Modafinil Elicits Sympathomedullary Activation

The autonomic effects of modafinil (Provigil), a psychostimulant widely used to attenuate fatigue and promote wakefulness, are currently unexplored. We assessed the effect of modafinil on autonomic nervous system. We compared oral modafinil (400 mgx1) versus placebo in 12 healthy hospitalized normal subjects in a randomized double-blind, placebo-controlled cross-over study for 3 days each with subjects in 150 mEq sodium, 70 mEq potassium balance at the Vanderbilt General Clinical Research Center. Modafinil increased resting heart rate (9.2+/-2.0 bpm; mean [+/-SE]; 95% confidence interval [CI], 4.7 to 13.6; P=0.001), resting systolic blood pressure (7.3+/-3.2 mm Hg; 95% CI, 0.2 to 14.4; P=0.044), and resting diastolic blood pressure (5.3+/-1.7 mm Hg; 95% CI, 1.4 to 9.1 mm Hg; P<0.012). Modafinil elicited a 42% higher orthostatic increase in plasma norepinephrine (0.8+/-0.3 nmol/L; 95% CI, 0.2 to 1.3; P=0.01), and caused a 33% increase in urine norepinephrine (5.1+/-1.1 nmol/L creatinine per day; 95% CI, 2.7 to 7.4, P=0.001), and an 81% increase in urine epinephrine (1.3+/-0.2 nmol/L creatinine per day; 95% CI, 1 to 2; P<0.001). The peroneal microneurographic sympathetic activity was attenuated by modafinil during orthostatic tilt (P<0.001). alpha1-Adrenoreceptor function was maintained. Modafinil substantially perturbs autonomic cardiovascular regulation by increase in heart rate and blood pressure. Autonomic changes of this magnitude encourage caution in use of modafinil in patients with cardiovascular disease.