Modafinil

Modafinil is a drug prescribed to increase wakefulness in adults who suffer from various sleep disorders. It is marketed by Cephalon as Provigil. Its chemical name is 2-benzhydrylsulfinylethanamide.

Uses
Provigil is prescribed to improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome (OSAHS), and shift work sleep disorder (SWSD).

In OSAHS, Provigil is typically prescribed along with a standard treatment for the underlying obstruction.

How Modafinil is Taken
The recommended dose of Provigil is 200 mg once daily. Doses up to 400 mg per day, given as a single dose, have been prescribed, but there is no evidence that this dose confers additional benefits beyond the standard 200 mg dose.

For patients with narcolepsy and OSAHS, Provigil should be taken as a single dose in the morning. For patients with SWSD, Provigil should be taken approximately one hour prior to the start of their work shift.

How Modafinil Works
The precise mechanism through which modafinil promotes wakefulness is unknown. Modafinil has wake-promoting actions similar to other stimulants like amphetamine and methylphenidate.

Preliminary lab studies show that modafinil binds to the dopamine transporter (DAT), thereby inhibiting dopamine reuptake. In genetically engineered mice lacking the DAT, modafinil lacked wake-promoting activity. This finding naturally suggests that modafinil acts through the DAT. This activity has been associated with increased extracellular dopamine levels in certain brain regions of animals.

In addition to its wake-promoting effects, modafinil can produce changes in mood, perception, and thought patterns typical of other stimulants. The mechanisms underlying these effects is unknown.

How the Body Affects Modafinil
Absorption of modafinil is rapid, with peak levels occurring at 2-4 hours after dosing. However, modafinil's absorption may be delayed by approximately one hour if taken with food.

Modafinil is metabolized by the liver with subsequently eliminated via urine through the kidneys.

Side Effects
Modafinil has been evaluated for safety in over 3500 patients. In clinical trials, modafinil has been found to be well tolerated and most side effects were mild to moderate.

The most common side effects( ≥ 5%) associated with the use of Provigil were:


 * headache
 * nausea
 * nervousness
 * runny nose (rhinitis)
 * diarrhea
 * back pain
 * anxiety
 * insomnia
 * dizziness
 * indigestion (dyspepsia)

Drug Interactions

 * Circulating levels of triazolam and its elimination half-life are decreased when taken with Provigil.


 * Drug interaction studies with monoamine oxidase (MAO) inhibitors have not been performed. However, since both drugs affect dopamine pathways, caution should be used when administering MAO inhibitors with Provigil.


 * Drugs that are largely eliminated via CYP2C19 (a liver metabolic pathway), such as diazepam, propranolol, phenytoin or S-mephenytoin may have prolonged elimination when taken with Provigil and may require dosage reduction and monitoring for toxicity.


 * Modafinil may cause elevation of the circulating levels of the tricyclic antidepressants in certain patients. A reduction in the dose of tricyclic agents might be needed in these patients.


 * Co-administration of potent inducers of CYP3A4 (a liver metabolic pathway) such as carbamazepine, phenobarbital, rifampin or inhibitors of CYP3A4 such as ketoconazole and itraconazole could alter the circulating levels of modafinil.

Effectiveness
The effectiveness of modafinil has been demonstrated in the following sleep disorders: narcolepsy, obstructive sleep apnea/hypopnea syndrome (OSAHS), and shift work sleep disorder (SWSD).

Narcolepsy
The effectiveness of modafinil in promoting wakefulness in narcoleptics was established in two U.S. studies. The primary measures of effectiveness were 1) sleep latency (measured by the number of minutes it took the patient to fall asleep) and 2) the change in the patient's overall clinical condition.

Both studies demonstrated improvement of excessive daytime sleepiness for both the 200 mg and 400 mg doses compared to placebo. Patients treated with either dose of modafinil showed a statistically significant improved ability to remain awake on the sleep latency test at 3, 6, and 9 weeks and a statistically significantly greater improvement in their overall clinical condition.

Obstructive Sleep Apnea/Hypopnea Syndrome (OSAHS)
The effectiveness of modafinil in promoting wakefulness associated with OSAHS was established in two clinical trials.


 * In the first study, 327 patients received modafinil 200 mg/day, modafinil 400 mg/day, or placebo. The primary measures of effectiveness were 1) sleep latency (measured by the number of minutes it took the patient to fall asleep) and 2) the change in the patient's overall clinical condition. Patients treated with modafinil showed a statistically significant improvement in the ability to remain awake compared to placebo-treated patients. In addition, modafinil-treated patients showed a statistically significant improvement in overall clinical condition. The two doses of modafinil performed similarly.


 * In the second study, 157 patients were tested on either modafinil 400 mg/day or placebo. The primary measure of effectiveness was the patient's score on a questionnaire called the Epworth Sleepiness Scale (ESS). At week 4, the ESS score was reduced by 4.6 in the Provigil group as compared to 2.0 reduction in the placebo group.

In both studies, nighttime sleep was not affected by the use of modafinil.

Shift Work Sleep Disorder (SWSD)
The effectiveness of modafinil for promoting wakefulness associated with SWSD was demonstrated in one clinical trial involving 209 patients with chronic SWSD. The patients received either modafinil 200 mg/day or placebo.

The primary measures of effectiveness were 1) sleep latency (measured by the number of minutes it took the patient to fall asleep) and 2) the change in the patient's overall clinical condition. Patients treated with modafinil showed a statistically significant prolongation in the time to sleep onset compared to placebo-treated patients. Improvement in overall clinical condition was also observed to be statistically significant.

Daytime sleep was not affected by the use of modafinil.

Alternatives
Several stimulants that promote wakefulness are currently available by prescription. These include methylphenidate (Concerta, Ritalin), amphetamines (Adderall), and sodium oxybate (Xyrem).

Other Potential Indications
Once a drug is approved by the FDA for any indication, a physician can be prescribe it "off-label" as he or she sees fit. It is sometimes described as a "smart pill" and as having an "underground life as a pick-me-up for the routinely sleep-deprived." The popularization of modafinil in the mainstream media is of concern to some physicians. Nonetheless, wider use of modafinil will probably occur in the areas of addiction, obesity , depression , and bipolar disorder , to name a few.

Other Forms of Modafinil
Modafinil itself is a mixture of two molecules that are mirror images of one another&mdash;"right-handed" and a "left-handed" versions of 2-benzhydrylsulfinylethanamide. The two forms behave slightly differently in the body. Cephalon has received FDA approval for the pure, longer-lived "right-handed" version, Armodafinil, on June 18, 2007 for the treatment of excessive sleepiness associated with OSAHS, narcolepsy, and SWSD.