Topical diltiazem and bethanechol decrease anal sphincter pressure without side effects

Abstract

Background: Topical nitrates lower anal sphincter pressure and heal anal fissures, but a majority of patients experience headache. The internal anal sphincter has a calcium dependent mechanism to maintain tone, and also receives an inhibitory extrinsic cholinergic innervation. It may therefore be possible to lower anal sphincter pressure using calcium channel blockers and cholinergic agonists without side effects.

Aims: To investigate the effect of oral and topical calcium channel blockade and a topical cholinomimetic on anal sphincter pressure.

Methods: Three studies were conducted, each involving 10 healthy volunteers. In the first study subjects were given oral 60 mg diltiazem or placebo on separate occasions. They were then given diltiazem once or twice daily for four days. In the second and third studies diltiazem and bethanechol gels of increasing concentration were applied topically to lower anal pressure.

Results: A single dose of 60 mg diltiazem lowered the maximum resting anal sphincter pressure (MRP) by a mean of 21%. Once daily diltiazem produced a clinically insignificant effect but a twice daily regimen reduced anal pressure by a mean of 17%. Diltiazem and bethanechol gel produced a dose dependent reduction of the anal pressure; 2% diltiazem produced a maximal 28% reduction, and 0.1% bethanechol a maximal 24% reduction, the effect lasting three to five hours.

Conclusions: Topical diltiazem and bethanechol substantially reduce anal sphincter pressure for a prolonged period, and represent potential low side effect alternatives to topical nitrates for the treatment of anal fissures.

Figure 1

Resting anal sphincter pressure in response to oral placebo* and 60 mg diltiazem†. *p=0.4, 97 (17) v 94 (16) cm H₂O, pre- versus post-treatment mean (SD) maximal resting pressure (MRP) (ANOVA); †p<0.0001, 97 (17) v 77 (11) cm H₂O.

Figure 2

Diltiazem gel dose-response curve in 10 healthy volunteers. *p<0.0001, maximal resting pressure (MRP) compared with pretreatment MRP (ANOVA).

Figure 3

Duration of action of 2% diltiazem gel following a single application in 10 healthy volunteers. MRP, maximal resting pressure.

Figure 4

Bethanechol gel dose-response curve in 10 healthy volunteers. *p<0.0001, maximal resting pressure (MRP) compared with pretreatment MRP (ANOVA).

Figure 5

Duration of action of 0.1% bethanechol gel following single application in 10 healthy volunteers. MRP, maximal resting pressure.