A Placebo-Controlled Study of Clonidine for Fecal Incontinence.

Available therapeutic options for idiopathic fecal incontinence (FI) are limited and
unsatisfactory. In addition to weak anal sphincters, our data suggest that reduced rectal
capacity may contribute to rectal hypersensitivity and the symptom of rectal urgency in FI.
Intravenous atropine restored rectal capacity in FI. During a 4 week study, oral clonidine
restored rectal capacity and improved fecal continence in women with urge-predominant FI.
Clonidine improves fecal continence and stool consistency in diarrhea-predominant IBS.
Therefore, we now propose a placebo-controlled study of clonidine for FI. Our hypotheses,
which pertain to women with urge GI, are that (i) clonidine will improve fecal continence,
increase rectal capacity and reduce rectal sensation to a greater extent than placebo in
women, (ii) atropine (i.v.) will increase rectal capacity and compliance and reduce rectal
sensation, and (iii) the effects of atropine, will predict the effects of clonidine, on
fecal continence and rectal sensorimotor functions. Our aims are to (i) compare the effects
of clonidine and placebo, to be given for 4 weeks, on symptoms, anal pressures, rectal
compliance and sensation in women with FI, (ii) evaluate the acute effects of atropine on
anorectal sensorimotor functions, and (iii) assess if these acute effects of atropine can
predict the subjective and objective response to oral clonidine. Forty four women (18-75 y)
with urge predominant "idiopathic" FI and ≥ 4 episodes of FI during a 4 week screening
period will be recruited to this study. Thereafter, patients will be treated with clonidine
or placebo for 4 weeks. Bowel symptoms will be recorded in a diary. Anal sphincter
pressures, rectal compliance and sensation will be evaluated before and during treatment
with clonidine. During the pre-treatment anorectal study, the effects of atropine and
saline on anorectal functions will be assessed. The primary outcome variables are the FI
severity score, which provides an overall assessment of symptoms, while the primary
objective outcome variables are rectal capacity and rectal sensory thresholds for desire to
defecate and urgency.

Inclusion Criteria:

- Women aged 18-75 years with urge predominant FI, as defined by a validated
questionnaire, for 1 year duration will be eligible to participate 20

- Absence of organic disease (i.e., ulcerative colitis, cancer) as evidenced by
colonoscopy, or barium enema and sigmoidoscopy within the last 3 years

Exclusion Criteria:

- History of clinically significant cardiovascular or pulmonary disease or EKG
abnormalities within the last 6 months [i.e., atrial flutter or fibrillation, sinus
tachycardia (> 110/minute) or bradycardia (< 45 beats/minute), or prolonged QTc
interval (> 460 msec)

- Current or past history of rectal cancer, scleroderma, inflammatory bowel disease,
congenital anorectal abnormalities, Grade 2 rectal prolapse, history of rectal
resection or pelvic irradiation

- Neurological disorders - Spinal cord injuries, dementia (Mini-mental status score
<20/25), multiple sclerosis, Parkinson's disease, peripheral neuropathy

- Conditions precluding safe use of clonidine, i.e., symptomatic hypotension, or
systolic blood pressure of <100 mm Hg on initial screening visit

- Pregnant or nursing women

- Severe diarrhea during the run in phase defined as greater than 6 liquid stools daily
(Bristol 6 or 7)

- Medications

- Absolute - opioid analgesics, anticholinergic drugs [low doses of tricyclic
antidepressants, e.g. nortriptyline (upto 50 mg/day) or amitriptyline (upto 25
mg/day) will be permitted provided they were begun 3 months prior to the screening
period]

- Relative - other antihypertensive agents (i.e. if there is concern about synergistic
effects and hypotension)