modafinil

モダフィニル

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/07/17 14:23:36」(JST)

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Modafinil

Clinical data
Trade names	Alertec, Modavigil, Modiodal, Provigil, Modalert
AHFS/Drugs.com	monograph
MedlinePlus	a602016
Licence data	US Daily Med:link
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Legal status	AU: Prescription Only (S4) CA: Schedule F UK: Prescription-only (POM) US: Schedule IV
Dependence liability	Very low
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	Not determined due to the aqueous insolubility
Protein binding	62%
Metabolism	Hepatic (primarily via amide hydrolysis; CYP1A2, CYP3A4, and CYP2B6)
Biological half-life	15 hours (R-enantiomer), 4 hours (S-enantiomer)
Excretion	Urine (80%)
Identifiers
CAS Registry Number	68693-11-8 Y
ATC code	N06BA07
PubChem	CID: 4236
IUPHAR/BPS	7555
DrugBank	DB00745 Y
ChemSpider	4088 Y
UNII	R3UK8X3U3D Y
KEGG	D01832 Y
ChEBI	CHEBI:31859 N
ChEMBL	CHEMBL1373 Y
Chemical data
Formula	C15H15NO2S
Molecular mass	273.35 g/mol
SMILES O=S(C(c1ccccc1)c2ccccc2)CC(=O)N
InChI InChI=1S/C15H15NO2S/c16-14(17)11-19(18)15(12-7-3-1-4-8-12)13-9-5-2-6-10-13/h1-10,15H,11H2,(H2,16,17) Y Key:YFGHCGITMMYXAQ-UHFFFAOYSA-N Y
N (what is this?)  (verify)

Modafinil is a wakefulness-promoting agent (or eugeroic) that is approved by the United States' Food and Drug Administration (FDA) for treatment of wakefulness disorders such as narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea. In English-speaking countries it is sold under the brand names: Alertec (CA), Modavigil (AU, NZ), and Provigil (IE, ZA, UK, US).

Uses

Medical

In 1998, modafinil was approved by the U.S. Food and Drug Administration for the treatment of narcolepsy and in 2003 for shift work sleep disorder and obstructive sleep apnea/hypopnea even though caffeine and amphetamine were shown to be more wakefulness promoting on the Stanford Sleepiness Test Score than modafinil. EEG studies indicate caffeine, amphetamine, and modafinil to all be theta wave reducing but only modafinil to be Alpha wave promoting during wakefulness as well as theta wave increasing during sleep.

For conditions other than shift work sleep disorder, modafinil is normally taken in one dose in the morning or in two doses: in the morning, and at midday. It is generally not recommended to take modafinil after noon: modafinil is a relatively long-acting drug with a half-life of 15 hours, and taking it during the later part of the day can make it harder to fall asleep at bedtime.

Because of the risk for development of skin or hypersensitivity reactions and neuropsychiatric disorders, the European Medicines Agency has recommended that new patient prescriptions should only be to treat sleepiness associated with narcolepsy. Because any serious side effects will usually appear within the first twelve weeks, the guidance does not require patients already receiving treatment to stop taking the drug.

ADHD

Modafinil was shown to be an effective treatment for ADHD with a more favorable overall side effect profile to approved treatments, but it did not receive FDA approval due to concerns over the unusually high rate of 2 non-fatal cases of Stevens–Johnson syndrome out of 933 children. U.S. Food and Drug Administration approval for attention deficit hyperactivity disorder (ADHD) in children was rejected in 2006. Cephalon's label for Provigil discourages its use by children for any purpose. In some countries, the drug is approved for other hypersomnias, such as idiopathic hypersomnia. The usual prescribed dosage for these disorders is 200 mg once a day (less commonly, 100 to 400 mg/day in one or two doses). Modafinil has also been linked in many articles to increasing concentration.

Off-label use for fatigue

Modafinil has also found off-label use with the neurological fatigue reported by some with multiple sclerosis. 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.

Modafinil is also used off-label to treat sedation and fatigue in many conditions, including depression, fibromyalgia, chronic fatigue syndrome, myotonic dystrophy, opioid-induced sleepiness, spastic cerebral palsy, and Parkinson's disease. Modafinil has been shown to improve excessive daytime somnolence and fatigue in primary biliary cirrhosis.

Military and astronauts

Militaries of several countries are known to have expressed interest in modafinil as an alternative to 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 from QinetiQ and spent £300,000 on one investigation. In 2011, the Indian Air Force announced that modafinil was included in contingency plans. The Indian Armed Forces Medical Services is researching its use.

In the United States military, modafinil has been approved for use on certain Air Force missions, and it is being investigated for other uses. As of November 2012, modafinil is the only drug approved by the Air Force as a "go pill" for fatigue management. The use of dextroamphetamine (a.k.a., Dexedrine) is no longer approved. 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; however, significant levels of nausea and vertigo were observed. A second helicopter study found modafinil was comparable to dextroamphetamine and was well-tolerated. 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. 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.

In law enforcement, tactical paramedics in Maryland (US) may administer 200 mg of modafinil once daily in order to "enhance alertness / concentration" and "facilitate functioning with limited rest periods."

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.

Contraindications

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

• Hypersensitivity to the drug or other constituents of the tablets (such as lactose or lactose monohydrate), or
• Previous cardiovascular problems, particularly while using other stimulants, or
• Cirrhosis, or
• Cardiac conditions, particularly:
  • Left ventricular hypertrophy, or
  • Mitral valve prolapse.
    • Asymptomatic MVP is not uncommon, but neither is it prominently discussed in modafinil's context.

Side effects

Although a nootropic, Modafinil is less likely than its parent drug, adrafinil, to cause side effects such as stomach pain, skin irritation, anxiety, and (with prolonged use) elevated liver enzymes. The patient should be aware that placebo-controlled clinical trials cannot be used to predict the frequency of adverse experiences in the course of usual medical practice, where patient characteristics and other factors may differ from those occurring during clinical studies. Reported effects from patient control groups during clinical trials include:

• Headache (~34%)
• Nausea (~11%)
• Nervousness (~7%)
• Diarrhea (~6%)
• Insomnia (~5%)
• Anxiety (~5%)
• Dizziness (~5%)
• Dyspepsia (~5%)
• Dry Mouth (~4%)
• Anorexia (~4%)
• Flu Syndrome (~4%)
• Chest Pain (~3%)
• Depression (~2%)
• Chills (~1%)
• Neck Rigidity (~1%)

Serious side effects include:

• Serious rash
• Serious allergic reaction involving the liver or blood cells
• Hives
• Mouth sores
• Blistering or peeling skin
• Swelling of the face, eyes, lips, tongue, legs, or throat
• Trouble swallowing or breathing
• Fever
• Shortness of breath

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 toxic epidermal necrolysis (TEN), DRESS syndrome, and Stevens-Johnson syndrome (SJS).

The long term safety and effectiveness of modafinil have not been determined.

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

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), SJS, TEN, and 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.

Addictive potential

A National Institute on Alcohol Abuse and Alcoholism (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. However, the synergistic actions of modafinil on both catecholaminergic and histaminergic pathways lower 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" and "does not possess an addictive potential in naive individuals."

Overdose

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. Clinical trials on humans involving taking up to 1200 mg/day for 7 to 21 days and known incidents of acute one-time overdoses 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, the 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. Bastuji and Jouvet describe a suicide attempt using 4500 mg of modafinil; the patient survived with no long-term effects but temporary nervousness, nausea, and insomnia. A similar incident involving a suicide attempt by a 15-year-old female using 5000 mg of the drug (102 mg/kg) was observed in 2008 in Israel; the patient experienced severe headache, nausea, abdominal pain, dyskinesia, insomnia, and mild tachycardia, but no cardiovascular distress or abnormalities in liver and kidney function, and recovered in a few days without any apparent long-term effects.

Interactions

Modafinil can make certain types of birth control pills less effective, which could result in an unplanned pregnancy. Modafinil in combination with yohimbine causes a dangerous increase in heart rate and blood pressure.

Pharmacology

Pharmacokinetics

Modafinil induces the cytochrome P450 enzymes CYP1A2, CYP3A4, and CYP2B6, as well as inhibiting CYP2C9 and CYP2C19 in vitro. It may also induce P-glycoprotein (Pgp), 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. C_max (peak levels) occurs approximately 2–3 hours after administration. Food slows absorption, but does not affect the total AUC(AUC - area under the curve - meaning, food may slow absorption, but the total amount of the chemical will be absorbed with or without food). 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.

Modafinil's efficacy in improving vigor and well-being in sleep deprivation subjects is dependent on COMT status. Research suggests that individuals with the Val/Val genotype experience a great improvement in their cognitive function, while those with the Met/Met genotype experience very little improvement.

Pharmacodynamics

Despite extensive research into the interaction of modafinil with numerous neurotransmitter systems, its precise mechanism or mechanisms of action remain unclear. Modafinil elevates hypothalamic histamine levels, leading some researchers to consider modafinil a "wakefulness-promoting agent" rather than a classic amphetamine-like stimulant. Modafinil seems to inhibit the reuptake action of the dopamine transporter, thus leading to an increase in extracellular and thus synaptic concentrations of dopamine.

The locus of the monoamine action of modafinil has also been the target of studies, identifying effects on dopamine in the striatum and nucleus accumbens, norepinephrine in the hypothalamus and ventrolateral preoptic nucleus, and serotonin in the amygdala and frontal cortex.

A considered mechanism of action involves brain peptides called orexins, also known as hypocretins. Orexin neurons are found in the hypothalamus but project to many 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. There are two orexin receptors, namely orexin receptor 1 (OX1/hcrt1) and orexin receptor 2 (OX2/hcrt2). Animals with defective orexin systems exhibit signs and symptoms similar to narcolepsy, for treatment of which modafinil is FDA-approved. Modafinil seems to activate these orexin neurons in animal models, which would be expected to promote wakefulness. However, modafinil is also able to promote wakefulness with similar efficacy to amphetamine in dogs with complete loss-of-function mutations in orexin receptor 2, suggesting that orexin activation is not required for these effects of modafinil. Additionally, a study of orexin-knockout mice found that not only did modafinil promote wakefulness in these mice, but that it did so even more effectively than in wild-type mice.

Modafinil's substantial, but incomplete, independence from both monoaminergic systems and those of the orexin peptides has proven difficult to explain, in contrast to the better-understood mechanisms of stimulants such as cocaine or substituted amphetamines. Alternative mechanisms of action that have been proposed include the activation of glutamatergic circuits while inhibiting GABAergic neurotransmission. Enhanced electrotonic coupling by enhancing the effectiveness of direct gap junctions between neurons has also been suggested by several studies. Most neurons are separated by synapses, and communication between cells is accomplished via release and diffusion of neurotransmitters. However, some neurons are directly connected to one another via gap junctions, and it is proposed that modafinil influences the effectiveness of these connections. Modafinil increased activity via this mechanism in the thalamocortical loop, which is critical in organizing sensory input and modulating global brain activity. Administration of the gap junction blocker mefloquine abolished this effect, providing good evidence that this result was a consequence of improved electrical coupling. The calmodulin kinase II (CaMKII) inhibitor, KN-93, abolishes modafinil's enhancement of electrotonic coupling. 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, 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.

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 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. 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. 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. Modafinil's beneficial effects on working memory and motor networks are suggestive of heightened gamma band activity.

Administration of modafinil enhances arousal-specific P13 evoked potentials in a gap-junction dependent manner which provides a direct link between electrotonic coupling and wakefulness. 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. For example, dopamine release in the nucleus accumbens has been demonstrated to be the result of decreased GABAergic tone. 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.

Recently, modafinil was screened at a large panel of receptors and transporters in an attempt to elucidate its pharmacology. Of the sites tested, it was found to significantly act only on the dopamine transporter (DAT), inhibiting the reuptake of dopamine with an IC₅₀ value of 4 μM. Accordingly, it increases locomotor activity and extracellular dopamine concentrations in a manner similar to the selective dopamine reuptake inhibitor vanoxerine, and also blocks methamphetamine-induced dopamine release. As a result, it appears that modafinil exerts its effects by acting as a weak dopamine reuptake inhibitor, though it cannot be ruled out that other mechanisms may also be at play. On account of its action as a dopamine reuptake inhibitor and lack of abuse potential, modafinil was suggested as a treatment for methamphetamine addiction by the authors of the study.

The (R)-enantiomer of modafinil, known as armodafinil, has also recently been found to act as a D₂ receptor partial agonist, with a K_i of 16 nM, an intrinsic activity of 48%, and an EC₅₀ of 120 nM, in rat striatal tissue. The (S)-enantiomer is inactive with respect to the D₂ receptor (K_i > 10,000).

Physical and chemical properties

Measurement in body fluids

Modafinil and/or its major metabolite, modafinilic acid, may be quantified in plasma, serum or urine to monitor dosage in those receiving the drug therapeutically, to confirm a diagnosis of poisoning in hospitalized patients or to assist in the forensic investigation of a vehicular traffic violation. Instrumental techniques involving gas or liquid chromatography are usually employed for these purposes. As of 2011, it is not specifically tested for by common drug screens (except for anti-doping screens) and is unlikely to cause false positives for other chemically-unrelated drugs such as substituted amphetamines.

History

Modafinil was originally developed in France by neurophysiologist and emeritus experimental medicine professor Michel Jouvet and Lafon Laboratories. Modafinil originated with the late 1970s invention of a series of benzhydryl sulfinyl compounds, including adrafinil, which was first offered as an experimental treatment for narcolepsy in France in 1986. Modafinil is the primary metabolite of adrafinil, lacking the polar -OH group on its terminal amide, and has similar activity to the parent drug 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 originally leased the rights from Lafon, but eventually purchased the company in 2001.

Cephalon began to market the R-enantiomer armodafinil of modafinil in the U.S. in 2007. After protracted patent litigation and negotiations (see below), generic versions of modafinil became available in the U.S. in 2012.

Patent protection and antitrust litigation

U.S. Patent 4,927,855 was issued to Laboratoire L. Lafon on May 22, 1990, covering the chemical compound modafinil. After receiving an interim term extension of 1066 days and pediatric exclusivity of six months, it expired on October 22, 2010. On October 6, 1994, Cephalon filed an additional patent, covering modafinil in the form of particles of defined size. That patent, U.S. Patent 5,618,845 was issued on April 8, 1997, but was reissued in 2002 as RE 37,516, which surrendered the 5618845 patent. With pediatric exclusivity, this patent expired on April 6, 2015.

On December 24, 2002, anticipating the expiration of exclusive marketing rights, generic drug manufacturers Mylan, Teva, Barr, and Ranbaxy applied to the FDA to market a generic form of modafinil. At least one withdrew its application after early opposition by Cephalon based on the '516 patent. There is some question 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.

As of October 31, 2011, U.S. Reissue Patent No. RE 37,516 has been declared invalid and unenforceable. The District Court for the Eastern District of Pennsylvania ruled that RE 37,516 was invalid because it: (1) was on sale more than one year prior to the date of the application in violation of 35 U.S.C. section 102(b); (2) was actually invented by someone else (the French company Laboratoire L. Lafon); (3) was obvious at the time the invention was made to a person having ordinary skill in the art under 35 U.S.C. section 103(a); and (4) failed the written description requirement of 35 U.S.C. section 112. The patent was also found to be unenforceable due to Cephalon's inequitable conduct during patent prosecution.

Cephalon made an agreement with four major generics manufacturers Teva, Barr Pharmaceuticals, Ranbaxy Laboratories, and Watson Pharmaceuticals between 2005 and 2006 to delay sales of generic modafinil in the US until April 2012 by these companies in exchange for upfront and royalty payments. Litigation arising from these agreements is still pending including an FTC suit filed in April 2008. Apotex received regulatory approval in Canada despite a suit from Cephalon's marketing partner in Canada, Shire Pharmaceuticals. Cephalon has sued Apotex in the US to prevent it from releasing a genericized armodafinil (Nuvigil). Cephalon's 2011 attempt to merge with Teva was approved by the FTC under a number of conditions, including granting generic US rights to another company; ultimately, Par Pharmaceutical acquired the US modafinil rights as well as some others.

In the United Kingdom, Mylan Inc. received regulatory approval to sell generic modafinil produced by Orchid in January 2010; Cephalon sued to prevent sale, but lost the patent trial in November.

Society and culture

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. However, one may legally bring modafinil into 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. U.S. residents are limited to 50 dosage units (i.e., pills). 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); Cephalon was reprimanded in 2002 by the FDA because its promotional materials were found to be "false, lacking in fair balance, or otherwise misleading". Cephalon pled guilty to a criminal violation and paid several fines, including $50 million and $425 million fines to the U.S. government in 2008.

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

• Canada (not listed in the Controlled Drugs and Substances Act, but it is a Schedule F prescription drug, so it is subject to seizure by Canada Border Services Agency)
• Mexico (Not listed as a controlled substance, in the National Health Law)
• United Kingdom (not listed in the Misuse of Drugs Act and is available without legal restrictions by prescription)
• Australia (listed as a Schedule 4 prescription drug)
• In Germany the classification has been changed from controlled substance (BtM) to prescription drug (RP) effective March 1, 2008.
• In India, generic retailing as Modalert is available from Sun Pharmaceuticals; Indian firms are not required to respect patents filed before 1995.

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.

Brand names

Modafinil is sold under a wide variety of brand names worldwide, including:

• Alertec - Canada, Ecuador
• BravaMax - Egypt, Morocco
• Carim - El Salvador, Guatemala, Honduras, Colombia, Ecuador, Uruguay
• Provake - India (also Modalert, Modapro, Modafil, Modvigil, Modatec)
• Modasomil Austria, Switzerland
• Modvigil - Australia, New Zealand
• Modiodal - Mexico, Philippines, Spain, France, Denmark, Iceland, Greece, Cyprus, Netherlands, Portugal, Sweden, Norway, Turkey, Japan, Iran
• Modiwake - Turkey
• Provigil - Belgium, Ireland, Italy, South Korea, United Kingdom, United States, South Africa, Israel, Finland
• Resotyl - Chile (also Mentix, Alertex, Zalux)
• Stavigile - Brazil
• Vigia - Colombia
• Vigicer - Argentina
• Vigil - Germany

Doping agent

Modafinil has received some publicity in the past when several athletes (such as sprinter Kelli White in 2004, cyclist David Clinger and basketball player Diana Taurasi in 2010) were discovered allegedly using it as a performance-enhancing doping agent. (Taurasi and another player, Monique Coker, tested at the same lab, were later cleared.) It is not clear how widespread this practice is. The BALCO scandal brought to light an as-yet unsubstantiated (but widely published) account of Major League Baseball's all-time leading home-run hitter Barry Bonds' supplemental chemical regimen that included modafinil in addition to anabolic steroids and human growth hormone. Modafinil has been shown to prolong exercise time to exhaustion while performing at 85% of VO_2max and also reduces the perception of effort required to maintain this threshold. Modafinil was added to the World Anti-Doping Agency "Prohibited List" in 2004 as a prohibited stimulant (see Modafinil Legal Status).

Research

Depersonalization disorder

Modafinil used alone has been reported to be effective in a subgroup of individuals with depersonalization disorder; the subgroup of people with depersonalization disorder most likely to respond are those who have attentional impairments, under-arousal, and hypersomnia. However, clinical trials have not been conducted. Dr. Evan Torch calls a combination of an SSRI and modafinil "the hidden pearl that can really help depersonalization disorder."

Psychiatric/neurodegenerative disorders

Other potentially effective, but unapproved uses include the treatment of depression, bipolar depression, opiate and cocaine dependence, Parkinson's disease, schizophrenia, and disease-related fatigue, as well as fatigue that is the side effect of another medication.

Modafinil may also be an effective and well-tolerated treatment in patients with seasonal affective disorder.

A randomized double-blind study of modafinil 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.

Cocaine addiction

Modafinil is under investigation as a possible method to treat cocaine dependence, for several reasons involving biochemical mechanisms of the two drugs, as well as the observation that clinical effects of modafinil are largely opposite to symptoms of cocaine withdrawal.

The pilot 8-week double-blind study of modafinil for cocaine dependence (2004) 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. 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.

A later double-blind study of modafinil in people seeking treatment for cocaine dependence found no statistically significant effect on the rate of change in percentage of cocaine non-use days, but noted a significant improvement in some secondary outcomes such as the maximum number of consecutive non-use days for cocaine.

Weight loss

Studies on modafinil (even those on healthy weight individuals) indicate that it has an appetite reducing/weight loss effect. 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. In 2008, one small-scale study on individuals performing simulated shift work quantified the effect as an 18% decrease in total caloric intake on 200 mg/day, and a 38% decrease on 400 mg/day.

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."

In experimental studies, the appetite reducing effect of modafinil appears to be similar to that of substituted amphetamines, but, unlike substituted 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. Conversely, a US patent (#6,455,588) on using modafinil as an appetite stimulating agent has been filed by Cephalon in 2000.

Jet lag

It has been reported to reduce jet lag and increase subjective mood and friendliness among shift workers. It is also prescribed by sleep physicians for delayed sleep phase syndrome, which causes excessive daytime somnolence when the natural (delayed) diurnal rhythm is replaced by a socially determined earlier or forward shifted sleep schedule. The resultant wakefulness and neuro-behavioural impairments are comparable to those of travel-associated jet lag and persist as long as the forward shifted sleep schedule is maintained. A similar phenomenon commonly experienced by students and workers with varying sleep schedules during the week is often referred to as "social jet lag" and has been implicated in metabolic disorders and obesity.

Cognitive enhancement

There is disagreement to whether the cognitive effects modafinil showed in healthy non-sleep-deprived people are sufficient to consider it to be a cognitive enhancer. 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. Some positive effects of modafinil may be limited to "lower-performing" individuals. One study found that modafinil restored normal levels of learning ability in methamphetamine addicts, but had no effect on non-addicts.

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", but in 2011 it was found to be no better than placebo. As of 2011 there was no evidence to support using it to reduce fatigue in palliative care.

See also

• Armodafinil
• CRL-40941
• Fluorenol
• Sleep disorder

References

Further reading

• Minzenberg MJ, Carter CS; Carter (June 2008). "Modafinil: a review of neurochemical actions and effects on cognition". Neuropsychopharmacology 33 (7): 1477–502. doi:10.1038/sj.npp.1301534. PMID 17712350. 
• "Stay Awake Pill May Get Wider Approval". ABC News. October 9, 2006. 

External links

• PROVIGIL - official website
  • Medication Guide for Patients
  • Full Prescribing Information
• RxList Patient Information for modafinil users
• "Mayo Clinic Proceedings Publishes Study of NUVIGIL in Patients with Shift Work Disorder"
• U.S. National Library of Medicine: Drug Information Portal - Modafinil

UpToDate Contents

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• 1. 緩和ケアにおける疲労、脱力および無力症の概要 overview of fatigue weakness and asthenia in palliative care
• 2. ナルコレプシーの治療 treatment of narcolepsy
• 3. 統合失調症に対するクロザピン投与のガイドライン guidelines for prescribing clozapine in schizophrenia
• 4. 成人における閉塞性睡眠時無呼吸の薬理学的治療 pharmacologic treatment of obstructive sleep apnea in adults
• 5. 癌関連疲労：治療 cancer related fatigue treatment

English Journal

• Medications between psychiatric and addictive disorders.

• Lalanne L1, Lutz PE2, Trojak B3, Lang JP4, Kieffer BL5, Bacon E6.
• Progress in neuro-psychopharmacology & biological psychiatry.Prog Neuropsychopharmacol Biol Psychiatry.2016 Feb 4;65:215-23. doi: 10.1016/j.pnpbp.2015.10.009. Epub 2015 Oct 27.
• PMID 26514592

• Modafinil Moderates the Relationship Between Cancer-Related Fatigue and Depression in 541 Patients Receiving Chemotherapy.

• Conley CC1, Kamen CS, Heckler CE, Janelsins MC, Morrow GR, Peppone LJ, Scalzo AJ, Gross H, Dakhil S, Mustian KM, Palesh OG.
• Journal of clinical psychopharmacology.J Clin Psychopharmacol.2016 Feb;36(1):82-5. doi: 10.1097/JCP.0000000000000442.
• OBJECTIVE: The aim of this study was to examine the effect of modafinil on depression via a secondary data analysis of a randomized clinical trial of modafinil for fatigue in cancer patients. The primary aim is to elucidate factors that contributed to the effectiveness of modafinil in the parent tri
• PMID 26658264

• Addiction to Armodafinil and Modafinil Presenting With Paranoia.

• Jerry JM1, Shirvani N, Dale R.
• Journal of clinical psychopharmacology.J Clin Psychopharmacol.2016 Feb;36(1):98-100. doi: 10.1097/JCP.0000000000000446.
• PMID 26658262

Japanese Journal

• 症例報告 高体温,過眠症を呈しMRIで両側視床下部病変をみとめモダフィニルが奏功した39歳女性例

• 斎藤 奈穂子,井上 雅人,蓮尾 金博 [他]
• 臨床神経学 = Clinical neurology 54(7), 550-555, 2014-07
• NAID 40020149514

• 高体温，過眠症を呈しMRIで両側視床下部病変をみとめモダフィニルが奏功した39歳女性例

• 斎藤 奈穂子,井上 雅人,蓮尾 金博,神林 崇,村山 繁雄,竹内 壯介
• 臨床神経学 54(7), 550-555, 2014
• 症例は39歳の女性である．2011年7月，41°Cの高体温，痙攣重積をみとめ緊急入院となった．MRI で両側視床から視床下部にT2強調およびFLAIR画像で高信号域をみとめた．脳生検病理所見より，neuromyelitis optica（NMO）に関連した病態がうたがわれた．入院後も過眠をみとめ，ステロイド治療で病変は縮小傾向を示したが覚醒障害に改善をみとめなかった．髄液オレキシン値＜40 pg/ …
• NAID 130004678996

• Modafinilが有効であった小児期特発性ナルコレプシーの1例

• 岡本 健太郎,伊藤 康,西川 愛子 [他],七字 美延,石垣 景子,舟塚 真,神林 崇,大澤 眞木子
• 東京女子医科大学雑誌 83(E1), E265-E268, 2013-01-31
• … Modafinil(MDL)はナルコレプシーの治療薬であるが、小児での使用経験は少ない。 …
• NAID 110009559419

Related Links

• Modafinil ( Provigil )

Modafinil is a mood-brightening and memory-enhancing psychostimulant which enhances wakefulness and vigilance. ... THE GOOD DRUG GUIDE "...modafinil ('Provigil', 'Alertec', 'Vigicer', 'Modalert', etc) is a memory-improving and ...

• Modafinil: MedlinePlus Drug Information - National Library of ...

Modafinil may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away: headache dizziness difficulty falling asleep or staying asleep drowsiness nausea diarrhea constipation gas

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