Modafinil: Difference between revisions

Modafinil
Clinical data
Trade names	Provigil, Alertec, Modavigil, others
Other names	CRL-40476; Diphenylmethyl-sulfinylacetamide
AHFS/Drugs.com	Monograph
MedlinePlus	a602016
License data	US DailyMed: Modafinil;
Pregnancy; category	AU: D; ;
Dependence; liability	Relatively low
Addiction; liability	Very low to low
Routes of; administration	By mouth
Drug class	CNS stimulant
ATC code	N06BA07 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only); BR: Class B1 (Psychoactive drugs); CA: ℞-only; UK: POM (Prescription only); US: WARNINGSchedule IV;
Pharmacokinetic data
Bioavailability	Not determined due to its aqueous insolubility
Protein binding	62.3%
Metabolism	Liver (primarily via amide hydrolysis); CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5 involved
Elimination half-life	12-15 hours (modafinil, the racemic mixture),; 15 hours (armodafinil, the (R)-enantiomer),; 4 hours (esmodafinil, the (S)-enantiomer).
Excretion	Urine (80%)
Identifiers
	IUPAC name 2-(diphenylmethanesulfinyl)acetamide;
CAS Number	68693-11-8 ;
PubChem CID	4236;
IUPHAR/BPS	7555;
DrugBank	DB00745 ;
ChemSpider	4088 ;
UNII	R3UK8X3U3D;
KEGG	D01832 ;
ChEBI	CHEBI:31859 ;
ChEMBL	ChEMBL1373 ;
CompTox Dashboard (EPA)	DTXSID0023329 ;
ECHA InfoCard	100.168.719
Chemical and physical data
Formula	C15H15NO2S
Molar mass	273.35 g·mol−1
3D model (JSmol)	Interactive image;
	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) ; Key:YFGHCGITMMYXAQ-UHFFFAOYSA-N ;
	(verify)

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Modafinil, sold under the brand name Provigil among others, is a central nervous system (CNS) stimulant medication used to treat sleepiness due to narcolepsy, shift work sleep disorder, and obstructive sleep apnea.^[3]^[12] It is sometimes prescribed off-label for treating attention deficit hyperactivity disorder (ADHD) in children.^[13] While it has seen off-label use as a purported cognitive enhancer to improve wakefulness, in animal and human studies the research on its effectiveness for this use is inconclusive.^[14]^[15] Modafinil is taken by mouth.^[3] It comes in oral tablet form of 100mg or 200mg. Clinical studies have not found evidence of diminished response or tolerance to modafinil's wakefulness-promoting properties at therapeutic doses over prolonged periods. In addition to its medical uses, modafinil has gained popularity among students, office workers, professionals, and others who seek enhanced wakefulness and cognitive function.^[16] However, studies have shown mixed results regarding its cognitive enhancement abilities.^[13]

While modafinil is generally well-tolerated, it does carry potential risks and side effects. Additionally, there are concerns about the potential abuse of modafinil due to its stimulant-like properties. Modafinil's side effects include headaches, anxiety, and nausea. Serious side effects in high doses include delusions, unfounded beliefs, paranoia, irrational thought, and transient depression, possibly due to its effects on dopamine receptors in the brain, as well as allergic reactions. The amount of medication used should be adjusted in those with kidney problems, as this medication has markedly increased side effects during renal insufficiency.^[17] It is not recommended in those with an arrhythmia, significant hypertension, or left ventricular hypertrophy.^[17] Modafinil appears to work by acting on dopamine and modulating the areas of the brain involved with the sleep cycle.^[3]

Originally developed in the 1970s by French neuroscientist Michel Jouvet and Lafon Laboratories, Modafinil has been prescribed in France since 1994,^[18] and was approved for medical use in the United States in 1998.^[12] Its legal status varies by jurisdiction; in the United States it is classified as a schedule IV controlled substance,^[7] whereas in the United Kingdom it is a prescription only medication.^[17] In some countries no controls apply. It is available as a generic medication.^[17] In 2020, modafinil was the 302nd most commonly prescribed medication in the United States, with just over 1000000 prescriptions.^[19] There are ongoing debates around using modafinil as a performance-enhancing drug or "smart drug", especially outside of medically approved uses like treating sleep disorders or ADHD. Some view its usage negatively due to ethical concerns about unfair advantages or reliance on drugs for improved productivity.^[13]

Usage

Medical

Sleep disorders

Due to modafinil's lack of euphoric effects, it is not considered to be a classical psychostimulant, but rather is classified as a eugeroic (wakefulness-promoting drug).^[3]

Modafinil is used primarily for the treatment of narcolepsy. It was also used for shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea.^[12]^[14]^[20]^[21]

For obstructive sleep apnea, it is recommended that patients use continuous positive airway pressure (CPAP) appropriately before they consider starting modafinil to help with daytime sleepiness.^[3] Modafinil was efficient in relieving symptoms of obstructive sleep apnea, but was associated with side effects that might outweigh the benefit of using modafinil for this condition.^[22] The use of modafinil in shift work sleep disorder also, despite being efficient, demonstrates serious side effects, so alternative approaches are recommended such as a coffee and a nap for the people who work in a night shift.^[23] Because of the risk of development of skin or hypersensitivity reactions and serious adverse psychiatric reactions, the European Medicines Agency recommended that new patient prescriptions should be only to treat sleepiness associated with narcolepsy. ^[24]

Modafinil is regarded as a first-line treatment for excessive sleepiness associated with narcolepsy, still, it does not help with cataplexy or other ancillary features of narcolepsy, such as hypnagogic hallucinations or sleep paralysis.^[25]^[26]^[27]

Multiple sclerosis-related fatigue

The UK National Institute for Health and Care Excellence (NICE) and Multipe Sclerosis (MS) NGOs suggest modafinil to help with multiple sclerosis (MS) fatigue^[28]^[29]^[30] off-label.^[13] Still, the results from two controlled studies are conflicting, given the lack of larger, long-term, randomized controlled studies.^[31]

Attention deficit hyperactivity disorder

Modafinil is sometimes prescribed off-label to people with attention deficit hyperactivity disorder (ADHD).^[32]^[33]^[34] However, there is a lack of research into modafinil for ADHD in adults, and, consequently, evidence supporting its use in adult ADHD compared to other treatments such as lisdexamfetamine.^[35]^[36] The effect of modafinil on ADHD symptoms in adults was not clearly demonstrated.^[37] In adults, modafinil is inferior to placebo in relieving ADHD symptoms, but in children modafinil is superior to placebo.^[38]

Nevertheless, because modafinil has an approved use in the US, medical doctors can legally prescribe it for off-label use, such as to treat ADHD in both children and adults.^[39]^[40]^[41]

Bipolar depression

A 2020 meta-analysis found that "augmentation with [modafinil or armodafinil] was associated with significantly greater rates of treatment response" in patients with bipolar depression "with no evidence of increased risk of mood switch or suicide attempts".^[42]

Occupational

Modafinil was fielded to military personnel in the French Air Force, Foreign Legion, and Marine infantry during the Gulf War.^[43]^[44]^[45]^[46]^[47]

Adrafinil, a prodrug of modafinil, was first offered as an experimental treatment for narcolepsy in France in 1986.^[18] Modafinil, being more efficient than adrafinil, was deemed combat-worthy by the French Ministry of Defense in 1989 and was subsequently administered to personnel by their officers under the name Virgyl. This was done to improve a unit's "operational tempo", which refers to the rate at which military operations or activities are conducted. The goal was to enhance the unit's overall performance and efficiency. This evaluation took place before the introduction of modafinil on the market as medication in 1994,^[18] and the personnel involved were not informed of the product's nature.^[48] Later studies did not confirm the benefit of modafinil in military contexts that do not involve sleep deprivation.^[43]

Since then, armed forces of several countries, including the United States, the United Kingdom, India, and France, have expressed interest in modafinil as an alternative to amphetamine—the drug traditionally employed in combat situations or lengthy missions in which troops face sleep deprivation. The French government indicated that the Foreign Legion used modafinil during certain covert operations.^[49] The United Kingdom's Ministry of Defence commissioned research into modafinil^[50] from QinetiQ and spent £300,000 on one investigation.^[51] In 2011, the Indian Air Force announced that modafinil was included in contingency plans.^[52]

In the United States military, modafinil has been approved for use on certain Air Force missions, and it was investigated for other military uses.^[53] In 2012, modafinil was the only drug approved by the Air Force as a "go pill" for fatigue management (replacing prior use of amphetamine-based medications such as dextroamphetamine).^[54]

The Canadian Medical Association Journal 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.^[55]

The use of modafinil in military contexts that do not involve sleep deprivation is not recommended due to limited evidence on its effectiveness as a cognitive enhancer for non-sleep-deprived individuals. Additionally, there are potential risks of abuse, overconfidence, and negative impact on physical performance associated with modafinil use outside the context of sleep deprivation.^[43]

Non-medical

Modafinil has been used non-medically as a "smart drug" by students,^[56] office workers, transhumanists,^[57] professionals in the corporate and tech fields,^[16] surgeons, truck drivers, and call-center workers.^[58]^[59]^[60] Its attention-promoting, cognitive-enhancing, and wakefulness-boosting properties are cited by those people as reasons behind modafinil's use.^[61]^[62] However, multiple studies have consistently shown that modafinil does not provide cognitive enhancement or attention improvement benefits in non-sleep-deprived individuals, with some studies even reporting impairments in certain cognitive functions.^[63]

Available forms

Modafinil is available as 100 and 200 mg oral tablets.^[12] It is also available as the (R)-enantiomer, armodafinil, and as a prodrug of modafinil, adrafinil.^[64]

Drug tolerance

Large-scale clinical studies have not found evidence of diminished response (drug tolerance) to modafinil's pro-wakefulness and anti-fatiguing properties at therapeutic doses over periods as long as three years.^[65]^[66]^[67]

Modafinil is generally well-tolerated in various studies, including in pediatric patients using the drug for narcolepsy. However, evidence suggests that long-term use of modafinil can lead to tolerance in some patients, so the patient may need higher daily doses to achieve the same cognitive enhancement advantages or the same level of relief from sleepiness problems. Patients with present or past addictions to substances such as alcohol, cocaine, or nicotine and individuals with a family history of addiction are at the highest risk of developing drug tolerance. Several mechanisms may be involved in inducing tolerance to modafinil, including its effects on dopamine and norepinephrine levels in the brain. The precise mechanism of modafinil tolerance is not entirely understood.^[68]

Contraindications

Modafinil is contraindicated in people with known hypersensitivity to modafinil or armodafinil.^[69]

US FDA does not approve modafinil for use in children for any medical conditions, in whom there is a higher risk of rare but serious dermatological toxicity.^[70]^[71]^[72] Still, in Europe modafinil may be used to treat narcolepsy in children.^[73]

Due to limited available information on the excretion of modafinil into breastmilk and its potential effects on infants, careful monitoring of the infant is recommended when breastfeeding mothers use modafinil or considering alternative drugs may be preferred until more safety data are available.^[74]

Modafinil also has contraindications for certain cardiac conditions. It is contraindicated in patients with uncontrolled moderate to severe hypertension, or arrhythmia, or cor pulmonale, or in case of clinically significant signs of CNS stimulant-induced mitral valve prolapse (including ischaemic ECG changes, chest pain, and arrhythmias), or in individuals who have previously been diagnosed with a condition called left ventricular hypertrophy. Modafinil is also contraindicated for some hereditary issues. It is contraindicated in patients with congenital problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.^[75]^[76]

Adverse effects

The incidence of adverse effects are reported as the following: less than 10% of users report having a headache, nausea (a sensation of having an urge to vomiit), and reduced appetite. Between 5% and 10% of users may be affected with anxiety, insomnia, dizziness, diarrhea, and rhinitis.^[13] Modafinil-associated psychiatric reactions have occurred in those with and without a preexisting psychiatric history.^[77] No clinically significant changes in body weight have been observed with modafinil in clinical trials,^[78] although decreased appetite and weight loss have been reported with modafinil in children and adolescents probably due to the much higher modafinil exposure in these individuals based on body weight (i.e., mg/kg doses).^[79]

Rare occurrences have been reported of more serious adverse effects, including severe skin rashes and other symptoms that are probably allergy-related. From the date of initial marketing, December 1998, to January 30, 2007, the US Food and Drug Administration received six cases of severe cutaneous adverse reactions associated with modafinil, including erythema multiforme (EM), Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and DRESS syndrome, 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 surveillance incidents^[80] which means adverse effects or reactions that have been reported after the drug was approved and made available on the market, indicating incidents that occurred in real-world use rather than just clinical trials.^[81]

In 2007, the FDA ordered Cephalon to modify the Provigil leaflet to add in bold-face print several serious and potentially fatal conditions attributed to modafinil use, including TEN, DRESS syndrome, and SJS. The long-term safety and effectiveness of modafinil have not been determined.^[82] However, a longitudinal study in pediatric patients treated for narcolepsy for up to ten years demonstrated that modafinil and armodafinil were safe and effective, with the study concluding that use of modafinil and armodafinil significantly improved patients' ability to stay awake and did not exacerbate preexisting psychiatric conditions.^[83]

According to an online survey conducted in 2020, modafinil users have statistically higher levels of illicit drug use and psychiatric diagnosis than would be expected from population-based data. More frequent reported modafinil use was associated with higher numbers of perceived benefits, while reported frequency of use was not associated with the number of perceived risks. There was also a tentative link between the reported use of modafinil and the reported presence of psychiatric disorders, largely depression and anxiety.^[84]

Addiction and dependence

The addiction and dependence liabilities of modafinil are very low.^[1]^[85] Modafinil shares biochemical mechanisms with addictive stimulant drugs, and some studies reported it to have similar mood-elevating properties, although to a lesser degree.^[85] It is not clear whether these effects are different from those from caffeine.^[86]^[87] Modafinil does not appear to produce euphoric effects nor deviations (i.e., abuse) from dosages assigned to the patient.^[88] Still, caution should be taken, because in clinical trials modafinil produced euphoric and psychoactive effects which could alter the way of thinking and perception, modify mood and bring new feelings, in ways similar to other CNS stimulants,^[13] so the risk of modafinil abuse still has to be assessed,^[13] as there are indications that modafinil may work on the same neurobiological mechanisms as other addictive stimulants.^[43]

Modafinil is classified by the United States Drug Enforcement Administration as a schedule IV controlled substance,^[7] a category for drugs with valid medical uses and low addiction potential.^[1]^[89] The International Narcotics Control Board does not consider modafinil a narcotic^[90] nor a psychotropic substance.^[91] Modafinil may increase abstinence rates in a subgroup of cocaine addicts, and modafinil-related discontinuation adverse effects are no different from placebo.^[92]

Overdose

Modafinil overdose can cause various symptoms and complications.^[93]^[94] Psychiatric symptoms of modafinil overdose may be manifested as psychosis, mania, hallucinations, and suicidal ideation, moreover, these symptoms may occur even in patients without a history of mental illness and may persist after the drug is discontinued. Neurological complications may include seizures, tremors, dystonia, and dyskinesia, these effects may be due to the modulation of glutamate, GABA, and serotonin receptors by modafinil, which can alter the excitability and activity of neurons. Modafinil overdose can also cause hepatic toxicity, such as elevated liver enzymes, jaundice, and hepatitis, and these effects may be caused by the metabolism of modafinil by the cytochrome P450 enzymes, which can generate reactive metabolites that can damage the liver cells.^[95]^[96]^[94] Modafinil overdose can also cause allergic reactions such as rash, angioedema, anaphylaxis, and Stevens-Johnson syndrome,^[97] and such reactions may be due to the immunological response of the body to modafinil or its metabolites, which can trigger the release of histamine and other inflammatory mediators.^[98]^[95]^[96] Cardiovascular complications of the overdose may include hypertension, tachycardia, chest pain, and arrhythmias, and these effects may be due to the sympathomimetic action of modafinil, which increases the release of norepinephrine and dopamine in the brain and peripheral tissues.^[93]^[99]

In mice and rats, the median lethal dose (LD₅₀) of modafinil is approximately or slightly greater than 1250 mg/kg. Oral LD₅₀ values for rats range from 1000 to 3400 mg/kg. Intravenous LD₅₀ for dogs is 300 mg/kg. Clinical trials on humans involve taking up to 1200 mg/day for 7–21 days. 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, tremor, palpitations, sleep disturbances, nausea, and diarrhea. Instances of modafinil overdose have been observed to precipitate symptoms such as heightened anxiety, increased irritability, aggressive behavior, cognitive disarray, and nervousness.^[12] In 2005, the FDA was not aware of any fatal overdoses involving modafinil alone (as opposed to multiple drugs including modafinil).^[12]

The management of modafinil overdose depends on the severity and type of symptoms. The general principles include supportive care, monitoring of vital signs, and treatment of specific complications, but in cases of recent consumption of modafinil, therapy may include activated charcoal, gastric lavage, or hemodialysis to reduce the absorption or elimination of modafinil. There is no specific antidote for modafinil overdose.^[93]^[100]^[99]

Interactions

Modafinil is known to interact with 463 drugs. These interactions can be classified as major (71), moderate (211), and minor (181).^[101]

Some of the drugs that frequently interact with modafinil include Abilify (aripiprazole), Adderall (amphetamine / dextroamphetamine), aspirin, Benadryl (diphenhydramine), and others.^[101]

Modafinil is a weak to moderate inducer of CYP3A4^[102]^[103] and a weak inhibitor of CYP2C19, enzymes of the cytochrome P450 group of enzymes.^[13] Modafinil also induces or inhibits other cytochrome P450 enzymes. One in vitro study predicts that modafinil may induce the cytochrome P450 enzymes CYP1A2, CYP3A4, and CYP2B6, as well as may inhibit CYP2C9 and CYP2C19.^[11] However, other in-vitro studies find no significant inhibition of CYP2C9.^[8]^[104] Modafinil may induce P-glycoprotein, which may affect drugs transported by P-glycoprotein, such as digoxin.^[105] Therefore, modafinil affects pharmacodynamics of drugs which are metabolized by CYP3A4 and other enzymes of the cytochrome P450 family.^[102]

For instance, induction of CYP3A4 by modafinil affects metabolism of the following medications and endogenous substances:^[106]

opioids, such as methadone, hydrocodone, oxycodone, or fentanyl - modafinil may result in a drop in opioid plasma concentrations because of faster clearance by CYP3A4. If the patient is not monitored closely, reduced efficacy or withdrawal symptoms can occur.^[106]
steroid hormones, such as estradiol, progesterone or cortisol. Modafinil may have an adverse effect on hormonal contraceptives for up to a month after discontinuation.^[107] In a 2006 study, a single dose of modafinil 200 mg caused a decrease in blood prolactin levels, although it did not affect human growth hormone or thyroid-stimulating hormone.^[108]^[109] Since modafinil induces the activity of the CYP3A4 enzyme involved in cortisol clearance,^[110] modafinil may reduce the bioavailability of hydrocortisone. Therefore, it may be necessary to adjust the steroid substitution dose in subjects receiving CYP3A4-metabolism-inducing drugs such as modafinil.^[111]

Pharmacology

Pharmacodynamics

Modafinil activity profile
Site	Potency	Type	Species	Refs
DATTooltip Dopamine transporter	1.8–2.6 μM 4.8 μM 6.4 μM 4.0 μM	K_i K_i IC₅₀^a IC₅₀^a	Human Rat Human Rat	^[112]^[113] ^[112] ^[114]^[115] ^[112]
NETTooltip Norepinephrine transporter	>10 μM >92 μM 35.6 μM 136 μM	K_i K_i IC₅₀^a IC₅₀^a	Human Rat Human Rat	^[112]^[113] ^[112] ^[114]^[115] ^[112]
SERTTooltip Serotonin transporter	>10 μM 46.6 μM >500 μM >50 μM	K_i K_i IC₅₀^a IC₅₀^a	Human Rat Human Rat	^[112]^[113] ^[112] ^[114]^[115] ^[112]
D₂	>10 μM 16 nM^b 120 nM^b	K_i K_i EC₅₀^a	Human Rat Rat	^[112] ^[116] ^[116]
Footnotes: ^a = Functional activity, not binding inhibition. ^b = Armodafinil at D₂^High. Notes: No activity at a variety of other assessed targets.^[112]

Mechanism of action

The precise therapeutic mechanism of action of modafinil for narcolepsy^[117] and sleep-wake disorders remains unknown,^[118]^[119] however, the effect seems to be caused by binding of modafinil to the dopamine transporter and inhibiting dopamine reuptake.^[117] Modafinil acts as an atypical, selective, and weak dopamine reuptake inhibitor and indirectly activates the release of orexin neuropeptides and histamine from the lateral hypothalamus and tuberomammillary nucleus, all of which may contribute to heightened arousal.^[118]^[119]^[120]^[121]

Dopamine reuptake inhibitor

Modafinil elevates dopamine levels in the hypothalamus in animals.^[122] The locus of the monoamine action of modafinil was also studied, with effects identified on dopamine in the striatum and, in particular, nucleus accumbens,^[123]^[124] norepinephrine in the hypothalamus and ventrolateral preoptic nucleus,^[125]^[126] and serotonin in the amygdala and frontal cortex.^[127] Modafinil was screened at a large panel of receptors and transporters in an attempt to elucidate its pharmacology.^[112] Of the sites tested, it was observed to significantly affect only the dopamine transporter (DAT), acting as a dopamine reuptake inhibitor (DRI) with an IC₅₀ value of 4 μM.^[112] Modafinil binds to the same site on the DAT as cocaine, but in a different manner.^[128]^[129] Modafinil increases locomotor activity and extracellular dopamine concentrations in animals in a manner similar to the selective DRI vanoxerine (GBR-12909),^[130] and also inhibits methamphetamine-induced dopamine release (a common property of DRIs, since DAT transport facilitates methamphetamine's access to its intracellular targets). As such, "modafinil is an exceptionally weak, but apparently very selective, [DAT] inhibitor".^[131] In addition to animal research, a human positron emission tomography (PET) imaging study observed that 200 mg and 300 mg doses of modafinil resulted in DAT occupancy of 51.4% and 56.9%, respectively, which is "close to that of methylphenidate".^[132] Another human PET imaging study similarly observed that modafinil occupied the DAT and also determined that it significantly elevated extracellular levels of dopamine in the brain, including in the nucleus accumbens.^[133]

Modafinil has been described as an "atypical" DAT inhibitor, and shows a profile of effects that is very different from those of other dopaminergic stimulants.^[134]^[135] For instance, modafinil produces wakefulness reportedly without the need for compensatory sleep, and shows relatively low, if any, potential for abuse.^[136]^[131]^[134]^[135] Aside from modafinil, other atypical DAT inhibitors include vanoxerine and benztropine, which have a relatively low abuse potential similar to modafinil.^[134] These drugs appear to interact with the DAT in a distinct way from "conventional" DAT blockers such as cocaine and methylphenidate.^[129]^[134] Analogues of modafinil with modafinil-like versus cocaine-like dopamine reuptake inhibition and effects have been synthesized.^[137]

Dopamine transporter-independent actions

Evidence against the hypothesis that modafinil exerts its effects by acting as a DRI is that tyrosine hydroxylase inhibitors (which deplete dopamine) fail to block the effects of modafinil in animals.^[138] Modafinil fails to reverse reserpine-induced akinesia, whereas dextroamphetamine, a dopamine releasing agent (DRA), is able to do so.^[139] One of the first published structure–activity relationship studies of modafinil found that DAT inhibition did not correlate with wakefulness-promoting effects in animals among modafinil analogues.^[140] A variety of analogues without significant DAT inhibition still produce wakefulness-promoting effects.^[140] "[The] neurochemical effects [of modafinil] and anatomical pattern of brain area activation differ from typical psychostimulants and are consistent with its beneficial effects on cognitive performance processes such as attention, learning, and memory".^[136] Another study found that modafinil-induced increased locomotor activity in animals was dependent on histamine release and could be abolished by depletion of neuronal histamine, whereas those of methylphenidate were not and could not be.^[122] Taken together, although it is established that modafinil is a clinically significant DRI, its full pharmacology remains unclear, and may include DAT-independent actions.^[128]^[136] One such action may be activation of the orexin system.^[121]^[128]^[136]

There is nonetheless evidence that modafinil produces at least some of its wakefulness-promoting effects by acting as a DRI, or at least via activation of the dopaminergic system. In support of the hypothesis that modafinil acts as a dopaminergic agent, its wakefulness-promoting effects are abolished in DAT knockout mice (although DAT knockout mice show D₁ and D₂ receptor and norepinephrine compensatory abnormalities that might confound this finding), reduced by both D₁ and D₂ receptor antagonists (although conflicting reports exist),^[139] and completely blocked by simultaneous inactivation of both D₁ and D₂ receptors.^[131] Modafinil shows full stimulus generalization (ability to produce similar effects or responses) to other DAT inhibitors including cocaine, methylphenidate, and vanoxerine, and discrimination (ability to differentiate or distinguish between different drugs) is blocked by administration of both ecopipam (SCH-39166), a D₁ receptor antagonist, and haloperidol, a D₂ receptor antagonist.^[135] Partial substitution (a phenomenon where a substance or drug partially replaces or mimics the effects of another substance or drug) was seen with the DRA dextroamphetamine and the D₂ receptor agonist PNU-91356A, as well as with nicotine (which indirectly elevates dopamine levels through activation of nicotinic acetylcholine receptors).^[135]

Modafinil may have an additional mechanism of action: Both modafinil and its metabolite, modafinil sulfone, possess anticonvulsant properties in animals, and modafinil sulfone is nearly as potent as modafinil in producing this effect.^[141] However, modafinil sulfone lacks wakefulness-promoting effects in animals, indicating that a distinct mechanism may be at play in the anticonvulsant effects of both compounds.^[141]

Dopamine D₂ receptor partial agonist

Armodafinil, the (R)-enantiomer of modafinil, acts as a D₂^High receptor partial agonist,^[142] with a K_i of 16 nM, an intrinsic activity of 48%, and an EC₅₀ of 120 nM, in rat striatal tissue.^[116] Esmodafinil, the (S)-enantiomer of modafinil, is inactive with respect to the D₂ receptor.^[116] Modafinil directly inhibits the firing of midbrain dopaminergic neurons in the ventral tegmental area and substantia nigra of rats via activation of D₂ receptors.^[143] However, modafinil seems not to interact with the human D₂ receptor (K_i = >10 μM).^[112]

Dampening of amygdala activity

There is some mouse and human evidence (via direct fMRI observation and anxiety questionnaires) to suggest that modafinil may reduce amygdala activity.^[144]^[145] The amygdala is involved in fear processing, and the dampening of its activity reduces perceptions of fear in response to environmental stress.^[146] One study documented a statistically significant reduction in fear response among human subjects given 100 mg of modafinil daily for 7 days.^[144] However, another study investigating the acute effects of modafinil on fear processing reported an increase in amygdala responses to fearful faces after administration of 600 mg of modafinil in human subjects.^[147] Modafinil's dose dependent effects on fear processing may exhibit a Yerkes–Dodson relationship.^[148]

Pharmacokinetics

C_max (peak levels) occurs approximately 2 to 3 hours after modafanil administration. Food slows absorption of modafanil, but does not affect the total AUC. In vitro measurements indicate that 60% of modafinil is bound to plasma proteins at clinical concentrations of the drug. This percentage changes very little when the concentration of modafinil is varied.^[149]

Renal excretion of unchanged modafinil usually accounts for less than 10% of an oral dose. This means that when modafinil is taken by mouth, less than 10% of the drug is eliminated from the body through the urine without being metabolized (broken down) by the liver or other organs. The rest of the drug is either metabolized or excreted through other routes, such as feces or bile.^[8] The two major circulating metabolites of modafinil are modafinil acid (CRL-40467) and modafinil sulfone (CRL-41056).^[150] Both of these metabolites have been described as inactive,^[151] and neither appears to contribute to the wakefulness-promoting effects of modafinil.^[150]^[8]^[152] However, modafinil sulfone does appear to possess anticonvulsant effects, a property that it shares with modafinil.^[141]

Elimination half-life is in the range of 10 to 12 hours, subject to differences in cytochrome P450 genotypes, liver function, and renal function. Modafinil is metabolized mainly in the liver,^[8] and its inactive metabolite is excreted in the urine. Urinary excretion of the unchanged drug is usually less than 10%, but can range from 0% to as high as 18.7%, depending on the factors mentioned.^[149]

Chemistry

Enantiomers

Armodafinil ((R)-(−)-modafinil)

Esmodafinil ((S)-(+)-modafinil)

Modafinil is a racemic mixture of two enantiomers, armodafinil ((R)-modafinil) and esmodafinil ((S)-modafinil).^[115]^[153]

Detection in body fluids

Modafinil and/or its major metabolite, modafinil 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.^[154]^[155] In 2011, modafinil was not 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.^[115]

Reagent testing can screen for the presence of modafinil in samples.^[156]^[157]

Colors produced by modafinil with various reagents
RC	Marquis Reagent	Liebermann	Froehde
Modafinil	Yellow/Orange > Brown^[156]^[157]	Darkening Orange^[156]	Deep orange/red^[157]

Structural analogues

Many derivatives and structural analogues of modafinil have been synthesized and studied.^[137]^[158]^[129] Examples include adrafinil, CE-123, fladrafinil (CRL-40941; fluorafinil), flmodafinil (CRL-40940; bisfluoromodafinil, lauflumide), and modafinil sulfone (CRL-41056).^[159]

History

Modafinil was originally developed in France by Neurophysiology professor Michel Jouvet and Lafon Laboratories. Modafinil was among a series of benzhydryl sulfinyl compounds invented in the 1970s, including adrafinil, which was first offered as an experimental treatment for narcolepsy in France in 1986.^[18] Modafinil is the primary metabolite of adrafinil, lacking the polar -OH group on its terminal amide,^[160] and has similar activity to the parent drug. Modafinil has been prescribed in France since 1994 under the name Modiodal,^[18] and in the US since 1998 as Provigil. In contrast, adrafinil does not have FDA approval, and it was marketed in France until 2011 and then withdrawn.^[161]

In 1998, modafinil was approved by the US Food and Drug Administration^[7]^[162] for the treatment of narcolepsy and in 2003, for shift work sleep disorder and obstructive sleep apnea/hypopnea^[163] even though caffeine and amphetamine were shown to be more wakefulness promoting on the Stanford Sleepiness Test Score than modafinil.^[119]

Modafinil was approved for use in the UK in December 2002. Modafinil is marketed in the United States by Cephalon,^[164] who originally leased the rights from Lafon, but eventually purchased the company in 2001.^[164]

Cephalon began to market armodafinil, the (R)-enantiomer of modafinil, in the United States in 2007. After protracted patent litigation and negotiations (see below), generic versions of modafinil became available in the US in 2012.^[165]^[166]

Patent protection and litigation

Modafinil's patent history involves several key developments. The original patent, U.S. patent 4,927,855, was granted to Laboratoire L. Lafon in 1990, covering the chemical compound of modafinil. This patent expired in 2010.^[167] In 1994, Cephalon filed a patent for modafinil in the form of particles of a defined size, represented by U.S. patent 5,618,845, which expired in 2015.^[168]

Following the nearing expiration of marketing rights in 2002, generic manufacturers, including Mylan and Teva, applied for FDA approval to market a generic form of modafinil, leading to legal challenges by Cephalon regarding the particle size patent^[169]. The patent RE 37,516 was declared invalid and unenforceable in 2011.^[170]

In addition, Cephalon entered agreements with several generic drug manufacturers to delay the sale of generic modafinil in the US. These agreements were subject to legal scrutiny and antitrust investigations, culminating in a ruling by the Court of Appeals in 2016, which found that the settlements did not violate antitrust laws.^[171]

Society and culture

Legal status

Australia

In Australia, modafinil is considered to be a Schedule 4 prescription-only medicine or prescription animal remedy.^[172]

Canada

In Canada, modafinil is not listed in the Controlled Drugs and Substances Act, but it is a Schedule F prescription drug.^[173]

China

In mainland China, modafinil is strictly controlled like other stimulants such as amphetamines and methylphenidate. It is classified as Class I psychotropic drug, requiring prescription.^[174]^[175]

Moldova

In the Republic of Moldova, modafinil is classified as a psychotropic drug and is available by prescription.^[176] Importation of modafinil may be considered illegal and subject to severe penalties.^[177] In Transnistria, modafinil is completely prohibited, with possession potentially leading to imprisonment.^[178]

Japan

In Japan, modafinil is Schedule I psychotropic drug.^[179]^[180] Cephalon licensed Alfresa Corporation to produce, and Mitsubishi Tanabe Pharma to sell modafinil products under the trade name Modiodal in Japan.^[181] There have been arrests of people who imported modafinil for personal use.^[182]^[183]

Romania

Modafinil is classified as a stimulant doping agent and is prohibited in sports competitions.^[184] In 2022, laws were passed making its importation or sale a felony, punishable by three to seven years in jail.^[185] Simple possession for personal use may result in a fine and confiscation.^[185]

Russia

In Russia, modafinil is Schedule II controlled substance like cocaine and morphine. Possession of a few modafinil pills can lead to three to ten years imprisonment.^[178]

Sweden

In Sweden, modafinil is classified as a schedule IV substance; possession is illegal without prescription.^[186]

United States

Modafinil is a Schedule IV controlled substance under US federal law.^[7] It is illegal to import it without a DEA-registered importer and a prescription.^[187] Individuals may legally bring modafinil into the US from a foreign country for personal use, limited to 50 dosage units, with a prescription and proper declaration at the border.^[188] Under the Pure Food and Drug Act, marketing drugs for off-label uses is prohibited.^[189] Cephalon, the manufacturer of Modafinil, faced legal issues for promoting off-label uses and paid significant fines in 2008.^[190]

Other countries

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

In Finland, modafinil is a prescription drug but not listed as a controlled substance.^[191]
In Denmark, modafinil is a prescription drug but not listed as a controlled substance.^[192]
Mexico (Not listed as a controlled substance, in the National Health Law. Can be purchased in pharmacies without prescription.)^[193]
South Africa Schedule V^[194]
United Kingdom (not listed in Misuse of Drugs Act so possession is not illegal, but a prescription is required) ^[195]

Brand names

A generic formulation of modafinil marketed under the Aspendos brand name

Modafinil is sold under a variety of brand names worldwide, including Alertec, Alertex, Altasomil, Aspendos, Bravamax, Forcilin, Intensit, Mentix, Modafinil, Modafinilo, Modalert, Modanil, Modasomil, Modvigil, Modiodal, Modiwake, Movigil, Provigil, Resotyl, Stavigile, Vigia, Vigicer, Vigil, Vigimax, Waklert, and Zalux.^[196]

Economics

The global sales figures for modafinil are not known, still, Modafinil sold under the brand name Provigil accounted for over 40% of Cephalon's global turnover for several years, according to the information published in 2020.^[197]

Concerns have been raised about the growing use of modafinil as a "smart drug" or cognitive enhancer among healthy individuals who use it to improve concentration and memory. The New York Times reported in 2004 that modafinil sales were skyrocketing, with some experts concerned that it had become a tempting pick-me-up for people looking for an extra edge in a productivity-obsessed society. The cost of modafinil can vary depending on factors such as location and insurance coverage. In 2013, the price was reported to be around $120 or more per monthly supply. However, the availability of generic versions has increased since then and may have driven down prices.^[198]^[199]^[200]

Sports

The regulation of modafinil as a doping agent has been controversial in the sporting world, with high-profile cases attracting press coverage since several prominent American athletes tested positive for the substance. Some athletes who used modafinil protested that the drug was not on the prohibited list at the time of their offenses.^[201] However, the World Anti-Doping Agency (WADA) maintains that modafinil 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.

Several athletes (such as sprinter Kelli White in 2003, cyclist David Clinger^[202] and basketball player Diana Taurasi^[203] in 2010, and rower Timothy Grant in 2015^[204]) were accused of using modafinil as a performance-enhancing doping agent. Taurasi and another player—Monique Coker, tested at the same lab—were later cleared.^[205] Kelli White, who tested positive after her 100m victory at the 2003 World Championships in Paris, was stripped of her gold medals.^[206] She claimed that she used modafinil to treat narcolepsy, but the International Association of Athletics Federations (IAAF) ruled that modafinil was a performance-enhancing drug.^[206]

The BALCO scandal brought to light an 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.^[207]

In a study on 15 healthy male subjects, published in Medicine & Science in Sports & Exercise, an academic journal, acute ingestion of modafinil of 4 mg·kg⁻¹ (at a dose of 4 mg per kilogram of body weight), prolonged exercise time to exhaustion while performing at 85% of VO_2max threshold, and also reduced the perception of effort required to maintain this threshold, ^[208] i.e., the control subjects were able to perform at 85% of their maximum oxygen consumption without feeling as much effort as without modafinil (with placebo).^[208]

Social views

The use of modafinil as a supposed cognitive enhancer is viewed differently among various groups.^[209] Some groups consider such use as cheating, unnatural, or risky.^[210] For instance, some academic institutions such as University of Sussex in the UK have explored this question raised by the students, although the university do not have a strong, official stance on its use, explaining that it is a prescription drug and the decision should be made by the doctor on whether to prescribe modafinil to a student.^[211] In the realm of bioethics, the President's Council on Bioethics in the US, chaired by Leon Kass, argued that excellence achieved through the use of drugs like modafinil is "cheap" as it obviates the need for hard work and study, and is not fully authentic because the excellence is partly attributable to the drug, not the individual.^[212] On the other hand, some people, particularly those in high-pressure environments like Wall Street traders, do not view the use of modafinil as cheating. They argue that if modafinil can give them an edge and they are aware of the risks involved, it should not be considered as cheating.^[213] Due to such varying views, modafinil users for nacrolepsy may cope with stigma by hiding, denying, or justifying their use, or by seeking support from others who share their views or experiences.^[84]^[214]

Music and entertainment

Peter Cullen, is an American-Canadian voice actor, wrote "Modafinil - Music to Mod to", an instrumental electronic composition influenced by modafinil.^[215]

Matthew Dear an American electronic music producer and DJ, wrote "Modafinil Blues", an indie rock song.^[216]

Joe Rogan, an American comedian, podcaster, and mixed martial arts commentator, has talked about modafinil on his show The Joe Rogan Experience.^[217]^[218]^[219]

Research

Psychiatric conditions

Major depression

Modafinil has been studied in the treatment of major depressive disorder.^[220]^[221]^[222] In a 2021 systematic review and meta-analysis of randomized controlled trials of psychostimulants for depression, modafinil and other stimulants such as methylphenidate and amphetamines improved depression in traditional meta-analysis.^[222] However, when subjected to network meta-analysis, modafinil and most other stimulants did not significantly improve depression, with only methylphenidate remaining effective.^[222] Modafinil and other stimulants likewise did not improve quality of life in the meta-analysis, although there was evidence for reduced fatigue and sleepiness with modafinil and other stimulants.^[222] While significant effectiveness of modafinil for depression has been reported,^[223]^[224]^[221] reviews and meta-analyses note that the effectiveness of modafinil for depression is limited, the quality of available evidence is low, and the results are inconclusive.^[225]^[222]

Bipolar depression

Modafinil and armodafinil have been repurposed as adjunctive treatments for acute depression in people with bipolar disorder.^[142] A 2021 meta-analysis concluded that add-on modafinil and armodafinil were more effective than placebo on response to treatment, clinical remission, and reduction in depressive symptoms, with only minor side effects, but the effect sizes are small and the quality of evidence is therefore low, limiting the clinical relevance of the evidence.^[142] Very low rates of mood switch (a change in mood from one extreme to another)^[226] have been observed with modafinil and armodafinil in bipolar disorder.^[224]

Attention deficit hyperactivity disorder (research)

Modafinil was seriously considered for the treatment of attention deficit hyperactivity disorder (ADHD) because of its lower abuse potential than conventional psychostimulants like methylphenidate and amphetamines.^[40]^[227] In 2008, an application to market modafinil for pediatric ADHD was submitted to the Food and Drug Administration in the USA.^[79]

However, evidence of modafinil for treatment of adult ADHD is mixed, and a 2016 systematic review of alternative drug therapies for adult ADHD did not recommend its use in this context.^[37] In a later large phase 3 clinical trial of modafinil for adult ADHD, modafinil was not effective in improving symptoms, and there was a high rate of side effects (86%) and discontinuation (47%).^[228] The poor tolerability of modafinil in this study was possibly due to the use of excessively high doses (210–510 mg/day).^[228] Another reason for the denial of the approval was due to concerns about rare but serious dermatological toxicity (Stevens–Johnson syndrome).^[79]

Substance dependence

Modafinil was studied for the treatment of stimulant dependence, but the results are mixed and inconclusive.^[137]^[229]

Treatment of cocaine addiction

Modafinil has been studied for the treatment of cocaine addiction.^[13] Modafinil binds to the dopamine transporter (DAT) in an open-to-out conformation, differently than cocaine and methylphenidate.^[230]^[231]^[232] Subjects pretreated with modafinil report experiencing less euphoria from cocaine administration.^[231] Modafinil does not potentiate self-administration of cocaine in pretreated rats.^[233]

The mechanism by which modafinil inhibits cocaine self-administration is likely more complex than the simple observation that modafinil occupies the DAT, as drugs like methylphenidate (another dopamine re-uptake inhibitor (DRI) fail to reduce cocaine self-administration.^[230]^[234] Atypical DRIs like modafinil that bind to the DAT in an open-to-out conformation often lack abuse potential relative to cocaine-like DAT ligands.^[235]

Schizophrenia

Modafinil and armodafinil were studied as a complement to antipsychotic medications in the treatment of schizophrenia. They showed no effect on positive symptoms or cognitive performance.^[236]^[237] A 2015 meta-analysis found that modafinil and armodafinil may slightly reduce negative symptoms in people with acute schizophrenia, though they do not appear useful for people with the condition who are stable, with high negative symptom scores.^[237] Among medications demonstrated to be effective for reducing negative symptoms in combination with antipsychotics, modafinil and armodafinil are among the smallest effect sizes.^[238]

Cognitive enhancement

A 2015 review of clinical studies of possible nootropic effects in healthy people found: "...whilst most studies employing basic testing paradigms show that modafinil intake enhances executive function, only half show improvements in attention and learning and memory, and a few even report impairments in divergent creative thinking. In contrast, when more complex assessments are used, modafinil appears to consistently engender enhancement of attention, executive functions, and learning. Importantly, we did not observe any preponderances for side effects or mood changes."^[14] A 2019 review of studies of a single-dose of modafinil on mental function in healthy, non-sleep-deprived people found a statistically significant but small effect and concluded that the drug has limited usefulness as a cognitive enhancer in non-sleep-deprived persons.^[239] A 2020 review of the cognitive enhancing potential of methylphenidate, d-amphetamine, and modafinil in healthy individuals across various domains found that modafinil has a small, positive effect on memory updating.^[240]

Modafinil has been used off-label in trials with people with post-chemotherapy cognitive impairment, also known as "chemobrain", but a 2011 review found that it was no better than a placebo.^[241]

Post-anesthesia sedation

General anesthesia is required for many surgeries, but may cause lingering fatigue, sedation, and/or drowsiness after surgery that lasts for hours to days. In outpatient settings in which patients are discharged home after surgery, this sedation, fatigue, and occasional dizziness is problematic, but it was only tested in one small study, and the results are inconclusive.^[39]

Multiple sclerosis-related fatigue (research)

Modafinil was studied for use in multiple sclerosis-associated fatigue, but the resulting evidence was weak and inconclusive.^[242]^[243]^[244] There were two small controlled studies with conflicting results, and no large, long-term, randomized controlled studies.^[31] Therefore, the benefit of using modafinil for the treatment of multiple sclerosis-related fatigue was not confirmed.^[31]

Postural orthostatic tachycardia syndrome

Caution should be exercised in patients who have narcolepsy in comorbidity with postural orthostatic tachycardia syndrome (POTS). Modafinil, like other centrally acting stimulants prescribed for patients in narcolepsy, increases POTS-related autonomic dysfunction and results in tachycardia/arrhythmia side effects in patients with cardiovascular risk factors. Sodium oxybate, a metabolite of GABA, is an alternative drug for stimulant-intolerant patients with POTS.^[245]

Inflammation

There is limited research on the potential use of modafinil as an anti-inflammatory agent,^[246]^[247] even though some studies predict that modafinil may have anti-inflammatory effects.^[248]^[249]

One probable explanation of the drug's supposed anti-inflammatory properties is that that modafinil may modulate the production of nitric oxide in various cells, potentially leading to anti-inflammatory effects.^[249]^[250] Nitric oxide is a signaling molecule that plays a complex role in inflammation.^[251]^[252] It is produced by a variety of cells in the body, including immune cells,^[253] and can have both pro-inflammatory and anti-inflammatory effects depending on the context.^[254]^[255] In a 2018 study, researchers noticed that modafinil reduced the production of pro-inflammatory cytokines in vitro in mouse brain cells.^[256] In a 2020 study, scholars observed modafinil reduced inflammation and oxidative stress in the brains of rats with traumatic brain injury.^[257] In a 2023 study, modafinil reduced neuroinflammation in rats induced by propionic acid.^[258]

Another probable explanation is that modafinil may exert anti-inflammatory effects by upregulating adenosine A2A and A2B receptors. These receptors activate cyclic adenosine monophosphate signaling, which suppresses inflammation and fibrosis. This suggests that modafinil's ability to upregulate these receptors may serve as a potential therapy for fibrotic diseases.^[259] In a 2020 in vitro study, using in nonalcoholic hepatitis human cell model, the authors predicted that modafinil may reduce inflammatory and fibrotic progression in the human liver.^[247]

The results of studies on the potential anti-inflammatory properties of modafinil still need to be more conclusive.^[247]

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@@ Line 308: / Line 308: @@
 ===Patent protection and litigation===
+Modafinil's patent history involves several key developments. The original patent, {{US patent|4927855}}, was granted to Laboratoire L. Lafon in 1990, covering the chemical compound of modafinil. This patent expired in 2010.<ref name="patent4927855">{{cite patent|number=4927855|country=US}}</ref> In 1994, Cephalon filed a patent for modafinil in the form of particles of a defined size, represented by {{US patent|5618845}}, which expired in 2015.<ref>{{cite web |url=http://www.bizjournals.com/philadelphia/stories/2006/03/27/daily13.html |title=Cephalon gets six-month Provigil patent extension |publisher=Philadelphia Business Journal |date=March 28, 2006 |access-date=July 21, 2007 |archive-date=August 4, 2008 |archive-url=https://web.archive.org/web/20080804204005/http://www.bizjournals.com/philadelphia/stories/2006/03/27/daily13.html |url-status=live }}</ref>
-{{US patent|4927855}} was issued to Laboratoire L. Lafon on May 22, 1990, covering the chemical compound modafinil. After receiving an interim term extension of 1066&nbsp;days and [[pediatric exclusivity]] of six months, the patent expired on October 22, 2010.<ref name="patent4927855">{{cite patent|number=4927855|country=US}}</ref>
-On October 6, 1994, Cephalon filed an additional patent, covering modafinil in the form of particles of defined size. That patent, {{US patent|5618845}} was issued on April 8, 1997. It was reissued in 2002 as RE&nbsp;37,516, which surrendered the 5618845 patent. With pediatric exclusivity, this patent expired on April 6, 2015.<ref>{{cite news |url=http://www.bizjournals.com/philadelphia/stories/2006/03/27/daily13.html |title=Cephalon gets six-month Provigil patent extension |publisher=Philadelphia Business Journal |date=March 28, 2006 |access-date=July 21, 2007 |archive-date=August 4, 2008 |archive-url=https://web.archive.org/web/20080804204005/http://www.bizjournals.com/philadelphia/stories/2006/03/27/daily13.html |url-status=live }}</ref><ref>{{cite web |url=http://www.drugpatentwatch.com/ultimate/preview/patent/index.php?query=RE37516 |title=Details for Patent: RE37516 |access-date=November 29, 2009 |archive-date=January 1, 2014 |archive-url=https://web.archive.org/web/20140101192226/http://www.drugpatentwatch.com/ultimate/preview/patent/index.php?query=RE37516 |url-status=live }}</ref>
+Following the nearing expiration of marketing rights in 2002, generic manufacturers, including Mylan and Teva, applied for FDA approval to market a generic form of modafinil, leading to legal challenges by Cephalon regarding the particle size patent<ref>{{cite web |url=http://www.drugpatentwatch.com/ultimate/preview/patent/index.php?query=RE37516 |title=Details for Patent: RE37516 |access-date=November 29, 2009 |archive-date=January 1, 2014 |archive-url=https://web.archive.org/web/20140101192226/http://www.drugpatentwatch.com/ultimate/preview/patent/index.php?query=RE37516 |url-status=live }}</ref>. The patent RE&nbsp;37,516 was declared invalid and unenforceable in 2011.<ref>{{cite web |url=http://law.justia.com/cases/federal/district-courts/pennsylvania/paedce/2:2006cv02768/205626/514 |title=Document 514 :: APOTEX, INC. v. CEPHALON, INC. et al |publisher=Pennsylvania Eastern District Court :: US Federal District Courts Cases :: Justia |date=October 31, 2010 |access-date=July 4, 2012 |archive-date=January 1, 2014 |archive-url=https://web.archive.org/web/20140101044356/http://law.justia.com/cases/federal/district-courts/pennsylvania/paedce/2:2006cv02768/205626/514 |url-status=live }}</ref>
+In addition, Cephalon entered agreements with several generic drug manufacturers to delay the sale of generic modafinil in the US. These agreements were subject to legal scrutiny and antitrust investigations, culminating in a ruling by the Court of Appeals in 2016, which found that the settlements did not violate antitrust laws.<ref>{{cite court|court=Court of Appeals, 3rd Circuit|litigants=IN RE: MODAFINIL ANTITRUST LITIGATION|date=2016}}</ref>
-On December 24, 2002, anticipating the expiration of exclusive marketing rights, generic drug manufacturers [[Mylan]], [[Teva Pharmaceuticals|Teva]], [[Barr Pharmaceuticals|Barr]], and [[Ranbaxy]] applied to the [[Food and Drug Administration|FDA]] to market a generic form of modafinil.<ref>{{cite web |title=Prescription Access Litigation (PAL) Project :: Prescription Access Litigation (PAL) Project :: Lawsuits & Settlements :: Current Lawsuits |publisher=Prescriptionaccess.org |url=http://www.prescriptionaccess.org/lawsuitssettlements/current_lawsuits?id=0024 |archive-date=June 19, 2012 |archive-url=https://web.archive.org/web/20120619012234/http://www.prescriptionaccess.org/lawsuitssettlements/current_lawsuits?id=0024 |url-status=dead }}</ref> At least one withdrew its application after early opposition by Cephalon based on the RE&nbsp;37,516 patent. There is uncertainty about whether a particle size patent is sufficient protection against the manufacture of generics: including 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" of this sort are required.<ref>{{Cite web |title=EU fines Teva and Cephalon €60.5m for 'pay for delay' scheme |url=https://pharmaphorum.com/news/eu-fines-teva-and-cephalon-e60-5m-for-pay-for-delay-scheme |access-date=2023-11-15 |website=pharmaphorum |language=en}}</ref>
-On October 31, 2011, US Reissue Patent No. RE&nbsp;37,516 was declared invalid and unenforceable.<ref>{{cite web |url=http://law.justia.com/cases/federal/district-courts/pennsylvania/paedce/2:2006cv02768/205626/514 |title=Document 514 :: APOTEX, INC. v. CEPHALON, INC. et al |publisher=Pennsylvania Eastern District Court :: US Federal District Courts Cases :: Justia |date=October 31, 2010 |access-date=July 4, 2012 |archive-date=January 1, 2014 |archive-url=https://web.archive.org/web/20140101044356/http://law.justia.com/cases/federal/district-courts/pennsylvania/paedce/2:2006cv02768/205626/514 |url-status=live }}</ref> The District Court for the Eastern District of Pennsylvania ruled that RE&nbsp;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&nbsp;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&nbsp;U.S.C. section 103(a); and (4) failed the written description requirement of 35&nbsp;U.S.C. section 112.<ref name="url_Justia">{{cite web |url=http://law.justia.com/cases/federal/district-courts/pennsylvania/paedce/2:2006cv02768/205626/513 |title=Document 513 :: APOTEX, INC. v. CEPHALON, INC. et al |date=October 31, 2010 |publisher=Pennsylvania Eastern District Court :: US Federal District Courts Cases :: Justia |access-date=July 4, 2012 |archive-date=January 1, 2014 |archive-url=https://web.archive.org/web/20140101044917/http://law.justia.com/cases/federal/district-courts/pennsylvania/paedce/2:2006cv02768/205626/513 |url-status=live }}</ref> The patent was also found to be unenforceable due to Cephalon's inequitable conduct during patent prosecution.<ref name="url_Justia" />
-Cephalon made an agreement with four major generics manufacturers [[Teva Pharmaceutical Industries|Teva]], [[Barr Pharmaceuticals]], [[Ranbaxy Laboratories]], and [[Actavis|Watson Pharmaceuticals]] between 2005 and 2006 to [[Reverse payment patent settlement|delay]] sales of generic modafinil in the US until April 2012 by these companies in exchange for upfront and royalty payments.<ref>{{cite web |url=https://www.sec.gov/Archives/edgar/data/873364/000104746909001690/a2190556z10-k.htm |title=Cephalon Inc., SEC 10K 2008 disclosure |pages=9–10 |date=February 23, 2009 |access-date=August 29, 2009 |archive-date=August 27, 2017 |archive-url=https://web.archive.org/web/20170827173309/https://www.sec.gov/Archives/edgar/data/873364/000104746909001690/a2190556z10-k.htm |url-status=live }}</ref><ref>{{cite news |title=CVS, Rite Aid Sue Cephalon Over Generic Provigil |url=https://www.bloomberg.com/apps/news?pid=20601103&sid=arNEtMSU7D9s |access-date=August 29, 2009 |publisher=Bloomberg News |date=August 21, 2009 }}</ref>
-This agreement was challenged by a class of wholesalers who bought Provigil directly from Cephalon, who claimed that Cephalon and the generic manufacturers conspired to keep the modafinil price artificially high and violated antitrust laws. The plaintiffs brought a case to the United States District Court for the Eastern District of Pennsylvania in 2006. They alleged that Cephalon, the patent holder of Provigil, and four generic drug manufacturers (Teva, Ranbaxy, Mylan, and Barr) entered into unlawful reverse payment settlements that delayed the entry of generic modafinil into the market and maintained Cephalon's monopoly. The plaintiffs claimed that they paid artificially inflated prices for Provigil due to the anticompetitive agreements. The plaintiffs sought damages and injunctive relief under the Sherman Act and various state laws. The district court dismissed the plaintiffs' claims in 2015, finding that they failed to allege that the settlements were anticompetitive plausibly. The court applied the rule of reason analysis, which weighs the procompetitive and anticompetitive effects of an agreement, and concluded that the plaintiffs did not show that the generic manufacturers would have entered the market earlier absent the settlements or that the patent was invalid or not infringed. The court also found that the settlements had some procompetitive benefits, such as allowing early entry of generic modafinil before the patent expired and providing compensation to consumers. The plaintiffs appealed to the Third Circuit Court of Appeals, which affirmed the district court's decision in 2016.  Therefore, the court concluded that the settlements did not violate antitrust laws.<ref>{{cite court|court=Court of Appeals, 3rd Circuit|litigants=IN RE: MODAFINIL ANTITRUST LITIGATION|date=2016}}</ref>
-[[Apotex]] received regulatory approval in Canada despite a suit from Cephalon's marketing partner in Canada, [[Shire Pharmaceuticals]].<ref>{{cite web |url=http://www.mondaq.com/article.asp?articleid=71906 |title=Canada IP Year in Review 2008 |date=January 1, 2009 |access-date=August 29, 2009 |archive-date=January 5, 2020 |archive-url=https://web.archive.org/web/20200105003822/http://www.mondaq.com/article.asp?articleid=71906 |url-status=live }}</ref><ref>{{cite web |title=Shire v. Canada |url=http://reports.fja-cmf.gc.ca/eng/2008/2008fc538/2008fc538.html |archive-url=https://web.archive.org/web/20100424223342/http://reports.fja-cmf.gc.ca/eng/2008/2008fc538/2008fc538.html |archive-date=April 24, 2010 |url-status=dead }}</ref> Cephalon sued Apotex in the US to prevent it from releasing a genericized armodafinil (Nuvigil).<ref>{{cite web |url=http://www.zacks.com/stock/news/39048/Cephalon+Sues+Apotex |title=Cephalon Sues Apotex |publisher=Zacks.com |date=August 20, 2010 |access-date=July 4, 2012 |archive-url=https://web.archive.org/web/20120305081801/http://www.zacks.com/stock/news/39048/Cephalon+Sues+Apotex |archive-date=March 5, 2012 |url-status=dead }}</ref> 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;<ref>"{{cite web |title=U.S. Federal Trade Commission Clears Teva's Acquisition of Cephalon |publisher=Business Wire |date=October 7, 2011 |url=http://www.thefreelibrary.com/U.S.+Federal+Trade+Commission+Clears+Teva%27s+Acquisition+of+Cephalon.-a0268983036 |quote=Teva will also grant non-exclusive U.S. rights to an undisclosed company to market modafinil tablets, the generic version of Provigil(R), which had annual brand sales in the U.S. of approximately $1.1&nbsp;billion |archive-date=April 18, 2016 |archive-url=https://web.archive.org/web/20160418230704/http://www.thefreelibrary.com/U.S.+Federal+Trade+Commission+Clears+Teva%27s+Acquisition+of+Cephalon.-a0268983036 |url-status=dead }}</ref> ultimately, [[Par Pharmaceutical]] acquired the US modafinil rights as well as some others.<ref name="url_Par_Pharmaceutical">{{cite web |url=http://www.prnewswire.com/news-releases/par-pharmaceutical-acquires-three-generic-products-from-teva-pharmaceuticals-132044783.html |title=Par Pharmaceutical Acquires Three Generic Products From Teva Pharmaceuticals |date=October 18, 2011 |work=Press Release |publisher=PRNewswire |access-date=July 4, 2012 |archive-date=April 16, 2012 |archive-url=https://web.archive.org/web/20120416024853/http://www.prnewswire.com/news-releases/par-pharmaceutical-acquires-three-generic-products-from-teva-pharmaceuticals-132044783.html |url-status=live }}</ref>
-In the United Kingdom, [[Mylan Inc.]] received regulatory approval to sell generic modafinil produced by [[Orchid pharma|Orchid]] in January 2010; Cephalon sued to prevent sale, but lost the patent trial.<ref>{{cite news | vauthors = Larson E |title=Cephalon Loses U.K. Bid to Halt Mylan, Orchid Generic-Drug Sales |publisher=bloomberg LP |date=November 19, 2010 |url=https://www.bloomberg.com/news/2010-11-19/cephalon-loses-u-k-bid-to-halt-mylan-orchid-generic-drug-sales.html |archive-url=https://web.archive.org/web/20101125113021/http://www.bloomberg.com/news/2010-11-19/cephalon-loses-u-k-bid-to-halt-mylan-orchid-generic-drug-sales.html |archive-date=November 25, 2010 |url-status=live |access-date=January 28, 2019 }}</ref>
 ==Society and culture==

v t e Stimulants
Adamantanes	Adapromine Amantadine Bromantane Memantine Rimantadine
Adenosine antagonists	8-Chlorotheophylline 8-Cyclopentyltheophylline 8-Phenyltheophylline Aminophylline Caffeine CGS-15943 Dimethazan Istradefylline Paraxanthine SCH-58261 Theobromine Theophylline
Alkylamines	Cyclopentamine Cypenamine Cyprodenate Heptaminol Isometheptene Levopropylhexedrine Methylhexaneamine Octodrine Propylhexedrine Tuaminoheptane
Ampakines	CX-516 CX-546 CX-614 CX-691 CX-717 IDRA-21 LY-404,187 LY-503,430 Nooglutyl Org 26576 PEPA S-18986 Sunifiram Unifiram
Arylcyclohexylamines	Benocyclidine Dieticyclidine Esketamine Eticyclidine Gacyclidine Ketamine Phencyclamine Phencyclidine Rolicyclidine Tenocyclidine Tiletamine
Benzazepines	6-Br-APB SKF-77434 SKF-81297 SKF-82958
Cathinones	3-Fluoromethcathinone 3,4-DMMC 4-BMC 4-CMC 4-Methylbuphedrone 4-Methylcathinone 4-MEAP 4-Methylpentedrone Amfepramone Benzedrone Buphedrone Bupropion Butylone Cathinone Dimethylcathinone Ethcathinone Ethylone Flephedrone Hexedrone Isoethcathinone Mephedrone Methcathinone Methedrone Methylenedioxycathinone Methylone Mexedrone N-Ethylbuphedrone N-Ethylhexedrone Pentedrone Pentylone Phthalimidopropiophenone
Cholinergics	A-84,543 A-366,833 ABT-202 ABT-418 AR-R17779 Altinicline Anabasine Arecoline Bradanicline Cotinine Cytisine Dianicline Epibatidine Epiboxidine GTS-21 Ispronicline Nicotine PHA-543,613 PNU-120,596 PNU-282,987 Pozanicline Rivanicline Sazetidine A SIB-1553A SSR-180,711 TC-1698 TC-1827 TC-2216 Tebanicline UB-165 Varenicline WAY-317,538
Convulsants	Anatoxin-a Bicuculline DMCM Flurothyl Gabazine Pentetrazol Picrotoxin Strychnine Thujone
Eugeroics	Adrafinil Armodafinil CRL-40,940 CRL-40,941 Fluorenol Modafinil
Oxazolines	4-Methylaminorex Aminorex Clominorex Cyclazodone Fenozolone Fluminorex Pemoline Thozalinone
Phenethylamines	1-(4-Methylphenyl)-2-aminobutane 1-Methylamino-1-(3,4-methylenedioxyphenyl)propane 2-Fluoroamphetamine 2-Fluoromethamphetamine 2-OH-PEA 2-Phenyl-3-aminobutane 2,3-MDA 3-Fluoroamphetamine 3-Fluoroethamphetamine 3-Methoxyamphetamine 3-Methylamphetamine 4-Fluoroamphetamine 4-Fluoromethamphetamine 4-MA 4-MMA 4-MTA 6-FNE AL-1095 Alfetamine a-Ethylphenethylamine Amfecloral Amfepentorex Amidephrine 2-Amino-1,2-dihydronaphthalene 2-Aminoindane 5-(2-Aminopropyl)indole 2-Aminotetralin Acridorex Amphetamine (Dextroamphetamine, Levoamphetamine) Amphetaminil Arbutamine β-Methylphenethylamine β-Phenylmethamphetamine Benfluorex Benzphetamine BDB BOH 3-Benzhydrylmorpholine BPAP Camfetamine Cathine Chlorphentermine Cilobamine Cinnamedrine Clenbuterol Clobenzorex Cloforex Clortermine Cypenamine D-Deprenyl Denopamine Dimethoxyamphetamine Dimethylamphetamine Dobutamine DOPA (Dextrodopa, Levodopa) Dopamine Dopexamine Droxidopa EBDB Ephedrine Epinephrine Epinine Etafedrine Ethylnorepinephrine Etilamfetamine Etilefrine Famprofazone Fencamfamin Fencamine Fenethylline Fenfluramine (Dexfenfluramine, Levofenfluramine) Fenproporex Feprosidnine Fludorex Formetorex Furfenorex Gepefrine Hexapradol HMMA Hordenine 4-Hydroxyamphetamine 5-Iodo-2-aminoindane Ibopamine Indanylamphetamine Iofetamine Isoetarine Isoprenaline L-Deprenyl (Selegiline) Lefetamine Lisdexamfetamine Lophophine MBDB MDA (tenamfetamine) MDBU MDEA MDMA (midomafetamine) MDMPEA MDOH MDPR MDPEA Mefenorex Mephentermine Metanephrine Metaraminol Mesocarb Methamphetamine (Dextromethamphetamine, Levomethamphetamine) Methoxamine Methoxyphenamine MMA Methoxyphenamine MMDA MMDMA MMMA Morforex N,alpha-Diethylphenylethylamine N,N-Dimethylphenethylamine Naphthylamphetamine Nisoxetine Norepinephrine Norfenefrine Norfenfluramine Normetanephrine L-Norpseudoephedrine Octopamine Orciprenaline Ortetamine Oxifentorex Oxilofrine PBA PCA PCMA PHA Pentorex Phenatine Phenpromethamine Phentermine Phenylalanine Phenylephrine Phenylpropanolamine Pholedrine PIA PMA PMEA PMMA PPAP Prenylamine Propylamphetamine Pseudoephedrine Ropinirole Salbutamol (Levosalbutamol) Sibutramine Solriamfetol Synephrine Theodrenaline Tiflorex Tranylcypromine Tyramine Tyrosine Xylopropamine Zylofuramine
Phenylmorpholines	3-Fluorophenmetrazine Fenbutrazate Fenmetramide G-130 Manifaxine Morazone Morforex Oxaflozane PD-128,907 Phendimetrazine Phenmetrazine 2-Phenyl-3,6-dimethylmorpholine Pseudophenmetrazine Radafaxine
Piperazines	2C-B-BZP 3C-PEP BZP CM156 DBL-583 GBR-12783 GBR-12935 GBR-13069 GBR-13098 GBR-13119 MeOPP MBZP oMPP Vanoxerine
Piperidines	1-Benzyl-4-(2-(diphenylmethoxy)ethyl)piperidine 2-Benzylpiperidine 2-Methyl-3-phenylpiperidine 3,4-Dichloromethylphenidate 4-Benzylpiperidine 4-Fluoromethylphenidate 4-Methylmethylphenidate Desoxypipradrol Difemetorex Diphenylpyraline Ethylnaphthidate Ethylphenidate Methylnaphthidate Isopropylphenidate JZ-IV-10 Methylphenidate (Dexmethylphenidate) Nocaine Phacetoperane Pipradrol Propylphenidate Serdexmethylphenidate SCH-5472
Pyrrolidines	2-Diphenylmethylpyrrolidine 4-Cl-PVP 5-DBFPV α-PPP α-PBP α-PCYP α-PHiP α-PHP α-PHPP α-PVP α-PVT Diphenylprolinol DMPVP FPOP FPVP MDPPP MDPBP MPBP MPHP MPPP MOPVP MOPPP Indapyrophenidone MDPV Naphyrone PEP Picilorex Prolintane Pyrovalerone
Racetams	Oxiracetam Phenylpiracetam Phenylpiracetam hydrazide
Tropanes	4-fluorotropacocaine 4'-Fluorococaine Altropane (IACFT) Brasofensine CFT (WIN 35,428) β-CIT (RTI-55) Cocaethylene Cocaine Dichloropane (RTI-111) Difluoropine FE-β-CPPIT FP-β-CPPIT Ioflupane (¹²³I) Norcocaine PIT PTT RTI-31 RTI-32 RTI-51 RTI-112 RTI-113 RTI-120 RTI-121 (IPCIT) RTI-126 RTI-150 RTI-177 RTI-229 RTI-336 RTI-354 RTI-371 RTI-386 Salicylmethylecgonine Tesofensine Troparil (β-CPT, WIN 35,065-2) Tropoxane WF-23 WF-33
Tryptamines	4-HO-αMT 4-Methyl-αET 4-Methyl-αMT 5-Chloro-αMT 5-Fluoro-αMT 5-MeO-αET 5-MeO-αMT 5-MeO-DIPT 6-Fluoro-αMT 7-Methyl-αET αET αMT
Others	2-MDP 3,3-Diphenylcyclobutanamine Amfonelic acid Amineptine Amiphenazole Atipamezole Atomoxetine Bemegride Benzydamine BTQ BTS 74,398 Centanafadine Ciclazindol Clofenciclan Cropropamide Crotetamide D-161 Desipramine Diclofensine Dimethocaine Efaroxan Etamivan Fenisorex Fenpentadiol Gamfexine Gilutensin GSK1360707F GYKI-52895 Hexacyclonate Idazoxan Indanorex Indatraline JNJ-7925476 Lazabemide Leptacline Lomevactone LR-5182 Mazindol Meclofenoxate Medifoxamine Mefexamide Methamnetamine Methastyridone Methiopropamine Naphthylaminopropane Nefopam Nikethamide Nomifensine O-2172 Oxaprotiline PNU-99,194 PRC200-SS Rasagiline Rauwolscine Rubidium chloride Setazindol Tametraline Tandamine Thiopropamine Thiothinone Trazium UH-232 Yohimbine
ATC code: N06B

Revision as of 05:09, 2 December 2023

Usage

Medical

Sleep disorders

Multiple sclerosis-related fatigue

Attention deficit hyperactivity disorder

Bipolar depression

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Addiction and dependence

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Mechanism of action

Dopamine reuptake inhibitor

Dopamine transporter-independent actions

Dopamine D2 receptor partial agonist

Dampening of amygdala activity

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Psychiatric conditions

Major depression

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Treatment of cocaine addiction

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Cognitive enhancement

Post-anesthesia sedation

Multiple sclerosis-related fatigue (research)

Postural orthostatic tachycardia syndrome

Inflammation

References

Dopamine D₂ receptor partial agonist