Oral clofilium produces sustained lowering of defibrillation energy requirements in a canine model. The effect of long-term oral administration of antiarrhythmic drugs on defibrillation energy requirements is not well understood. We examined the effect of clofilium, a drug that prolongs cardiac action potential duration without slowing cardiac conduction, on defibrillation energy requirements and ventricular effective refractory periods in a canine model during a 3-week period. Epicardial patch electrodes were implanted in 12 dogs, and baseline testing was conducted under fentanyl anesthesia on day 7. An oral clofilium (100 mg/day) regimen was started on day 8. Six clofilium-treated and six control dogs underwent repeated testing on days 14, 21, and 28 after surgery. Truncated trapezoidal shocks were given repeatedly at various stored energies in random order; delivered current and impedance were measured; and delivered energy was calculated. The energy and current for 50% success in defibrillation (E50 and I50, respectively) were determined. For control animals, E50 increased by a mean 34 +/- 78%, 60 +/- 83%, and 69 +/- 122% compared with baseline (day 7) on days 14, 21, and 28, respectively. In contrast, E50 in clofilium-treated dogs decreased by 39 +/- 62%, 24 +/- 33%, and 32 +/- 15% on days 14, 21, and 28, respectively. Mean current requirements (I50) remained relatively stable compared with baseline in control animals (-7 +/- 39%, +25 +/- 36%, +40 +/- 75% on days 14, 21, and 28, respectively). After clofilium administration I50 decreased by 36 +/- 22%, 32 +/- 17%, and 33 +/- 17% on days 14, 21, and 28, respectively. 