520618

research-article2014
PENXXX10.1177/0148607113520618Journal of Parenteral and Enteral NutritionKumpf

Invited Review
Journal of Parenteral and Enteral
Nutrition
Pharmacologic Management of Diarrhea in Patients With Volume 38 Supplement 1
May 2014 38S­–44S
Short Bowel Syndrome © 2014 American Society
for Parenteral and Enteral Nutrition
DOI: 10.1177/0148607113520618
jpen.sagepub.com
hosted at
online.sagepub.com
Vanessa J. Kumpf, PharmD, BCNSP1

Abstract
Diarrhea associated with short bowel syndrome (SBS) can have multiple etiologies, including accelerated intestinal transit, gastric acid
hypersecretion, intestinal bacterial overgrowth, and malabsorption of fats and bile salts. As a result, patients may need multiple medications
to effectively control fecal output. The armamentarium of antidiarrheal drugs includes antimotility agents, antisecretory drugs, antibiotics
and probiotics, bile acid–binding resins, and pancreatic enzymes. An antidiarrheal regimen must be individualized for each patient and
should be developed using a methodical, stepwise approach. Treatment should be initiated with a single first-line medication at the
low end of its dosing range. Dosage and/or dosing frequency can then be slowly escalated to achieve maximal effect while minimizing
adverse events. If diarrhea remains poorly controlled, additional agents can be incorporated sequentially. If modification of the regimen
is required, a single medication should be altered or exchanged at a time. After each adjustment of the regimen, sufficient time should
be permitted to fully assess response (≥3–5 days) before initiating additional changes. SBS-associated malabsorption is a major obstacle
to optimization of an antidiarrheal regimen because drug absorption is impaired. Patients may benefit from high dosages and/or frequent
dosing intervals, liquid preparations, or nonoral routes of drug delivery. Although the diarrhea associated with SBS can be debilitating,
effective pharmaceutical management has the potential to substantially improve health outcomes and quality of life for these patients.
(JPEN J Parenter Enteral Nutr. 2014;38(suppl 1):38S-44S)

Keywords
gastroenterology; research and diseases; adult; life cycle; probiotics; home nutrition support; nutrition; internal medicine

Management of short bowel syndrome (SBS) focuses on replace-
ment of fluid and nutrient losses, achieving or maintaining ade-
quate weight, and controlling diarrhea. Multiple factors contribute
to diarrhea in patients with SBS, including accelerated intestinal
transit, increased gastrointestinal (GI) secretions, bacterial over-
growth, and malabsorption of fats and bile salts. Diarrhea can
negatively affect health outcomes for patients with SBS. For
example, diarrhea leaves patients at increased risk of dehydration,
micronutrient deficiencies, and weight loss. Furthermore, quality
of life can be diminished by severe diarrhea associated with SBS.
Patients have expressed fears related to eating because of probable
increased stool output and reluctance to leave home because of
possible fecal incontinence.1,2 In fact, patients with ostomies may
face fewer disruptions to daily life than patients with colon-in-
continuity because of reduced bathroom dependency.3 Both
dietary manipulation and pharmacologic management of diarrhea
have the potential to substantially improve overall health and
quality of life for this patient population. This article focuses on
pharmacologic management of diarrhea. Please refer to other
resources for a discussion of diet manipulation for diarrhea reduc-
tion in patients with SBS.4-6
time.7 The etiology underlying increased intestinal motility in
SBS is unclear but has been assumed to be related to the loss of
an inhibitor of intestinal motility normally released from the
distal GI tract. Indeed, patients with end jejunostomy experi-
ence more rapid intestinal transit of liquids than patients with
colon-in-continuity, perhaps because of lower plasma levels of
peptide YY, glucagon-like peptide 1, and/or glucagon-like
peptide 2.8-12
Accelerated intestinal motility is typically treated with opi-
oids or opioid receptor agonists that inhibit contraction of
intestinal smooth muscles. The resulting increase in intestinal
From the 1Vanderbilt University Medical Center, Nashville, Tennessee.
Financial disclosure: The publication of the supplement in which
this article appears is supported by an educational grant from NPS
Pharmaceuticals, Inc (Bedminster, NJ). Funding for medical writing
assistance was provided by NPS Pharmaceuticals, Inc. V.J.K. has served
as a consultant for NPS Pharmaceuticals, Inc. No financial compensation
was provided to V.J.K. for the preparation of this work.
Received for publication October 30, 2013; accepted for publication
December 30, 2013.

Corresponding Author:
Antimotility Agents Vanessa J. Kumpf, PharmD, BCNSP, Vanderbilt University Medical
Center, 1211 21st Ave S, 514 Medical Arts Bldg, Nashville, TN 37232,
A primary cause of diarrhea in patients with SBS is increased USA.
intestinal motility, resulting in accelerated small bowel transit Email: vanessa.kumpf@vanderbilt.edu

Downloaded from pen.sagepub.com at UNIV OF WASHINGTON LIBRARY on May 29, 2014

Kumpf 39S
Figure 1.  Treatment algorithm for the pharmacologic management of diarrhea associated with short bowel syndrome. H2 = histamine
type-2 receptor.
transit time allows for greater nutrient absorption.13,14
Loperamide and diphenoxylate-atropine are typically the first-
line choices for antimotility agents (Figure 1). As a peripher-
ally restricted µ-opioid receptor agonist, loperamide does not
engender undesirable central nervous system (CNS) effects,
such as sedation, euphoric effects, or addiction.15 Furthermore,
loperamide is effective; in patients with ileostomy, loperamide
treatment resulted in a 27% decrease in the wet weight of
ostomy effluent (P < .02).16 Unlike loperamide, the opioid
receptor agonist diphenoxylate crosses the blood-brain bar-
rier.17 Nonetheless, diphenoxylate is limited in its abuse poten-
tial, because added atropine induces unpleasant anticholinergic
effects when taken at high doses (eg, xerostomia, tachycardia,
mydriasis).18,19 In small clinical studies, diphenoxylate and
loperamide had similar efficacy for the treatment of chronic
diarrhea, although some trials have shown a modest advantage
for loperamide over diphenoxylate.20
Other antimotility agents include codeine, morphine, and
opium tincture. These opioids are not restricted to the periph-
eral nervous system and so can generate CNS effects.21
Although patients often develop tolerance to the analgesic
properties of opioids or opioid receptor agonists, tolerance to
the antidiarrheal effect is rare, and the effective dose may
remain constant for months to years.22
Recommendations for Use of Antimotility
Agents
Dosage of the selected first-line antimotility agent should be
escalated in a stepwise manner at intervals of 3–5 days, until
benefit is observed, adverse events occur, or the recommended
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maximum dosage is reached (Table 1 and Figure 1). For
diphenoxylate, some patients may benefit from doses that
exceed the recommended maximum dosage. If the agent con-
fers no benefit or induces adverse events, then administration
should be suspended and treatment with a second-line agent
initiated. If the patient experiences a partial response to the
first-line agent, a second agent can be added and the dose esca-
lated in the same stepwise fashion until the desired response is
achieved. Patients may require multiple antimotility agents to
attain maximal effect. Throughout the optimization process,
patients should be provided with guidelines on dose titration
because responses may vary with alterations in diet and/or
changes in the course of the disease. Because of the gastrocolic
reflex, antimotility agents should be administered 30–60
minutes preprandially.23 An additional dose provided immediately
before sleep may help minimize trips to the bathroom at night.
Gastric Acid Hypersecretion
Healthy individuals secrete an average of 750 mL/d (range,
100–1500 mL/d) of gastric fluid. Following intestinal resec-
tion, more than half of patients experience an increase in
gastric acid release, which can reach up to 4100 mL/d.24
Gastric acid hypersecretion is usually transient and often
resolves within a few weeks or months following resec-
tion.24,25 Although the mechanisms underlying this phenom-
enon have not been clearly defined, gastric acid hypersecretion
may be caused by the loss of 1 or more endogenous intestinal
inhibitors of gastric acid secretion.25 Prime candidates for
the intestinal inhibitor include cholecystokinin, secretin, and
neurotensin.26
40S Journal of Parenteral and Enteral Nutrition 38(Suppl 1)

Table 1.  Medications Commonly Used to Treat Diarrhea in Patients With Short Bowel Syndrome.

Agent (OTC or Rx and

Etiology
Rapid intestinal transit
 
 
 
Gastric acid hypersecretion
 
 
 
 
 
 
 
 
 
 
Intestinal bacterial
 overgrowth
 
 
 
 
 
Fat malabsorption
Therapeutic Class Schedule, if Applicable) Dosage
Antimotility agent Loperamide (OTC) 2–6 mg PO QID; maximum daily dose,
16 mg
Diphenoxylate (Rx, CV) 2.5–7.5 mg PO QID; maximum daily
dose, 20–25 mga
Codeine (Rx, CII to CIV) 15–60 mg PO QID
Opium tincture (Rx, CII) 0.3–1 mL PO QID
Proton pump inhibitor Lansoprazole (OTC/Rx) 15–30 PO BID
Pantoprazole (Rx) 20–40 mg PO/IV BID
Omeprazole (OTC/Rx) 20–40 mg PO BID
Esomeprazole (Rx) 20–40 mg PO/IV BID
Rabeprazole (Rx) 20 mg PO BID
Dexlansoprazole (Rx) 30–60 mg PO BID
Histamine receptor antagonist Famotidine (OTC) 20–40 mg PO/IV BID
Ranitidine (OTC) 150–300 mg PO/IV BID
Cimetidine (OTC) 200–400 mg PO/IV QID
α2-Adrenergic receptor agonist Clonidine (Rx) 0.1–0.3 mg PO BID
0.1- to 0.3-mg patch Q7D
Somatostatin analogue Octreotide (Rx) 50–250 µg SC TID or QID
Antibiotic Metronidazole (Rx) 250 mg PO TID for 7–14 days
Ciprofloxacin (Rx) 500 mg PO BID for 7–14 days
Rifaximin (Rx) 200–550 mg PO TID for 7–14 days
Augmentin (Rx) 500 mg PO BID for 7–14 days
Doxycycline (Rx) 100 mg PO BID for 7–14 days
Neomycin (Rx) 500 mg PO BID for 7–14 days
Tetracycline (Rx) 250–500 mg PO QID for 7–14 days
Pancreatic enzyme replacement Pancrelipase (Rx) 500 lipase units/kg per meal; maximum
dose is 2500 lipase units/kg per meal
or 10,000 lipase units/kg/d

BID, twice daily; CII–CV, drug schedule as established by the US Drug Enforcement Administration schedule of controlled drugs; IV, intravenous;
OTC, over the counter; PO, by mouth; Q7D, every 7 days; QID, 4 times per day; Rx, available by prescription only; SC, subcutaneous; TID, 3 times
per day.
a
Doses that exceed the maximum recommended dose may be required in some cases.

Gastric acid hypersecretion may have negative conse-
quences for affected individuals, including aggravation of diar-
rhea, inactivation of pancreatic enzymes, and precipitation of
peptic ulcer disease.23,25,27 Fortunately, patients have several
pharmacologic options available. Proton pump inhibitors
(PPIs), including lansoprazole, pantoprazole, omeprazole, and
esomeprazole, are typical first-line agents of choice (Table 1
and Figure 1). PPIs irreversibly block the function of H+/K+
ATPase proton pumps, which normally secrete hydrogen ions
into the gastric lumen.28 PPIs are highly effective. For exam-
ple, omeprazole achieves near-complete suppression of gastric
acid secretion among healthy adults.29 In patients with SBS,
intravenous (IV) omeprazole 40 mg twice daily increased wet
weight absorption by 0.78 kg/d (P < .05).30 Although generally
well tolerated, PPIs are associated with small increases in the
risks of community-acquired pneumonia over the short term
and osteoporosis, bone fracture, and vitamin B12 deficiency
over the long term.31,32 The risk of microscopic colitis is also
greater with PPI treatment.33 Furthermore, discontinuation
may cause an increase in acid-related symptoms (rebound
hypersecretion).34 Finally, because gastric acids normally act
to reduce the concentration of ingested bacteria, acid suppres-
sors may promote overgrowth of bacteria in the GI tract (see
below).23
Typical second-line agents used to combat gastric hyperse-
cretion include histamine type 2 receptor (H2) antagonists (eg,
famotidine, ranitidine, cimetidine) and α2-adrenergic receptor
agonists (eg, clonidine). H2 antagonists block the function of
histamine, a local mediator of acid secretion released from the
gastric mucosa in response to the hormone gastrin.35 In gen-
eral, H2 antagonists are considered second-line treatment
because of their decreased efficacy relative to PPIs.23,30
The effects of clonidine are not limited to inhibition of gas-
tric acid hypersecretion. Clonidine stimulates α2-adrenergic
receptors on enteric neurons that also reduce gastric and
colonic motility and intestinal fluid secretion.36 Evidence

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Kumpf 41S
supporting clonidine use in patients with SBS is limited. In a
study of 8 end-jejunostomy patients dependent on parenteral
nutrition (PN), a 0.3-mg clonidine patch reduced fecal weight
by 9% (P = .05) and decreased fecal sodium loss by 11%
(P = .04).37 In addition, a case report describes 2 patients with
SBS who were refractory to multiple antidiarrheal agents;
treatment with clonidine reduced their ostomy output by
approximately 2.5–3 L/d.38
Octreotide may be effective for patients who fail to respond
sufficiently to other antidiarrheal therapies. Octreotide, a long-
acting analogue of the peptide hormone somatostatin, inhibits
diarrhea through multiple mechanisms, including inhibition of
gastrin and other GI hormones.39 Octreotide also inactivates
adenylate cyclase and thereby inhibits movement of ions
across the intestinal epithelium.39 In addition, octreotide pro-
longs intestinal transit time in patients with SBS.40 In a study of
10 end-jejunostomy patients dependent on PN support, octreo-
tide reduced ostomy output by an average of 3.3 L/d (P < .03)
and permitted reductions of PN volume of 1.3 L/d (P < .002).41
Use of octreotide is limited by its high cost, the inconvenience
of administration by subcutaneous injection, and risk of associ-
ated adverse events, including cholelithiasis, which is already
increased in patients with SBS.41,42 Furthermore, octreotide
reduced intestinal adaptation following resection in some pre-
clinical studies.43-46
Recommendations for Use of Acid
Suppression Therapy
Administration of acid suppression therapy should decrease
stool output; if not, an increase in dosage or dosing frequency
may be warranted.23 As with antimotility agents, acid suppres-
sors should be initiated at a low dose and titrated upward to
yield maximal efficacy with minimal adverse events. PPI treat-
ment should be discontinued in the event of worsening diar-
rhea. If oral administration fails to achieve sufficient absorption,
IV administration is an option for PPIs and H2 antagonists.30 H2
receptor antagonists may also be added to PN formulations.
Patients should be closely monitored for acid rebound when
PPIs or H2 antagonists are discontinued, and therapy should be
restarted if necessary.31 Because clonidine was originally
developed as an antihypertensive agent, hypotension is a con-
cern when it is used for SBS.47 Therefore, slow escalation of
clonidine dose along with regular blood pressure testing is
recommended.38
Choleretic Diarrhea
Because bile salts are absorbed primarily in the distal ileum,
some patients with ileal resections <100 cm and colon-in-con-
tinuity may have spillover of bile salts into the colon.48 Colonic
bacteria deconjugate these salts into free bile acids, stimulating
movement of chloride and water into the colon.49 The resulting
choleretic diarrhea can be treated with bile acid–binding resins
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(eg, cholestyramine, colestipol, colesevelam), nondigestible
anion exchange polymers that bind to bile acids in the colon.
These resins form insoluble complexes with bile salts, which
are then excreted.
Recommendations for Use of Bile Acid–
Binding Resins
Patients with limited ileal resection (<100 cm) and colon-in-
continuity with watery diarrhea may have excess colonic bile
acids and therefore may benefit from treatment with bile acid–
binding resins.48 In contrast, patients with more extensive ileal
resections experience a net loss of bile acids because more bile
acids are excreted than can be replaced through liver synthesis.
For these patients, who constitute the majority of the SBS pop-
ulation,50 bile acid–binding resins can exacerbate steatorrhea
and fat malabsorption and should be avoided.48,51 Even in
patients for whom they may be appropriate, bile acid–binding
resins should be administered with caution because of potential
interactions with nontarget drugs and nutrients. Bile acid–
binding resins can bind several pharmaceutical agents, includ-
ing loperamide and some nonsteroidal anti-inflammatory
agents, reducing their activity.52 To prevent deficiencies of fat-
soluble vitamins during treatment with bile acid–binding
resins, patients should receive supplementation with water-
miscible formulations of vitamins A, D, E, and K.49
Bacterial Overgrowth
Several factors increase the risk of intestinal bacterial over-
growth among patients with SBS. The anatomy of the GI rem-
nant can be a primary driver of bacterial overgrowth. For
example, patients with blind loops or small-bowel dilation
have reduced intestinal motility, which can result in stagnation
of intestinal contents and promote local bacterial fermenta-
tion.23,53 Patients with resections that include removal of the
terminal ileum and/or ileocecal valve may experience migra-
tion of anaerobic colonic bacteria into the small intestine
because of a breakdown of this anatomical transition zone.54
Finally, medications commonly prescribed to patients with
SBS, including antimotility agents and acid-suppressing thera-
pies, have the potential to disrupt normal bacterial flora and
permit overgrowth.23,53
Intestinal bacterial overgrowth has multiple ramifications.
Symptoms include diarrhea, abdominal pain, bloating, and
flatulence.25 Postprandial bloating and abdominal cramping
lead to premature satiety, which can inhibit nutrient intake and
result in weight loss. Affected patients can also experience
vitamin deficiencies because anaerobic bacteria sequester vita-
min B12 and deconjugate bile salts, disrupting absorption of fat
and fat-soluble vitamins.25,54 Adhesion of bacteria to the intes-
tinal epithelium and release of bacterial toxins can promote
mucosal inflammation and injury, potentially leading to
increased intestinal permeability.54 Rarely, patients with SBS
42S Journal of Parenteral and Enteral Nutrition 38(Suppl 1)
and an intact colon can develop D-lactic acidosis and encepha-
lopathy following colonic proliferation of bacteria producing
D-lactic acid, an enantiomer normally synthesized and metab-
olized by humans in very low concentrations. The D-lactate–
producing bacteria thrive in the colon of patients with SBS
because malabsorption increases local availability of carbohy-
drates, their preferred substrate for fermentation.
Intestinal bacterial overgrowth is treated with antibiotic
therapy. Increasingly, however, probiotics are being prescribed
as an add-on therapy (Table 1 and Figure 1). According to
results from a preclinical study, probiotics can promote intesti-
nal adaptation and reduce the permeability of the GI epithe-
lium.55 Little information is available regarding the efficacy of
probiotics in human patients with SBS. Limited evidence from
pediatric studies suggests that probiotics may increase the rate
of height and weight gain and improve the bacterial composi-
tion of feces.56
Recommendations for Management of
Bacterial Overgrowth
When treating symptomatic intestinal bacterial overgrowth
with antibiotics, drug rotation and inclusion of antibiotic-free
intervals may decrease the potential for the development of
resistant strains.4 If antibiotic therapy fails to resolve symp-
toms, consider changing the antibiotic agent. Alternatively, a
probiotic can be added to the regimen. Probiotic products are
not regulated by any federal agencies. Therefore, commer-
cially available preparations may not contain sufficient num-
bers of live organisms to achieve maximal therapeutic effect or
may not have been tested to ensure survival throughout the GI
tract. If probiotic therapy is pursued, administration of bacte-
rial species that do not produce D-lactic acid is recommended
to mitigate the risk of D-lactic acidosis.56 If symptoms persist
despite antibiotic and probiotic therapy, consider reducing dos-
ages of motility- and acid-suppressing drugs or switching
antidiarrheal agents.
Fat Malabsorption
The etiology of fat malabsorption associated with SBS is mul-
tifactorial. Gastric acid hypersecretion lowers stomach pH,
which in turn can denature pancreatic enzymes and decrease
the ability to metabolize fats.23,27 In addition, extensive resec-
tion of the distal ileum interrupts bile acid recycling, leading to
a decreased bile acid pool and a resulting impairment of the
solubilization and absorption of lipids.57 Other factors contrib-
uting to fat malabsorption in patients with SBS include accel-
erated GI transit, reduced intestinal surface area, and small
bowel bacterial overgrowth. Fat malabsorption, which can
result in dietary deficiencies and steatorrhea, is primarily con-
trolled with diet optimization.4 However, adjunctive medica-
tions may improve steatorrhea that persists in the context
of a well-managed diet. For example, pancreatic enzyme
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replacement may enhance fat absorption during the period of
resection-induced gastric acid hypersecretion.23 Furthermore,
bile acid supplementation may benefit patients who cannot
synthesize sufficient amounts of bile acid to replace losses
through excretion. Among 4 patients with SBS in 1 study, treat-
ment with the synthetic bile acid cholylsarcosine was associ-
ated with a significant increase in fat absorption (+17 g/d with
6 g/d cholylsarcosine [P < .05] and +20 g/d with 12 g/d cholyl-
sarcosine [P < .001]).58
Recommendations for Use of Pancreatic
Enzyme Replacements and Bile Acid
Supplements
To maximize the effectiveness of pancreatic enzyme replace-
ment, therapy should be initiated following normalization of
gastric pH and GI motility with acid suppression and antimotil-
ity therapy.23 Both pancreatic enzymes and bile acids should be
taken with meals to increase availability during digestion.
Currently, bile acids are sold only as supplements and thus are
not regulated by the U.S. Food and Drug Administration
(FDA). Therefore, these agents should be used with extreme
caution. Bile acids should be taken only in the context of nor-
malized gastric pH because of the potential for precipitation in
the presence of gastric acid hypersecretion.59 Supplemental
bile acids may also exacerbate diarrhea58,60; patients receiving
bile acid replacement therapy should be carefully monitored
for worsening symptoms.
Overall Clinical Recommendations and
Conclusions
Because of malabsorption associated with SBS, patients may
require larger doses of medications than are typically recom-
mended (Table 1).61 In some patients, tablets or capsules pass
through the digestive system intact; in these cases, medications
can be pulverized before ingestion or replaced with liquid sus-
pensions, if available.61 However, liquid preparations that con-
tain sorbitol should be avoided because they can exacerbate
diarrhea.61 Enterically coated or delayed-release formulations
should not be used in patients with SBS because limited intes-
tinal surface area, accelerated intestinal transit, and gastric acid
hypersecretion may alter pharmacokinetic properties and
diminish bioavailability. If oral administration does not yield
sufficient absorption, consider alternative delivery methods
such as transdermal, buccal, rectal, and IV routes, if feasible.25
Finally, dosages of antidiarrheal medications, particularly
those with narrow therapeutic ranges, may require adjustment
following initiation of treatment with newer trophic therapies
that act to increase intestinal absorption.
Management of diarrhea in patients with SBS requires a
stepwise approach. As a general rule, better-tolerated medica-
tions should be selected as first-line choices. The number of
medications and dosages of each should be slowly escalated to
Kumpf 43S
achieve the desired effect while minimizing adverse events. If
the regimen needs to be modified, medications should be
exchanged one at a time, with sufficient time permitted to
assess response (≥3–5 days) before initiating additional
changes. A trial-and-error approach may be required to opti-
mize symptom management.
Most patients with SBS experience debilitating diarrhea
over the course of their disease, which can negatively affect
health outcomes and quality of life. Management of diarrhea in
these patients is challenging. Because diarrhea associated with
SBS can have several etiologies, multiple medications may be
required. This patient population is highly heterogeneous in
terms of the residual anatomy, nutrition requirements, and
severity of disease. Therefore, treatment must be individual-
ized to achieve maximal efficacy. A stepwise approach to regi-
men optimization, with slow titration of dosages and careful
consideration of potential drug-drug interactions, is key to
achieving diarrhea control.
Acknowledgments
Medical writing assistance was provided by Heather Heerssen,
PhD, of Complete Healthcare Communications, Inc (Chadds Ford,
PA) under the direction of the author.
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