Modafinil Generic Manufacturers

[Elisabet Schwartzkopf]

Modafinilsold under the brand name Provigil among others, is a wakefulness-promoting medication used primarily to treat narcolepsy, [3][8][12] a sleep disorder characterized by excessive daytime sleepiness and sudden sleep attacks.[13] 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 17 years old.[8]

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.[14]

While modafinil is used as a cognitive enhancer or "smart drug" among healthy individuals seeking improved focus and productivity,[15][16] its use outside medical supervision raises concerns regarding potential misuse or abuse.[3][8][17] 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 at high doses.[18][19]

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.[13] Being a central nervous system (CNS) stimulant (psychostimulant) itself, modafinil has lower addictive potential than classical psychostimulants, such as amphetamines, cocaine or methylphenidate,[10][20][21] but still produces psychoactive, euphoric, and subjective effects typical of classical stimulants.[3][8][17]

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 (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, that is a sleep breathing apparatus to prevent apnea, before starting modafinil.[8][19][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.[17] 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]

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.[17][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]

Modafinil is occasionally prescribed off-label for individuals with attention deficit hyperactivity disorder (ADHD).[38][39][40] It has not consistently shown 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]

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][55] Modafinil does not significantly increase the risk of mood switch to mania or suicide attempts in people with bipolar disorder.[56][53] Modafinil may also have cognitive benefits in people with bipolar disorder who are in a remission state.[57][58][55]

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.[59] 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.[59] 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.[59][60] Very low rates of mood swing (a change in mood from one extreme to another)[56][61] have been observed with modafinil and armodafinil in depressive phase of bipolar disorder.[51][62]

Modafinil was used by the French Foreign Legion,[63] U.S. Air Force,[64][65] and U.S. Marine[66] 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.[65][67][68]

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.[69] The US military approved modafinil for specific Air Force missions, replacing amphetamines for fatigue management.[70] 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.[64]

Modafinil has been used non-medically as a "smart drug"[15][16] by various groups, including students,[72][73][74] office workers, transhumanists,[75][76] and professionals in various sectors. Its use is attributed by these individuals to its potential for enhancing attention, cognitive capabilities, and alertness.[77][78]

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.[79][80][49][81] In some cases, it has even been associated with impairments in certain cognitive functions.[18][19][82] It has been shown that modafinil's positive impact on cognitive abilities is more noticeable on sleep deprived individuals.[83] Therefore, in people who are not sleep-deprived, the potential of modafinil as a cognitive enhancer may be limited.[84]

Modafinil is contraindicated during pregnancy and 2 months before getting pregnant.[86] 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][87] Modafinil therapy during pregnancy increases the risk of birth defects,[14][88][89][86] such as with congenital torticollis, hypospadias, and congenital heart defects.[88]

Modafinil is also contraindicated in certain cardiac conditions, including uncontrolled moderate to severe hypertension, arrhythmia, cor pulmonale,[90][91] and in cases with signs of CNS stimulant-induced mitral valve prolapse or left ventricular hypertrophy.[92][93] 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.[94] 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.[95] 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.[96]

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