Modafinil
Eugeroic medication / From Wikipedia, the free encyclopedia
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Modafinil, sold under the brand name Provigil among others, is a wakefulness-promoting medication used primarily to treat narcolepsy.[3][8][12] Modafinil is also approved for stimulating wakefulness in people with sleep apnea and shift work sleep disorder.[3] It is taken by mouth.[3][8] Modafinil is not approved by the US Food and Drug Administration (FDA) for use in people under age 17.[8]
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Trade names | Provigil, Alertec, Modavigil, others |
Other names | CRL-40476; Diphenylmethyl-sulfinylacetamide |
AHFS/Drugs.com | Monograph |
MedlinePlus | a602016 |
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Dependence liability | Relatively low[2] |
Addiction liability | Low[2] |
Routes of administration | By mouth[3] |
Drug class | CNS stimulant eugeroic |
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Pharmacokinetic data | |
Protein binding | 62.3% |
Metabolism | Liver (primarily via amide hydrolysis);[9] CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5 involved[10] |
Elimination half-life | 12–15 h[9] |
Duration of action | 11.5 h[11] |
Excretion | Urine (80%) |
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ECHA InfoCard | 100.168.719 |
Chemical and physical data | |
Formula | C15H15NO2S |
Molar mass | 273.35 g·mol−1 |
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Modafinil has potential for causing severe allergic reactions, mental (psychiatric) effects,[3] hypersensitivity, adverse interactions with prescription drugs, and misuse or abuse.[3][8][12] Modafinil may harm the fetus if taken during or two months prior to pregnancy.[13]
While modafinil is used as a cognitive enhancer or "smart drug" among healthy individuals seeking improved focus and productivity,[14][15] its use outside medical supervision raises concerns regarding potential misuse or abuse.[3][8][16] Research on the cognitive enhancement effects of modafinil in non-sleep-deprived individuals has yielded mixed results, with some studies suggesting modest improvements in attention and executive functions, while others show no significant benefits or even a decline in cognitive functions.[17][18]
Medical
Sleep disorders
Modafinil, a eugeroic or wakefulness-promoting drug, is primarily used for treating narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and sudden sleep attacks.[19] Being a central nervous system (CNS) stimulant (psychostimulant) itself, modafinil has lower addictive potential than classical psychostimulants, such as amphetamines, cocaine or methylphenidate,[11][20][21] but still produces psychoactive, euphoric, and subjective effects typical of classical stimulants.[3][8][16]
Narcolepsy causes a strong urge to sleep during the day and can include symptoms like cataplexy (sudden muscle weakness), sleep paralysis (inability to move or speak while falling asleep or waking up), and hallucinations. Narcolepsy is linked to a lack of the brain chemical hypocretin (or orexin), primarily produced in the hypothalamus.[22][23] Modafinil is not a cure for narcolepsy, but it can help manage the symptoms. While modafinil is primarily used to treat excessive sleepiness, it may also help reduce the frequency and severity of cataplexy attacks in some people. Modafinil is approved for management of narcolepsy with or without cataplexy. However, it is not specifically approved for the treatment of cataplexy.[24][25]
Modafinil is also prescribed for shift work sleep disorder and excessive daytime sleepiness caused by obstructive sleep apnea, though it is recommended that people with apnea use continuous positive airway pressure (CPAP) therapy before starting modafinil.[8][18][26]
Modafinil's use varies by region. In the US, it is approved for adult narcolepsy, shift work sleep disorder, and obstructive sleep apnea, but not for children.[16] In the UK and the EU, since 2014, it is approved solely for narcolepsy, including in children (pediatric narcolepsy), with its use for other conditions restricted by the European Medicines Agency.[24][27]
As of 2024,[update] both the French and the American Academy of Sleep Medicine strongly recommend modafinil as the first-choice treatment for narcolepsy.[28] In Europe, modafinil is considered one of the primary drugs recommended for treating narcolepsy according to the guidelines.[29]
Multiple sclerosis-related fatigue
The National Institute for Health and Care Excellence (NICE) in the UK, along with various non-governmental organizations focused on multiple sclerosis (MS), endorse the off-label use of modafinil to alleviate fatigue associated with MS.[16][30][31]
MS-related fatigue is a common and often debilitating symptom experienced by people with multiple sclerosis.[32][33][34][35] It can significantly impact their daily functioning, quality of life, and ability to perform everyday activities. When prescribed for MS-related fatigue management, modafinil works by promoting wakefulness and increasing alertness without causing drowsiness or disrupting nighttime sleep. People with multiple sclerosis often report increased energy levels, reduced feelings of tiredness, improved cognitive function, and an overall improvement in their quality of life when taking modafinil. While modafinil can provide relief from MS-related fatigue symptoms, it does not treat the underlying cause or cure MS itself. The primary goal of using modafinil in MS is symptom management and improving daily functioning.[34][35][36] The effects of modafinil on other aspects of MS-related fatigue, such as severity and cognitive function, are less clear.[37]
While modafinil has been shown to be effective in managing fatigue in people with MS, optimal dosing and treatment schedules are not well established.[34][35][36][37]
Attention deficit hyperactivity disorder
Modafinil is occasionally prescribed off-label for individuals with attention deficit hyperactivity disorder (ADHD).[38][39][40] It has shown no efficacy in treating adult ADHD, especially when compared to other treatments such as lisdexamfetamine.[41][42] In children, modafinil is efficient in treating ADHD symptoms.[43][44]
Given its approved status in the US to treat narcolepsy, physicians can also prescribe modafinil for off-label uses, such as treating ADHD in both children and adults.[45][46][47]
The Canadian Network for Mood and Anxiety Treatments (CANMAT) suggests modafinil as a second-line choice for ADHD, after the first-line choices such as bupropion are exhausted.[48]
Bipolar disorder
Modafinil is used off-label as an adjunctive treatment (i.e., in combination therapy) for acute depressive phase in bipolar disorder.[49][50][51][52] The depressive phase of bipolar disorder may feature excessive sleepiness and fatigue. Adjunctive treatment with modafinil can be used as an augmentation for the main treatment to increase its effect and is safe and effective, especially for people who do not respond well to standard antidepressants.[53][54] Modafinil does not significantly increase the risk of mood switch to mania or suicide attempts in people with bipolar disorder.[55][53] Modafinil may also have cognitive benefits in people with bipolar disorder who are in a remission state.[56][57]
Whereas modafinil and armodafinil are approved for narcolepsy, they have been repurposed as adjunctive treatments to alleviate symptoms of acute depressive phase in people with bipolar disorder.[58] Drug repurposing in psychiatry is a strategy for discovering new uses for drugs that have already been approved or tested in clinical trials for other illnesses. As such, drug repurposing is a rapid, cost-effective, and reduced-risk strategy for the development of new treatment options for psychiatric disorders.[58] 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.[58][59] Very low rates of mood swing (a change in mood from one extreme to another)[55][60] have been observed with modafinil and armodafinil in depressive phase of bipolar disorder.[51][61]
Occupational
Modafinil was used by the French Foreign Legion,[62] U.S. Air Force,[63][64] and U.S. Marine[65] infantry during the Gulf War to enhance "operational tempo" (a term that denotes the speed and intensity at which military operations or activities are executed), aiming to optimize the overall performance and efficiency of the unit.[64][66][67]
Armed forces in various countries, including the United States, the United Kingdom, India, and France, have considered modafinil as an alternative to traditional amphetamines for managing sleep deprivation in combat or extended missions.[68] The US military approved modafinil for specific Air Force missions, replacing amphetamines for fatigue management.[69] The use of modafinil in military contexts without sleep deprivation is not recommended due to inconclusive evidence on its cognitive enhancement benefits and potential risks of adverse effects.[63]
Modafinil is also available to astronauts aboard the International Space Station for the management of fatigue caused by circadian dyssynchrony in orbit.[70]
Non-medical
Modafinil has been used non-medically as a "smart drug"[14][15] by various groups, including students,[71][72][73] office workers, transhumanists,[74][75] and professionals in various sectors. Its use is attributed by these individuals to its potential for enhancing attention, cognitive capabilities, and alertness.[76][77]
The effectiveness of modafinil as cognitive enhancer is still debated. Some studies suggest significant increases in cognitive abilities, while others indicate mild to non existent cognitive improvements.[78][79][49][80] In some cases, it has even been associated with impairments in certain cognitive functions.[17][18][81] It has been shown that modafinil's positive impact on cognitive abilities is more noticeable on sleep deprived individuals.[82] Therefore, in people who are not sleep-deprived, the potential of modafinil as a cognitive enhancer may be limited.[83]
Modafinil is commercially available in 100 mg and 200 mg oral tablet forms.[8] Additionally, it is offered as the (R)-enantiomer, known as armodafinil, and as a prodrug named adrafinil.[84]
Modafinil is contraindicated during pregnancy and 2 months before getting pregnant.[85] Women who take modafinil should not become pregnant, and, additionally, should be aware that modafinil reduces effectiveness of hormonal contraceptives, increasing chances of getting pregnant.[8][12][86] Modafinil therapy during pregnancy increases the risk of birth defects,[13][87][88][85] such as with congenital torticollis, hypospadias, and congenital heart defects.[87]
Modafinil is contraindicated for individuals with known hypersensitivity to either modafinil or armodafinil.[8][11]
Modafinil is also contraindicated in certain cardiac conditions, including uncontrolled moderate to severe hypertension, arrhythmia, cor pulmonale,[89][90] and in cases with signs of CNS stimulant-induced mitral valve prolapse or left ventricular hypertrophy.[91][92] The package insert in the United States cautions about using modafinil in people with a documented medical history of left ventricular hypertrophy or those diagnosed with mitral valve prolapse who have previously exhibited symptoms associated with the mitral valve prolapse syndrome while undergoing treatment involving central nervous system stimulants.[93] The reasons why modafinil is contraindicated in certain cardiac conditions are because modafinil affects the autonomic nervous system and, in particular, exerts significant effects on autonomic cardiovascular regulation, leading in some people to notable increases in heart rate and blood pressure. These substantial changes in the autonomic system warrant careful consideration when prescribing modafinil to people with pre-existing cardiovascular conditions.[94] The increase in heart rate and blood pressure can worsen the symptoms of such pre-existing conditions as hypertension, arrhythmia, and cor pulmonale. These changes in the autonomic system induced by modafinil can increase the risk of heart attack, stroke, and heart failure. Modafinil can stimulate the release of norepinephrine and epinephrine, hormones that activate the sympathetic nervous system. This can cause vasoconstriction, which is the narrowing of blood vessels, and increase the heart's workload, which is not desired in people with pre-existing heart conditions. In particular, modafinil can worsen the consequences of mitral valve prolapse or left ventricular hypertrophy, which are structural abnormalities of the heart. These can affect the blood flow and oxygen delivery to the heart and other organs.[95]
Modafinil is also contraindicated in people with congenital problems like galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.[96][89][90]
Modafinil is generally well-tolerated but can have potential risks and side effects. Common adverse effects of modafinil, experienced by less than 10% of users, include headaches, nausea, and reduced appetite.[97][98][16] Anxiety, insomnia, dizziness, diarrhea, and rhinitis are also reported in 5% to 10% of users.[16] Psychiatric reactions have occurred in individuals with and without a preexisting psychiatric history.[99]
No significant changes in body weight have been observed in clinical trials, although decreased appetite and weight loss have been noted in children and adolescents.[100] Modafinil can cause a slight increase in aminotransferase enzymes, indicative of liver function, but there is no evidence of serious liver damage when levels are within reference ranges.[101]
Rare but serious adverse effects include severe skin rashes and allergy-related symptoms. Between December 1998 and January 2007, the FDA received reports of six cases of severe cutaneous adverse reactions, including erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, and DRESS syndrome. The FDA has issued alerts regarding these risks and also noted reports of angioedema and multi-organ hypersensitivity reactions in postmarketing surveillance.[102][103] In 2007, the FDA required Cephalon to modify the Provigil leaflet to include warnings about these serious conditions. The long-term safety and effectiveness of modafinil have not been conclusively established.[104]
The FDA does not endorse modafinil for children's medical conditions due to an increased risk of rare but serious dermatological toxicity (Stevens–Johnson syndrome).[105][56][106] However, in Europe, modafinil may be prescribed for treating narcolepsy in children.[107]
Extensive clinical research has not demonstrated drug tolerance, defined as a reduction in response, to wakefulness-promoting and anti-fatigue properties of modafinil, even with therapeutic use extending up to 40 weeks.[108][109][104]
While modafinil is generally found to be safe and significant adverse effects are rare, including in pediatric narcolepsy cases (sleep disorders in children), there is evidence that long-term usage can lead to tolerance in some individuals.[18] This necessitates higher doses to maintain the same level of cognitive enhancement or relief from sleepiness.[18]
People with current or past substance addictions and those with a family history of addiction are particularly at risk for developing tolerance.[18][107][110]
The mechanisms driving tolerance to modafinil, which may involve its impact on dopamine and norepinephrine levels in the brain, are not fully understood.[18][107][110]
Repeated administration of modafinil for off-label use, such as increased alertness and cognitive-enhancing effects in sleep deprivation, can lead to drug tolerance, which means that the effectiveness of the drug may decrease over time. Still, modafinil therapy as a eugeroic agent to treat narcolepsy does not typically lead to drug tolerance, i.e., the effectiveness does not usually decrease on prolonged use, although individual responses may vary.[18][107][110]
Despite being a CNS stimulant, the addiction and dependence liabilities of modafinil are considered low.[8][2][21][111] The exact mechanisms of action of modafinil are not known,[112] and it is believed that pharmacological profile of modafinil is different from that of the classical stimulants.[11] Although modafinil shares biochemical mechanisms with stimulant drugs, it is less likely to have mood-elevating properties.[8] The similarities in effects with caffeine are not clearly established.[11][113] Unlike other stimulants, modafinil does not induce a strong subjective feeling of pleasure or reward, which is commonly associated with euphoria, an intense feeling of well-being.[18] Euphoria is a potential indicator of drug abuse, which is the compulsive and excessive use of a substance despite adverse consequences.[114] In comparison to classical stimulants, modafinil exhibits a low propensity for abuse, as it lacks significantly expressed pleasurable or euphoric effects.[18] Albeit to a lower degree than classical stimulants, modafinil still produces psychoactive, euphoric, and subjective effects typical for abused stimulants.[8][3]
Modafinil was not observed to promote overuse or misuse, even in people who have a history of cocaine addiction.[115] Despite the initial belief that modafinil carried no abuse potential, emerging evidence suggests that it works at the same neurobiological mechanisms as other addictive stimulants. Consequently, there exists a potential risk of modafinil abuse, necessitating prudent consideration and caution when prescribing or using this medication.[83] Modafinil exhibits a lower response on the amphetamine scale of the addiction research center inventory, suggesting reduced propensity for abuse compared to amphetamine.[116]
The US Drug Enforcement Administration has classified modafinil as a Schedule IV controlled substance;[2][8] the medicine is recognized for having valid medical uses with low addiction potential.[111][45] The International Narcotics Control Board does not classify it as a narcotic or a psychotropic substance.[117][118]
An overdose of modafinil can lead to a range of symptoms and complications. Psychiatric symptoms may include psychosis, mania, hallucinations, and suicidal ideation, which can occur even in individuals without a history of mental illness and may persist after discontinuation of the drug.[119] Neurological complications, such as seizures, tremors, dystonia, and dyskinesia, may arise from modafinil's interaction with various neurotransmitter systems.[119]
Allergic reactions such as rash, angioedema, anaphylaxis, and Stevens–Johnson syndrome may be triggered by an immunological response to modafinil or its metabolites.[120][121] Cardiovascular complications like hypertension, tachycardia, chest pain, and arrhythmias may also be observed due to modafinil's sympathomimetic action.[119]
In animal studies, the median lethal dose (LD50) of modafinil varies among species and depends on the route of administration. In mice and rats, the LD50 is approximately 1250 mg/kg if administered via an injection, but the oral LD50 for rats is 3400 mg/kg.[122][123] The LD50 value for humans have not been established. Human clinical trials have involved total daily doses up to 1200 mg/d for 7–21 days. Acute one-time total overdoses up to 4500 mg have not been life-threatening but resulted in symptoms like agitation, insomnia, tremor, palpitations, and gastrointestinal disturbances.[8][124]
The management of modafinil overdose involves supportive care, monitoring of vital signs, and treatment of specific complications. In cases of recent consumption, activated charcoal, gastric lavage, or hemodialysis may be used.[119] There is no specific antidote for modafinil overdose.[124][125][126] The main way to deal with modafinil overdose is supportive care, which includes sedating the patient and stabilizing their blood pressure, and muscle activity in case of manifestations such as agitation or tremor.[124]
Some of the drugs that frequently interact with modafinil include aripiprazole (an antipsychotic), amphetamine (including its enantiomers and salts; stimulants), aspirin, diphenhydramine (an antihistamine), and others.[127]
Modafinil is a weak to moderate inducer of CYP3A4[86][128][129] and a weak inhibitor of CYP2C19, enzymes of the cytochrome P450 group of enzymes.[16] Modafinil also induces or inhibits other cytochrome P450 enzymes.[86] 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.[10] However, other in-vitro studies find no significant inhibition of CYP2C9.[9][130] Modafinil may induce P-glycoprotein, which may affect drugs transported by P-glycoprotein, such as digoxin.[131] It was clinically found that modafinil affects pharmacodynamics of drugs which are metabolized by CYP3A4 and other enzymes of the cytochrome P450 family, so that interactions of modafinil with these drugs were observed in real people, rather than being predicted in a lab setting.[86][128] For instance, it was observed that induction of CYP3A4 by modafinil affects metabolism of the following medications and endogenous substances:[132]
- opioids, such as methadone, hydrocodone, oxycodone, or fentanyl – modafinil may result in a drop in opioid plasma concentrations because of faster clearance of opioids by CYP3A4. If the patient is not monitored closely, reduced efficacy or withdrawal symptoms can occur.[132]
- steroid hormones, such as estradiol, progesterone or cortisol. Modafinil may have an adverse effect on hormonal contraceptives (such as birth control pills, patches, etc.) for up to a month after discontinuation.[133] Both modafinil and armodafinil in the United States and the United Kingdom come with package inserts that highlight the interaction between these medications and hormonal birth control.[86] Modafinil may induce cytochrome P450 enzymes that are involved in the clearance of steroid hormones taken as hormonal contraceptives, reducing their effectiveness, which may lead to pregnancy despite taking the birth control medication. Besides steroid hormones, modafinil may affect pituitary gland hormones. 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.[134][135] Since modafinil induces the activity of the CYP3A4 enzyme involved in cortisol clearance,[136] modafinil may reduce the bioavailability of hydrocortisone. Therefore, it may be necessary to adjust the steroid substitution dose in people receiving modafinil, which is a CYP3A4-metabolism-inducing drug.[137]
Pharmacodynamics
Site | Potency | Type | Species | Refs |
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DATTooltip Dopamine transporter | 1.8–2.6 μM 4.8 μM 6.4 μM 4.0 μM | Ki Ki IC50a IC50a | Human Rat Human Rat | [138][139] [138] [140][141] [138] |
NETTooltip Norepinephrine transporter | >10 μM >92 μM 35.6 μM 136 μM | Ki Ki IC50a IC50a | Human Rat Human Rat | [138][139] [138] [140][141] [138] |
SERTTooltip Serotonin transporter | >10 μM 46.6 μM >500 μM >50 μM | Ki Ki IC50a IC50a | Human Rat Human Rat | [138][139] [138] [140][141] [138] |
D2 | >10 μM 16 μMb 120 μMb | Ki Ki EC50a | Human Rat Rat | [138] [142] [142] |
Footnotes: a = Functional activity, not binding inhibition. b = Armodafinil at D2High. Notes: No activity at a variety of other assessed targets.[138] |
The precise mechanism of action of modafinil for narcolepsy and other sleep disorders remains unclear.[3][112][143][144] Although modafinil may have interactions with neurotransmitter systems, its exact mode of action is not fully understood.[112][145]
From laboratory research, modafinil has little to no affinity for serotonin or norepinephrine transporters and does not directly interact with these systems.[16][144] However, studies have shown that elevated concentrations of norepinephrine and serotonin can occur as an indirect effect following modafinil administration due to increased extracellular dopamine activity.[144][16] Unlike traditional psychostimulant drugs, such as cocaine or amphetamine, modafinil shows low potential for causing euphoria due to differences in how it interacts with dopamine transporters at a cellular level.[112][144][145]
In addition to its influence on dopaminergic pathways, modafinil may impact other neurotransmitter systems, such as orexin or hypocretin.[144] Orexin neurons play a crucial role in promoting wakefulness and regulating arousal states. Modafinil may increase signaling within hypothalamic orexin pathways, potentially contributing to its wake-promoting effects.[16][144]
Pharmacokinetics
Cmax (peak levels) occurs approximately 2 to 3 hours after modafinil administration.[9] 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.[146]
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 by the liver or other organs. The rest of the drug is either metabolized or excreted through other routes, such as feces or bile.[9]
The two major circulating metabolites of modafinil are modafinil acid (CRL-40467) and modafinil sulfone (CRL-41056). Both of these metabolites have been described as inactive, and neither appears to contribute to the wakefulness-promoting effects of modafinil.[56][147] However, modafinil sulfone does appear to possess anticonvulsant effects, a property that it shares with modafinil.[56][148]
Elimination half-life is in the range of 10 to 12 hours,[9][146] subject to differences in sex,[86] in cytochrome P450 genotypes, liver function and renal function. Modafinil is metabolized mainly in the liver,[9] and its inactive metabolites are 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.[146]
Modafinil exhibits sex-specific pharmacokinetic differences.[86] It demonstrates higher bioavailability in women compared to men. The mean Cmax is higher in women than in men, 5.2 mg/L vs. 4.2 mg/L (p < 0.05), following a single 200 mg oral dose of modafinil.[86] This difference persists even after adjusting for body weight (0.88 ml/min/kg vs. 0.72 ml/min/kg).[86] The clearance of modafinil is 30% higher in men than in women, and plasma concentrations after a single dose are significantly higher in women than in men. These sex-specific pharmacokinetic differences may have implications for the efficacy and safety of modafinil.[86]