Provigil / Modafinil (Provigil/Alertec/Modavigil/Modalert, in India) is an analeptic drug manufactured by Cephalon, and is approved by the U.S. Food and Drug Administration (FDA) for the treatment of narcolepsy, shift work sleep disorder,[1] and excessive daytime sleepiness associated with obstructive sleep apnea.[2]

Modafinil, like other stimulants, increases the release of monoamines, specifically the catecholamines norepinephrine and dopamine, from the synaptic terminals. However, modafinil also elevates hypothalamic histamine levels,[3] leading some researchers to consider Modafinil a "wakefulness promoting agent" rather than a classic amphetamine-like stimulant (as evidenced by the difference in c-Fos distribution caused by modafinil as compared to amphetamine).[4] Despite modafinil's histaminergic action, it still partially shares the actions of amphetamine-class stimulants due to its effects on norepinephrine and dopamine.

An NIAAA study highlighted "the need for heightened awareness for potential abuse of and dependence on modafinil in vulnerable populations" due to the drug's effect on dopamine in the brain's reward center.[5] The synergistic actions of modafinil on both catecholaminergic and histaminergic pathways lowers abuse potential as compared to traditional stimulant drugs while maintaining the effectiveness of the drug as a wakefulness promoting agent. Studies have suggested that modafinil "has limited potential for large-scale abuse"[6] and "does not possess an addictive potential in naive [new] individuals."[7]

Although modafinil is thought to be effective in the treatment of attention-deficit hyperactivity disorder (ADHD), in 2006 it was specifically rejected by the FDA for use by children for that purpose after Cephalon was rebuffed in its effort to introduce modafinil as a children's drug under the trade name, Sparlon. Cephalon's own label for Provigil now discourages its use by children for any purpose.[8]

Modafinil shows potential effectiveness in the treatment of depression,[9] cocaine dependence,[10] Parkinson's disease,[11] schizophrenia,[12] shift worker's sleep disorder, [13] and disease-related fatigue.[14][15] By law drug companies are not allowed to market their drugs for off-label uses (conditions other than those officially approved by the FDA)[16]; Cephalon was reprimanded in 2002 by the FDA, and paid a $425 million fine in 2008 due to its marketing[17].

Modafinil and its chemical precursor adrafinil were developed by Lafon Laboratories, a French company acquired by Cephalon in 2001.[18] Modafinil is the primary metabolite of adrafinil, and, while its activity is similar, adrafinil requires a higher dose to achieve equipotent effects. Modafinil is a racemic mixture; the (R)-enantiomer is known as armodafinil (Nuvigil)

Indications

In the United States, modafinil is approved by the U.S. Food and Drug Administration for the treatment of narcolepsy, obstructive sleep apnea/hypopnea and shift work sleep disorder. In some countries, it is also approved for idiopathic hypersomnia (all forms of excessive daytime sleepiness where causes can't be established).

Off-label use

Modafinil is widely used off-label to suppress the need for sleep. It is also used off-label in combating general fatigue unrelated to lack of sleep such as in treating ADHD and as an adjunct to antidepressants (particularly in individuals with significant residual fatigue).

There is a disagreement whether the cognitive effects modafinil showed in healthy non-sleep-deprived people are sufficient to consider it to be a cognitive enhancer.[19][20][21] The researchers agree that modafinil improves some aspects of working memory, such as digit span, digit manipulation and pattern recognition memory, but the results related to spatial memory, executive function and attention are equivocal.[19][20][21][22] Some of the positive effects of modafinil may be limited to "lower-performing"[22] individuals or to the individuals with lower IQ.[23]

There is also evidence that it has neuroprotective effects.[24]

Modafinil may be also an effective and well-tolerated treatment in patients with seasonal affective disorder/winter depression [25]

Doping agent

Modafinil has received some publicity in the past when several athletes were discovered allegedly using it as a performance-enhancing doping agent. It is not clear how widespread this practice is. Since there are no studies pertaining to this sort of use, it is unknown what impact modafinil has on an athlete's performance. However, anecdotal evidence indicates that modafinil does indeed enhance physical performance. Modafinil was added to the World Anti-Doping Agency "Prohibited List" in 2004 as a prohibited stimulant (see #Legal status).

Multiple sclerosis

Modafinil has been used to allay symptoms of the neurological fatigue reported by some with multiple sclerosis. Patients follow either the standard usage or take a single dose of 200–400 mg at the start of days self-assessed as being potentially excessively fatiguing. In 2000, Cephalon conducted a study to evaluate modafinil as a potential treatment for MS-related fatigue. A group of 72 people with MS of varying degrees of severity tested two different doses of modafinil and an inactive placebo over nine weeks. Fatigue levels were self-evaluated on standardized scales. Participants taking a lower dose of modafinil reported feeling less fatigued and there was a statistically significant difference in fatigue scores for the lower dose versus the placebo. The higher dose of modafinil was not reported to be significantly more effective.[26]

ADHD

As of February 2007, there are at least seven English-language articles on randomized clinical trials in humans in the Medline database addressing the use of modafinil for the treatment of attention deficit/hyperactivity disorder (ADHD)[citation needed]. Some studies have shown the use of modafinil in the treatment of ADHD is associated with significant improvements in primary outcome measures.[citation needed] Cognitive function in ADHD patients was also found to improve following modafinil treatment, in some studies.[citation needed] Studies for ADHD report insomnia and headache were the most common adverse effects, seen in approximately 20% of treated individuals.[citation needed] These studies were not adequate to demonstrate that the beneficial effects of modafinil are maintained with chronic administration. Additional large, long-term studies using flexible titration methods to establish safety and efficacy and head-to-head comparisons between modafinil and stimulants are needed to determine the role of modafinil in the treatment of ADHD.[27]

In December 2004, Cephalon submitted a supplemental new drug application (sNDA) to market Sparlon, a brand name of tablets containing higher doses of modafinil for the treatment of ADHD in children and adolescents ages 6 through 17. However, in March 2006, the FDA advisory committee voted 12 to 1 against approval, citing concerns about a number of reported cases of skin rash reactions in a 1000-patient trial, including one which was thought to be likely a case of Stevens-Johnson syndrome.[28][29] Final rejection occurred in August 2006, although subsequent follow-up indicated that the skin rash reaction was not Stevens-Johnson syndrome.[citation needed] Cephalon then decided to discontinue development of the Sparlon product for use in pediatric cases, though there is potential for use in treating Adult ADHD.

Modafinil is relatively contraindicated for patients with a history of cardiac events. However, one 2005 case report[30] positively describes transitioning a 78 year old with "significant cardiac comorbidity" from methylphenidate (5 mg b.i.d.) to modafinil; however, this was in the context of severe treatment resistant depression, not ADHD.

Other uses

Modafinil is also used off-label to treat sedation and fatigue in depression,[31][32], fibromyalgia, chronic fatigue syndrome, myotonic dystrophy,[33] opioid-induced sleepiness,[34] spastic cerebral palsy,[35] and Parkinson’s disease.[36] It increases subjective mood and friendliness, at least among shift workers.[37]

It has been used to help jet-lag[38].

Military and astronaut use

Militaries of several countries are known to have expressed interest in Modafinil as an alternative for amphetamine—the drug traditionally employed in combat situations where troops face sleep deprivation, such as during lengthy missions. The French government indicated that the Foreign Legion used modafinil during certain covert operations. The United Kingdom's Ministry of Defence commissioned research into Modafinil[57] from QinetiQ and spent £300,000 on one investigation.[58]

In the United States military, Modafinil has been approved for use on certain Air Force missions, and it is being investigated for other uses.[59] One study of helicopter pilots suggested that 600 mg of modafinil given in three doses can be used to keep pilots alert and maintain their accuracy at pre-deprivation levels for 40 hours without sleep.[60] However, significant levels of nausea and vertigo were observed. Another study of fighter pilots showed that modafinil given in three divided 100 mg doses sustained the flight control accuracy of sleep-deprived F-117 pilots to within about 27 percent of baseline levels for 37 hours, without any considerable side effects.[61] In an 88-hour sleep loss study of simulated military grounds operations, 400 mg/day doses were mildly helpful at maintaining alertness and performance of subjects compared to placebo, but the researchers concluded that this dose was not high enough to compensate for most of the effects of complete sleep loss.[62]

The Canadian Medical Association Journal also reports that Modafinil is used by astronauts on long-term missions aboard the International Space Station. Modafinil is "available to crew to optimize performance while fatigued" and helps with the disruptions in circadian rhythms and with the reduced quality of sleep astronauts experience.

History

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. It was approved for use in the UK in December 2002. Modafinil is marketed in the US by Cephalon Inc., who leased the rights from Lafon. Cephalon eventually purchased Lafon in 2001. In 2005, a petition by a private individual was filed with the FDA requesting over-the-counter sale of modafinil.[79]

Source: Wikipedia