Chicago, IL - A new study in normal subjects suggests that modafinil (Provigil®, Cephalon Inc), a drug used to treat daytime sleepiness, should be used cautiously in patients with cardiovascular disease. Compared with placebo, modafinil significantly increased heart rate and blood pressure and caused other autonomic changes in these subjects.
The study was presented at the American Heart Association 58th Annual High Blood Pressure Research Conference.
"In contrast to previous perceptions, modafinil substantially perturbs autonomic cardiovascular regulation," the researchers, with first author Dr Indu Taneja (Vanderbilt University, Nashville, TN), conclude. "The finding of autonomic changes of this magnitude encourages caution in use of modafinil in patients with cardiovascular disease."
Modafinil was approved in 1998 to improve wakefulness in patients with excessive sleepiness associated with narcolepsy, shift-work sleep disorder, and sleep apnea/hypopnea syndrome, where it's indicated as an adjunct to continuous positive airway pressure therapy. It has effects similar to amphetamines, Taneja told heartwire , but with less addiction potential.
A drug with profound stimulant activity would be expected to have cardiovascular effects as well, she said. FDA labeling currently notes that the drug should not be used in patients with left ventricular hypertrophy or mitral valve prolapse or in patients with a recent history of MI or unstable angina, since it has not been evaluated to any extent in that population. Studies of short-term use did not reveal any significant effect on blood pressure, but retrospective analysis showed that more patients already taking antihypertensive medication had to have their dosage increased, particularly among the sleep-apnea patients. Increased monitoring of blood pressure may be appropriate in patients on the drug, the labeling suggests.
In this randomized, double-blind, crossover study, the researchers compared the effects of 400 mg of modafinil vs placebo in 11 hospitalized normal subjects with an average age of about 31.
Subjects were monitored for BP and heart rate at rest, during standing, and, on a separate study day, during 60 head-up tilt. They also measured urinary and plasma catecholamines, assessed adrenoreceptor and baroreflex sensitivity, and conducted microneurography to test muscle sympathetic nerve activity in the lower extremity.
"We found that modafinil significantly increases heart rate and blood pressure," Taneja said.
Modafinil effects on heart rate and blood pressure| Measure |
Increase in response to drug (95% CI) |
p |
| 6.3+5.1 (2.8 to 9.8) |
0.0002 |
|
| 4+7 (-0.7 to 9) |
0.03 |
|
| 5.5+12 (-2.5 to 13) |
0.06 |
In addition, the drug doubled the level of urine norepinephrine (NE) and increased plasma norepinephrine by about 40%, she noted.
Modafinil effects on urine and plasma norepinephrine, and urine epinephrine| Measure |
Increase in response to drug (95% CI) |
p |
| 153+152 (51-255) |
0.007 |
|
| 6+5 (3-10) |
0.001 |
|
| 2+0.8 (1.2-2.4) |
0.001 |
Peroneal microneurographic sympathetic activity did not increase, and alpha-1 adrenoceptor and baroreflex function was not significantly impaired by treatment.
These changes could be a problem in patients with hypertension or tachycardia, for example, Taneja said. "It's better not to be used, but if it is used, it has to be under constant supervision, or we should add on other drugs that would take care of these effects."
|
Heartwire from Medscape © 2004
Cite this: Alertness medication should be used with caution in patients with CVD - Medscape - Oct 15, 2004.
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