Treatment of Diabetic Diarrhea with Clonidine
RICHARD N. FEDORAK, M.D.; MICHAEL FIELD, M.D.; and EUGENE B. CHANG, M.D.; Chicago, Illinois
Stimulation of alpha2-adrenergic receptors on enterocytes
promotes fluid and electrolyte absorption and inhibits
anion secretion. Loss of adrenergic innervation may play a
role in impaired intestinal fluid and electrolyte absorption
in diabetic patients with autonomic neuropathy. Clonidine,
an alpha2-adrenergic agonist, was used to treat three
patients with "idiopathic" diabetic diarrhea after other
treatments had failed: The volume of diarrhea declined
significantly (p < 0.01). Diarrhea recurred when the drug
was withdrawn, but the patient's condition improved again
when clonidine treatment was reintroduced. Hypotension
did not occur as a side effect presumably because of the
autonomic neuropathy of these patients.
D I A R R H E A can be one of the most troublesome gastroin-
testinal complications of diabetes. The typical patient has
insulin-dependent diabetes that is poorly controlled, in
addition to advanced neuropathic and other diabetic
complications (1, 2). Characteristically, the diarrhea is
intermittent, voluminous, and watery; however, it can oc-
casionally be persistent and is often associated with noc-
turnal incontinence. There is no clinical test or procedure
pathognomonic of diabetic diarrhea; the diagnosis is
made by exclusion. Therapeutic trials with diet modifica-
tion, cholestyramine, metoclopramide, antidiarrheal
agents, opiates, and antibiotic agents have all proved dis-
appointing.
The pathophysiology of diabetic diarrhea is poorly un-
derstood. Diabetic diarrhea has been attributed to dis-
turbed gastrointestinal motility, but convincing evidence
is lacking (3, 4 ) . Recently, chronically diabetic rats were
shown to have impaired intestinal fluid and electrolyte
absorption as a result of the loss of adrenergic innerva-
tion to the intestinal mucosa—specifically, lack of stimu-
lation of alpha2-adrenergic receptors on enterocytes ( 5 ) .
Stimulation of these receptors ordinarily promotes fluid
and electrolyte absorption, and inhibits anion secretion
(6, 7). We report the cases of three patients whose dia-
betic diarrhea responded to oral therapy with clonidine,
an alpha2-adrenergic agonist.
Methods and Patients
Three patients with insulin-dependent diabetes mellitus were
referred for evaluation of persistent and severe chronic diar-
rhea, which was diagnosed as diabetic diarrhea by the process
of exclusion. After giving informed consent, patients were ad-
mitted to the Clinical Research Center to participate in the
study. Daily caloric intake of carbohydrates, fat, and protein for
each patient was constant during the study period. Stool was
collected in disposable plastic pots, allowing patients to easily
collect stool separate from urine; frequency, weight, and con-
• From the Section of Gastroenterology, Division of Biological Sciences, Depart-
ment of Medicine, The University of Chicago Hospitals and Clinics; Chicago,
Illinois.
Annals of Internal Medicine. 1985;102:197-199.
Downloaded From: http://annals.org/ by a University of Birmingham User on 08/25/2013
sistency of stool were recorded daily. Blood pressure and pulse,
with the patient supine and standing, were recorded every 4
hours.
Clonidine was given to each patient for two separate time
periods, separated by a clonidine-free interval. The first dose
was given after a 1-week baseline stool collection. Patients were
started on 0.1 mg every 12 hours and advanced to 0.5 or 0.6 mg
every 12 hours over the next 3 days. This dosage was main-
tained for 19 to 21 days, after which clonidine was slowly with-
drawn over 72 hours. A 10- to 14-day drug-free interval fol-
lowed, and clonidine was then restarted. During the outpatient
phase of the study, stool weight and frequency were recorded by
the patients. Each patient was supplied with disposable plastic
pots for collection, a balance, and a diary and compliance was
monitored daily. Stool weights were compared for the periods
of clonidine treatment and drug-free periods using the Student's
Mest.
The patients had had poorly controlled insulin-dependent di-
abetes mellitus for 6 to 15 years. Diabetes was complicated by
peripheral sensory neuropathy, retinopathy, and gastroparesis
in each patient. Autonomic neuropathy was characterized by
postural hypotension greater than 25 mm Hg (despite euvole-
mia) in two patients, and by gustatory sweating and impotence
in the third.
Diarrhea 7 to 12 times a day had begun 2 to 3 years earlier,
with associated urgency and nocturnal incontinence. There was
no history of foreign travel or laxative or diuretic abuse. Seven-
ty-two-hour stool fat collections were normal. Stool tests for
occult blood, culture, ova and parasites, and Clostridium diffi-
cile toxin assay were negative in each patient. Complete blood
count and differential, SMA-12, serum magnesium, triiodothy-
ronine (T3), thyrotrophin, T3 reverse uptake, Cortisol, immuno-
globulins, serum gastrin, eosinophil count, serum folate, serum
iron, total iron binding capacity, and vitamins A, D, E, and B12
were all normal. Creatinine clearance was normal in two pa-
tients and minimally elevated in a third. The patients' D-xylose
and urinary 5-hydroxyindole acetic acid levels were normal.
Results of the (2H) lactose and (14C) glycocholate breath tests
were normal. Air contrast barium studies, including upper gas-
trointestinal, small bowel, and colon, were normal. Peroral jeju-
nal biopsy samples showed a normal villous pattern and ab-
sence of infective pathogens. Colonoscopy and random biopsy
samples were normal. During a 72-hour fasting period while on
intravenous administration of fluids, stool volume fell to near
zero. In all patients, previous trials with lactose-free or low-fat
diets, metoclopramide, metronidazole, tetracycline, cholestyra-
mine, bulk agents, loperamide, diphenoxylate, codeine, and opi-
ates had failed to control the diarrhea.
Results
All three patients had a significant decline in the vol-
ume of their diarrhea while receiving clonidine (p <
0.01). Diarrhea resumed when the drug was withdrawn,
and each patient's condition improved again when thera-
py was reintroduced (Figure 1).
All patients tolerated the medication well. Symptoms
of gastroparesis were not aggravated. Clonidine did not
worsen the already existent postural hypotension, and did
not induce postural hypotension where it was not previ-
© 1985 American College of Physicians 197
 tion over 72 hours when the study required its withdraw-
al. Despite this warning, one patient abruptly stopped the
clonidine and had transient, mild rebound hypertension,
anxiety, headache, and sleeplessness. Resumption of clo-
nidine resulted in rapid reversal of the symptoms. When
clonidine was removed in tapering doses, the other pa-
tients either had no symptoms of withdrawal or reported
a mild, transient headache without hypertension during
the first full day off clonidine therapy.
Although the frequency of bowel movements did not
significantly change, patients reported a clustering of
movements into one or two periods during the day. An
increase in stool consistency was also seen with improve-
ment of nocturnal incontinence. Clonidine has been used
to control these patients' diarrhea for 6 to 24 months.

Discussion
Adrenergic regulation of intestinal ion transport plays
a major role in the homeostasis of fluid and electrolyte
absorption. Thus, patients who have had bilateral sympa-
thectomy for hypertension sometimes develop persistent
diarrhea ( 9 ) . In 1973, Field and McColl (10) showed
that alpha adrenergic agonists in vitro stimulated sodium
and chloride absorption in the intestine. This finding sug-
gested that alpha-adrenergic agonists could be useful as
antidiarrheal agents, but cardiovascular side effects have
limited their usefulness.
Clonidine, a specific alpha2-adrenergic receptor ago-
nist, has been predominantly used as an antihypertensive
agent. Clonidine's hypotensive effect appears to be medi-
ated centrally by alpha2-receptor sites in the brain stem,
resulting in suppression of sympathetic outflow (11). In
vitro, clonidine, by stimulation of alpha2~adrenergic re-
ceptors, enhances mucosal absorption of fluid and elec-
trolytes and inhibits anion secretion (12). In vivo, cloni-
dine has been shown to diminish castor oil-induced and
naloxone-precipitated withdrawal diarrhea in rats (13-
15). In humans, clonidine inhibited secretory diarrhea in
a patient with bronchogenic adenocarcinoma (16) and,
in controlled studies, inhibited or prevented opiate with-
drawal symptoms including diarrhea (17).
In chronically diabetic rats treated with streptozotocin,
fluid and electrolyte absorption was impaired in the ileum
and colon; functional evidence suggested that this impair-
ment was due to loss of alpha2-adrenergic innervation of
the enterocytes ( 5 ) . In another study, neurochemical and
histochemical evidence showed a selective loss of adre-
nergic innervation in the myenteric plexus of streptozoto-
cin-treated rats (18). Whether diabetic diarrhea in hu-
mans can be explained by a similar pathophysiologic
Figure 1 . Effect of clonidine on stool weights. Each bar shows the mechanism remains to be established. Whether the ob-
average stool weight over a 48-hour period. Mean stool weights served antidiarrheal action of clonidine is mediated by
( ± SE) during periods when patients received no or full doses of
clonidine are shown by the bold lines. (Drug initiation and tapering direct stimulation of alpha2-adrenergic receptors on en-
intervals were not included.) For Patient 1 , periods during which terocytes or by a less direct pathway is not yet clear.
diabetic ketoacidosis (DKA) occurred were not used in assessing
stool weights. Asterisks indicate p < 0 . 0 1 .
Clonidine may also modify intestinal motility or rectal
sphincter tone as a part of its antidiarrheal effect.
ously present. Blood glucose, diabetic control, and renal Our diabetic patients treated with clonidine did not
function were unaltered. Because withdrawal symptoms develop hypotension, and preexisting postural hypoten-
have previously been seen after the abrupt cessation of sion was not aggravated. The absence of this known side
clonidine therapy ( 8 ) , our patients tapered the medica- effect of clonidine in diabetic patients contrasts with our

198 February 1985 • Annals of Internal Medicine • Volume 102 • Number 2

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 experience in nondiabetic patients with diarrhea. It is
possible that the central effects of clonidine were not
manifested and only its peripheral antidiarrheal action
was seen because our patients with diabetic diarrhea had
severe autonomic neuropathy. Other side effects were
minimal; diabetic control and renal function were unal-
tered. Withdrawal symptoms of clonidine could be avoid-
ed or minimized by tapering the dosage. The develop-
ment of alpha2-adrenergic agonists that do not cross the
blood brain barrier or with preferential gut action would
further reduce side effects.
ACKNOWLEDGMENTS: Grant support: Dr. Fedorak is a recipient of the
Alberta Heritage Foundation for Medical Research Fellowship. Dr. Chang
is a recipient of the New Investigator Research Award (AM-31810), the
John A. and George L. Hartford Fellowship, and the Hoffman-LaRoche
Research Scholar's Award of the American Gastroenterological Associa-
tion.
• Requests for reprints should be addressed to Richard N. Fedorak, M.D.;
Department of Medicine, Division of Gastroenterology, College of Physi-
cians and Surgeons of Columbia University, 630 West 168th Street; New
York, NY 10032.
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Fedorak et al. • Diabetic Diarrhea 199