Modafinil

Modafinil is a eugeroic drug generally prescribed to treat narcolepsy, made by the pharmaceutical company Cephalon Inc. It is not a typical stimulant and is often described as a "wakefulness promoting agent." The drug is sometimes prescribed off-label for ADD/ADHD. In mass-media advertisements and websites, Cephalon markets the drug for improving 'alertness' and reducing 'excessive daytime sleepiness.'

Commercial Trade Names

 * Provigil (US, UK, Italy)
 * Vigil (Germany)
 * Modalert, Provake (India)
 * Modiodal (France, Mexico, Turkey, Greece, Sweden)
 * Modavigil (Australia)
 * Alertec (Canada), and possibly Vigicer
 * Resoty, Mentix (Chile)

Indications
The patient insert for Modafinil states that it is meant for the treatment of narcolepsy, obstructive sleep apnea/hypopnea and shift work sleep disorder. In some countries, it is also approved for idiopathic hypersomnia (excessive daytime sleepiness).

A single dose of 200 mg taken shortly after waking is the usual initial dosage, which may be increased up to 400 mg per day if necessary. Some patients will need to divide their total dose over two or more smaller doses in order to maintain effectiveness throughout the day and/or to reduce the incidence of side-effects. In patients with cirrhosis of the liver or severely compromised renal function, these figures should be halved.

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

In suppressing the need for sleep, it is generally administered up to three times daily in doses of 100-200 mg. Users without prior experience with stimulants generally respond well to lower doses.

Cephalon hopes to soon release the longer-lasting Nuvigil (R-modafinil)  as a "truly once-a-day" wakefulness medication. In 2006, the FDA sent Cephalon an "approvable letter" for Nuvigil, pending agreement on the final product labeling.

Yet another off-label use for modafinil is as a nootropic, or a "smart drug." As a nootropic, it is taken by healthy non-sleep-deprived users in doses of 100-200 mg once a day. It is believed to have cognitive enhancing and neuroprotective effects.

Modafinil has received some publicity in the past when several athletes were discovered allegedly using it as a 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 whether modafinil can have any positive impact on an athlete's performance.

Modafinil is sometimes used to treat intense "neurological fatigue" experienced by the vast majority of multiple sclerosis sufferers. In some cases, patients are recommended to follow the standard usage pattern for the drug. In other cases, patients are instructed to take 100 to 200 mg early in the morning on days when they feel they will be extremely fatigued. In 2000, the manufacturer, Cephalon, conducted a study of modafinil in people with MS to evaluate it as a potential treatment for MS-related fatigue. Seventy-two people with different forms of MS took two different doses of modafinil and inactive placebo over nine weeks, and self-evaluated their fatigue levels using standard fatigue and sleepiness scales. Participants reported feeling least fatigued while taking a lower dose of modafinil, and there was a statistically significant difference in fatigue scores for the lower dose versus placebo. The higher dose of modafinil was not reported to be effective.

ADHD (off label indication)
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). Some studies have shown the use of modafinil in the treatment of ADHD is associated with significant improvements in primary outcome measures. Cognitive function in ADHD patients may also improve following modafinil treatment, in some studies. Studies for ADHD report insomnia and headache were the most common adverse effects, seen in approximately 20% of treated individuals. 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.

Contraindications and warnings
Modafinil should not be used by
 * patients with hypersensitivity to the drug or other constituents of the tablets, or
 * patients that have previously experienced cardiovascular problems while using other stimulants, or
 * patients with left ventricular hypertrophy, or
 * patients that have previously experienced mitral valve prolapse.

It should be used with extreme caution in patients that are currently using monoamine oxidase inhibitors such as Parnate (tranylcypromine), Nardil (phenelzine), Emsam (deprenyl), or Marplan (isocarboxazid), as well as patients that have used such drugs in the past 2 weeks. Such combinations have not been tested, and these drugs are expected to significantly potentiate the drug response (factor of 4 or more), creating the potential for hazardous and potentially fatal side-effects.

Patients with severe anxiety should be carefully supervised, as modafinil may exacerbate their condition. It may be necessary to coadminister an anxiolytic. High blood pressure should be stabilized before initiating treatment with modafinil or any other stimulant.

The patient should inform the prescribing physician of any other drugs they are currently taking, as modafinil may interact with a great number of drugs.

Modafinil should not be used while pregnant or breastfeeding, and may reduce the effectiveness of contraceptives.


 * Alcohol and similar depressants should be avoided if at all possible while taking Modafinil.

Side-effects
The most common side-effects observed with modafinil, as compared to placebo, when prescribed in the recommended doses for the approved indications, are as follows:


 * Common
 * Headache (34% vs 23%)
 * Nausea (11% vs 3%)
 * Uncommon
 * Nervousness (7% vs 3%)
 * Insomnia (5% vs 1%)
 * Anxiety (5% vs 1%)
 * Anorexia (4% vs 1%)
 * Dry mouth (4% vs 2%)
 * Rare
 * Chest pain (3% vs 1%)
 * Hypertension (3% vs 1%)
 * Tachycardia (2% vs 1%)
 * Vasodilation (2% vs 0%)
 * Dizziness (5% vs 4%)
 * Paresthesia (2% vs 0%)
 * Somnolence (2% vs 1%)
 * Pharyngitis (4% vs 2%)

Additionally, gastrointestinal distress, which may be alleviated by taking the drug after a meal, aggressiveness and skin irritation have been reported, but are rare.

Most side-effects subside after a few weeks without reducing the dose. Only headaches and anxiety have been shown to be proportional to dose, and these may benefit from a temporary reduction.

A single case of premature ventricular contractions appeared causally linked to administration of modafinil (Oskooilar 2005).

Modafinil may have an adverse effect on hormonal contraceptives, lasting for a month after cessation of dosage.

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). Consequently, oral LD50 of modafinil in humans is not known exactly. However, it appears to be higher than oral LD50 of caffeine.

Research
In January 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). 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 1,000 patient trial, including one which was thought to be likely a Stevens-Johnson syndrome. Final rejection occurred in August 2006, although subsequent follow-up indicated that the skin rash reaction was not Stevens-Johnson syndrome. 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.

A few studies have indicated that modafinil may have an appetite reducing effect on some people, leading to weight loss. During 9-week double-blind clinical trials of 320 mg/day and 425 mg/day doses of modafinil in children suffering from ADHD, patients receiving modafinil lost an average of 1.7 kg compared to those receiving placebo. This appetite reducing effect appears to be similar to that of amphetamines, but, unlike amphetamine, the dose of modafinil that is efficacious in decreasing food intake does not significantly increase heart rate. Conversely, a U.S. patent (#6,455,588) on using modafinil as an appetite stimulating agent has been filed by Cephalon in 2000.

Military use
Militaries of several countries are known to have expressed interest in Modafinil as an alternative for amphetamine - the medicine traditionally employed in sleep-deprivation situations. The consensus seems to be that Modafinil is generally well received, but it is not quite as efficient as amphetamines.

The French government indicated that the Foreign Legion used modafinil during certain covert operations. The UK's Ministry of Defence has admitted conducting ongoing research into Modafinil. In the United States military, Modafinil has been approved for use on certain Air Force missions, and it is being investigated for other uses. One study on 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. However, significant levels of nausea and vertigo were observed. Another study of fighter pilots showed that 300 mg 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. 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, and it was concluded that the dosing regimen was too low to obviate the majority of performance decrements brought about from complete sleep loss.

It's unclear what the long-term effects on the brain would be from this sort of sleep deprivation.

Pharmacology
The exact mechanism of action is unclear, although in vitro studies have shown it to inhibit the reuptake of dopamine and, more potently, norepinephrine. While the co-administration of a dopamine antagonist is known to decrease the stimulant effect of amphetamine, it does not negate the wakefulness-promoting actions of modafinil. Modafinil activates glutamatergic circuits while inhibiting GABAergic neurotransmission. 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 norepinephrine 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 coefficient (Ki) of about 4,000 nmol/L for the dopamine reuptake transporter, and in excess of 10,000 nmol/L for the norepinephrine 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 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 and norepinephrine reuptake, as well as orexin activation.

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.

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.

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.

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.

Formulation patent
A 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.

Particle size patent
Cephalon filed for, 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. However, a settlement in which Cephalon apparently paid out US$ 200 million to four generic drug manufacturers may mean that generic forms of the drug will become available in April 2012 (October 2011 prior to the six month extension).

Some competing pharmaceutical manufacturers have applied to the FDA to market a generic form of modafinil in 2006. At least one withdrew their application after early opposition by Cephalon based on their new patent on particle sizes. 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.

Price
Brand-name Provigil is very expensive. Currently it retails in the United States for $7-8 per one 200 mg pill. Modiodal and Alertec are somewhat cheaper. Modalert, the version of Modafinil produced by an Indian company Sun Pharma, is the most affordable and can be found as cheaply as $1-2 per one 200 mg pill; however, it is sometimes claimed not to be as effective as Provigil. As of January 2007, no generic versions of Provigil exist yet; prices can be expected to go down considerably if Cephalon's monopoly in the U.S. market is successfully challenged.

Not all U.S. health insurance companies cover Modafinil/Provigil, and those that do may require proof of severity of one's condition before paying for the drug. As a result, many Americans in need of this medication turn towards online pharmacies or try to bring Modafinil from neighboring countries (Canada and Mexico). One is advised to examine the following section before attempting to buy Modafinil.

Legal status
Currently, use of modafinil is controversial in the sporting world, with high profile cases attracting press coverage as prominent United States athletes have tested positive for the substance. Some athletes who were found to have used modafinil protested that the drug was not on the prohibited list at the time of their offence. However, the World Anti-Doping Agency (WADA) maintains it is related to already banned substances, so the decisions stand. The agency added modafinil to the list of prohibited substances on August 3, 2004, ten days before the start of the 2004 Summer Olympics.

Modafinil is currently classified as a non-narcotic Schedule IV controlled substance under United States federal law; it is illegal to import by anyone other than a DEA-registered importer ( and, therefore, to buy from most online pharmacies ), with or without a prescription. It is also illegal to possess without a valid prescription. However, one may legally buy Modafinil in United States or bring up to 50 dosage units (i.e. pills) 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.

The following countries do not classify Modafinil as a controlled substance:
 * Canada (not listed in the Controlled Drugs and Substances Act)
 * Mexico
 * United Kingdom (not listed in the Misuse of Drugs Act and is available by prescription without legal restrictions)