) for IBS compared to control txcontrol tx

1.1. Cognitive-behavioral tx more likely Cognitive-behavioral tx more likely to have a reduction in GI symptomsto have a reduction in GI symptoms

2.2. Estimated number sessions was two Estimated number sessions was two ( range of sessions typically 4 to 15 ( range of sessions typically 4 to 15 sessions)sessions)

• PsychotherapyPsychotherapy

• Herbal remedies (complementary Herbal remedies (complementary alternative medication): no quality alternative medication): no quality control in this area control in this area

• Acupuncture: no improvement in Acupuncture: no improvement in quality of life compared to sham quality of life compared to sham treatments for IBS treatments for IBS

conclusionsconclusions

• Holistic approach Holistic approach • Detailed history including diet, lifestyleDetailed history including diet, lifestyle• Recognition of pathophysiology in combination with pt’s Recognition of pathophysiology in combination with pt’s

psychosocial factors psychosocial factors • Peripheral management target symptoms of constipation, Peripheral management target symptoms of constipation,

diarrhea, bloating, paindiarrhea, bloating, pain• Ongoing study involving manipulating flora with probiotics Ongoing study involving manipulating flora with probiotics

and antibiotics to exert antibacterial, immune-modulating and antibiotics to exert antibacterial, immune-modulating and anti-inflammatory effectsand anti-inflammatory effects

• Central agents affect homeostatic afferent processing;may Central agents affect homeostatic afferent processing;may or may not improve individual IBS symptoms but tend to or may not improve individual IBS symptoms but tend to reduce global symptoms and improve well-being.reduce global symptoms and improve well-being.

• Thank you for your attention.Thank you for your attention.