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Systematic (IUPAC) name
(±)-2-[di(phenyl)methylsulfinyl]acetamide
Identifiers
CAS number 68693-11-8
ATC code N06BA07
PubChem 4236
DrugBank APRD00534
Chemical data
Formula C15H15NO2S 
Mol. mass 273.35
SMILES eMolecules & PubChem
Physical data
Melt. point 164–166 °C (327–331 °F)
Solubility in water 0.622 mg/mL (20 °C)
Pharmacokinetic data
Bioavailability Not determined due to the aqueous insolubility
Protein binding 60%
Metabolism Hepatic, including CYP3A4 and other pathways
Half life 12–15 hours
Excretion Urine (as metabolites)
Therapeutic considerations
Licence data

US FDA:link
Pregnancy cat. B3(AU) C(US)
Legal status Prescription Only (S4) (AU) ℞-only (CA) POM (UK) Schedule IV (US)
Routes Oral
 Yes check.svgY(what is this?)  (verify)

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][2] and excessive daytime sleepiness associated with obstructive sleep apnea.[3]

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,[4] 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).[5] 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.[6] 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"[7] and "does not possess an addictive potential in naive [new] individuals."[8]

Although there was some speculation modafinil could be effective in the treatment of attention-deficit hyperactivity disorder (ADHD) due to its similarity to amphetamine-class stimulants, in 2006 it was specifically found by the FDA to be unfit for use by children for that purpose. Cephalon's own label for Provigil now discourages its use by children for any purpose.[9] Other potentially effective, but similarly unapproved targets include the treatment of depression,[10] cocaine dependence,[11] Parkinson's disease,[12] schizophrenia,[13] and disease-related fatigue.[14][15]

Under the US Food and Drug Act, 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 because its promotional materials were found to be "false, lacking in fair balance, or otherwise misleading".[17] Cephalon plead guilty to a criminal violation and paid several fines, including $50 and $425 million fines to the U.S. government in 2008 due to its marketing[18].

Modafinil and its chemical precursor adrafinil were developed by Lafon Laboratories, a French company acquired by Cephalon in 2001.[19] 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).

Contents

Indications

In the United States, modafinil is approved by the U.S. Food and Drug Administration only 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). It generally begins to work within one to two days.

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.[20][21][22] 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.[20][21][22][23] Some of the positive effects of modafinil may be limited to "lower-performing"[23] individuals or to the individuals with lower IQ.[24]

There is also evidence that it has neuroprotective effects.[25]

Modafinil may be also an effective and well-tolerated treatment in patients with seasonal affective disorder/winter depression [26]

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, likely due to its amphetamine-mimicking properties. Modafinil was added to the World Anti-Doping Agency "Prohibited List" in 2004 as a prohibited stimulant (see Modafinil Legal Status).

Multiple sclerosis

Modafinil is not approved for, but 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.[27]

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.[28]

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.[29][30] 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. The high coincidence of day time sleepyness, sudden onset of day time sleep episodes (clinically indistinguishable from narcolepsy) in adult ADHD patients during inattentive-boring episodes of inactivity suggest a potential benefit of modafinil in ADHD patients suffering from episodic sleep disturbances.

Modafinil is relatively contraindicated for patients with a history of cardiac events. However, one 2005 case report[31] 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,[32][33], fibromyalgia, chronic fatigue syndrome, myotonic dystrophy,[34] opioid-induced sleepiness,[35] spastic cerebral palsy,[36] and Parkinson’s disease.[37] It increases subjective mood and friendliness, at least among shift workers.[38]

It has been used to help jet-lag[39].

During high-risk, large-scale, and extended law enforcement or homeland security operations, tactical paramedics in Maryland (US) may administer 200 mg of modafinil once daily to law enforcement personnel in order to "enhance alertness / concentration" and "facilitate functioning with limited rest periods."[40]

Experimental uses

Cocaine addiction

A single 8-week double-blind study of modafinil for cocaine dependence produced inconclusive results. The number of cocaine-positive urine samples was significantly lower in the modafinil group as compared to the placebo group in the middle of the trial, but by the end of the 8 weeks the difference stopped being significant. Even before the treatment began, the modafinil group had lower cocaine consumption further confounding the results. As compared to placebo, modafinil did not reduce cocaine craving or self-reported cocaine use, and the physicians ratings were only insignificantly better.[41] Dan Umanoff, of the National Association for the Advancement and Advocacy of Addicts, criticized the authors of the study for leaving the negative results out of the discussion part and the abstract of the article.[42][43]

Weight loss

Studies on modafinil (even those on healthy weight individuals) indicate that it has an appetite reducing/weight loss effect.[38][44][45][46][47] All studies on modafinil in the Medline database that are for one month or longer which report weight changes find that modafinil users experience weight loss compared to placebo.[48] However, the prescribing information for Provigil notes that "There were no clinically significant differences in body weight change in patients treated with PROVIGIL compared to placebo-treated patients in the placebo-controlled clinical trials." [49]

In experimental studies, the appetite reducing effect of modafinil appears to be similar to that of amphetamines, but, unlike amphetamines, the dose of modafinil that is effective at decreasing food intake does not significantly increase heart rate. Also, an article published in the Annals of Clinical Psychiatry, presented the case of a 280 pound patient (BMI=35.52) who lost 40 pounds over the course of a year on Modafinil (to 30.44 BMI). After three years, his weight stabilized at a 50 pound weight loss (29.59 BMI). The authors conclude that placebo controlled studies should be conducted on using Modafinil as a weight loss agent.[44] Conversely, a US patent (#6,455,588) on using modafinil as an appetite stimulating agent has been filed by Cephalon in 2000.

Primary biliary cirrhosis

Modafinil has been shown to improve excessive daytime somnolence and fatigue in primary biliary cirrhosis. After two months of treatment significant improvement was observed in symptoms of fatigue using the Epworth Sleepiness Scale.[50]

Post-chemotherapy cognitive impairment

Modafinil has been used off-label in trials with people with symptoms of Post-chemotherapy cognitive impairment, also known as "chemobrain".[51] A University of Rochester study of 68 subjects had significant results. "We knew from previous studies that modafinil does alleviate problems with memory and attention, and were hoping it would do the same for breast-cancer patients experiencing chemo-brain, which it did," related the study's lead author Sadhna Kohli, Ph.D, a research assistant professor at the University of Rochester's James P. Wilmot Cancer Center.[52]

Mood elevation

Modafinil used in a randomized double-blind study showed that normal healthy volunteers between the ages of 30-44 showed general improvement in alertness as well as mood. In the three-day study, counterbalanced, randomized, crossover, inpatient trial of modafinil 400 mg was administered as well as a placebo to the control group. The conclusion demonstrated that modafinil may have general mood-elevating effects in particular for the adjunctive use in treatment-resistant depression.[50]

Contraindications and warnings

Literature distributed by maker Cephalon advises that it is important to consult with your physician before using Modafinil, particularly for those with:

  • Hypersensitivity to the drug or other constituents of the tablets, or
  • Previous cardiovascular problems, particularly while using other stimulants, or
  • Cirrhosis, or
  • Cardiac conditions, particularly:

Side effects

In 2007, the FDA ordered Cephalon to modify the Provigil leaflet in bold-face print of several serious and potentially fatal conditions attributed to modafinil use, including TEN, DRESS syndrome, and Stevens-Johnson Syndrome (SJS).

The long term safety and effectiveness of modafinil has not been determined.[53]

Modafinil may have an adverse effect on hormonal contraceptives, lasting for a month after cessation of dosage.[54] Modafinil toxicity levels vary widely among species. In mice and rats, the median lethal dose LD50 of modafinil is approximately or slightly greater than 1250 mg/kg. Oral LD50 values reported for rats range from 1000 mg/kg to 3400 mg/kg. Intravenous LD50 for dogs is 300 mg/kg. In clinical trials on humans, taking up to 1200 mg/day for 7 to 21 days or one-time doses up to 4500 mg did not appear to cause life-threatening effects, although a number of adverse experiences were observed, including excitation or agitation, insomnia, anxiety, irritability, aggressiveness, confusion, nervousness, tremor, palpitations, sleep disturbances, nausea, and diarrhea. As of 2004, FDA is not aware of any fatal overdoses involving modafinil alone (as opposed to multiple drugs, including modafinil).[55] Consequently, oral LD50 of modafinil in humans is not known exactly. However, it appears to be higher than oral LD50 of caffeine. Basti and Jouvet (1988) describe a suicide attempt using 4500 mg of modafinil; the suicidee survived with no long-term effects but temporary nervousness, nausea, and insomnia[56]

Severe adverse reactions

Modafinil may induce severe dermatologic reactions requiring hospitalization. From the date of initial marketing, December 1998, to January 30, 2007, FDA received six cases of severe cutaneous adverse reactions associated with modafinil, including erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) involving adult and pediatric patients. The FDA issued a relevant alert. In the same alert, the FDA also noted that angioedema and multi-organ hypersensitivity reactions have also been reported in postmarketing experience. "Modafinil (marketed as Provigil): Serious Skin Reactions". FDA. Fall, 2007. http://www.fda.gov/cder/dsn/2007_fall/postmarketing.htm#modafinil. 

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.[63]

Pharmacology

The exact mechanism of action of Modafinil is unclear, although numerous in vitro studies have shown it to increase the levels of various monoamines, namely; dopamine in the striatum and nucleus accumbens,[64][65] noradrenaline in the hypothalamus and ventrolateral preoptic nucleus,[66][67] and serotonin in the amygdala and frontal cortex.[68] While the co-administration of a dopamine antagonist is known to decrease the stimulant effect of amphetamine, it does not entirely negate the wakefulness-promoting actions of modafinil. Modafinil activates glutamatergic circuits while inhibiting GABAergic neurotransmission.

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, and excites histaminergic tuberomammillary neurons increasing histamine levels there. It has been shown in rats that modafinil increases histamine release in the brain, and this may be a possible mechanism of action in humans.[69] 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 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.

Since modafinil's substantial, but incomplete, independence from both monoaminergic systems and those of the orexin peptides has proven baffling with respect to the better understood mechanisms of stimulants such as cocaine, enhanced electrotonic coupling has been suggested by several studies. While chemical synapses present an obvious target for drug treatments, neurons are also be coupled electrotonically via gap junctions. In support of this theory, Urbano et al. determined that modafinil increased activity in the thalamocortical loop (critical in organizing sensory input and modulating global brain activity) via enhancements in electrotonic coupling.[70] Administration of the gap junction blocker mefloquine abolished this effect, verifying the suspicion that the effect was consequent of improved electrical coupling. Further research by the same group also noted the capacity of the calmodulin kinase II (CaMKII) inhibitor, KN-93, to abolish modafinil's enhancement of electrotonic coupling. They came to the conclusion that modafinil's effect is mediated, at least in part, by a CaMKII-dependent exocytosis of gap junctions between GABAergic interneurons and possibly even glutamatergic pyramidal cells. Additionally, Garcia-Rill et al. discovered that modafinil has pro electrotonic effects on specific populations of neurons in two sites in the reticular activating system. These sites, the subcoeruleus nucleus and the pedunculopontine nucleus, are thought to enhance arousal via cholinergic inputs to the thalamus.[71]

Looking more closely at electrotonic coupling, gap junctions permit the diffusion of current across linked cells and result in higher resistance to action potential induction since excitatory post-synaptic potentials must to diffuse across a greater membrane area. This means, however, that when action potentials do arise in coupled cell populations, the entire populations tend to fire in a synchronized manner.[72] Thus enhanced electrotonic coupling results in lower tonic activity of the coupled cells while increasing rhythmicity. Agreeing with data implicating catecholaminergic mechanisms, modafinil increases phasic activity in the locus coeruleus (the source for CNS norepinephrine) while reducing tonic activity with respect to interconnections with the prefrontal cortex.[73] This implies an increased signal-to-noise ratio in the circuits connecting the two regions. Greater neuronal coupling theoretically could enhance gamma band rhythmicity, a potential explanation for modafinil's nootropic effects.[74] Modafinil's beneficial effects on working memory and motor networks are suggestive of heightened gamma band activity.[74]

Direct links between electrotonic coupling and wakefulness were provided by Beck et al. who showed that administration of modafinil enhanced arousal-specific P13 evoked potentials in a gap-junction dependent manner.[75] Tying into inconclusive effects on monoamine systems, enhanced electrotonic coupling is thought to reduce activity in localized populations of GABAergic neurons whose normal function is to reduce neurotransmitter release in other cells.[72] For example, dopamine release in the nucleus accumbens has been demonstrated to be the result of to decreased GABAergic tone.[76] Thus, while modafinil's unique stimulant profile features interactions with monoamine systems, these may very well be downstream events secondary to effects on specific, electrotonically-coupled populations of GABAergic interneurons. It is likely that modafinil's exact pharmacology will feature the interaction of direct effects on electrotonic coupling and various receptor-mediated events.

Pharmacokinetics

Modafinil induces the cytochrome P450 enzymes CYP1A2, CYP2B6 and CYP3A4, as well as inhibiting CYP2C9 and CYP2C19 in vitro. It may also induce P-glycoprotein, which may affect drugs transported by Pgp, such as digoxin. The bioavailability of Modafinil is greater than 80% of the administered dose. In vitro measurements indicate that 60% of Modafinil is bound to plasma proteins at clinical concentrations of the drug. This percentage actually changes very little when the concentration is varied.[77] Cmax occurs approximately 2–3 hours after administration. Food will slow absorption, but does not affect the total AUC. Half-life is generally in the 10–12 hour range, subject to differences in CYP genotypes, liver function and renal function. It is metabolized in the liver, and its inactive metabolite is excreted in the urine. Urinary excretion of the unchanged drug ranges from 0% to as high as 18.7%, depending on various factors.[77]

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.[78]

Patent protection and antitrust litigation

A U.S. Patent 4,927,855 was granted to Lafon for modafinil in 1990. The FDA granted modafinil orphan drug status in 1993. The formulation patent expired on 30 March 2006. The particle size patent was filed by Cephalon U.S. Patent 5,618,845, covering pharmaceutical compositions of modafinil, in 1994. That patent, granted in 1997, was reissued in 2002 as RE 37,516, which provides Cephalon with patent protection for certain preparations of the drug in the United States until 2014, which is now apparently extended to April 6, 2015 after Cephalon received a six-month patent extension from the FDA.[79][80]

Some competing generic pharmaceutical manufacturers applied to the FDA to market a generic form of modafinil in 2006 (the year of patent expiry of the active ingredient). At least one withdrew its application after early opposition by Cephalon based on its new patent on particle sizes (set to expire in 2015). There is some question as to whether a particle size patent is sufficient protection against the manufacture of generics. Pertinent questions include whether modafinil may be modified or manufactured to avoid the granularities specified in the new Cephalon patent, and whether patenting particle size is invalid because particles of appropriate sizes are likely to be obvious to practitioners skilled in the art. However, under United States patent law, a patent is entitled to a legal presumption of validity, meaning that in order to invalidate the patent, much more than "pertinent questions" are required. To date, no generic manufacturer has been able to invalidate Cephalon's particle size patent, and, indeed, those that attempted to do so were not successful such that the patent remains in force.

Cephalon made an agreement with four major generics manufacturers Teva, Barr Pharmaceuticals, Ranbaxy Laboratories, Mylan Inc, and Carlsbad Technologies/Watson Pharmaceuticals between 2005-2006 to delay sales of generic modafinil in the US until April 2012 by these companies in exchange for upfront and royalty payments.[81] Litigation arising from these agreements is still pending including an FTC suit filed in April 2008.[82] Apotex received regulatory approval in Canada despite a suit from Cephalon's marketing partner in Canada, Shire Pharmaceuticals.[83] [84]

Legal status

Modafinil is currently classified as a Schedule IV controlled substance under United States federal law; it is illegal to import by anyone other than a DEA-registered importer without a prescription.[85] However, one may legally bring up to 50 dosage units (i.e. pills) of Modafinil to the United States in person from a foreign country, provided that he or she has a prescription for it, and the drug is properly declared at the border crossing.[86] Note that Adrafinil, a drug that is closely related to Modafinil, is currently not classified as a controlled substance, and therefore it is not as severely regulated.

The following countries do not classify Modafinil as a controlled substance:

Currently, use of modafinil is controversial in the sporting world, with high profile cases attracting press coverage since several prominent American athletes have tested positive for the substance (see Modafinil as a doping agent). Some athletes who were found to have used modafinil protested that the drug was not on the prohibited list at the time of their offenses. However, the World Anti-Doping Agency (WADA) maintains that it was related to already banned substances. The Agency added modafinil to its list of prohibited substances on August 3, 2004, ten days before the start of the 2004 Summer Olympics.

See also

References

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