131

Unfortunately, there seems to be significant heterogeneity when looking at the

efficacy of single agents in this class. Additionally, many agents studied in clinical

trials are not available in the United States. Current treatment guidelines list

antispasmodics as options for pain or bloating associated with IBS. If prescribed, an

as-needed strategy of use has been advocated by some experts as opposed to

continuous dosing owing to anticholinergic adverse effects.

109 Peppermint oil

capsules also have smooth muscle relaxation properties and have been shown to be

beneficial in IBS-related pain and cramping.

132

ANTIDEPRESSANTS

Current treatment guidelines recommend the use of either tricyclic antidepressants or

selective serotonin reuptake inhibitors (SSRIs) for patients with severe or continuous

abdominal pain.

114 The analgesic effects of these agents are well known, and it is

believed that these agents may work by a similar mechanism in IBS-associated pain

and bloating as well as global well-being. One recent meta-analysis examined the

class as a whole in IBS patients and found low-dose tricyclic antidepressants

significantly improved pain, bloating, and IBS symptoms compared with placebo.

133

A dose–response relationship was not noted, and low doses of tricyclic

antidepressants (e.g., amitriptyline 10–25 mg at bedtime) are often effective in

relieving abdominal pain and diarrhea. A 3-month trial at a target dose of a drug

(e.g., amitriptyline 50 mg) should be attempted before therapeutic failure is

confirmed. Secondary amine tricyclic antidepressants (nortriptyline, desipramine)

are better tolerated by many patients than tertiary amines (amitriptyline, imipramine)

owing to decreased anticholinergic adverse effects such as sedation, dry mouth and

eyes, urinary retention, and weight gain. SSRI use is more controversial in IBS

patients as conclusive evidence of efficacy is lacking.

134 Still, practice guidelines

note that these agents are also reasonable agents to consider in patients with pain or

bloating associated with IBS.

p. 535

p. 536

Information on other antidepressants for IBS symptoms is limited. A recent pilot

study suggested that duloxetine may improve pain and diarrhea in IBS patients, but

more data are needed before this drug can be recommended.

135 Nortriptyline 10 mg

orally at bedtime should be initiated with titration to symptom relief and lack of

adverse effects.

Irritable Bowel Syndrome with Diarrhea

CASE 24-4, QUESTION 2: Two weeks after L.K. starts nortriptyline 25 mg at bedtime, she reports

significant relief from both her abdominal pain and fatigue. She reports that she is sleeping better, and she now

rates her pain as a 2 on a 1–10 scale. Her diarrhea has improved somewhat; however, she still suffers from a

“diarrhea attack” before each presentation. What other treatments are available for IBS-D? What are the risks

and benefits of these treatments?

STANDARD ANTIDIARRHEALS

Small bowel and colonic transit is accelerated in patients with IBS-D; thus, drugs

that slow this process should be effective in relieving diarrhea.

136 Loperamide, an

opioid agonist that penetrates poorly into the central nervous system, is the preferred

agent for IBS-D. Meta-analyses have found loperamide to be an effective agent for

improving diarrhea and, in some cases, improving patients’ global well-being.

137 As

with the antispasmodics, as-needed treatment is preferred to scheduled dosing (e.g.,

2–4 mg PO up to QID as needed). Prophylactic dosing before a stressful situation or

an event during which bathroom access is limited is particularly effective.

Diphenoxylate with atropine is generally considered a second-line agent because of

its increased risk of anticholinergic adverse effects. Finally, cholestyramine is

occasionally used in refractory cases of IBS-D, especially when bile acid

malabsorption is suspected or confirmed.

138 This agent is often poorly tolerated as a

result of palatability problems. Cholestyramine also has a significant number of drug

interactions of which the clinician must be aware.

ALOSETRON

Alosetron is a highly potent 5-HT3

receptor antagonist that slows colonic transit time,

increases intraluminal sodium absorption, and decreases small intestinal

secretions.

139 Constipation is the most frequently reported adverse effect in clinical

studies (approximately 30% of alosetron patients), with approximately 10% of

patients withdrawing from studies for this reason. Postmarketing reports of severe

constipation with cases of bowel obstructions and ischemic colitis were reported.

140

Bowel perforation and, rarely, death were also reported with alosetron use, and the

drug was voluntarily withdrawn from the market in November 2000. After extensive

lobbying by several patient groups, alosetron was reintroduced to the US market in

June 2002, with restricted conditions for use. Prescribers must be registered with the

drug manufacturer, and patients must sign a patient–physician agreement and be

provided with a written medication guide. The starting dose and regimen for

alosetron is 0.5 mg BID for 1 month. If, after 4 weeks, this is well tolerated but does

not adequately control IBS symptoms, then the dosage can be increased to 1 mg

BID.

141

It is imperative that patients not start alosetron if they have a history of

problems with constipation, bowel obstruction or ischemic colitis, IBD, or a

thromboembolic disorder. Patients must immediately discontinue alosetron if they

become constipated or have symptoms of ischemic colitis, such as new or worsening

abdominal pain, bloody diarrhea, or blood in the stool. A recent review of the

mandatory postmarketing surveillance system designed to monitor the safety of the

drug found an overall low rate of ischemic colitis.

142

Newer Agents for IBS

In May 2015, the FDA approved two new drugs, rifaximin (Xifaxan) and eluxadoline

(Viberzi), to treat IBS with diarrhea. Rifaximin was previously approved for

traveler’s diarrhea. Because some evidence exists concerning a possible association

of bacterial GI infection and IBS symptoms, this has prompted some investigators to

postulate that small bowel flora overgrowth may contribute to IBS symptoms. The

nonabsorbable antibiotic rifaximin had been shown in two small studies to improve

global symptoms in IBS for up to 10 weeks.

143,144 More recently a report of two

randomized, double-blind, placebo-controlled trials of rifaximin in IBS (without

constipation) was published.

145

In this trial a 14-day course of rifaximin 550 mg TID

was found to significantly improve relief of global IBS symptoms during the first 4

weeks after treatment compared with placebo. The magnitude of improvement was

small, but was considered clinically relevant. Rifaximin is approved for a dosage of

550 mg TID for 14 days for IBS-D. The patient can be treated 2 times with the same

regimen if there is recurrence.

146 The most common side effects in patients treated

with rifaximin for IBS-D include nausea and an increase in alanine aminotransferase

(ALT). Caution should be used when using rifaximin in patients with severe liver

impairment.