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Topical glyceryl trinitrate heals anal fissures, but a majority of patients experience headache. Topical gels of the calcium channel blocker diltiazem and the cholinomimetic bethanechol significantly lower and sphincter pressure in volunteers. This study investigated the use of these two new pharmacologic agents in the treatment of patients with chronic anal fissure.Two studies were conducted, each involving 15 patients with chronic anal fissure. In each study patients underwent anal manometry and laser doppler flowmetry before treatment. They were treated with either 2 percent diltiazem gel or 0.1 percent bethanechol gel three times daily for eight weeks. Assessment every two weeks was by clinical examination, repeat anal manometry, and laser doppler flowmetry. Daily pain was assessed by linear analog charts.Fissures healed in 10 of 15 (67 percent) patients treated with 2 percent diltiazem gel and in 9 (60 percent) patients treated with 0.1 percent bethanechol gel. There was no significant difference in the pretreatment maximum resting sphincter pressure (MRP) between responders and nonresponders in either group. There was significant reduction in the pain score after treatment with diltiazem ( P=0.002) and bethanechol ( P=0.005) compared with that before treatment. MRP was significantly lower after diltiazem ( P=0.0001) and bethanechol ( P=0.02) compared with pretreatment MRP. No headaches or side effects were reported.Both topical diltiazem and bethanechol substantially reduce anal sphincter pressure and achieve fissure healing to a similar degree reported with topical nitrates, but without side effects.