Modafinil

From Wikipedia, the free encyclopedia

Modafinil chemical structure
Modafinil
Systematic (IUPAC) name
2-benzhydrylsulfinylethanamide
Identifiers
CAS number 68693-11-8
ATC code N06BA07
PubChem 4236
DrugBank APRD00534
Chemical data
Formula C15H15NO2S
Mol. weight 273.351 g/mol
Pharmacokinetic data
Bioavailability  ?
Protein binding 60%
Metabolism Hepatic, including CYP3A4 and other pathways
Half life 8-18 hours
Excretion Urine (as metabolites)
Therapeutic considerations
Pregnancy cat.

C
Legal status

Schedule IV (USA)
Routes Oral

Modafinil (commercial trade names Provigil (US, UK, Italy), Vigil (Germany), Modalert (India), Modiodal (France, Mexico, Turkey), Modavigil (Australia), Alertec (Canada), and possibly Vigicer) 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.' Cephalon has also developed and tested Nuvigil, a non-racemic version of modafinil with a longer duration of action.

Contents

[edit] 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.

[edit] 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.

[edit] ADHD (off label indication)

As of October 2006, there are approximately four 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. [1]

[edit] 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.

[edit] 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:

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. [2]

[edit] 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 that a single reported case of a skin rash reaction in a 1,000 patient trial could be Stevens-Johnson syndrome[3]. Final rejection occurred in August of 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.

[edit] Military use

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,[4] while it has also reportedly been investigated by the United States military for use by soldiers to replace the current amphetamine derivatives. One study on helicopter pilots suggested that 600 mg of modafinil given in three doses can be used to keep pilots alert with only 8 hours of sleep in an 88 hour period. 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. It's unclear what the long-term effects on the brain would be from this sort of sleep deprivation.

[edit] 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.[5]

[edit] 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.

[edit] 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.[6]

[edit] Formulation patent

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.

[edit] Particle size patent

Cephalon filed for 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.[7] However, a settlement in which Cephalon apparently paid out US$ 200 million to four generic drug manufacturers[8] 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.

[edit] 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 Schedule IV controlled substance under United States federal law.

It is not a controlled substance under the Misuse of Drugs Act in the United Kingdom and is available on prescription without legal restrictions.

[edit] See also

[edit] References

  1. ^ Use of modafinil for the treatment of attention deficit/hyperactivity disorder. The Annals of Pharmacotherapy October 2006, retrieved December 7,2006.
  2. ^ NIH MedicinePlus Drug Information
  3. ^ Briefing document (2006) (PDF format)
  4. ^ BBC report on MoD research into Modafinil
  5. ^ Ishizuka T, Sakamoto Y, Sakurai T, Yamatodani A (2003). "Modafinil increases histamine release in the anterior hypothalamus of rats.". Neurosci Lett 339 (2): 143-6. PMID 12614915.
  6. ^ FDA
  7. ^ "bizjournals.com"
  8. ^ E. Pringle (2006)

[edit] External links


Stimulants - edit

Adrafinil, Armodafinil, Caffeine, Modafinil, Nicotine

Sympathomimetic amines (R01, A08, and others) edit

Aminorex, Amphetamine, Benzylpiperazine, Cathinone, CFT, Chlorphentermine, Clobenzorex, Cocaine, Cyclopentamine, Diethylpropion, Ephedrine, Fenfluramine, Mazindol, 4-Methyl-aminorex, Methylone, Methylphenidate, Pemoline, Phendimetrazine, Phenmetrazine, Phentermine, Phenylephrine, Propylhexedrine, Pseudoephedrine, Sibutramine, Synephrine
See also amphetamines
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