Best Practice & Research Clinical Gastroenterology 26 (2012) 677–687

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Best Practice & Research Clinical

Gastroenterology

11

Treatment of chronic diarrhoea

Zhongzhen Li, MD a,1, Haleh Vaziri, MD b, *
a
St. Vincent’s Medical Center, Department of Medicine, 2800 Main St., Bridgeport, CT 06606, United States
b
University of Connecticut Health Center, Division of Gastroenterology and Hepatology, 263 Farmington Ave,
Farmington, CT 06030-1845, United States

a b s t r a c t
Keywords:
Chronic diarrhoea The treatment of chronic diarrhoea can be challenging. While Oral
Oral Rehydration Solutions (ORS) Rehydration Solution is an important step in treating diarrhoeal
Anti-diarrhoeal agents illnesses, various medications can be used to alleviate the symp-
Opiates
toms while the patient is undergoing diagnostic work up or to
Bile acid resins
target the underlying mechanism responsible for their diarrhoea.
Anti-cholinergic
Bulk forming agent Medications are also being prescribed in cases when there is
Silicate a strong suspicious about a diagnosis or when there is no specific
Bismuth treatment for an underlying aetiology. This chapter discusses the
Somatostatin treatment options for diarrhoeal disorders.
Probiotics Ó 2012 Elsevier Ltd. All rights reserved.
Enkephalinase inhibitors
Calcium channel blockers
Alpha 2 adrenergic agonists
Budesonide

Oral rehydration therapy (ORT)

Oral rehydration therapy (ORT) was a breakthrough in the management of diarrhoeal disease by
improving hydration and decrease in morbidity and mortality [1]. The decreased mortality is largely
due to the implementation of the standard World Health Organization-oral rehydration solution
(WHO-ORS) in 1960s. Compared with intravenous fluid therapy (IVT), ORT is convenient to administer,
inexpensive and is as effective as IVT [2,3]. It has been used in treatment of acute diarrhoeal illnesses
especially in paediatric population, travellers’ diarrhoea, and in patients with short bowel syndrome to

* Corresponding author. Tel.: þ1 860 679 6524; fax: þ1 860 679 3159.
E-mail addresses: lizhongzhen@gmail.com (Z. Li), hvaziri@uchc.edu (H. Vaziri).
1
Tel.: þ1 203 576 5576; fax: þ1 203 576 5730.

1521-6918/$ – see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bpg.2012.11.005
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decrease IVT requirement. Even though it has been successful in acute diarrhoeal illness management,
ORTs are important for adequate hydration of patients with chronic diarrhoea.
The first recommended ORS by WHO was standard WHO-ORS (311 mosM/l, Na 90 mmol/l, K
20 mmol/l, Cl 80 mmol/l, citrate 10 mmol/l and glucose 111 mmol/l) which significantly decreased the
mortality caused by acute diarrhoea; however it did not reduce fecal volume or diarrhoea duration.
This has led to various modifications of its compositions and developing new solutions including
reduced osmolarity ORS, polymer-based ORS and zinc supplementation.
Reduced osmolarity ORS (245 mosM/l) has less sodium (75 mmol/l), chloride (65 mmol/l) and glucose
(75 mmol/l). A meta-analysis compared the effectiveness and complications of reduced-osmolarity ORS
versus those of the standard WHO-ORS in 2397 paediatric patients and reported a reduction in stool
output, episodes of vomiting and the need for intravenous hydration in the reduced-osmolarity ORS group
[4]. The incidence of hyponatremia was not different between the two groups. Based on the available
results, WHO recommended the use of reduced osmolarity ORS instead of standard ORS in 2002. The
recommendation is applicable to adult population even though the trials were done in children.
Polymer-based ORS is a formula with substitution of glucose monomer in the ORS with glucose
polymers such as rice powder and wheat. It is superior to standard ORS in the treatment of diarrhoea of
all causes including cholera and non-cholera diarrhoea, in both adults and children. In a Cochrane
review published in 2009, patients who were treated with the Polymer-based ORS were found to have
fewer unscheduled IVT and shortened diarrhoea duration compare to the group who was treated with
glucose based ORS, although the analysis was under powered [5].
Zinc supplementation is based on the fact that zinc deficiency caused by diarrhoea can lead to
a vicious cycle of worsening duration and severity of diarrhoea. Two large meta-analysis that included
paediatric subjects with acute or persistent diarrhoea (diarrhoea > 14 days) concluded that use of zinc
supplementation may result in reduction of the mean duration of both acute and persistent diarrhoea
as well as stool frequency in children older than 6 months old; however it is also associated with more
frequent vomiting [6,7]. Therefore, WHO recommends zinc supplementation of 20 mg per day for 10–
14 days for children older than six months old and 10 mg per day in infants younger than 6 months
with acute diarrhoeal illnesses. Although this may be applicable to the adult population, no specific
recommendation is available for zinc supplementation in adults, due to the lack of data. Zinc is
available in tablet and oral solution forms.

Dietary modifications

Dietary modifications can significantly alter the course of certain gastrointestinal conditions. For
instance, avoidance of lactose or gluten-containing foods can greatly benefit patients with lactose
intolerance or coeliac disease, respectively. Avoidance of lactose is also advised in cases of extensive
small bowel damage for any reason to decrease the delivery of large amounts of lactose to the colon and
subsequent colonic water retention.

Antibiotics

Chronic diarrhoea in developed countries can be due to either organic or functional disorders.
Infectious agents are infrequently involved, and are usually found in high risk populations, namely in
travellers returning from tropical countries and in immunocompromised patients. While infectious
agents often cause acute diarrhoea, chronic infectious diarrhoea can be caused by Clostridium difficile,
Giardia lamblia, Entamoeba histolytica, Cryptosporidium, Aeromonas, Campylobacter and Yersinia, espe-
cially in immunocompromised patients.
Most of infectious gastroenteritis is self-limiting and antibiotics should be preserved for severe
cases, high-risk patients and chronic persistent infections. Antibiotic therapy should generally rest on
a microbiological diagnosis; however, there may be a role for empirical antibiotic treatment in well
defined circumstances, such as persistent traveller’s diarrhoea, day care or institutional exposure,
suspected Giardiasis, febrile patients with moderate to severe diarrhoea [8] and suspected small
intestinal bacterial overgrowth [9,10].
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Antibiotics can also be considered if cancer chemotherapy induced diarrhoea persists for more than
24 hours [11].
Because of changing patterns of resistance, knowledge of recent local patterns of susceptibility and
giving consideration to the current guideline can help regarding the initial choice of antibiotics [12].

Anti-diarrhoeal agents

When treating chronic diarrhoea, one should know that the maximal benefit of treatment is ach-
ieved from scheduled dosing of the anti-diarrhoeal agents and not necessarily from after the fact
dosing.
Table 1 summarizes some of the agents that are more commonly used as empiric or specific
treatment of chronic diarrhoea.
A more detailed discussion is reviewed individually for these agents in the following sections.

Absorbents

Absorbents act by binding to fluids, toxins and other substances to improve stool consistency and
eliminate the toxins. Side effects include constipation, dark stools and confusion. Absorbents also
decrease the absorption of many agents.

Diosmectite (DS)

DS is a natural aluminium and magnesium silicate clay. Its anti-diarrhoeal effect is through: (1)
absorption of toxins, bacteria and viruses; (2) reinforcement of the intestinal mucus barrier with the
reduction of penetration of luminal antigens through the mucus layer; and (3) reduction of inflam-
mation. A randomized controlled trial has shown its efficacy in reducing the duration of the diarrhoeal

Table 1
Medications being used for chronic diarrhoea.

Drug class Agent Dose

Opiates Loperamide (Imodium) Start 4 mg  1, then 2 mg
after each loose stool.
Max: 16 mg/daily.
Codeine 15–60 mg four times a day
Diphenoxylate with atropine (Lomotil) 2.5/0.025 mg/tab, 1–2 tabs
four times a day
Deodorized tincture of opium 0.6 ml up to 4 times a day
(10 mg morphine/ml) (5–20 drops four times a day
Paregoric or camphorated tincture of opium 5–10 ml four times a day
(0.4 mg morphine/mL)
Morphine sulphate 20 mg/mL 2–20 mg four times a day
Enkephalinase inhibitor Racecadotril (Acetorphan) 1.5 mg/kg three times a day
Anticholinergics Methscopolamine (Biosol-M) 2.5 mg four times a day
Hyoscyamine (Anspaz, cystospaz, levsin) 0.125–0.25 mg six times a day
Dicyclomine (Bentyl) 20 mg four times a day
Glycopyrrolate (Robinul) 1–2 mg 2–3 times a day
Somatostatin analogue Octreotide 50–250 mg three times a day
Absorbents Bismuth subsalicylate 2 tabs or 30 ml every hour
prn. Maximum of eight doses
in 24 hours.
Fibre supplements Psyllium 10–20 g daily
Polycarbophil 5–10 g daily
Methylcellulose 5–20 g daily
Bile acid resins Cholestyramine 4 g up to four times a day
Colestipol 4 g up to four times a day
Calmodulin antagonist Zaldaride 20 mg four times a day
Alpha adrenergic agonist Clonidine 0.1–0.3 mg three times a day
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illnesses and excellent safety profile in children [13]. DS is recommended for treatment of acute
infectious and non-infectious diarrhoea as an adjunct therapy to oral rehydration. It can also be
considered in treatment of IBS-D [14].
Other indications include prevention of radiation induced diarrhoea [15], chemotherapy induced
diarrhoea [16] and Acquired Immune Deficiency Syndrome (AIDS)-associated chronic diarrhoea [17].
Compared with loperamide, DS treatment was more effective in relieving the associated digestive
symptoms in patients with chronic functional diarrhoea in a prospective RCT [18].

Attapulgite

This has been used for decades in several anti-diarrhoeal agents including Kaopectate. Kaopectate is
a combination of an aluminium silicate, Kaolin, and a carbohydrate (pectin). This agent has not been
listed as safe and effective in the Food and Drug Administration’s (FDA) Anti-Diarrhoeal Drug Products
Final Monograph. In 2003, Kaopectate was reformulated as bismuth subsalicylate which is available
over the counter.

Bismuth subsalicylate

Although its mechanism of action is not well understood, bismuth acts as an anti-diarrhoeal agent
through its anti-secretory, anti-inflammatory, and antimicrobial properties. It is mainly used as
a preventive and therapeutic agent for travelers’ diarrhoea. Bismuth can be considered in the treatment
of diarrhoea of microscopic colitis [19,20]. Secondary to the theoretical risk of development of Reye’s
syndrome and encephalopathy while taking subsalicylate, Bismuth subsalicylate is not recommended
in treatment of children younger than 3 years old and those with viral illnesses [21].
Other potential adverse effects include tinnitus and hyperpigmentation of the tongue and stool.
The treatment period should not exceed 6–8 weeks at a time to decrease the risk of bismuth toxicity
[22].

Fibre supplements

Fibres can promote the retention of water by stool and formation of a gel. It can add firmness to the
stool by altering the texture and increasing the viscosity. These changes can improve the patients’
symptoms as the stool consistency is being changed from watery to semi-formed.
This group should not be used in patients suspected of having any gastrointestinal stricture.
Adverse effects are usually mild, including bloating, abdominal fullness and discomfort. Although
there may not be a beneficial effect of fibre treatment in improving pain in patients with IBS [23], these
supplements can be used to improve the stool consistency and frequency in this group of patients.
Other diarrhoeal illnesses that benefit from fibre supplementation include: enterally fed patients
[24,25], diarrhoea of unknown aetiology [26,27], protease inhibitors-associated diarrhoea in HIV
patients [28], collagenous colitis [29] and decreasing night time soiling in patients with ileal J pouch
anastomosis [30].

Probiotics

Probiotics are live microorganisms which may benefit the host when ingested in adequate amounts.
Their efficacy is dependent on the strain, the dose and the viability of the microorganisms being used in
these preparations. The commonly studied probiotic species are Lactobacillus sp, Bifidobacteria sp and
VSL#3 (combination of Bifidobacterium, Lactobacillus and Streptococcus sp) which are bacterial and
Saccharomyces boulardii which is yeast.
Although there may be a role for probiotics in the prevention of acute diarrhoea [31,32], much less is
known on the potential role of these agents in treatment of persistent diarrhoea [33].
Data is still conflicting with respect to probiotic use in Inflammatory Bowel Diseases (IBD) patients.
Although a number of clinical trials and a meta-analysis of VSL#3 have demonstrated a possible benefit
in induction and/or maintenance of remission in mild ulcerative colitis [34], recently published studies
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including a Cochrane systemic review concluded that there was insufficient evidence to make
conclusions about the efficacy of probiotics in maintenance of remission in UC [35]. A similar
conclusion was drawn for probiotic usage in patients with Crohn’s disease [36]. There may be a role for
preventing pouchitis or maintaining remission after treatment of pouchitis in patients with ileal pouch
anal anastomosis [37–40].
Prevention of antibiotic-associated diarrhoea is another area where probiotics can be considered
[41–45].
Although probiotics may not specifically improve IBS associated diarrhoea, they may be effective in
alleviating IBS symptoms [46–51] and can be considered in this patient population.

Anticholinergics (antispasmodics)

This category includes: atropine, propantheline, methscopolamine, hyoscyamine (Levsin), dicy-

clomine (Bentyl), Belladona alkaloids (Donnatal) and glycopyrrolate (Robinul).
Anticholinergics function through an effect on the gut motility by blocking the binding of the
neurotransmitter acetylcholine to its receptor. As indicated in its name, antispasmodics are used to
relieve cramps or spasms of the stomach and intestine, which makes them a good treatment option for
Irritable Bowel Syndrome – Diarrhoea predominant (IBS-D). Anticholinergics also reduce acid secre-
tion. A meta-analysis showed traditional anti spasmodic therapy has a moderate efficacy in treating
IBS-D patients [52].
Side effects can be divided into two types: peripheral and central. Common peripheral side effects
are dry mouth, hyperthermia, increased pupil size, blurred vision, tachycardia, urinary retention and
constipation. Central side effects include impaired concentration, attention deficit and confusion.
Anticholinergics’ use in the treatment of diarrhoea is limited due to their side effects.
Caution is advised when taking these medications concurrently with other medications with anti-
cholinergic effect including but not limited to tricyclic antidepressants, antihistamines and some of the
antipsychotics.

Opiates and opiate-like medications

Opiates and opiate-like medications have been used as anti-diarrhoeal drugs for centuries and they
are still the most effective, non-specific anti-diarrhoeal treatment.
Drugs in this category include paregoric, loperamide, codeine, tincture of opium, diphenoxylate
with atropine, and racecadotril.
The anti-diarrhoeal action is mediated through m-receptor in the intestinal wall. Opiates increases
non-propulsive activity and decreases peristalsis in several gut segments, as well as inhibits fluid
secretion, resulting in longer gastrointestinal transit time and increased absorption of fluids and
electrolytes from the gastrointestinal tract [53,54].
In most cases, the effective dose of narcotics remains the same for years as the tolerance to the anti-
diarrhoeal effect of these agents is unlikely.
Side effects of narcotics are: delayed gastric emptying with resultant nausea and vomiting, central
nervous system and respiratory depression and addiction. Although the potential of abuse is very low
in patients who do not have any history of drug abuse, it would be wise to start with loperamide which
does not have a potential for abuse and addiction and diphenoxylate with the least addiction potential
when treating diarrhoea [55]. Loperamide is a peripherally restricted opioid agonist which devoid of
central opiate-like effects.
Opiates and any anti spasmodic are contraindicated in severely ill inflammatory bowel disease
patients due to the risk of developing toxic megacolon.
Cautious is advised in prescribing these medications in patients with severe infectious colitis
especially with C. difficile, as their anti spasmodic effects may increase the risk of microorganism
invasion and prolongation of the carrier state.
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Loperamide (Imodium)

This is a synthetic phenylpiperidine derivative with potent m-opioid receptor agonist and extensive
first-pass metabolism. Unlike other opiates, it has no analgesic or euphoric effects even at high doses
because of its low systemic circulation and inability to cross the blood–brain barrier. It has a longer
duration of action than diphenoxylate and better safety profile than codeine phosphate and diphe-
noxylate. Since loperamide is more potent, more specific, longer acting and lacking of CNS effects, it is
a popular first-line choice used in painless diarrhoea, diarrhoea-predominant IBS, short bowel
syndrome, non severe uncomplicated diarrhoea induced by radiotherapy or chemotherapy [11,56,57]
and protease inhibitor associated diarrhoea [28,58]. Loperamide was also shown to increase anal
sphincter tone after restorative proctocolectomy and may improve continence in patients with fecal
incontinence [59–61].
Loperamide has varied formulations including tablets, capsules, chewable tablet, oral solution, and
a combination product with simethicone. The loperamide–simethicone combination chewable product
provides faster and more complete relief of acute non-specific diarrhoea and associated gas-related
abdominal discomfort.
The most common side effects of loperamide are related to the impact on bowel motility including
abdominal pain, distention, bloating, nausea, vomiting, and constipation. Loperamide is not recom-
mended for treatment of acute diarrhoea in children younger than three years old [62,63] or in children
who are malnourished, moderately to severely dehydrated or have bloody diarrhoea.
Loperamide is metabolized by the cytochrome P450 (CYP450) system; therefore the risk of side
effects may be increased when it is used in patients with hepatic diseases or concurrent administration
with CYP450 inhibitors.

Diphenoxylate with atropine (Lomotil)

This is a synthetic phenylpiperidine derivative which is available in a fixed-dose combination with

atropine (2.5 mg/0.025 mg) in both tablet and liquid form. It may be used in combination with
loperamide for the treatment of mild to moderate diarrhoea induced by cancer treatment [11]. Even
though it is a low potent opiate, it is not uncommon to see case reports of overdose and dependency or
abuse [64]. The euphoric effects of diphenoxylate are produced at 2–3 times the clinical doses. Atropine
reduces the likelihood of abuse of diphenoxylate by producing unpleasant side effects.

Codeine

This is a pro-drug which is metabolized and activated by CYP2D6 into morphine with ten times
more potency than codeine. Codeine is used in palliative care for symptoms of pain and diarrhoea [65].

Racecadotril (Acetorphan)

Racecadotril (pro-drug of thiorphan) is a pure anti-secretory agent. It acts as an enkephalinase

inhibitor and thus prevents the inactivation of enkephalins, the neurotransmitters found in the
epithelial cells of the intestine. When bound to the delta receptors, enkephalins will reduce cAMP
levels, and thus reduce the secretion of water and electrolytes. Unlike opiates agents, it has no effect on
intestinal motility, therefore it does not induce constipation, bacterial overgrowth and toxic megacolon
and it has a similar tolerability profile to placebo. Racecadotril is as effective as loperamide in resolving
acute diarrhoea but with greater reduction in pain and abdominal distension. The efficacy and safety of
racecadotril as an adjuvant to oral rehydration therapy have been demonstrated in a wide age group of
patients with diarrhoea of infectious or non-infectious aetiology [66–68].

Tincture of opium

Tincture of opium is an alcoholic herbal preparation of opium. Tincture of opium is used as a second
line treatment for persistent diarrhoea which is unresponsive to other treatments. There are two
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preparations available in this category: (1) Deodorized tincture of opium which contains the equivalent
of 10 mg/mL morphine. (2) Paregoric or camphorated tincture of opium, a less-concentrated prepa-
ration which contains the equivalent of 0.4 mg/mL morphine. Tincture of opium is a recommended 2nd
line treatment in chemotherapy induced diarrhoea [11,57].

Bile acid binders

Cholestyramine is used mainly in treatment of watery diarrhoea caused by bile acid malabsorption
regardless of the cause and severity [69]. High doses may cause steatorrhoea and therefore should be
avoided.
In a trial comparing mesalazine with or without cholestyramine in controlling diarrhoea in patients
with collagentous colitis, it was suggested that cholestyramine may play a role in the control of
diarrhoea in this group of patients, but not in patients with lymphocytic colitis [70]. Cholestyramine
may also be a safe and useful adjunct for the treatment of idiopathic diarrhoea and fecal incontinence
[71].

Budesonide

Budesonide is a glucocorticoid with minimal systemic action due to extensive first-pass metabo-
lism. It is approved by the FDA for use in patients with mild to moderate Crohn’s disease of the ileum
and ascending colon. Budesonide MMX, a once daily oral formulation, was shown to be safe and more
effective than placebo in inducing remission in patients with active, mild to moderate ulcerative colitis
[72].
Budesonide can be used in treatment of patients with microscopic colitis [73–76]. Relapse has been
observed after treatment cessation.

Somatostatin analogues

Octreotide

Octreotide is a synthetic analogue of somatostatin with the same pharmacologic effects but a longer
half-life and a greater potency. It binds to somatostatin receptors found throughout the body and
works as an inhibitory hormone. The mechanisms of action of somatostatin analogues in treating
diarrhoea include inhibition of hormone secretion such as gastrin, cholecystokinin, secretin, pancreatic
polypeptide (PP), vasoactive intestinal peptide (VIP); inhibition of gastrointestinal motility as well as
increase in water and electrolyte absorption.
This medication is mainly being used to treat diarrhoea and other hormone-mediated symptoms
caused by carcinoid tumour, VIPomas, glucagonomas and gastrinomas [77,78]. It has also been used to
treat severe refractory diabetic diarrhoea [79,80], dumping syndrome [81] and severe diarrhoea
induced by chemotherapy and radiotherapy [11,57], AIDS associated diarrhoea [82] and diarrhoea in
patients with graft-vs-host disease [83].
Octerotide should be discontinued after 2 weeks in patients who have not demonstrated a response
to treatment as late response is rare and the drug is expensive.
Common side effects of octreotide include abdominal pain, nausea and flatulence and loose stools.
Mild steatorrhoea may occur at the beginning of treatment and usually subsides spontaneously in few
weeks. After long term treatment, asymptomatic gallbladder stone/sludge may develop [84].

Alpha adrenergic agonists

Activation of alpha 2-adrenergic receptors on enterocytes increases fluid and electrolyte absorption
and inhibits secretion. Secondary to the potential adverse effects including hypotension, this category
should be cautiously used in treating diarrhoea especially in dehydrated patients.
Due to the less central hypotensive effect, Clonidine is the medication of choice in this category.
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Clonidine can be used in treatment of chronic secretory diarrhoea of unknown aetiology, diarrhoea
associated with narcotics withdrawal [85] and diabetic diarrhoea [86], diarrhoea caused by chemo-
therapy or graft versus host disease.

PPIs and antihistamines

Proton pump inhibitors and histamine 2 antagonists can be used in the treatment of gastrinoma
induced diarrhoea.
Histamine 1 antagonists should be considered in systemic mastocytosis.

Calcium channel blockers (CCBs)

Although CCBs like verapamil can be used to alleviate diarrhoea symptoms, their use is limited due
to the adverse effects including hypotension, bradycardia and other cardiovascular side effects.
Calmodulin is a calcium binding protein involved in the intra-cellular calcium messenger system. In
the intestinal epithelium, intra-cellular calcium stimulates electrolyte secretion by binding with
calmodulin. Zaldaride, a calmodulin antagonist, not only has been well tolerated, but also was shown to
be as effective as loperamide in travelers’ diarrhoea in a randomized double blind controlled study [87].

Summary

In an ideal world, the treatment of diarrhoea should be tailored to the underlying aetiology;
however not every underlying aetiology has a specific treatment available, the underlying aetiology
may not be diagnosed despite extensive diagnostic work up and specific treatment can sometimes be
considered to establish a diagnosis.
Healthcare providers should consider a step-wise approach for treatment of patients with chronic
diarrhoea in a timely manner to decrease the risk of complications.

Practice points

 ORSs play an important role in treating patients with diarrhoea.

 Dietary modification can play a role in some diarrhoeal illnesses including lactose avoidance,
gluten free diet in patients with coeliac disease and low fat diet in patients with extensive
ileal resection
 When possible, treatment should target the underlying pathophysiology, but empiric treat-
ment should be considered while the patient is undergoing diagnostic work up, when there is
a strong suspicious about a diagnosis or when no specific treatment is available for an
underlying aetiology.
 Empiric treatment with simple opiate such as loperamide is a reasonable first step when no
specific cause for diarrhoea is identified. If more potent medication is needed, other medi-
cations such as codeine and opium should be considered.

Research points

 Controlled studies are necessary to define the role of probiotics in treatment of different type
of diarrhoeal illnesses.
 Although Zinc supplementation has been studied in paediatric population, there is not
enough data available in adults. More studies are needed before specific recommendation is
available for zinc supplementation in this population.
 Asimadoline is a drug which acts as a peripherally selective k-opioid agonist. This drug is
currently being evaluated in the clinical trial for treatment of patients with IBS-D.
 Z. Li, H. Vaziri / Best Practice & Research Clinical Gastroenterology 26 (2012) 677–687 685

Conflict of interest statement

None.

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