Modafinil (sold as Provigil, Alertec, and Vigicer) is a drug used to treat narcolepsy, made by the pharmaceutical company Cephalon. It is not a typical stimulant and is marketed as a "wakefulness promoting agent."
Modafinil is the most widely available narcolepsy treatment, but is more frequently prescribed off-label for "excessive sleepiness," which is often a euphemism for insufficient sleep. Modafinil apparently allows people who suffer from fatigue to remain awake without impairment of performance. In some cases modafinil produces side-effects such as headache (13% of users), nervousness (8%), nausea (5%), rashes, and intestinal problems.
The usual prescription is for a single dose to be taken shortly after waking; its effects last for most of the day without preventing normal sleep at night, though in narcolepsy twice-daily administration is required. Under no-sleep conditions, a dose is taken at 8 hour intervals. Dosage varies and the drug is more effective on patients who are using modafinil for the first time. The half-life in the human body is about 15 hours.
Modafinil is not indicated for complaints of lack of energy or fatigue; but it appears to be very helpful for some patients. Also, it has been used in the treatment of hypersomnia, a disorder in which patients lack the capacity for meaningful sleep and may require ten or more hours per day.
In January of 2005, researchers at the University of Pennsylvania published the results of a small study, which found that modafinil may help recovering cocaine addicts fight their addiction. Similar published case reports suggest that modafinil might also be useful in the treatment of amphetamine addiction.
Clinical trials have suggested that modafinil may be effective for treatment of Attention Deficit Hyperactivity Disorder (ADHD). In November 2005, pharmaceutical company Cephalon received an approval letter from the US Food and Drug Administration (FDA) to market Sparlon (TM), a brand name of a tablet containing modafinil, for the treatment of ADHD in children and adolescents ages 6 through 17. Data from three clinical trials were submitted by the company to the FDA for evaluation as part of the approval process.
The exact mechanism of action is unclear, although in vitro studies have shown it to inhibit the reuptake of dopamine. While co-administration of a dopamine antagonist mitigates the stimulant effect of amphetamine, it does not negate the wakefulness-promoting actions of modafinil. Modafinil activates glutaminergic circuits while inhibiting GABA. Modafinil is thought to have less potential for abuse than other stimulants due to the absence of any significant euphoric or pleasurable effects.
The central stimulating effect of modafinil shows dose and time-related features. The effect tends to be enhanced by chlorination but reduced by methylation. Modafinil blocks the reuptake of noradrenaline by the noradrenergic terminals on sleep-promoting neurons from the ventrolateral preoptic nucleus (VLPO). Such a mechanism could be at least partially responsible for the wake-promoting effect of modafinil.
Modafinil has a binding affinity (Ki) of about 4,000 nmol/L for the dopamine reuptake transporter, and no significant binding to the noradrenaline reuptake transporter.
A newly proposed mechanism of action involves brain peptides called orexins, also known as hypocretins. Orexin neurons are found in the hypothalamus but project to many different parts of the brain, including several areas that regulate wakefulness. Activation of these neurons increases dopamine and norepinephrine in these areas. There are two receptors for hypocretins, namely hcrt1 and hcrt2. Animal studies have shown that animals with defective orexin systems show signs and symptoms similar to narcolepsy. Modafinil seems to activate these orexin neurons by greatly elevating c-fos expression, thus promoting wakefulness. However, a study of genetically modified dogs lacking orexin receptors showed that modafinil still promoted wakefulness in these animals, suggesting that orexin activation is not required for the effects of modafinil.
It is possible that modafinil acts by a synergistic combination of mechanisms including direct inhibition of dopamine reuptake, indirect inhibition of noradrenaline reuptake in the VLPO and orexin activation.
Modafinil originated with the late 1970s invention of a series of benzhydryl sulfinyl compounds, also including adrafinil, by scientists working with the French pharmaceutical company Lafon. Adrafinil was first offered as an experimental treatment for narcolepsy in France in 1986. Modafinil is the primary metabolite of adrafinil and has similar activity but is much more widely used. It has been prescribed in France since 1994 under the name Modiodal, and in the US since 1998 as Provigil. Modafinil was marketed in the US by Cephalon Inc., who leased the rights from Lafon. Cephalon eventually purchased Lafon in 2001. Cephalon has planned to market an enantiomerically pure form of modafinil (the more active armodafinil) under the name Nuvigil. In 2005, a petition by a private individual was filed with the FDA requesting over-the-counter sale of modafinil
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