DIET AND PROBIOTICS

Food intolerance may cause symptoms similar to those associated with IBS. Patients

with lactose intolerance can experience pain, bloating, and diarrhea after ingesting

milk-based products. A dietary and symptom diary may reveal such an intolerance,

and avoidance of the implicated foods would constitute effective treatment.

Unfortunately, most patients with IBS have difficulty complying with exclusion diets

or will not achieve significant relief with them.

Gluten-free diets eliminate gluten found in wheat, barley, and rye and a wide

variety of processed foods, while FODMAPs diets consist of eliminating a group of

short-chain carbohydrates such as fermentable oligosaccharides, disaccharides,

monosaccharides, and polyols called FODMAPs because they are unable to be

properly absorbed by patients with IBS and cause fermentation by bacteria in the gut

producing gas.

120,121 Recent guidelines suggest that gluten-free and low FODMAPs

diets show promise, but their role is still questionable.

114 Guidelines also suggest

there is not enough data to recommend prebiotics or synbiotics. However, probiotics

have shown promise with a decrease in flatulence or bloating, although there are no

comparative studies to suggest one product over another.

114

CASE 24-3, QUESTION 2: V.H. has gradually increased her dietary fiber, mainly bran, during the past 6

weeks. She still feels constipated and did not experience any improvement. In addition, new symptoms of

abdominal bloating have occurred in the past week. What is a reasonable strategy to treat V.H.’s IBS-C?

Patients with IBS-C may benefit from increased dietary consumption of soluble

fiber; with a recent study finding that psyllium significantly improved IBS symptoms

during 3 months of treatment compared with placebo.

122

Insoluble fiber such as bran

can worsen symptoms of bloating, cramping, or flatulence.

114 Patients should be

counseled that large doses of fiber can lead to abdominal gas and bloating, and

overall objective long-term evidence in IBS is lacking.

V.H. should be encouraged to keep a food diary to identify food intolerances.

Currently, there is very little evidence to suggest a gluten-free or a FODMAPs diet

for this patient. She can consider probiotics, but there is insufficient evidence to

suggest one probiotic over the other. When choosing fiber for constipation, she

should substitute bran fiber for soluble fiber, such as psyllium, to reduce abdominal

gas and bloating.

CASE 24-3, QUESTION 3: Several months have passed since V.H. was first diagnosed with IBS-C. She

has had therapeutic trials of several over-the-counter agents that were either poorly tolerated or lacked

effectiveness. What other options are available for treating V.H.’s IBS-C?

Pharmacotherapy for Irritable Bowel Syndrome with

Constipation (IBS-C)

In patients with IBS-C in whom fiber therapy fails, other standard laxatives may be

tried for symptomatic relief. These may include milk of magnesia, lactulose, senna,

or polyethylene glycol without electrolytes (Miralax). This last agent was shown to

improve the number of bowel movements in a cohort of adolescents with IBS-C, but

had no effect on abdominal pain or bloating.

123 Few well-designed trials looking at

any laxative for IBS have been published. These agents are usually well tolerated,

although they can occasionally cause abdominal bloating. Other adverse effects of the

osmotic laxatives include diarrhea, taste disturbances, and hypermagnesemia

(especially in patients with renal impairment). Although laxatives may provide relief

of constipation, they will not effectively treat abdominal pain. Thus, other treatments

will be required in many patients.

TEGASEROD

Stimulation of the 5-HT4

receptor accelerates colonic transit and has been exploited

as a target for pharmacotherapy of IBS-C. The first of these agents, tegaserod, was

originally approved in the United States for women with IBS-C. Tegaserod is a

specific 5-HT4 partial agonist that was evaluated in women with at least a 3-month

history of IBS-C symptoms.

124 Clinical studies demonstrated a modest but significant

benefit with tegaserod. Unfortunately, postmarketing analysis by the US Food and

Drug Administration found an increased incidence of heart attack, stroke, and

unstable angina in patients receiving the drug, and in April 2008, the manufacturer of

tegaserod halted all sales and marketing of this agent.

p. 534

p. 535

LUBIPROSTONE

Lubiprostone, a GI chloride-channel activator (CIC-2 channels) that enhances

intestinal fluid secretion and acts as a laxative, was approved in the United States for

IBS-C in women older than 18 years of age. The drug has several actions on GI

function including increased small and large bowel transit time and decreased gastric

emptying.

125 The dose of lubiprostone for IBS-C is 8 mcg orally twice daily with

food and water, which is a lower dose than used for chronic idiopathic constipation.

Mechanical GI obstruction is a contraindication to lubiprostone’s use.

126 A recent

analysis of two randomized controlled studies of lubiprostone versus placebo in

women with IBS-C found that the drug was moderately effective in improving patient

perception of constipation symptoms (17.9% vs. 10.1% of placebo groups

responded; p = 0.001).

127 Primary adverse effects of lubiprostone include nausea and

vomiting, but the effects are less likely at the dose of the drug approved for IBS-C

and can be somewhat ameliorated by taking the medication with food.

125 Too few

men with IBS-C were enrolled in the clinical trials with lubiprostone to draw any

conclusions about its effectiveness in this population. Because the drug is associated

with teratogenic effects in animals, the manufacturer recommends that women who

could become pregnant have a negative pregnancy test before beginning therapy and

be able to comply with effective contraceptive measures during therapy.

126 The drug

is significantly more expensive than traditional laxatives, and should generally be

reserved for patients who have failed other therapy for IBS-C.

Linaclotide

Linaclotide (Linzess) is a guanylate cyclase-C (GC-C) agonist and together with its

active metabolite bind to GC-C receptors acting locally on the luminal surface of the

intestinal epithelium to increase intracellular and extracellular cyclic guanosine

monophosphate (cGMP) concentrations.

128 Elevated cGMP stimulates chloride and

bicarbonate secretions into the intestinal lumen, resulting in increased intestinal fluid

and gastrointestinal movement with decreased response to pain.

Linaclotide’s approval was based on two randomized, double-blind, placebocontrolled phase III trials.

129,130 Results from clinical trials show that patients

receiving linaclotide reported small but statistically significant improvements in

abdominal pain, discomfort, and bloating with some improvements in bowel

straining, constipation, and stool consistency compared to placebo-treated

patients.

129,130 On withdrawal of linaclotide therapy, abdominal pain returned and

bowel movements decreased to levels similar to the placebo group, but there was no

rebound effect noted.

130 Linaclotide is approved for use in male and female adult

patients >18 years at a dosage of 290 mcg daily taken 30 minutes before breakfast.

There is a boxed warning for contraindicated use in children less than 6 years old

and patients with known or suspected mechanical GI obstruction. Use should be

avoided in children 6 to 17 years because of deaths from dehydration in younger

juvenile mice.

128 Because of low systemic exposure, drug interactions are unlikely.

The main side effect is diarrhea, abdominal pain, and flatulence.

128

Because there are no head-to-head comparative trials with lubiprostone and

linaclotide, both of these agents are viable options for V.H. Therefore, a trial of

lubiprostone 8 mcg orally twice daily with meals or linaclotide 290 mcg daily taken

30 minutes before breakfast would be reasonable.

Irritable Bowel Syndrome–Associated Pain and

Bloating

tients with IBS-C in whom fiber therapy fails, other standar

ANTISPASMODICS

CASE 24-4

QUESTION 1: L.K. is a 38-year-old woman who has a long history of abdominal pain and episodic diarrhea.

L.K. works as a sales representative for a major software vendor and is called on periodically to make formal

presentations. She finds that just before these presentations she experiences “attacks” of abdominal pain and

diarrhea. Her past medical history is significant for fibromyalgia, which manifests as chronic tiredness and

fatigue. She has no other medical problems and takes no medications. She has no known drug allergies. She

does not drink, smoke, or use illicit drugs. She has undergone an extensive workup, including colonoscopy, upper

GI endoscopy with small bowel follow-through, computed tomography abdominal scans, serum electrolytes,

thyroid function tests, and stool studies. These procedures and tests were negative, and L.K.’s

gastroenterologist has diagnosed her with IBS. L.K. currently has one to two loose stools daily. They are not

greasy appearing or foul smelling. She has bouts of abdominal pain (severity of 7 on a 1–10 pain scale) with or

without diarrhea several times daily. She describes the pain as “stabbing” and “cramping.” She has not noted

any temporal relationship to meals or that certain foods exacerbate her condition. What pharmacologic options

are available for L.K.’s abdominal pain? What adverse effects are associated with these medications?

Drugs that possess smooth muscle relaxation properties, usually by anticholinergic

pathways, have long been used to treat IBS. In the United States, the two most

commonly prescribed antispasmodics are hyoscyamine and dicyclomine, both of

which possess significant anticholinergic properties.

98 Clinical trials that have

examined the use of these agents in IBS have been plagued by small numbers and

methodological problems, and recently several meta-analyses have been conducted

to provide insight in this area. In general, these systematic reviews have found that,

as a class, smooth muscle relaxants were superior to placebo in improving

abdominal pain, although they are less effective at treating other IBS symptoms.