Provigil & Nuvigil | Wakefulness Drugs for Excessive Sleepiness
Provigil (modafinil) and Nuvigil (armodafinil) are oral prescription drugs used to improve wakefulness in adults with excessive sleepiness associated with narcolepsy, obstructive sleep apnea (OSA) and shift work disorder (SWD), a sleep disorder affecting people who work overnight or nontraditional shifts.
The U.S. Food and Drug Administration approved Provigil in 1998 and Nuvigil in 2007. Cephalon originally manufactured these medications. Teva Pharmaceutical Industries Ltd. bought the company in 2011.
The U.S. Department of Justice Drug Enforcement Administration classified the drugs’ active ingredients, modafinil and armodafinil, as Schedule IV controlled substances.
This classification means they carry a low potential for abuse compared with other drugs in Schedules II and III.
Modafinil and armodafinil have effects similar to stimulants such as amphetamine, but amphetamines carry a higher risk for abuse that may lead to dependence.
Because these drugs increase alertness, healthy people have used them as “smart drugs” to increase mental performance and wakefulness.
For example, students have used modafinil to improve focus while studying — similar to how they use other drugs Adderall and Ritalin. Working adults have also used them to work longer hours without sleeping.
This type of use is not approved by the FDA to be included in the product labeling, and is termed “off-label” use.
“[Provigil] can be the difference between I’m just making it through the day to I had the best day of my life,” entrepreneur Dave Asprey told ABC News in 2012. Asprey had used the drug off-label, claiming it enhanced his work ability as an executive of a billion-dollar company.
The military has even used modafinil to keep soldiers and pilots alert while deployed, ABC News reported. The media has compared these drugs to the brain-enhancing drug NZT-48 featured in the 2011 movie Limitless starring Bradley Cooper.
Provigil and Nuvigil may help people who suffer sleepiness from shift work disorder stay more alert.
Still, experts warn that there are no long-term studies on the effects of these drugs on a healthy brain. The American Academy of Sleep Medicine has warned that Provigil should be used only under a doctor’s supervision for the treatment of excessive sleepiness caused by shift work disorder, narcolepsy or obstructive sleep apnea.
“Provigil should not be prescribed off-label or purchased independently by consumers for cognitive or performance enhancement,” according to the professional society. “There is little evidence to support the use of Provigil or any other drug to improve learning and memory, and no medication provides such benefits without side effects.”
Researchers admit that they don’t know exactly how Provigil and Nuvigil work to increase wakefulness. Scientists think modafinil increases histamine levels, which can make people feel more awake. It also stimulates other neurotransmitters in the brain, including dopamine, a chemical which affects mood.
According to the drugs’ labels, both medications reach maximum concentration in the blood in about two to four hours. Food doesn’t have an effect on the drugs, but it may take longer for the drugs to take effect if they are taken with food. Asprey told ABC News it took about 17 minutes for him to feel the effects.
In clinical trials of modafinil and armodafinil, patients reported improvements in scores measuring excessive sleepiness and maintaining wakefulness. Un amphetamine, modafinil and armodafinil generally do not cause severe crashes or withdrawals.
Provigil vs Nuvigil
Although Provigil and Nuvigil work in the same way, they come in different dosages and have different chemical makeups and side effects.
The advantage of Nuvigil is the flexibility of strengths available. It allows people to start at lower doses and go up to higher doses over time if needed.
A study by M. Darwish and colleagues published in 2009 in Clinical Drug Investigation found that Nuvigil blood concentrations were higher than Provigil late in the day. The authors said it may mean improved wakefulness throughout the day with Nuvigil.
Differences Between Provigil and Nuvigil
|Active Ingredient/Generic Name||modafinil||armodafinil|
|Inactive ingredients||lactose monohydrate, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, povidone, and magnesium stearate||lactose monohydrate, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, povidone, and magnesium stearate|
|FDA-Approved Uses||Improve wakefulness in adults with narcolepsy, obstructive sleep apnea or shift work disorder||Improve wakefulness in adults with narcolepsy, obstructive sleep apnea or shift work disorder|
|How is the drug taken?||Oral tablet||Oral tablet|
|Strengths||100 mg and 200 mg||50 mg, 150 mg, 200 mg, 250 mg|
|Average retail price according to Good Rx||$697.73 for 30 tablets at 200 mg||$498.85 for 30 tablets at 250 mg|
|Half-life||15 hours||15 hours|
|Controlled substance||Yes, Schedule IV||Yes, Schedule IV|
|Top four side effects||Headache, nausea, nervousness and rhinitis||Headache, nausea, dizziness, and insomnia|
Although modafinil and armodafinil have wakefulness effects similar to the stimulants amphetamine and methylphenidate, the FDA approved the drugs for different uses.
Stimulants such as Adderall (amphetamine), Ritalin (methylphenidate), and Concerta (methylphenidate) are used to treat attention deficit hyperactivity disorder (ADHD) in patients as young as 6 years old. Provigil and Nuvigil are approved only for adults with certain sleep disorders.
Also, studies have found modafinil has fewer side effects than amphetamine. For example, Provigil is less habit-forming, has no reports of withdrawal symptoms, and has milder side effects than Adderall.
Adderall is a Schedule II substance, not a Schedule IV substance Provigil. This means there is a greater risk for abuse with Adderall. Adderall can also cause sexual side effects and withdrawal symptoms.
While reports of side effects with Provigil and Nuvigil are generally few, drug labels warn that the medications can rarely cause serious side effects. These include: a serious rash called Stevens-Johnson Syndrome, allergic reactions, persistent sleepiness, psychiatric symptoms and in people with cardiovascular disease, effects such as palpitations or increased blood pressure.
Common side effects of these drugs include headaches, nausea and diarrhea. The most commonly reported side effect in clinical trials was headache.
There are also concerns about drug interactions and how the drugs affect unborn babies.
Drug interactions can occur when modafinil and armodafinil are taken with other drugs. These interactions may result in other drugs influencing the effectiveness and side effects of modafinil and armodafinil, and similarly, modafinil and armodafinil can influence the effectiveness and side effects of other drugs.
Drugs that interact with Provigil and Nuvigil include:
- Steroidal contraceptives (effectiveness may be reduced)
- Cyclosporine (blood levels may be reduced)
- Prilosec (omeprazole; blood levels may be increased)
- Phenytoin (blood levels may be increased)
- Diazepam (blood levels may be increased)
This isn’t a complete list, so make sure you let your doctor and pharmacist know of all drugs, vitamins and herbal supplements you take.
Women of childbearing age should tell their doctor immediately if they use any form of hormonal birth control. This includes patches, pills, intrauterine devices (IUDs), implants, vaginal rings or shots. Your birth control may not work while you take Provigil or Nuvigil and for up to one month after you stop taking the drugs.
The drugs’ labels also discourage patients from using alcohol while taking the medications.
Pregnancy Warnings and Risk of Birth Defects
Drug labels in the United States say there are not enough studies to determine whether it’s safe to take Provigil or Nuvigil during pregnancy, and they say it’s unknown whether these drugs pass into mothers’ breast milk.
During animal studies, these drugs were associated with growth restriction, spontaneous abortions and other toxic effects in fetuses. As a result, the FDA asked the manufacturer to set up a pregnancy registry to track side effects.
FDA-approved drug labels warn that these drugs should only be used in pregnant women if the benefits outweigh the risks.
Doctors may encourage their patients to enroll in registries for pregnant women taking modafinil and armodafinil to evaluate their effects in these patients.
Data gathered from the pregnancy registry led Teva Pharmaceuticals Ireland to release a warning on June 7, 2019, saying use of modafinil during pregnancy is suspected to cause congenital malformations.
Then, on June 20, 2019, Health Canada sent a warning to health care professionals about modafinil and the risk of congenital anomalies. Although these new findings have not led to a change in the labeling of the FDA-approved products, these alerts from Ireland and Canada suggested that modafinil should not be used in women who are pregnant or may become pregnant.
Lawyers in the United States are actively pursuing Provigil and Nuvigil lawsuits involving birth defects in children whose mothers took the drugs during pregnancy.
Lawyers are accepting Provigil and Nuvigil cases on behalf of children with birth defects whose mothers took the drugs while pregnant. Read more. View Lawsuits
Modafinil and armodafinil come in pill form and are taken orally. Patients can take their dose with or without food.
Your doctor will prescribe the dose that is right for your situation. He or she may prescribe one dose and increase it slowly or decrease it depending on effectiveness and side effects. Take the medication exactly as prescribed, and do not make changes to your dose without first consulting your doctor.
Provigil and Nuvigil Recommended Dosing
|Narcolepsy or obstructive sleep apnea||200 mg once a day in the morning||150 mg to 250 mg once a day in the morning|
|Shift work disorder||200 mg once a day about one hour before start of shift||150 mg once a day about one hour before start of shift|
|Patients with severe hepatic impairment||Reduced to one-half the recommended dose||Reduced dose|
|Geriatric patients||Consider lower doses and close monitoring||Consider lower doses and close monitoring|
Ask your doctor what time of day is best to take your medication. Taking the drug too close to when you go to bed can make it harder to fall asleep.
Generally, people with obstructive sleep apnea or narcolepsy take their dose in the morning. People with shift work disorder typically take the medicine about an hour before they have to start work.
Be careful about doing things that could be dangerous. Until you can gauge how the medication affects you, don’t drive or do other risky activities. You shouldn’t modify your routine until your doctor says you can.
People have reported fatal overdoses involving modafinil alone or involving armodafinil or modafinil in combination with other drugs.
The most common symptoms of a Nuvigil or Provigil overdose include:
- shortness of breath
- trouble sleeping
- central nervous system symptoms such as hallucinating or feeling confused, disoriented, excited, agitated or restless
- digestive changes such as diarrhea and nausea
- cardiovascular changes such as chest pain, high blood pressure, or fast or slow heart rate
There is no antidote for an overdose. Seek help immediately if you suspect an overdose.
Provigil and Nuvigil Facts Please seek the advice of a medical professional before making health care decisions. Provigil and Nuvigil Facts
- Uses Improve wakefulness in adults with excessive sleepiness associated with narcolepsy, obstructive sleep apnea or shift work disorder
- Side Effects Common side effects include dizziness, headache, trouble sleeping and nausea. Serious side effects include serious rash, allergic reaction, mental symptoms, symptoms of a heart problem and birth defects
- Manufacturer Cephalon Inc., Teva Pharmaceutical Industries Ltd.
Modafinil and Armodafinil — Mechanism of Action & Clinical Application
Posted on:July 21, 2021
Last Updated: September 9, 2021
Time to read: 10 minutes
Modafinil is a synthetic non-amphetamine stimulant approved for the first-line treatment of excessive sleepiness (ES). [Mignot, 2004]
Modafinil is a racemate, with the two enantiomers conferring approximately equipotent effects on the brain, although the R-isomer has a different pharmacological profile:
- Modafinil is a racemic mixture (R– and S-isomers) of diphenylmethylsulfinylacetamide
Modafinil is indicated for ES caused by narcolepsy and sleep work shift disorder (SWSD) and obstructive sleep apnoea with continuous positive airway pressure use (res-OSA).
Armodafinil, modafinil, is also a wakefulness promoter indicated for ES associated with narcolepsy, SWSD, and res-OSA.
However, it is important to note that in 2011 the European Medicines Agency removed the SWSD and res-OSA indications and restricted modafinil to the treatment of narcolepsy.
The wake-promoting pharmacological profile of modafinil is notably different from other psychostimulants such as amphetamine and methylphenidate, with studies suggesting a complex profile of neurochemical and behavioural effects. [Ballon and Feifel 2006]
Effects on Dopamine :
- Modafinil is primarily a weak dopamine reuptake inhibitor through its competitive binding to the cell-membrane dopamine transporter (DAT). Its binding affinity to DAT is lower than Bupropion. This interaction with DAT and the subsequent increase in a dopaminergic tone is central to its wake-promoting effects. It has no direct or indirect effects on dopamine receptors.
- However, research also shows evidence that modafinil similarly binds to the norepinephrine transporter (NET) and that it has additional effects on several other CNS systems such as GABA, glutamate, histamine, and orexin pathways. [Minzenberg and Carter 2008]
- Of note, modafinil and armodafinil demonstrate similar binding and functional activities at DAT and NAT; however, there are stereospecific differences in elimination kinetics.
- Overall, Modafinil increases HA, NE, 5-HT, and DA levels in the brain.
Mechanism of Enhancing Wakefulness:
- Histamine, serotonin, and norepinephrine tone is directly related to the arousal state and that neurons releasing these chemicals are almost silent in REM sleep. The peptide orexin (ORX) released from neurons of the lateral hypothalamus plays an important role in the maintenance of vigilance.
Modafinil is readily absorbed and has dose-dependent pharmacokinetics between 200 mg and 600 mg, reaching peak plasma concentrations 2–4 hours after dosing. The starting dose is 200 mg PO (dosed in am), with steady-state occurring after 2–4 days. [Robertson and Hellriegel 2003]
- The S-isomer has a relatively short terminal elimination half-life of 4–5 hours compared with that of armodafinil, which is approximately 15 hours [Wong et al. 1999]
Modafinil has been observed to have variable wakefulness-promoting effects throughout the day with a once-daily dose of 200 mg. As such, some patients may require a 400 mg or a 600 mg split dose of modafinil to alleviate ES later in the day.
Interestingly, armodafinil at 200 mg can maintain wakefulness later in the day due to its long elimination half-life. [Dinges et al. 2006]
- Armodafinil plasma concentration at 7–11 hours after dosing was 43% higher in comparison with modafinil.
- Furthermore, pharmacokinetic studies have shown that over a 24-hour period, armodafinil had 28% less fluctuation and 42% less swing in plasma concentrations. [Darwish et al 2009a] and [Darwish et al 2009b]
- 200 to 400 mg/day, given as a single dose in the morning or two divided doses in the morning and at noon.
- Doses of 400 mg/day have been well-tolerated, but there is no statistically significant evidence that this dose confers additional benefit beyond the 200 mg dose.
- For patients who require more than 200 mg/day, the dose should be increased, to a maximum of 400 mg/day, in increments of 100 mg as needed and tolerated.
- 150 mg or 250 mg given once daily in the morning
Obstructive sleep apnea-hypopnea syndrome (OSAHS) :
- In OSAHS, modafinil is indicated as an adjunct to continuous positive airway pressure (CPAP).
- Clinicians should make a maximal effort to treat OSAHS with CPAP for an adequate period of time before initiating modafinil.
- If modafinil is used adjunctively with CPAP, encouraging CPAP and periodic assessment of CPAP compliance is necessary.
- 200 to 400 mg/day, given as a single dose in the morning or two divided doses in the morning and at noon. Doses of 400 mg/day have been well-tolerated, but there is no statistically significant evidence that this dose confers additional benefit beyond the 200 mg dose.
- The recommended dose of Armodafinil for patients with OSAHS is 150 mg or 250 mg, given once daily in the morning.
- In patients with OSAHS, doses up to 250 mg/day, given as a single dose, have been well-tolerated, but there is no consistent evidence that these doses confer additional benefit beyond the 150 mg/day dose
- There was a slight trend for reduced CPAP use over time with Armodafinil use.
Moderate to Severe Chronic Shift Work Sleep Disorder
- 200 mg daily as a single dose approximately 1 hour before the start of the work shift.
- 150 mg daily approximately 1 hour before the start of their work shift.
Modafinil and armodafinil are well tolerated, with most adverse events classified as mild or moderate in severity. The most common adverse events (≥5%) reported in randomized controlled trials are: [PROVIGIL package insert]
- Back pain
When comparing modafinil 200, 300, and 400 mg/day, headache and anxiety were dose-related.
For armodafinil 150 and 250 mg/day, adverse events that are potentially dose-dependent include headache, rash, depression, dry mouth, insomnia, and nausea. [NUVIGIL package insert]
Serious rash requiring hospitalisation and discontinuation of treatment has been reported in adults in association with the use of Modafinil and Armodafinil.
Clinicians should exercise caution in giving modafinil to patients with a history of psychiatric disorders, including psychosis, depression, mania, major anxiety, agitation, insomnia or substance abuse.
It has been reported that there is abuse and dependency potential with modafinil. Although this has not been investigated for armodafinil, it is ly to be similar to modafinil. Although it is important to state that this potential is lower in comparison with amphetamine- stimulants. [Myrick et al. 2004]
Cardiac evaluation and blood pressure should be monitored.
Patients with a history of substance use should be closely monitored as modafinil and armodafinil produce psychoactive and euphoric effects and feelings consistent with other scheduled CNS stimulants. (methylphenidate or dexamphetamine).
Modafinil has displayed some interactions in vitro with the CYP isoenzyme system, although it is less apparent in vivo. Of note, modafinil exerts a reversible inhibition of CYP2C19 as well as a concentration-dependent induction of CYP1A2, CYP2B6, and CYP3A4. [Robertson et al. 2000]
It has also been shown that there is also a small degree of CYP2C9 activity inhibition.
- As such, there is potential for modafinil to interact with substrates of CYP2C19, which includes diazepam, phenytoin, and omeprazole.
- Although caution is advised, a clinically significant effect is ly to be low with substrates of CYP2C19. [Robertson and Hellriegel 2003]
Interestingly, armodafinil (250 mg/day) does not induce CYP1A2. However, it does moderately induce CYP3A4 and moderately inhibits CYP2C19. [Darwish et al. 2008]
The pharmacokinetics of CYP3A4 (e.g., midazolam, ciclosporin, triazolam, and steroidal contraceptives) and CYP2C19 (e.g., diazepam, omeprazole, and phenytoin) may be affected if co-administered with armodafinil.
Due to the potential for the concurrent administration of modafinil/armodafinil and methylphenidate, interactions studies have been performed, with one study showing a significant increase in the Cmax for modafinil [Wong et al. 1998]; however, it was suggested that this interaction had no clinical significance (the same lack of significance is suggested for armodafinil).
Finally, two case reports have reported drug-drug interactions: cyclosporin [Le Cacheux et al. 1997] and clomipramine. [Grözinger et al. 1998]
- Cyclosporin concentrations were significantly lower after treatment with modafinil, although this patient had recently undergone a kidney transplant.
- Clomipramine concentrations were significantly higher after treatment with modafinil; however, this patient was genotyped as a CYP2D6 poor metabolizer.
Please read our detailed article on pharmacogenomics with tables of medications that affect CYP enzymes in psychiatry.
Modafinil and Armodafinil are evidence-based in the treatment of:
- Obstructive Sleep Apnoea as an adjunct to continuous positive airway pressure (CPAP)
- Moderate to Severe Chronic Shift Work Sleep Disorder
- Treatment-resistant Depression
- Negative symptoms of Schizophrenia
- Multiple trials and a pooled analysis noted decreased depression and fatigue and improved cognition in patients receiving modafinil augmentation than mood stabilisers or antidepressants in bipolar depression. [ Pary et al., 2015]
- Armodafinil in patients with bipolar depression added to a mood-stabilizing agent (lithium, valproate, aripiprazole, olanzapine, lamotrigine, risperidone, or ziprasidone), and patients receiving armodafinil reported significant reductions in depression. [Calabrese et al., 2010], [Calabrese et al., 2014]
Cognitive Function Improvement:
- Modafinil and armodafinil are regularly used off-label as cognitive enhancers after translational experiments reported promising results. [Turner et al. 2003]
- This includes patients with schizophrenia [Farrow et al. 2006], patients with ADHD [Swanson et al. 2006], and patients with substance abuse that demonstrate impaired cognitive function. [Brady et al. 2011]
- Several brain areas associated with cognitive processes are activated after modafinil treatment, including the central nucleus of the amygdala, the paraventricular nucleus of the hypothalamus, and the anterior hypothalamus. [Gerrard and Malcolm 2007]
- Furthermore, one animal study showed that fronto-cortical areas related to arousal and higher cognitive function were also activated, hinting at modafinil’s wake-promoting and pro-cognitive effects. [Gozzi et al. 2012]
Modafinil and its longer-acting R–isomer, armodafinil, are effective psychostimulants that improve wakefulness although they do have different pharmacokinetic profiles. Their action on the wakefulness pathways help in the treatment of sleep disorders such as Narcolepsy, OSAHS and Shift work disorder.
Additionally, through their inhibitory action on DAT, they increase dopamine (similar to Bupropion albeit at a lower potency) which makes them useful as an adjunct in the management of treatment-resistant depression and bipolar depression.
A review of psychostimulants for adults with depression.
Pary, R., Scarff, J. R., Jijakli, A., Tobias, C., & Lippmann, S. (2015). A review of psychostimulants for adults with depression. Federal Practitioner, 32(Suppl 3), 30S.
Adjunctive armodafinil for major depressive episodes associated with bipolar I disorder: A randomized multicenter, double-blind, placebo-controlled, proof-of-concept study.