Irritable bowel syndrome medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Medical Therapy

Medical therapy of IBS

• The multimodal treatment regimen is preferred for Irritable Bowel Syndrome (IBS).
• IBS is heterogeneous in its presentation, which makes it difficult to treat.
• It is necessary to build a good physician patient rapport due to the following reasons:
  • IBS has a remarkably high placebo response rate
  • Patient regimens need to be individualized in IBS patients
  • Appropriate goals need to be set with emphasis on the chronic nature of the syndrome
  • Patient counseling plays an important role

Dietary Measures

• General instructions:
  • Careful dietary history must be taken
  • Caffeine and alcohol avoidance decreases anxiety in patients
  • Legume avoidance decreases symptoms of flatulence
  • Skipping entire meals may worsen IBS symptoms
  • Avoidance of large meals
  • Reduced fat intake
  • Elimination diets help remove the most common dietary allergens
  • Judicious water intake for the constipation-predominant IBS patients
  • Fiber supplementation
  • Individualized dietary recommendations are preferable
  • Avoidance of gluten as gluten sensitivity may manifest in a subset of IBS patients

Exclusion of gas-producing foods:

• Beans, onions, celery, carrots, raisins, bananas, apricots, prunes, cabbage, onions, brussels sprouts, wheat germ, pretzels, and bagels

• Low FODMAP diet:
  • A diet low in fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs) is preferred in IBS patients.
  • Education consists of:
    • Elimination of dietary FODMAPs for 6-8 weeks
    • Reintroduction of foods high in FODMAPs to determine individual tolerance to specific foods
  • High FODMAP foods include:
    • honey, mangoes cherries, high-fructose corn syrup, apples, pears, or oligosaccharides such as wheat
    • mannitol, sorbitol, fructose, lactose, fructans, xylitol, and galactans
    • sugar-alcohols such as isomalt, maltitol, erythritol, lactitol, mannitol and xylitol
  • High FODMAP foods are poorly absorbed by the gut and are osmotically active short chain carbohydrates.
  • Rapid fermentation of high FODMAP foods results in symptoms of abdominal discomfort and flatulence.
• Lactose avoidance:
  • IBS patients have more subjective lactose intolerance complaints (flatulence and diarrhea) as compared to other individuals.
  • Lactose ingestion leads to production of hydrogen gas.
  • Bacterial fermentation of the unabsorbed lactose causes symptoms of bloating and distension.
  • Lactose intolerance can be diagnosed using breath testing.
  • IBS patients with lactose intolerance should be given a lactose-restricted diet.

• Fiber in the diet:
  • Dietary fiber decreases symptoms of bloating in IBS patients.
  • Soluble fibers are preferred as compared to insoluble fibers for treating symptoms of constipation.

Psychological therapy

• The 2009 American College of Gastroenterologists (ACG) states that:
  • A psychiatric referral must be considered in all IBS patients.
• Patients may be given the following therapies for symptom control:
  • Cognitive-behavioral therapy
  • Interpersonal psychotherapy
  • Dynamic psychotherapy
  • Hypnotherapy
  • Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) and Tricyclic antidepressants (TCAs)

Adjunctive pharmacologic therapy

Chloride channel activators

Linaclotide and lubiprostone enhance chloride-rich intestinal fluid secretions without altering sodium and potassium concentrations in the serum.

• Lubiprostone (Amitiza)
  • MOA: activates chloride channels in the apical part of the small bowel epithelium. As a result, chloride ions are secreted and sodium and water passively diffuse into the lumen to maintain isotonicity.
• Linaclotide (Linzess)
  • Chloride channel activators
  • Guanylate cyclase C (GC-C) agonists: Linaclotide for the management of the constipation-predominant disease (IBS-C) subtype
  • Guanylate cyclase agonist; activates chloride channels in intestinal epithelial cells to increase intestinal fluid secretion

Diarrhea-predominant IBS

• Alosetron (Lotronex): Alosetron is a 5-HT3 receptor antagonist.
  • 5-HT3 receptors are located on the enteric neurons of the GI tract, and stimulation causes hypersensitivity and hyperactivity of the intestine.
• Eluxadoline (Viberzi): Eluxadoline is a mu opioid receptor agonist, delta opioid receptor antagonist, and a kappa opioid receptor agonist.

Anticholinergics

• MOA: inhibit intestinal smooth-muscle depolarization at the muscarinic receptor, relieving symptoms of intestinal spasms in irritable bowel syndrome
  • Dicyclomine hydrochloride (Bentyl)
  • MOA: blocks the action of acetylcholine at parasympathetic sites in secretory glands, smooth muscle, and CNS, decreasing fecal urgency and pain.
  • Hyoscyamine sulfate (Levsin)
  • MOA: blocks the action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and the CNS, which, in turn, has antispasmodic effects, decreases fecal urgency and pain.

Antidiarrheals

• MOA: nonabsorbable synthetic opioids.
  • They prolong the GI transit time
  • decrease secretion via peripheral µ-opioid receptors
  • reduce visceral nociception via afferent pathway inhibition

• Diphenoxylate hydrochloride 2.5 mg with atropine sulfate 0.025 mg (Lomotil)

• Diphenoxylate is a constipating meperidine congener and 0.025 mg of atropine discourages abuse.
• MOA: inhibits excessive GI propulsion and motility, but it may exacerbate constipation.

• Loperamide (Imodium)
• Loperamide effectively reduced stool frequency and improved stool consistency
  • MOA: acts on intestinal muscles to inhibit peristalsis and to slow intestinal motility
  • prolongs the movement of electrolytes and fluid through bowel
  • increases the viscosity and loss of fluids and electrolytes
  • Loperamide improves stool frequency and consistency, reduces abdominal pain and fecal urgency, and may exacerbate constipation
  • MOA:  increase gastrointestinal transit time by interacting with the GI musculature, thus allowing for more water absorption Side effects: used with extreme caution because severe constipation

addiction potential.

• Tricyclic Antidepressants:

imipramine and amitriptyline have both antidepressive and analgesic properties.

MOA:

facilitate endogenous endorphin release

blockade of norepinephrine leading to enhancement of descending inhibitory pain pathways

blockade of the pain neuromodulator, serotonin

TCAs, via their anticholinergic properties, also slow intestinal transit time, which may provide benefit in diarrhea-predominant IBS

reduce the visceral hypersensitivity

side effects of constipation and sedation is essential.

• • Imipramine (Tofranil)
  • increases pain threshold in the gut, thereby providing a visceral analgesic effect.
  • prolongs oral-cecal transit time; reduces abdominal pain, mucorrhea, and stool frequency

• Amitriptyline (Elavil)
  • MOA: provides a visceral analgesic effect at doses subtherapeutic for antidepressive actions
  • prolongs oral-cecal transit time, reduces abdominal pain, mucorrhea, and stool frequency

Antibiotics

• benefit from treatment appears to be transient.

• routine use of antibiotics in all IBS patients is not recommended.

• try a 2-wk trial of rifaximin in those patients with IBS without constipation and with moderate to severe symptoms, especially bloating, who have failed other therapies. 

• MOA: prevent the overgrowth of intestinal bacteria

Rifaximin (Xifaxan)

• Rifaximin is a semisynthetic derivative of rifampin
• Rifaximin (550 mg PO q8h for 14 d) for bloating, abdominal pain, diarrhea
• MOA: binding to the beta-subunit of bacterial DNA-dependent RNA polymerase, blocking one of the steps in transcription.
• inhibition of bacterial protein synthesis thereby inhibiting bacterial growth

Bulk-Forming Laxatives

• Composition: natural and semi-synthetic hydrophilic polysaccharides and cellulose derivatives that form emollient gels in water and facilitate intestinal passage and stimulate peristalsis.
• As fiber supplements, these products improve symptoms of constipation and diarrhea

• Methylcellulose (Citrucel)
  • MOA: promotes bowel evacuation by forming a viscous liquid and promoting peristalsis.

• Psyllium (Metamucil, Fiberall, Reguloid, Konsyl)
  • Psyllium promotes bowel evacuation by forming a viscous liquid and promoting peristalsis.

INITIAL THERAPY 

Education and reassurance — Patient must be involved in treatment decisions.

Physical activity — potential benefit with regard to IBS symptoms and the general health benefits of exercise

• Exercise relieves symptoms by : 
  • maintain GI function
  • reduce stress
  • protects against GI symptom aggravation
  • alleviates gas  
  • Pranayama yoga increases sympathetic tone, which is decreased in IBS-D

ADJUNCTIVE PHARMACOLOGIC THERAPY 

Constipation — 

IBS with constipation (IBS-C) who have failed a trial of soluble fiber (eg, psyllium/ispaghula), we suggest polyethylene glycol (PEG).
treat patients with persistent constipation despite treatment with PEG with lubiprostone or linaclotide.  

• increase  consumption of fiber-enriched foods

• fluid intake to prevent stool dehydration

• schedule times for bowel evacuations with the aid of stimulating substances such as coffee or prunes allows for a regimental routine

•  Bulking agents (corn fiber, bran, psyllium, polycarbophil, ispaghula husk, and methylcellulose)

• MOA: increases luminal water, which adds bulk to the stool and allows easier stool passage.

Osmotic laxatives — Bulk-forming laxatives

PEG is inexpensive, widely available, and has fewer side effects as compared with other osmotic laxatives (eg, lactulose, milk of magnesia).

Polyethylene glycol : polyethylene glycol can be considered for refractory cases as it was shown to improve stool frequency 

Lubiprostone — Lubiprostone is a locally acting chloride channel activator that enhances chloride-rich intestinal fluid secretion.

Guanylate cyclase agonists — Linaclotide is a guanylate cyclase agonist that stimulates intestinal fluid secretion and transit. Diarrhea was the most common side effect.

Prokinetics

5-hydroxytryptamine (serotonin) 4 receptor agonists  prokinetics or secretagogues for patients with constipation predominant

Agonists of the 5-hydroxytryptamine-4 (5-HT4) receptor stimulate the release of neurotransmitters and increase colonic motility.

However, the first partial 5-HT4 receptor agonist, tegaserod has cardiovascular side effects.

Diarrhea —

Use antidiarrheals (eg, loperamide) as initial treatment Use bile acid sequestrants as second-line therapy

Antidiarrheal agents — loperamide 2 mg 45 minutes before a meal on regularly scheduled doses. Antidiarrheal agents inhibit peristalsis, prolong transit time, and reduce fecal volume.

• Eluxadoline is an agent that combines a mu-opioid receptor agonist and a delta-opioid receptor antagonist.

Adverse events associated with eluxadoline were nausea, constipation, and abdominal pain.

Pancreatitis developed in a small fraction of patients treated with eluxadoline.

Bile acid sequestrants — 

side effects including bloating, flatulence, abdominal discomfort, and constipation. 50 percent of patients with functional diarrhea and IBS-D have bile acid malabsorption

Cholestyramine

Bile acids cause diarrhea by stimulating colonic secretion and motility.

5-hydroxytryptamine (serotonin) 3 receptor antagonists  Alosetron, a 5-hydroxytryptamine-3 receptor (5HT-3) antagonist, for the treatment of severe diarrhea-predominant IBS who have failed to respond to all other conventional treatment. Alosetron modulates visceral afferent activity from the gastrointestinal tract, thereby decreasing colonic motility and secretion, and may improve abdominal pain Side effects of ischemic colitis and complications of severe constipation

Abdominal pain and bloating — In patients with abdominal pain due to IBS, we use antispasmodics. In patients with persistent abdominal pain despite antispasmodics, we recommend a trial of antidepressants.

Antispasmodic agents  — Antispasmodic include those that directly affect intestinal smooth muscle relaxation (eg, mebeverine and pinaverine), and those that act via their anticholinergic properties (eg, dicyclomine and hyoscyamine).

• Antispasmodics such as peppermint oil, pinaverium, trimebutine, and cimetropium/dicyclomine
• Peppermint oil, which has antispasmodic properties by relaxing smooth muscle, Use: abdominal discomfort pain and abdominal distention
• S/E constipation

MOA: The selective inhibition of gastrointestinal smooth muscle by antispasmodics and peppermint oil reduce stimulated colonic motor activity and may be beneficial in patients with postprandial abdominal pain, gas, bloating, and fecal urgency.

Typical doses include:

●Dicyclomine 20 mg orally four times daily

●Hyoscyamine 0.125 to 0.25 mg orally or sublingually three to four times daily as needed

●Sustained release hyoscyamine 0.375 to 0.75 mg orally every 12 hours

Side effects:

constipation

dry mouth

visual disturbances

urinary retention

Antidepressants —  Antidepressants have analgesic properties independent of their mood improving effects.

Tricyclic antidepressants (TCAs), via their anticholinergic properties, also slow intestinal transit time, which may provide benefit in diarrhea-predominant IBS.

Due to the delayed onset of action of antidepressants, three to four weeks of therapy should be attempted before increasing the dose. 

Amitriptyline, nortriptyline, and imipramine can be started at a dose of 10 to 25 mg at bedtime.

Desipramine should be started at a dose of 12.5 to 25 mg at bedtime. If the patient is intolerant of one TCA, another may be tried.

Antibiotics — In patients with moderate to severe IBS without constipation, particularly those with bloating, who have failed to respond to other therapies (eg, a diet low in fermentable oligo-, di-, and monosaccharides and polyols [FODMAPs], antispasmodics, and TCAs), we suggest a two-week trial of rifaximin.

Probiotics — Probiotics are not routinely recommended in patients with IBS.

 Use: reduce pain, bloating, and defecatory difficulty and to normalize stool habit in IBS patients, regardless of predominant bowel habit.

Probiotics relieve pain, bloating, and flatulence

REFRACTORY SYMPTOMS —presence of alarm features that should prompt further evaluation.

Behavior modification — Patients with unrelenting symptoms that are associated with psychiatric impairment may benefit from behavioral modification in conjunction with antidepressants.

Anxiolytics —  limited to short-term (less than two weeks) reduction of acute situational anxiety that may be contributing to symptoms. Side effects of anxiolytics include the risk of habituation, rebound withdrawal, and drug interactions. Furthermore, benzodiazepines may lower pain thresholds by stimulating gamma aminobutyric acid (GABA) receptors, thereby decreasing brain serotonin.

Other therapies —  Other therapies have been evaluated in patients with IBS (eg, herbs, acupuncture, enzyme supplementation, and mast cell stabilizers) but their role in the treatment of IBS remains uncertain.

• herbal medicines

• Apuncture: specific targets for acupuncture on serotonergic, cholinergic, and glutamatergic pathways as well as reductions in blood cortisol level

• mind-body therapies:
  • hypnotherapy
  • cognitive-behavioral therapy

• Relaxation techniques

Ketotifen, a mast cell stabilizer, has been studied for the treatment of IBS based upon the theory that mast cell activation contributes to visceral hypersensitivity.

Tight-junction modulators (e.g., larazotide) for patients with evidence of immune activation or increased mucosal permeability.

Disease Name

• 1 Stage 1 - Name of stage
  • 1.1 Specific Organ system involved 1
    • 1.1.1 Adult
      • Preferred regimen (1): drug name 100 mg PO q12h for 10-21 days (Contraindications/specific instructions)
      • Preferred regimen (2): drug name 500 mg PO q8h for 14-21 days
      • Preferred regimen (3): drug name 500 mg q12h for 14-21 days
      • Alternative regimen (1): drug name 500 mg PO q6h for 7–10 days
      • Alternative regimen (2): drug name 500 mg PO q12h for 14–21 days
      • Alternative regimen (3): drug name 500 mg PO q6h for 14–21 days
    • 1.1.2 Pediatric
      • 1.1.2.1 (Specific population e.g. children < 8 years of age)
        • Preferred regimen (1): drug name 50 mg/kg PO per day q8h (maximum, 500 mg per dose)
        • Preferred regimen (2): drug name 30 mg/kg PO per day in 2 divided doses (maximum, 500 mg per dose)
        • Alternative regimen (1): drug name10 mg/kg PO q6h (maximum, 500 mg per day)
        • Alternative regimen (2): drug name 7.5 mg/kg PO q12h (maximum, 500 mg per dose)
        • Alternative regimen (3): drug name 12.5 mg/kg PO q6h (maximum, 500 mg per dose)
      • 1.1.2.2 (Specific population e.g. 'children < 8 years of age')
        • Preferred regimen (1): drug name 4 mg/kg/day PO q12h（maximum, 100 mg per dose）
        • Alternative regimen (1): drug name 10 mg/kg PO q6h (maximum, 500 mg per day)
        • Alternative regimen (2): drug name 7.5 mg/kg PO q12h (maximum, 500 mg per dose)
        • Alternative regimen (3): drug name 12.5 mg/kg PO q6h (maximum, 500 mg per dose)
  • 1.2 Specific Organ system involved 2
    • 1.2.1 Adult
      • Preferred regimen (1): drug name 500 mg PO q8h
    • 1.2.2 Pediatric
      • Preferred regimen (1): drug name 50 mg/kg/day PO q8h (maximum, 500 mg per dose)

• 2 Stage 2 - Name of stage
  • 2.1 Specific Organ system involved 1

    Note (1):

    Note (2):

    Note (3):

    • 2.1.1 Adult
      • Parenteral regimen
        • Preferred regimen (1): drug name 2 g IV q24h for 14 (14–21) days
        • Alternative regimen (1): drug name 2 g IV q8h for 14 (14–21) days
        • Alternative regimen (2): drug name 18–24 MU/day IV q4h for 14 (14–21) days
      • Oral regimen
        • Preferred regimen (1): drug name 500 mg PO q8h for 14 (14–21) days
        • Preferred regimen (2): drug name 100 mg PO q12h for 14 (14–21) days
        • Preferred regimen (3): drug name 500 mg PO q12h for 14 (14–21) days
        • Alternative regimen (1): drug name 500 mg PO q6h for 7–10 days
        • Alternative regimen (2): drug name 500 mg PO q12h for 14–21 days
        • Alternative regimen (3):drug name 500 mg PO q6h for 14–21 days
    • 2.1.2 Pediatric
      • Parenteral regimen
        • Preferred regimen (1): drug name 50–75 mg/kg IV q24h for 14 (14–21) days (maximum, 2 g)
        • Alternative regimen (1): drug name 150–200 mg/kg/day IV q6–8h for 14 (14–21) days (maximum, 6 g per day)
        • Alternative regimen (2):  drug name 200,000–400,000 U/kg/day IV q4h for 14 (14–21) days (maximum, 18–24 million U per day) '(Contraindications/specific instructions)'
      • Oral regimen
        • Preferred regimen (1): drug name 50 mg/kg/day PO q8h for 14 (14–21) days (maximum, 500 mg per dose)
        • Preferred regimen (2): drug name (for children aged ≥ 8 years) 4 mg/kg/day PO q12h for 14 (14–21) days (maximum, 100 mg per dose)
        • Preferred regimen (3): drug name 30 mg/kg/day PO q12h for 14 (14–21) days (maximum, 500 mg per dose)
        • Alternative regimen (1): drug name 10 mg/kg PO q6h 7–10 days (maximum, 500 mg per day)
        • Alternative regimen (2): drug name 7.5 mg/kg PO q12h for 14–21 days (maximum, 500 mg per dose)
        • Alternative regimen (3): drug name 12.5 mg/kg PO q6h for 14–21 days (maximum,500 mg per dose)
  • 2.2 Other Organ system involved 2

    Note (1):

    Note (2):

    Note (3):

    • 2.2.1 Adult
      • Parenteral regimen
        • Preferred regimen (1): drug name 2 g IV q24h for 14 (14–21) days
        • Alternative regimen (1): drug name 2 g IV q8h for 14 (14–21) days
        • Alternative regimen (2): drug name 18–24 MU/day IV q4h for 14 (14–21) days
      • Oral regimen
        • Preferred regimen (1): drug name 500 mg PO q8h for 14 (14–21) days
        • Preferred regimen (2): drug name 100 mg PO q12h for 14 (14–21) days
        • Preferred regimen (3): drug name 500 mg PO q12h for 14 (14–21) days
        • Alternative regimen (1): drug name 500 mg PO q6h for 7–10 days
        • Alternative regimen (2): drug name 500 mg PO q12h for 14–21 days
        • Alternative regimen (3):drug name 500 mg PO q6h for 14–21 days
    • 2.2.2 Pediatric
      • Parenteral regimen
        • Preferred regimen (1): drug name 50–75 mg/kg IV q24h for 14 (14–21) days (maximum, 2 g)
        • Alternative regimen (1): drug name 150–200 mg/kg/day IV q6–8h for 14 (14–21) days (maximum, 6 g per day)
        • Alternative regimen (2):  drug name 200,000–400,000 U/kg/day IV q4h for 14 (14–21) days (maximum, 18–24 million U per day)
      • Oral regimen
        • Preferred regimen (1): drug name 50 mg/kg/day PO q8h for 14 (14–21) days (maximum, 500 mg per dose)
        • Preferred regimen (2): drug name 4 mg/kg/day PO q12h for 14 (14–21) days (maximum, 100 mg per dose)
        • Preferred regimen (3): drug name 30 mg/kg/day PO q12h for 14 (14–21) days (maximum, 500 mg per dose)
        • Alternative regimen (1): drug name 10 mg/kg PO q6h 7–10 days (maximum, 500 mg per day)
        • Alternative regimen (2): drug name 7.5 mg/kg PO q12h for 14–21 days (maximum, 500 mg per dose)
        • Alternative regimen (3): drug name 12.5 mg/kg PO q6h for 14–21 days (maximum,500 mg per dose)