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EDITORIAL COMMENTARY CID 2008:47 (15 October) 1015

E D I T O R I A L C O M M E N T A R Y

Loperamide for the Treatment of Travelers Diarrhea:

Broad or Narrow Usefulness?

Thomas Butler

Department of Microbiology and Immunology, Ross University School of Medicine, North Brunswick, New Jersey

(See the article by Riddle et al. on pages 100714)

Received 2 July 2008; accepted 2 July 2008; electronically

published 9 September 2008.

Reprints or correspondence: Dr. Thomas Butler, Ross

University, 630 US Hwy. 1, North Brunswick, NJ 08902

(tomxanadu@gmail.com).

Clinical Infectious Diseases 2008;47:10156

2008 by the Infectious Diseases Society of America. All

rights reserved.

1058-4838/2008/4708-0005$15.00

DOI: 10.1086/591704

The meta-analysis by Riddle et al. in this

issue ofClinical Infectious Diseases [1] fo-

cuses on the antidiarrheal drug loperam-

ide hydrochloride and its efficacy when

combined with antimicrobials to shorten

illness in adults with travelers diarrhea.

Loperamide is a piperadine derivative that

slows intestinal motility because of its ac-

tivation ofm-opiate receptors. By decreas-

ing peristalsis and increasing anal sphinc-

ter tone, it increases intestinal transit time,

thus retaining luminal contents and giving

more time for reabsorption of secreted

fluid. The drug has a less prominent effect

through inhibition of intestinal secretionby its action on G

1-linked receptors to

counter increases in cyclic adenosine

monophosphate caused by bacterial en-

terotoxins. It is available over the counter

as a diarrheal remedy and has been rec-

ommended for travelers diarrhea for 125

years [2]. A newer form of the drug, lo-

peramide oxide, was tested in Germany

and was shown to be more effective than

placebo against diarrhea [3]. Itsadvantage,

as a prodrug that is changed to loperamide

by anaerobic bacteria in the intestine, is

to give more-prolonged and higher drug

concentrations in the intestinal lumen,

with less absorption into the blood, po-

tentially causing fewer systemic adverse ef-

fects, such as CNS depression, than when

loperamide hydrochlorideis administered.

Clinical studies in the meta-analysis en-

rolled young US students or military per-

sonnel in prospective randomized trials in

Mexico, Thailand, and Egypt. The most

common microbial cause of diarrhea

identified in study participants were en-

terotoxigenic Escherichia coli, followed by

Shigella species, Campylobacter species,Salmonella species, enteroaggregative E.

coli, Giardia lamblia, Entamoeba histoly-

tica, and Cryptosporidium species. Patho-

genesis of travelers diarrhea occurs at the

epithelial cell surface of the intestine,

where enterotoxins cause fluid production

or invasive pathogens elicit inflammation.

Neural signals are transmitted from this

surface to smooth muscle to increase peri-

stalsis, giving rise to symptoms of cramps

and frequent bowel movements. Travelers

diarrhea is unique for a high attack ratebecause of a low level of immunity in trav-

elers against prevalent pathogens in the

food and water from the visited countries.

Travelers are also a selected population of

usually young, healthy adults who develop

mild or moderately severenondehydrating

illnesses that do not require hospitaliza-

tion. They do not die as young children

and malnourished inhabitants of devel-

oping countries sometimes do when in-

fected with the same pathogens, and the

travelers usually recover in a few days,

even when treated with placebo [4]. Al-

though initially not immune against local

pathogens, travelers mount effective im-

mune responses that are instrumental in

their recoveries from self-limited illness.

Absence of significant dehydration in

most cases was demonstrated in a ran-

domized trial of oral rehydration solutions

in addition to loperamide, which showed

no benefit of oral rehydration solutions to

hasten recovery from symptomatic illness[5].

Trials in the analysis pertinently com-

pared treatments of loperamide hydro-

chloride plus an antimicrobial drug with

the same antimicrobial drug alone. Most

of the analyzed studies reported that lo-

peramide conferred a substantial benefit

by reducing frequency of loose stools by

approximately one-half and by shortening

the average duration of diarrhea from1.5

days to !1 day, with a range of mean re-

ductions of duration of 223 h. Howbroadly applicable are these results to all

diarrheal illness in travelers and other per-

sons? Two studies in the analysis were

partly discordant with regard to beneficial

action: patients with Campylobacterinfec-

tion in Thailand, where these infections

showed fluoroquinolone resistance [6],

and patients with Shigella infections in

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1016 CID 2008:47 (15 October) EDITORIAL COMMENTARY

Mexico [7] showed no benefit from lo-

peramide. Antimicrobial drugs without

loperamide reduced diarrheal duration by

approximately one-half when compared

with placebo, as was demonstrated for tri-

methoprim-sulfamethoxazole in Mexico

[4]. When used alone, loperamide reduces

the duration of diarrhea and the frequencyof bowel movements, compared with pla-

cebo [4, 8] but has less effect than in com-

bination with an antimicrobial drug [4, 9].

In countries visited by travelers, children

who have not yet acquired immunity to

enterotoxigenic E. coli are susceptible to

disease, but children !6 years of age are

not advised to receive loperamide because

of potential overdoses that could cause

CNS depression. Patients with bloody di-

arrhea or high temperatures were ex-cluded from the analyzed studies. It is not

known whether loperamide therapy will

be effective against diarrhea caused by no-

rovirus, the most common cause of out-

breaks of nonbacterial gastroenteritis

worldwide [10].

The analyzed studies, nevertheless, were

soundly designed as prospective and ran-

domized studies, with most using loper-

amide placebos in a double-blind manner.

An unavoidable fault of the study methods

was quantitative imprecision, because the

studies used patients self-reported fre-

quency of stools and time since their last

unformed stools. These data were subjec-

tive, according to different perceptions of

what constitutes an unformed stool. An-

other problem, perhaps related to subjec-

tive reporting of symptoms, is heteroge-

neity of enrolled patients responses to

loperamide. In 4 separate studies of stu-

dents in Mexico, the mean and median

durations of diarrhea after the start of lo-

peramide therapy had a range of 027 h.

A conclusion from the analyzed trials is

that loperamide should be combined nar-

rowly with an antimicrobial drug for trav-

elers to areas where enterotoxigenic E. coli

is anticipated to be the major diarrheal

pathogen. Loperamide should not be re-garded as a broad empirical fix, because it

does not benefit patients with excessive

diarrhea, such as those with cholera, and

should not be used to treat bloody dys-

entery; patients with Shigella or Campy-

lobacterinfection may not derive any ben-

efit from the drug, but they seem not to

be harmed by it. What explains the drugs

success? It works especially well in low-

volume secretory diarrhea, probably be-

cause a decrease in peristalsis and an in-

crease in anal sphincter tone causes

retention of secreted fluid, giving more

time for intestinal mucosa distal to secre-

tion sites to reabsorb excess luminal fluid.

Reduced peristalsis also diminishes fecal

urgency and frequency of bowel move-

ments. It makes mild or moderately severe

diarrhea even milder. A healthy distal co-

lon absorbs water and salt avidly and

should be the major site of absorption of

additional fluid presented to it during se-

cretory diarrhea. Shigella and Campylo-

bacterspecies cause primarily distal colitis,

whereas enterotoxigenic E. coliaffects the

small intestine; therefore, impaired ab-

sorption in the colon may explain refrac-

toriness of infection due to Shigella and

Campylobacter when treated with loper-

amide [11]. Although loperamide should

continue to be used by travelers, priority

should be placed on selecting an appro-

priate antimicrobial to be combined with

it. This selection will burden practitioners

of travel medicine to be familiar with prev-

alent microbes in different countries and

their antimicrobial susceptibilities.

Acknowledgments

Potential conflicts of interest. T.B.: no

conflicts.

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