Modafinil (Provigil)

Wake promoting agent that improves alertness, attention and daily activities of functioning.

Modafinil is a racemic mixture of two enantiomers, armodafinil and esmodafinil.

Trade name Provigil.

Pregnancy category AU: D

US: Schedule IV 

Indicated to improve wakefulness in patients with excessive sleepiness from narcolepsy, obstructive sleep apnea and shift work disorder.

The addiction and dependence liabilities of modafinil are very low.

It shares biochemical mechanisms with addictive stimulant drugs.

It may have similar mood-elevating properties, although to a lesser degree.

Modafinil increases alertness, particularly in sleep-deprived individuals, and facilitates reasoning and problem solving in non-ADHD youth.

Modafinil intake enhances executive function.

Modafinil may not produce improvements in mood or motivation in sleep deprived or non-sleep deprived individuals.

Modafinil does not appear to produce euphoric effects.

It is not considered a narcotic nor a psychotropic substance.

It may increase abstinence rates in a subgroup of cocaine addicts while discontinuation adverse effects are no different from placebo.

It is not recommended with: arrhythmia, significant hypertension, or left ventricular hypertrophy.

 It is contraindicated in people with known hypersensitivity to modafinil or armodafinil.

Works by acting on dopamine and modulating the areas of the brain involved with the sleep cycle.

Not considered a classical psychostimulant, but rather is classified as a eugeroic.

For obstructive sleep apnea, it is recommended that continuous positive airway pressure (CPAP) be appropriately used before considering starting modafinil to help with daytime sleepiness.

There is no evidence of tolerance with modafinil at therapeutic doses even with prolonged use.

It helps with the disruptions in circadian rhythms and with the reduced quality of sleep astronauts experience.

Most frequent adverse events include headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness and dyspepsia.

Bioavailability not determined due to its aqueous insolubility.

Protein binding 62.3%

Metabolism Liver CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5 involved 

15 hour half-life.

A racemic compound with equal amounts of R-modafinil (armodafinil) with a half-life of 15 hours and S-modafinil with a 3-4 hour half-life.

Modafinil is available in the form of 100 and 200 mg oral tablets.

It is also available as the (R)-enantiomer, armodafinil, and as a prodrug of modafinil, adrafinil.

Armodafinil 200mg (Nuvigil) associated with more sustained wakefulness and better neurobehavioral performance in the final third of a simulated night shift comapred to modafinil 200mg (Dinges DF).

It is a central nervous system (CNS) stimulant medication used to treat sleepiness due to narcolepsy, shift work sleep disorder, and obstructive sleep apnea.

Off-label use as a purported cognitive enhancer to improve wakefulness is not conclusive.

Oral agent.

Side effects including headache, trouble sleeping, and nausea.

Rare serious dermatological reactions may occur in people with genetic predisposition.

This drug is not approved for use in children for any medical conditions, in whom there is a higher risk of rare but serious dermatological toxicity.

Dermatological reactions more commonly in pediatric patients. 

Serious rare side effects may include allergic reactions such as anaphylaxis and Stevens–Johnson syndrome, as well as hallucinations in people with a history of psychosis.

Adverse reactions:

Fewer than 10% of users report having a headache, nausea, and decreased appetite. 

Between 5% to 10% of users are affected with anxiety, insomnia, dizziness, diarrhea, and rhinitis.

Modafinil-associated psychiatric reactions have occurred.

No clinically significant changes in body weight have been observed: although decreased appetite and weight loss have been reported with in children and adolescents probably due to the much higher modafinil exposure in these individuals based on body weight.

Clinical trials on humans involving taking up to 1200 mg/day for 7–21 days and known incidents of acute one-time overdoses up to 4500 mg did not appear to cause life-threatening effects.

Adverse effects with overdosage include excitation or agitation, insomnia, anxiety, irritability, aggressiveness, confusion, nervousness, tremor, palpitations, sleep disturbances, nausea, and diarrhea.

Rare occurrences of severe skin rashes and other symptoms that are probably allergy-related: including erythema multiforme (EM), Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and DRESS syndrome, involving adult and pediatric patients. 

Modafinil is an inducer of the CYP3A4 enzymes, and Coadministration with opioids such as methadone, hydrocodone, oxycodone and fentanyl may result in a drop in opioid plasma concentrations.

Modafinil may have an adverse effect on hormonal contraceptives.

It induces the activity of the CYP3A4 enzyme involved in cortisol clearance, and may reduce the bioavailability of hydrocortisone. 

It  is classified as a weak to moderate inducer of CYP3A4.

Precise mechanism of action of modafinil for narcolepsy and sleep-wake disorders remains unknown.

It 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, that may contribute to heightened arousal.

It significantly elevated extracellular levels of dopamine in the brain, including in the nucleus accumbens.

It produces wakefulness reportedly without the need for compensatory sleep, and shows relatively low, if any, potential for abuse.

There is evidence to indicate that modafinil is producing at least a portion of its wakefulness-promoting effects via activation of the dopaminergic system. 

Modafinil may induce the cytochrome P450 enzymes CYP1A2, CYP3A4, and CYP2B6, as well as may inhibit CYP2C9 and CYP2C19.

It may also induce P-glycoprotein, which may affect drugs transported by P-glycoprotein, such as digoxin.

Its bioavailability is greater than 80% of the administered dose.

Peak levels occur approximately 2 to 3 hours after administration. 

Food slows absorption.

60% of modafinil is bound to plasma proteins.

The two major circulating metabolites of modafinil are modafinil acid and modafinil sulfone: both inactive for wakefulness.

Modafinil sulfone possess anticonvulsant effects, a property that it shares with modafinil.

Elimination half-life is generally in the range of 10 to 12 hours.

It is metabolized in the liver, and its inactive metabolite is excreted in the urine. 

Urinary excretion of the unchanged drug ranges from 0% to as high as 18.7%.

Modafinil and/or its major metabolite, modafinil acid, may be quantified in plasma, serum or urine to monitor dosage, confirm a diagnosis of poisoning in hospitalized patients or to assist in the forensic investigation.

It is not specifically tested for by common drug screens.

Modafinil prolongs exercise time to exhaustion while performing at 85% of VO2max and also reduces the perception of effort required to maintain this threshold.

Modafinil has been studied in the treatment of major depressive disorder: modafinil and other stimulants such as methylphenidate and amphetamines improved depression in traditional meta-analysis.

In network meta-analysis, modafinil and most other stimulants did not significantly improve depression, with only methylphenidate remaining effective.

Modafinil and other stimulants do not improve quality of life in meta-analyses, although there was evidence for reduced fatigue and sleepiness with modafinil and other stimulants.

Modafinil and armodafinil are adjunctive treatments for acute depression in people with bipolar disorder.

2021 meta-analysis found modafinil and armodafinil were more effective than placebo, clinical remission, and reduction in depressive symptoms, with only minor side effects, but the effect sizes are small and the quality of evidence has to be considered low.

Very low rates of mood switch have been observed with modafinil in bipolar disorder.

Modafinil is effective in the treatment of attention deficit hyperactivity disorder (ADHD), with significantly less abuse potential than conventional psychostimulants like methylphenidate and amphetamines.

FDA approval has been denied for pediatric ADHD due to concerns about rare but serious dermatological toxicity, specifically, the occurrence of Stevens–Johnson syndrome.

Evidence of modafinil for treatment of adult ADHD is mixed, and a 2016 systematic review of alternative drug therapies for adult ADHD could not recommend its use in this context.

A 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%). 

Modafinil intake enhances executive function, but only half of studies show improvements in attention and learning and memory, and a few even report impairments in divergent creative thinking. 

Modafinil consistently enhances attention, executive functions, and learning. 

A single-dose of modafinil effect 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.

The user’s perception that modafinil is an effective cognitive enhancer is not supported by the evidence in healthy non-sleep-deprived adults.

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