Transcript Irritable Bowel Syndrome - The Kansas Association of

Treatment options in Irritable
Bowel Syndrome
 Phillis
Ling MPH, DO
Definition and epidemiology
• Revised Rome III diagnostic criteria
include the following:
Recurrent abd pain or discomfort at least
3 days per month in the last 3 months
associated with 2 or more of the
following:
-improvement with defecation
-Onset associated with a change in stool
frequency
-Onset associated with a change in stool
form
Most important step in the diagnosis is to
listen, review symptoms in detail
recognizing the key feature being the
presence of abdominal pain or discomfort
associated with bowel dysfunction
-this separates IBS from functional
constipation and functional diarrhea
• IBS affects up to 10%-20% of adolescents
and adults.
• Prevalence in women of 14.5% compared
to 7.7% of men with a 2:1 (F:M) ratio
• 40% to 60% of referrals to outpatient
gastroenterology clinics.
Pathophysiology
• Visceral hypersensitivity
• Abnormal gut motility
• Genetics ( 2 fold increase in IBS in
monozygotic twins, having a parent with
IBS is an independent and stronger
predictor of IBS than having a twin with
disease)
• Psychosocial factors: heightened pain
sensitivity to visceral stimulation of the
brain-gut axis
- Fibromyalgia( 49%pts have IBS), chronic
fatigue syndrome (51%), chronic pelvic
pain (50%), TMJ syndrome (64%)
• Post –infectious causes
• Luminal irritation: small bowel bacterial
overgrowth (SIBO), gas, ?food allergy
Symptoms and treatment
• Dietary triggers: caffeine,excess fatty foods, sorbitol,
glucose, fructose, lactose, beans, uncooked broccoli,
cabbage, cauliflower, carbonated drinks, certain spices
• Dietary fiber: soluble (starches) vs insoluble (tough skin,
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peel seeds, pods)
soluble fiber is fermented in the proximal colon results in
increased stool viscosity
Insoluble fiber binds water but more resistant to
fermentation; increases stool bulk, decreases colonic
transit time but can cause bloating, diarrhea, abd pain.
AGA recommends 20-35g/day fiber;typical
diet contains 11-13g/day
- Bulking agents include
metamucil,benefiber, citrucel,konsyl are
considered soluble fiber, may be beneficial
-metamucil –psyllium seed (ispaghula
seed) 4/5RCTS improve ease of stool
passage but no change in pain
• Antispasmodics (hyoscyamine,
didydoline, glycopyrrolate)
-Relax gut smooth muscle ; best given
30-60 minutes before meals if related to
eating
-insufficient data for recommendation
Antidiarrheal
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Loperamide (IBS-D) opioid agonist inhibits intestinal
secretion and peristalsis, slows intestinal transit, allow
absorption of fluid and electrolytes
Minimal analgesia
Longer duration of action than diphenoxylate, less
abuse potential, no anticholinergic agent added (eg
atropine)
Generally safe and effective for treatment of diarrhea
but needs monitoring in chronic patients to avoid
megacolon
• Tricyclic antidepressants (TCAs)
1. Better than placebo at relieving global
2.
symptoms and abd pain
Used at a lower dose than in treating
depression and anxiety
(eg: nortryptiline 10mg daily, desipramine
50mg daily, amitryptiline 10-25mg daily)
• Secondary agents (nortryptiline,
desipramine) preferred over tertiary
agents (amitriptyline, imipramine) due to
more favorable side effect profile
• No evidence one more effective than
another
• Selective serotonin reuptake inhibitor
(SSRI)
1. May have beneficial effects on general
well-being
2. No evidence one agent is better than
another
• Serotonin-norepinephrine reuptake
inhibitor (SNRI) such as duloxetine and
venlafaxine
1. Effective in reducing pain in chronic pain
such as fibromyalgia but
2. Data from RCT of their role in IBS
lacking
Serotonin (5hydroxytryptamine, 5HT) seems to
be the most important neurotransmitter in the
enteric nervous system in gut sensitization
Serotonin receptor modulating drugs:
Alosetron 5 HT3 receptor antagonist -used in
IBS-D by antagonizing the release of serotonin
to mucosal stimulation that results in increased
intestinal secretion, motility and sensation
Alosetron
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Introduced in spring 2000;
Placebo-controlled RCT at 1mg po bid for 12 weeks
Improved symptoms overall
Efficacy in women with IBS-D based on phase 2 trials
Complications from ileus, fecal impaction, ischemic
colitis (latter prev 0.15% vs 0.06% in placebo group)
Reintroduced with strict guidelines in 2002 for IBS-D
women with at least 6 months of symptoms not
responsive to conventional treatment
Tegaserod (initially approved in July 2002)
Used in IBS-C by stimulating 5 HT4 receptors
to increase gastric emptying, small bowel and
colonic motility
- 0.11% (13/11600 pts) increased cv events vs
0.01% ( 1/7031pts)
- Reintroduced July 2007: restricted access for
use in women 18 to 54 years with IBS-C or CC
with unsatisfactory response to other
treatment
• Alosetron and Tegaserod – Grade A AGA
recommendations
-evidence based on a minimum of 2 RCTs,
p value <0.05; adequate sample size and
appropriate methods
•
Chloride channel activators (Lubiprostone)
- acts on epithelial cells to increase intestinal fluid to
promote spontaneous bowel movements
1. Drossman et al ( Gastro 2007) showed proportion of
pts with symptom relief was significantly higher at
dose of 8mcg po bid compared to placebo, in two 12
week phase 3 placebo-controlled randomized double
blind trials
2. FDA approved at 24mcg po bid for CC
Antibiotics and Probiotics
Postinfectious (PI IBS) causes first suggested in the 1960s.
• 90 % of people recover spontaneously following a bout of enteritis
• 10 % develop PI IBS
• Overall incidence of 4% to 36% of new onset IBS after an acute
enteritis.
• Symptoms can persist for years (6years)
• Risk factors: Women, patients with anxiety, depression, severe or
prolonged symptoms of gastroenteritis, absence of vomiting.
• Salmonella infection results in the highest incidence approx 10%;
other pathogens include Campylobacter, E Coli, Giardia, Shigella
• Mucosal inflammation develops as a
response to initial bacterial infection
• Low-grade inflammation is an abnormal
reaction to the normal flora or response to
changes in the intrinsic flora
• Rifaximin –luminal nonabsorbable
(<0.4%) antibiotic
• No clinically relevant antimicrobial
resistance
• ? Prevent traveler’s diarrhea to reduce
new-onset IBS symptoms being assessed.
• Hypothesis that symptoms of IBS may result
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from abnormal fermentation assoc with small
intestinal bowel overgrowth (SIBO)
Prevalence by lactulose breath test of 65 % to
84% in IBS patients
Rifaximin relieved global symptoms up to 10
weeks after discontinuation of therapy (Pimental
et al)
Improve gas/bloating at lower dose
Need more study
Other antibiotics
• Neomycin
-oral aminoglycoside that is systemically
absorbed
-neomycin 1g/day for 10 days improved IBS
scores compared to placebo (N=111,
p<0.05)
• Normalization of LBT with neomycin leads to
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decrease in IBS symptoms
Subanalysis on IBS –C pts(n=39) 20 received
placebo and 19 received neomycin;global
improvement seen, constipation improved
Methane producers receiving neomycin showed
significantly improved constipation (p<0.05)
• Definition of probiotics: live organisms
that, when ingested in adequate amounts,
exert a health benefit on the host
• ?inhibit visceral perception of pain
• normalize epithelial barrier function
• Reduce inflammation (reduce IL10/IL 12
ratio)
• One controlled pilot study of 77pts with IBS randomized
to lactobacillus salivarius, Bifidobacterium infantis or
placebo for eight weeks (O’ Mahony 2005)
-those treated with Bifidobacterium showed greater
reduction of symptoms throughout 8 week treatment
period and some of the 4 week washout period
• Efficacy of B. infantis further studied in
362 women with IBS of any subtype
(Whorwell, 2006)
• 1X10 8 cfu/ml more effective
• Bifidobacterium infantis 35624 formulation
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showed statistical improvement in IBS symptoms
VSL#3 study inconclusive
At least 15 RCTs thus far
Occasional reports of endocarditis and abscesses
receiving probiotics usually been secondary
superinfections rather than primary
• PEG 3350 ( Grade A AGA recommendation)
- Nonabsorbable nonmetabolized osmotic agent
- Recent six month study suggested that PEG
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3350 is effective over this period compared to
placebo (52% vs 11%,P<0.001)
Concerns over long-term efficacy
Other agents in development
• Cilansetron similar to alosetron, a 5HT3
antagonist for abd pain/discomfort
• Renzapride-a full 5-HT4 receptor agonist
/5-HT 3 antagonist for IBS-C
Renzapride
• Pilot study in 17pts with IBS –C ;received
placebo, renzapride 2mg po qd and
renzapride 2mg po bid for 28 days
1. Improvement at 2mg po bid
2. Reduced abd pain, improved stool
consistency, increased number of painfree days
3. Well –tolerated by pts
• Linaclotide-agonist of human guanylate
cyclase for IBS-C (phase 2)
• Clonidine 0.1mg po bid alpha 2 agonist
(phase 2/3) for IBS-D
• Fedotizine, asimadoline- peripheral opioid
agonists (phase 2)
• Alvimopan opioid antagonist
• Dextofisopam-benzodiazepine receptor agonist
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(phase 2) for IBS-D and IBS-mixed
AT1-7505 5HT4 receptor agonist similar to
cisapride
GW876008 CRF antagonist (phase 2) for IBS-D
Pindolol- beta blocker and 5HT antagonist
(phase 2)
Additional therapy
• Cognitive –behavioral therapy
1. Cognitive-Change thinking patterns
underlying somatization
2. Behavioral-modify behavior through
relaxation, contingency ( reward healthy
behavior) and assertion training
• Hypnotherapy –improve symptoms, QOL
• Metanalysis of 17 RCTs of cog tx, beh
tx,or both ( including hypnotherapy ) for
IBS compared to control tx
1. Cognitive-behavioral tx more likely to
have a reduction in GI symptoms
2. Estimated number sessions was two (
range of sessions typically 4 to 15
sessions)
• Psychotherapy
• Herbal remedies (complementary
alternative medication): no quality control
in this area
• Acupuncture: no improvement in quality of
life compared to sham treatments for IBS
conclusions
• Holistic approach
• Detailed history including diet, lifestyle
• Recognition of pathophysiology in combination with pt’s
psychosocial factors
• Peripheral management target symptoms of constipation, diarrhea,
bloating, pain
• Ongoing study involving manipulating flora with probiotics and
antibiotics to exert antibacterial, immune-modulating and antiinflammatory effects
• Central agents affect homeostatic afferent processing;may or may
not improve individual IBS symptoms but tend to reduce global
symptoms and improve well-being.
• Thank you for your attention.