Buy Modafinil online - Stay Awake
| Drug Name | Modafinil / Provigil |
|---|---|
| Dosage | 100 – 200 mg |
| Price | from AUD$1.21 per pill |
| Check Now | Go to the Pharmacy |
-
What are the most commonly reported adverse effects of modafinil in placebo-controlled trials?
-
What factors explain modafinil’s low potential for abuse compared with traditional stimulants?
Treatment of Narcolepsy
Narcolepsy is a disorder of sleep–wake regulation marked by excessive daytime sleepiness. It is often accompanied by cataplexy and other REM-sleep–related symptoms. Patients typically present with overwhelming sleepiness that may appear as brief, hard-to-resist “sleep attacks,” frequently involving rapid entry into REM sleep. Additional features may include hypnagogic or hypnopompic hallucinations and episodes of sleep paralysis.
For many years, therapy relied mainly on amphetamine-like stimulants such as methylphenidate (Ritalin) and dextroamphetamine (Dexadrine), both FDA-approved for narcolepsy. However, these agents are Schedule II controlled substances and may lead to tachyphylaxis or withdrawal symptoms.
Placebo-controlled studies of modafinil online
Two large randomized, placebo-controlled trials conducted by the US Modafinil in Narcolepsy Multicenter Study Group (with 283 and 271 participants) evaluated modafinil at 200 mg/day, 400 mg/day, and placebo over 9 weeks. The second trial also assessed potential withdrawal effects.
In both studies, patients taking provigil demonstrated statistically significant reductions in subjective and objective sleepiness. After 9 weeks in the second trial, participants receiving 200 mg/day scored 13.0 on the Epworth Sleepiness Scale compared with 15.8 in the placebo group; those on 400 mg/day scored 12.3. Maintenance of Wakefulness Test results showed a similar pattern: 4.9 minutes for the 200-mg group, 3.5 minutes for placebo, and 5.1 minutes for the 400-mg group. In the active-treatment groups, all measures improved significantly from baseline. On the Multiple Sleep Latency Test, only the 400-mg group showed a significant increase in mean sleep latency. No withdrawal syndrome was observed.
Should a second dose be given at noon?
The standard starting dosage for narcolepsy is 200–400 mg taken in the morning, with titration guided by clinical response. In a randomized, double-blind study by Schwartz et al., patients who continued to experience afternoon or evening sleepiness while taking 400 mg in the morning were given an additional 200-mg noon dose or placebo. The noon dose produced a statistically greater improvement on evening Maintenance of Wakefulness Test trials and yielded better subjective ratings, although overall test results between the groups were not significantly different.
Modafinil dosing and timing should be individualized. Some patients with persistent sleepiness benefit from divided doses up to 800 mg/day, often combined with other wake-promoting medications. While dosing later than noon is generally avoided, a midday dose does not appear to disrupt sleep architecture.
How does modafinil compare with other stimulants?
There are currently no head-to-head human studies comparing modafinil with traditional stimulants for narcolepsy. In narcoleptic dogs, modafinil 5 mg/kg and amphetamine 0.1 mg/kg show comparable wake-promoting effects.
A review by Mitler and Hajdukovic estimated normalization of the Maintenance of Wakefulness Test in 55.3% of patients treated with provigil, 80% with dextroamphetamine, and 70% with methylphenidate. These comparisons lead some clinicians to regard modafinil as relatively less potent.
Buy Modafinil or Sodium Oxybate
Sodium oxybate (Xyrem) is not a stimulant but a central nervous system depressant. It is taken at night—once before going to bed and again about four hours later. The medication is FDA-approved for treating cataplexy associated with narcolepsy and for managing excessive daytime sleepiness in these patients.
Most clinical trials assessing sodium oxybate have compared it with placebo in individuals already receiving a stimulant as maintenance therapy. However, one study evaluated patients previously stabilized on modafinil and randomly assigned them to one of four regimens: placebo, sodium oxybate, modafinil, or a combination of sodium oxybate and modafinil. Those continuing modafinil remained on their usual dose (200–600 mg/day), with no dose adjustments during the trial. Sodium oxybate was initiated at 6 g nightly and increased to 9 g.
Sodium oxybate demonstrated an alerting effect comparable to modafinil on the Maintenance of Wakefulness Test. Still, because modafinil was not titrated to its maximum effective dose, the study could not definitively determine whether one agent is superior as monotherapy. The combination of sodium oxybate and modafinil produced the greatest improvement in mean sleep latency, with a statistically significant advantage compared with placebo.
Since these medications act through different mechanisms, they may be used together when clinically appropriate.
Obstructive Sleep Apnea Syndrome
Most individuals with obstructive sleep apnea (OSA) experience excessive daytime sleepiness and non-restorative sleep. Continuous positive airway pressure (CPAP) remains the gold-standard therapy, though weight loss, positional strategies, oral appliances, and upper airway surgery may benefit selected patients. Consistent nightly use of CPAP often eliminates obstructive events and substantially reduces sleepiness.
Modafinil as an Adjunct to CPAP
In a multicenter, double-blind, placebo-controlled trial involving 157 patients with residual daytime sleepiness despite CPAP therapy, those receiving modafinil 400 mg/day showed a reduction in Epworth Sleepiness Scale scores from 14.2 to 9.6 (P < .001). The placebo group showed a nonsignificant change from 14.4 to 12.4. On the Multiple Sleep Latency Test, modafinil increased mean latency from 7.4 to 8.6 minutes (P < .05), though the values remained outside the normal range; the placebo group showed a slight decrease.
A second multicenter trial of 305 CPAP-treated patients confirmed that adjunctive modafinil (200–400 mg/day) increased mean sleep latency on the Maintenance of Wakefulness Test, although results again did not return to normal levels.
In January 2004, the FDA approved modafinil as adjunct therapy for persistent daytime sleepiness in patients with OSA who are optimally treated with CPAP. Nevertheless, inadequate sleep duration and poor CPAP adherence frequently contribute to residual sleepiness and must be addressed before considering wake-promoting medications.
In an open-label study of patients receiving CPAP plus modafinil, average nightly CPAP use declined modestly—from 6.3 hours to 5.9 hours—over 12 weeks. This effect was not seen in the blinded trial where CPAP compliance was directly monitored.
Encourage Continued CPAP Use
Because wake-promoting agents do not relieve upper airway obstruction or reduce long-term cardiovascular and metabolic risks associated with OSA, clinicians should emphasize the importance of maintaining CPAP therapy and practicing good sleep hygiene. Many patients with OSA also have hypertension or other cardiovascular conditions, so anyone receiving modafinil requires careful monitoring of cardiovascular status.
| 60 pills | AUD$1.77 | A$39.72 | A$145.63 A$105.91 | |
| 90 pills | AUD$1.54 | A$79.44 | A$218.45 A$139.01 | |
| 120 pills | AUD$1.43 | A$119.15 | A$291.26 A$172.11 | |
| 180 pills | AUD$1.32 | A$198.59 | A$436.90 A$238.31 | |
| 270 pills | AUD$1.25 | A$317.74 | A$655.34 A$337.60 | |
| 360 pills | AUD$1.21 | A$436.90 | A$873.80 A$436.90 |
Shift-Work Sleep Disorder
Approximately 6% of full-time workers in the United States are employed on night shifts or rotating schedules. These individuals are susceptible to shift-work sleep disorder due to misalignment between their internal circadian rhythm and the external environment.
People with this condition generally sleep 1 to 4 hours less per day than those with conventional schedules. Over time, this cumulative sleep loss can impair alertness, reduce job performance, and raise the risk of workplace accidents. One study using ambulatory electroencephalography reported that about 20% of shift workers fell asleep at least once during a single night shift.
In January 2004, the FDA approved modafinil for managing excessive sleepiness associated with shift-work sleep disorder. The approval was based on a 12-week double-blind trial in which 209 patients received either modafinil 100 mg or placebo 30–60 minutes before each night shift. All participants had severe sleepiness, with baseline mean sleep latency below 6 minutes on the Multiple Sleep Latency Test.
Modafinil produced a statistically significant 1.7-minute increase in mean sleep latency compared with placebo, though not enough to restore normal values. It also improved performance on a vigilance test administered every two hours during a simulated night shift. However, sleep diaries showed no significant differences between groups in the number of sleep episodes, near-accidents, or caffeine intake.
Another randomized study involving 32 patients found significant improvements in vigilance and on the Maintenance of Wakefulness Test during a simulated night shift, although placebo scores were mostly within normal limits. Neither study demonstrated adverse effects on recovery sleep following night-shift work.
Off-Label Uses of Modafinil
Multiple Sclerosis
Fatigue is both common and disabling in many patients with multiple sclerosis (MS). In one report, 28% of patients identified fatigue as their most troubling symptom. Fatigue in MS is often assessed using the Fatigue Severity Scale, a validated nine-item questionnaire that distinguishes pathological fatigue from normal tiredness.
Historically, amantadine (Symmetrel) and pemoline (Cylert) were used, though both are associated with notable adverse effects. Concerns about hepatotoxicity led to the discontinuation of pemoline in 2005.
Provigil has shown mixed results in MS-related fatigue. In a single-blind study, 72 patients received placebo for 2 weeks, followed by modafinil 200 mg/day for 2 weeks, then 400 mg/day for 2 weeks, and finally placebo for 3 weeks. Significant improvements were observed with 200 mg/day, but not with the higher dose. Epworth Sleepiness Scale scores also decreased with both doses, although baseline values were already normal.
By contrast, two double-blind, placebo-controlled trials found no significant improvement in fatigue with modafinil. The larger study enrolled 115 participants and titrated modafinil up to 400 mg/day as tolerated.
ADHD
Modafinil has been evaluated in both adults and children with attention-deficit hyperactivity disorder (ADHD) and is considered an alternative to traditional stimulants in adult patients.
In a double-blind, placebo-controlled crossover study of 22 adults with ADHD, modafinil (mean dose ~207 mg/day) and dextroamphetamine (mean dose ~22 mg/day) both produced improvements across five outcome measures, including subjective assessments and cognitive testing of word association and digit span.
Another crossover trial involving 20 adults treated with modafinil 200 mg/day demonstrated reduced impulsivity on neuropsychiatric tasks. Larger studies are still needed to define its role in adult ADHD more clearly.
No large double-blind trials in children have been completed. In a 6-week trial of 24 children aged 5–15 years, modafinil 200–300 mg/day outperformed placebo on a computerized attention test (Test of Variables of Attention), but not on the ADHD Rating Scale. Notably, modafinil did not produce significant appetite suppression or weight loss—side effects commonly seen with traditional stimulants—suggesting potential advantages in pediatric settings.
Parkinson Disease
Sleep disturbances are common among individuals with Parkinson disease; approximately 60% report nighttime sleep problems, and up to 50% experience excessive daytime sleepiness.
Modafinil has been evaluated for Parkinson-related daytime sleepiness, but study sizes have been small. The largest randomized, double-blind, placebo-controlled study included 21 patients receiving either modafinil 200 mg/day or placebo. In those treated with modafinil, Epworth Sleepiness Scale scores improved from 17.8 to 14.4—statistically significant, though still outside the normal range. No meaningful improvements were observed in fatigue or motor function as measured by the Hoehn and Yahr Scale and the Unified Parkinson Disease Rating Scale.
Larger, well-designed trials using quality-of-life outcomes are needed to clarify modafinil’s therapeutic value in Parkinson disease.
Modafinil as Adjunctive Therapy in Depression
Fatigue and sleep disturbances are extremely common in major depressive disorder and may persist despite otherwise successful antidepressant treatment. In one study, 44% of patients who responded well to fluoxetine reported continued sleep difficulties, and 38% reported persistent fatigue.
The Modafinil in Depression Study Group evaluated modafinil for residual vegetative symptoms in 136 individuals with partially treated major depression. All participants had received at least five weeks of antidepressant therapy. Those randomized to modafinil began at 100 mg/day, titrated up to a maximum of 400 mg/day according to clinical response. After two weeks, patients receiving modafinil reported significantly less fatigue, but the effect was no longer significant at six weeks. No differences in mood outcomes were detected.
Another open-label study examined modafinil 200 mg/day in combination with fluoxetine or paroxetine as initial treatment for major depression. Significant improvements were seen on the Hamilton Rating Scale, Fatigue Severity Scale, and Epworth Sleepiness Scale compared with baseline, although the absence of a placebo arm limits interpretation.
At present, there is no clear consensus on the role of modafinil as an adjunct in depression, and further research is required.
Chronic Fatigue Syndrome
In a double-blind crossover trial, Randall and colleagues treated chronic fatigue syndrome patients with modafinil 200 mg/day, 400 mg/day, or placebo. Although 17 patients were enrolled, only 14 completed the study. No significant improvements were found in self-reported fatigue or quality of life. Larger trials are needed to assess potential benefits in this population.
Adverse Events and Safety
Modafinil is typically initiated at 200 mg/day and may be increased to 400 mg/day; higher doses are sometimes divided. Elderly patients and those with hepatic impairment should begin at 100 mg/day.
In placebo-controlled narcolepsy trials, the most frequently reported adverse effects included headache, nausea, and nervousness. Withdrawal rates ranged from 5% to 14% in the modafinil groups, compared with 4% to 11% for placebo. Headache is the most common side effect but often resolves after several days of treatment. Although modafinil generally does not disrupt sleep architecture on polysomnography, about 5% of patients report insomnia. Occasional cases of nervousness, anxiety, or stereotypic behaviors have been documented, though these appear less common than with traditional stimulants at therapeutic doses.
Cardiovascular Effects
Animal data suggest minimal differences between modafinil and classical stimulants regarding cardiovascular impact when adjusted for equivalent alerting doses. One study in dogs found no significant increases in heart rate or blood pressure with either agent, although amphetamine produced greater increases in motor activity. Comparable human studies using equipotent doses are lacking.
Modafinil does not raise heart rate in humans. Initially thought to have no effect on blood pressure, a retrospective analysis later showed that 2.4% of patients taking modafinil required initiation or adjustment of antihypertensive therapy, compared with 0.7% on placebo.
Abuse Potential
Classified as a Schedule IV medication, modafinil has been extensively studied for abuse liability in both humans and animals, including individuals with prior substance-use disorders. Across operant conditioning studies, comparative assessments of stimulant-like effects, and “willingness to pay” paradigms, modafinil consistently demonstrated low abuse potential—even at doses up to 800 mg/day.
Several factors may contribute: unlike amphetamines and cocaine, modafinil does not strongly engage dopaminergic receptors in the nucleus accumbens, a key reward center. In addition, its poor water solubility and instability at high temperatures make it difficult to inject or smoke. No withdrawal syndrome has been identified.
Pregnancy and Lactation
Modafinil is designated FDA pregnancy category C, indicating adverse fetal effects in animal studies and insufficient data in humans; potential benefits may outweigh risks in selected cases. Sodium oxybate is category B, meaning no fetal risks have been observed in animals, though human studies are lacking.
Embryotoxicity was observed in rats at doses approximately 5–10 times the maximal recommended human dose. The extent of excretion in breast milk remains unknown.
Women of childbearing potential should be counseled about potential teratogenic risks associated with stimulant medications. In general, these drugs should be discontinued prior to conception unless the risk of stopping—such as in severe narcolepsy—outweighs potential fetal risks.
| Drug Name | Modafinil / Provigil |
|---|---|
| Dosage | 100 – 200 mg |
| Price | from AUD$1.21 per pill |
| Check Now | Go to the Pharmacy |
-
What are the most commonly reported adverse effects of modafinil in placebo-controlled trials?
-
What factors explain modafinil’s low potential for abuse compared with traditional stimulants?
Treatment of Narcolepsy
Narcolepsy is a disorder of sleep–wake regulation marked by excessive daytime sleepiness. It is often accompanied by cataplexy and other REM-sleep–related symptoms. Patients typically present with overwhelming sleepiness that may appear as brief, hard-to-resist “sleep attacks,” frequently involving rapid entry into REM sleep. Additional features may include hypnagogic or hypnopompic hallucinations and episodes of sleep paralysis.
For many years, therapy relied mainly on amphetamine-like stimulants such as methylphenidate (Ritalin) and dextroamphetamine (Dexadrine), both FDA-approved for narcolepsy. However, these agents are Schedule II controlled substances and may lead to tachyphylaxis or withdrawal symptoms.
Placebo-controlled studies of modafinil online
Two large randomized, placebo-controlled trials conducted by the US Modafinil in Narcolepsy Multicenter Study Group (with 283 and 271 participants) evaluated modafinil at 200 mg/day, 400 mg/day, and placebo over 9 weeks. The second trial also assessed potential withdrawal effects.
In both studies, patients taking provigil demonstrated statistically significant reductions in subjective and objective sleepiness. After 9 weeks in the second trial, participants receiving 200 mg/day scored 13.0 on the Epworth Sleepiness Scale compared with 15.8 in the placebo group; those on 400 mg/day scored 12.3. Maintenance of Wakefulness Test results showed a similar pattern: 4.9 minutes for the 200-mg group, 3.5 minutes for placebo, and 5.1 minutes for the 400-mg group. In the active-treatment groups, all measures improved significantly from baseline. On the Multiple Sleep Latency Test, only the 400-mg group showed a significant increase in mean sleep latency. No withdrawal syndrome was observed.
Should a second dose be given at noon?
The standard starting dosage for narcolepsy is 200–400 mg taken in the morning, with titration guided by clinical response. In a randomized, double-blind study by Schwartz et al., patients who continued to experience afternoon or evening sleepiness while taking 400 mg in the morning were given an additional 200-mg noon dose or placebo. The noon dose produced a statistically greater improvement on evening Maintenance of Wakefulness Test trials and yielded better subjective ratings, although overall test results between the groups were not significantly different.
Modafinil dosing and timing should be individualized. Some patients with persistent sleepiness benefit from divided doses up to 800 mg/day, often combined with other wake-promoting medications. While dosing later than noon is generally avoided, a midday dose does not appear to disrupt sleep architecture.
How does modafinil compare with other stimulants?
There are currently no head-to-head human studies comparing modafinil with traditional stimulants for narcolepsy. In narcoleptic dogs, modafinil 5 mg/kg and amphetamine 0.1 mg/kg show comparable wake-promoting effects.
A review by Mitler and Hajdukovic estimated normalization of the Maintenance of Wakefulness Test in 55.3% of patients treated with provigil, 80% with dextroamphetamine, and 70% with methylphenidate. These comparisons lead some clinicians to regard modafinil as relatively less potent.
Buy Modafinil or Sodium Oxybate
Sodium oxybate (Xyrem) is not a stimulant but a central nervous system depressant. It is taken at night—once before going to bed and again about four hours later. The medication is FDA-approved for treating cataplexy associated with narcolepsy and for managing excessive daytime sleepiness in these patients.
Most clinical trials assessing sodium oxybate have compared it with placebo in individuals already receiving a stimulant as maintenance therapy. However, one study evaluated patients previously stabilized on modafinil and randomly assigned them to one of four regimens: placebo, sodium oxybate, modafinil, or a combination of sodium oxybate and modafinil. Those continuing modafinil remained on their usual dose (200–600 mg/day), with no dose adjustments during the trial. Sodium oxybate was initiated at 6 g nightly and increased to 9 g.
Sodium oxybate demonstrated an alerting effect comparable to modafinil on the Maintenance of Wakefulness Test. Still, because modafinil was not titrated to its maximum effective dose, the study could not definitively determine whether one agent is superior as monotherapy. The combination of sodium oxybate and modafinil produced the greatest improvement in mean sleep latency, with a statistically significant advantage compared with placebo.
Since these medications act through different mechanisms, they may be used together when clinically appropriate.
Obstructive Sleep Apnea Syndrome
Most individuals with obstructive sleep apnea (OSA) experience excessive daytime sleepiness and non-restorative sleep. Continuous positive airway pressure (CPAP) remains the gold-standard therapy, though weight loss, positional strategies, oral appliances, and upper airway surgery may benefit selected patients. Consistent nightly use of CPAP often eliminates obstructive events and substantially reduces sleepiness.
Modafinil as an Adjunct to CPAP
In a multicenter, double-blind, placebo-controlled trial involving 157 patients with residual daytime sleepiness despite CPAP therapy, those receiving modafinil 400 mg/day showed a reduction in Epworth Sleepiness Scale scores from 14.2 to 9.6 (P < .001). The placebo group showed a nonsignificant change from 14.4 to 12.4. On the Multiple Sleep Latency Test, modafinil increased mean latency from 7.4 to 8.6 minutes (P < .05), though the values remained outside the normal range; the placebo group showed a slight decrease.
A second multicenter trial of 305 CPAP-treated patients confirmed that adjunctive modafinil (200–400 mg/day) increased mean sleep latency on the Maintenance of Wakefulness Test, although results again did not return to normal levels.
In January 2004, the FDA approved modafinil as adjunct therapy for persistent daytime sleepiness in patients with OSA who are optimally treated with CPAP. Nevertheless, inadequate sleep duration and poor CPAP adherence frequently contribute to residual sleepiness and must be addressed before considering wake-promoting medications.
In an open-label study of patients receiving CPAP plus modafinil, average nightly CPAP use declined modestly—from 6.3 hours to 5.9 hours—over 12 weeks. This effect was not seen in the blinded trial where CPAP compliance was directly monitored.
Encourage Continued CPAP Use
Because wake-promoting agents do not relieve upper airway obstruction or reduce long-term cardiovascular and metabolic risks associated with OSA, clinicians should emphasize the importance of maintaining CPAP therapy and practicing good sleep hygiene. Many patients with OSA also have hypertension or other cardiovascular conditions, so anyone receiving modafinil requires careful monitoring of cardiovascular status.
| 60 pills | AUD$1.77 | A$39.72 | A$145.63 A$105.91 | |
| 90 pills | AUD$1.54 | A$79.44 | A$218.45 A$139.01 | |
| 120 pills | AUD$1.43 | A$119.15 | A$291.26 A$172.11 | |
| 180 pills | AUD$1.32 | A$198.59 | A$436.90 A$238.31 | |
| 270 pills | AUD$1.25 | A$317.74 | A$655.34 A$337.60 | |
| 360 pills | AUD$1.21 | A$436.90 | A$873.80 A$436.90 |
Shift-Work Sleep Disorder
Approximately 6% of full-time workers in the United States are employed on night shifts or rotating schedules. These individuals are susceptible to shift-work sleep disorder due to misalignment between their internal circadian rhythm and the external environment.
People with this condition generally sleep 1 to 4 hours less per day than those with conventional schedules. Over time, this cumulative sleep loss can impair alertness, reduce job performance, and raise the risk of workplace accidents. One study using ambulatory electroencephalography reported that about 20% of shift workers fell asleep at least once during a single night shift.
In January 2004, the FDA approved modafinil for managing excessive sleepiness associated with shift-work sleep disorder. The approval was based on a 12-week double-blind trial in which 209 patients received either modafinil 100 mg or placebo 30–60 minutes before each night shift. All participants had severe sleepiness, with baseline mean sleep latency below 6 minutes on the Multiple Sleep Latency Test.
Modafinil produced a statistically significant 1.7-minute increase in mean sleep latency compared with placebo, though not enough to restore normal values. It also improved performance on a vigilance test administered every two hours during a simulated night shift. However, sleep diaries showed no significant differences between groups in the number of sleep episodes, near-accidents, or caffeine intake.
Another randomized study involving 32 patients found significant improvements in vigilance and on the Maintenance of Wakefulness Test during a simulated night shift, although placebo scores were mostly within normal limits. Neither study demonstrated adverse effects on recovery sleep following night-shift work.
Off-Label Uses of Modafinil
Multiple Sclerosis
Fatigue is both common and disabling in many patients with multiple sclerosis (MS). In one report, 28% of patients identified fatigue as their most troubling symptom. Fatigue in MS is often assessed using the Fatigue Severity Scale, a validated nine-item questionnaire that distinguishes pathological fatigue from normal tiredness.
Historically, amantadine (Symmetrel) and pemoline (Cylert) were used, though both are associated with notable adverse effects. Concerns about hepatotoxicity led to the discontinuation of pemoline in 2005.
Provigil has shown mixed results in MS-related fatigue. In a single-blind study, 72 patients received placebo for 2 weeks, followed by modafinil 200 mg/day for 2 weeks, then 400 mg/day for 2 weeks, and finally placebo for 3 weeks. Significant improvements were observed with 200 mg/day, but not with the higher dose. Epworth Sleepiness Scale scores also decreased with both doses, although baseline values were already normal.
By contrast, two double-blind, placebo-controlled trials found no significant improvement in fatigue with modafinil. The larger study enrolled 115 participants and titrated modafinil up to 400 mg/day as tolerated.
ADHD
Modafinil has been evaluated in both adults and children with attention-deficit hyperactivity disorder (ADHD) and is considered an alternative to traditional stimulants in adult patients.
In a double-blind, placebo-controlled crossover study of 22 adults with ADHD, modafinil (mean dose ~207 mg/day) and dextroamphetamine (mean dose ~22 mg/day) both produced improvements across five outcome measures, including subjective assessments and cognitive testing of word association and digit span.
Another crossover trial involving 20 adults treated with modafinil 200 mg/day demonstrated reduced impulsivity on neuropsychiatric tasks. Larger studies are still needed to define its role in adult ADHD more clearly.
No large double-blind trials in children have been completed. In a 6-week trial of 24 children aged 5–15 years, modafinil 200–300 mg/day outperformed placebo on a computerized attention test (Test of Variables of Attention), but not on the ADHD Rating Scale. Notably, modafinil did not produce significant appetite suppression or weight loss—side effects commonly seen with traditional stimulants—suggesting potential advantages in pediatric settings.
Parkinson Disease
Sleep disturbances are common among individuals with Parkinson disease; approximately 60% report nighttime sleep problems, and up to 50% experience excessive daytime sleepiness.
Modafinil has been evaluated for Parkinson-related daytime sleepiness, but study sizes have been small. The largest randomized, double-blind, placebo-controlled study included 21 patients receiving either modafinil 200 mg/day or placebo. In those treated with modafinil, Epworth Sleepiness Scale scores improved from 17.8 to 14.4—statistically significant, though still outside the normal range. No meaningful improvements were observed in fatigue or motor function as measured by the Hoehn and Yahr Scale and the Unified Parkinson Disease Rating Scale.
Larger, well-designed trials using quality-of-life outcomes are needed to clarify modafinil’s therapeutic value in Parkinson disease.
Modafinil as Adjunctive Therapy in Depression
Fatigue and sleep disturbances are extremely common in major depressive disorder and may persist despite otherwise successful antidepressant treatment. In one study, 44% of patients who responded well to fluoxetine reported continued sleep difficulties, and 38% reported persistent fatigue.
The Modafinil in Depression Study Group evaluated modafinil for residual vegetative symptoms in 136 individuals with partially treated major depression. All participants had received at least five weeks of antidepressant therapy. Those randomized to modafinil began at 100 mg/day, titrated up to a maximum of 400 mg/day according to clinical response. After two weeks, patients receiving modafinil reported significantly less fatigue, but the effect was no longer significant at six weeks. No differences in mood outcomes were detected.
Another open-label study examined modafinil 200 mg/day in combination with fluoxetine or paroxetine as initial treatment for major depression. Significant improvements were seen on the Hamilton Rating Scale, Fatigue Severity Scale, and Epworth Sleepiness Scale compared with baseline, although the absence of a placebo arm limits interpretation.
At present, there is no clear consensus on the role of modafinil as an adjunct in depression, and further research is required.
Chronic Fatigue Syndrome
In a double-blind crossover trial, Randall and colleagues treated chronic fatigue syndrome patients with modafinil 200 mg/day, 400 mg/day, or placebo. Although 17 patients were enrolled, only 14 completed the study. No significant improvements were found in self-reported fatigue or quality of life. Larger trials are needed to assess potential benefits in this population.
Adverse Events and Safety
Modafinil is typically initiated at 200 mg/day and may be increased to 400 mg/day; higher doses are sometimes divided. Elderly patients and those with hepatic impairment should begin at 100 mg/day.
In placebo-controlled narcolepsy trials, the most frequently reported adverse effects included headache, nausea, and nervousness. Withdrawal rates ranged from 5% to 14% in the modafinil groups, compared with 4% to 11% for placebo. Headache is the most common side effect but often resolves after several days of treatment. Although modafinil generally does not disrupt sleep architecture on polysomnography, about 5% of patients report insomnia. Occasional cases of nervousness, anxiety, or stereotypic behaviors have been documented, though these appear less common than with traditional stimulants at therapeutic doses.
Cardiovascular Effects
Animal data suggest minimal differences between modafinil and classical stimulants regarding cardiovascular impact when adjusted for equivalent alerting doses. One study in dogs found no significant increases in heart rate or blood pressure with either agent, although amphetamine produced greater increases in motor activity. Comparable human studies using equipotent doses are lacking.
Modafinil does not raise heart rate in humans. Initially thought to have no effect on blood pressure, a retrospective analysis later showed that 2.4% of patients taking modafinil required initiation or adjustment of antihypertensive therapy, compared with 0.7% on placebo.
Abuse Potential
Classified as a Schedule IV medication, modafinil has been extensively studied for abuse liability in both humans and animals, including individuals with prior substance-use disorders. Across operant conditioning studies, comparative assessments of stimulant-like effects, and “willingness to pay” paradigms, modafinil consistently demonstrated low abuse potential—even at doses up to 800 mg/day.
Several factors may contribute: unlike amphetamines and cocaine, modafinil does not strongly engage dopaminergic receptors in the nucleus accumbens, a key reward center. In addition, its poor water solubility and instability at high temperatures make it difficult to inject or smoke. No withdrawal syndrome has been identified.
Pregnancy and Lactation
Modafinil is designated FDA pregnancy category C, indicating adverse fetal effects in animal studies and insufficient data in humans; potential benefits may outweigh risks in selected cases. Sodium oxybate is category B, meaning no fetal risks have been observed in animals, though human studies are lacking.
Embryotoxicity was observed in rats at doses approximately 5–10 times the maximal recommended human dose. The extent of excretion in breast milk remains unknown.
Women of childbearing potential should be counseled about potential teratogenic risks associated with stimulant medications. In general, these drugs should be discontinued prior to conception unless the risk of stopping—such as in severe narcolepsy—outweighs potential fetal risks.
| Drug Name | Modafinil / Provigil |
|---|---|
| Dosage | 100 – 200 mg |
| Price | from AUD$1.21 per pill |
| Check Now | Go to the Pharmacy |
-
What are the most commonly reported adverse effects of modafinil in placebo-controlled trials?
-
What factors explain modafinil’s low potential for abuse compared with traditional stimulants?
Treatment of Narcolepsy
Narcolepsy is a disorder of sleep–wake regulation marked by excessive daytime sleepiness. It is often accompanied by cataplexy and other REM-sleep–related symptoms. Patients typically present with overwhelming sleepiness that may appear as brief, hard-to-resist “sleep attacks,” frequently involving rapid entry into REM sleep. Additional features may include hypnagogic or hypnopompic hallucinations and episodes of sleep paralysis.
For many years, therapy relied mainly on amphetamine-like stimulants such as methylphenidate (Ritalin) and dextroamphetamine (Dexadrine), both FDA-approved for narcolepsy. However, these agents are Schedule II controlled substances and may lead to tachyphylaxis or withdrawal symptoms.
Placebo-controlled studies of modafinil online
Two large randomized, placebo-controlled trials conducted by the US Modafinil in Narcolepsy Multicenter Study Group (with 283 and 271 participants) evaluated modafinil at 200 mg/day, 400 mg/day, and placebo over 9 weeks. The second trial also assessed potential withdrawal effects.
In both studies, patients taking provigil demonstrated statistically significant reductions in subjective and objective sleepiness. After 9 weeks in the second trial, participants receiving 200 mg/day scored 13.0 on the Epworth Sleepiness Scale compared with 15.8 in the placebo group; those on 400 mg/day scored 12.3. Maintenance of Wakefulness Test results showed a similar pattern: 4.9 minutes for the 200-mg group, 3.5 minutes for placebo, and 5.1 minutes for the 400-mg group. In the active-treatment groups, all measures improved significantly from baseline. On the Multiple Sleep Latency Test, only the 400-mg group showed a significant increase in mean sleep latency. No withdrawal syndrome was observed.
Should a second dose be given at noon?
The standard starting dosage for narcolepsy is 200–400 mg taken in the morning, with titration guided by clinical response. In a randomized, double-blind study by Schwartz et al., patients who continued to experience afternoon or evening sleepiness while taking 400 mg in the morning were given an additional 200-mg noon dose or placebo. The noon dose produced a statistically greater improvement on evening Maintenance of Wakefulness Test trials and yielded better subjective ratings, although overall test results between the groups were not significantly different.
Modafinil dosing and timing should be individualized. Some patients with persistent sleepiness benefit from divided doses up to 800 mg/day, often combined with other wake-promoting medications. While dosing later than noon is generally avoided, a midday dose does not appear to disrupt sleep architecture.
How does modafinil compare with other stimulants?
There are currently no head-to-head human studies comparing modafinil with traditional stimulants for narcolepsy. In narcoleptic dogs, modafinil 5 mg/kg and amphetamine 0.1 mg/kg show comparable wake-promoting effects.
A review by Mitler and Hajdukovic estimated normalization of the Maintenance of Wakefulness Test in 55.3% of patients treated with provigil, 80% with dextroamphetamine, and 70% with methylphenidate. These comparisons lead some clinicians to regard modafinil as relatively less potent.
Buy Modafinil or Sodium Oxybate
Sodium oxybate (Xyrem) is not a stimulant but a central nervous system depressant. It is taken at night—once before going to bed and again about four hours later. The medication is FDA-approved for treating cataplexy associated with narcolepsy and for managing excessive daytime sleepiness in these patients.
Most clinical trials assessing sodium oxybate have compared it with placebo in individuals already receiving a stimulant as maintenance therapy. However, one study evaluated patients previously stabilized on modafinil and randomly assigned them to one of four regimens: placebo, sodium oxybate, modafinil, or a combination of sodium oxybate and modafinil. Those continuing modafinil remained on their usual dose (200–600 mg/day), with no dose adjustments during the trial. Sodium oxybate was initiated at 6 g nightly and increased to 9 g.
Sodium oxybate demonstrated an alerting effect comparable to modafinil on the Maintenance of Wakefulness Test. Still, because modafinil was not titrated to its maximum effective dose, the study could not definitively determine whether one agent is superior as monotherapy. The combination of sodium oxybate and modafinil produced the greatest improvement in mean sleep latency, with a statistically significant advantage compared with placebo.
Since these medications act through different mechanisms, they may be used together when clinically appropriate.
Obstructive Sleep Apnea Syndrome
Most individuals with obstructive sleep apnea (OSA) experience excessive daytime sleepiness and non-restorative sleep. Continuous positive airway pressure (CPAP) remains the gold-standard therapy, though weight loss, positional strategies, oral appliances, and upper airway surgery may benefit selected patients. Consistent nightly use of CPAP often eliminates obstructive events and substantially reduces sleepiness.
Modafinil as an Adjunct to CPAP
In a multicenter, double-blind, placebo-controlled trial involving 157 patients with residual daytime sleepiness despite CPAP therapy, those receiving modafinil 400 mg/day showed a reduction in Epworth Sleepiness Scale scores from 14.2 to 9.6 (P < .001). The placebo group showed a nonsignificant change from 14.4 to 12.4. On the Multiple Sleep Latency Test, modafinil increased mean latency from 7.4 to 8.6 minutes (P < .05), though the values remained outside the normal range; the placebo group showed a slight decrease.
A second multicenter trial of 305 CPAP-treated patients confirmed that adjunctive modafinil (200–400 mg/day) increased mean sleep latency on the Maintenance of Wakefulness Test, although results again did not return to normal levels.
In January 2004, the FDA approved modafinil as adjunct therapy for persistent daytime sleepiness in patients with OSA who are optimally treated with CPAP. Nevertheless, inadequate sleep duration and poor CPAP adherence frequently contribute to residual sleepiness and must be addressed before considering wake-promoting medications.
In an open-label study of patients receiving CPAP plus modafinil, average nightly CPAP use declined modestly—from 6.3 hours to 5.9 hours—over 12 weeks. This effect was not seen in the blinded trial where CPAP compliance was directly monitored.
Encourage Continued CPAP Use
Because wake-promoting agents do not relieve upper airway obstruction or reduce long-term cardiovascular and metabolic risks associated with OSA, clinicians should emphasize the importance of maintaining CPAP therapy and practicing good sleep hygiene. Many patients with OSA also have hypertension or other cardiovascular conditions, so anyone receiving modafinil requires careful monitoring of cardiovascular status.
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Shift-Work Sleep Disorder
Approximately 6% of full-time workers in the United States are employed on night shifts or rotating schedules. These individuals are susceptible to shift-work sleep disorder due to misalignment between their internal circadian rhythm and the external environment.
People with this condition generally sleep 1 to 4 hours less per day than those with conventional schedules. Over time, this cumulative sleep loss can impair alertness, reduce job performance, and raise the risk of workplace accidents. One study using ambulatory electroencephalography reported that about 20% of shift workers fell asleep at least once during a single night shift.
In January 2004, the FDA approved modafinil for managing excessive sleepiness associated with shift-work sleep disorder. The approval was based on a 12-week double-blind trial in which 209 patients received either modafinil 100 mg or placebo 30–60 minutes before each night shift. All participants had severe sleepiness, with baseline mean sleep latency below 6 minutes on the Multiple Sleep Latency Test.
Modafinil produced a statistically significant 1.7-minute increase in mean sleep latency compared with placebo, though not enough to restore normal values. It also improved performance on a vigilance test administered every two hours during a simulated night shift. However, sleep diaries showed no significant differences between groups in the number of sleep episodes, near-accidents, or caffeine intake.
Another randomized study involving 32 patients found significant improvements in vigilance and on the Maintenance of Wakefulness Test during a simulated night shift, although placebo scores were mostly within normal limits. Neither study demonstrated adverse effects on recovery sleep following night-shift work.
Off-Label Uses of Modafinil
Multiple Sclerosis
Fatigue is both common and disabling in many patients with multiple sclerosis (MS). In one report, 28% of patients identified fatigue as their most troubling symptom. Fatigue in MS is often assessed using the Fatigue Severity Scale, a validated nine-item questionnaire that distinguishes pathological fatigue from normal tiredness.
Historically, amantadine (Symmetrel) and pemoline (Cylert) were used, though both are associated with notable adverse effects. Concerns about hepatotoxicity led to the discontinuation of pemoline in 2005.
Provigil has shown mixed results in MS-related fatigue. In a single-blind study, 72 patients received placebo for 2 weeks, followed by modafinil 200 mg/day for 2 weeks, then 400 mg/day for 2 weeks, and finally placebo for 3 weeks. Significant improvements were observed with 200 mg/day, but not with the higher dose. Epworth Sleepiness Scale scores also decreased with both doses, although baseline values were already normal.
By contrast, two double-blind, placebo-controlled trials found no significant improvement in fatigue with modafinil. The larger study enrolled 115 participants and titrated modafinil up to 400 mg/day as tolerated.
ADHD
Modafinil has been evaluated in both adults and children with attention-deficit hyperactivity disorder (ADHD) and is considered an alternative to traditional stimulants in adult patients.
In a double-blind, placebo-controlled crossover study of 22 adults with ADHD, modafinil (mean dose ~207 mg/day) and dextroamphetamine (mean dose ~22 mg/day) both produced improvements across five outcome measures, including subjective assessments and cognitive testing of word association and digit span.
Another crossover trial involving 20 adults treated with modafinil 200 mg/day demonstrated reduced impulsivity on neuropsychiatric tasks. Larger studies are still needed to define its role in adult ADHD more clearly.
No large double-blind trials in children have been completed. In a 6-week trial of 24 children aged 5–15 years, modafinil 200–300 mg/day outperformed placebo on a computerized attention test (Test of Variables of Attention), but not on the ADHD Rating Scale. Notably, modafinil did not produce significant appetite suppression or weight loss—side effects commonly seen with traditional stimulants—suggesting potential advantages in pediatric settings.
Parkinson Disease
Sleep disturbances are common among individuals with Parkinson disease; approximately 60% report nighttime sleep problems, and up to 50% experience excessive daytime sleepiness.
Modafinil has been evaluated for Parkinson-related daytime sleepiness, but study sizes have been small. The largest randomized, double-blind, placebo-controlled study included 21 patients receiving either modafinil 200 mg/day or placebo. In those treated with modafinil, Epworth Sleepiness Scale scores improved from 17.8 to 14.4—statistically significant, though still outside the normal range. No meaningful improvements were observed in fatigue or motor function as measured by the Hoehn and Yahr Scale and the Unified Parkinson Disease Rating Scale.
Larger, well-designed trials using quality-of-life outcomes are needed to clarify modafinil’s therapeutic value in Parkinson disease.
Modafinil as Adjunctive Therapy in Depression
Fatigue and sleep disturbances are extremely common in major depressive disorder and may persist despite otherwise successful antidepressant treatment. In one study, 44% of patients who responded well to fluoxetine reported continued sleep difficulties, and 38% reported persistent fatigue.
The Modafinil in Depression Study Group evaluated modafinil for residual vegetative symptoms in 136 individuals with partially treated major depression. All participants had received at least five weeks of antidepressant therapy. Those randomized to modafinil began at 100 mg/day, titrated up to a maximum of 400 mg/day according to clinical response. After two weeks, patients receiving modafinil reported significantly less fatigue, but the effect was no longer significant at six weeks. No differences in mood outcomes were detected.
Another open-label study examined modafinil 200 mg/day in combination with fluoxetine or paroxetine as initial treatment for major depression. Significant improvements were seen on the Hamilton Rating Scale, Fatigue Severity Scale, and Epworth Sleepiness Scale compared with baseline, although the absence of a placebo arm limits interpretation.
At present, there is no clear consensus on the role of modafinil as an adjunct in depression, and further research is required.
Chronic Fatigue Syndrome
In a double-blind crossover trial, Randall and colleagues treated chronic fatigue syndrome patients with modafinil 200 mg/day, 400 mg/day, or placebo. Although 17 patients were enrolled, only 14 completed the study. No significant improvements were found in self-reported fatigue or quality of life. Larger trials are needed to assess potential benefits in this population.
Adverse Events and Safety
Modafinil is typically initiated at 200 mg/day and may be increased to 400 mg/day; higher doses are sometimes divided. Elderly patients and those with hepatic impairment should begin at 100 mg/day.
In placebo-controlled narcolepsy trials, the most frequently reported adverse effects included headache, nausea, and nervousness. Withdrawal rates ranged from 5% to 14% in the modafinil groups, compared with 4% to 11% for placebo. Headache is the most common side effect but often resolves after several days of treatment. Although modafinil generally does not disrupt sleep architecture on polysomnography, about 5% of patients report insomnia. Occasional cases of nervousness, anxiety, or stereotypic behaviors have been documented, though these appear less common than with traditional stimulants at therapeutic doses.
Cardiovascular Effects
Animal data suggest minimal differences between modafinil and classical stimulants regarding cardiovascular impact when adjusted for equivalent alerting doses. One study in dogs found no significant increases in heart rate or blood pressure with either agent, although amphetamine produced greater increases in motor activity. Comparable human studies using equipotent doses are lacking.
Modafinil does not raise heart rate in humans. Initially thought to have no effect on blood pressure, a retrospective analysis later showed that 2.4% of patients taking modafinil required initiation or adjustment of antihypertensive therapy, compared with 0.7% on placebo.
Abuse Potential
Classified as a Schedule IV medication, modafinil has been extensively studied for abuse liability in both humans and animals, including individuals with prior substance-use disorders. Across operant conditioning studies, comparative assessments of stimulant-like effects, and “willingness to pay” paradigms, modafinil consistently demonstrated low abuse potential—even at doses up to 800 mg/day.
Several factors may contribute: unlike amphetamines and cocaine, modafinil does not strongly engage dopaminergic receptors in the nucleus accumbens, a key reward center. In addition, its poor water solubility and instability at high temperatures make it difficult to inject or smoke. No withdrawal syndrome has been identified.
Pregnancy and Lactation
Modafinil is designated FDA pregnancy category C, indicating adverse fetal effects in animal studies and insufficient data in humans; potential benefits may outweigh risks in selected cases. Sodium oxybate is category B, meaning no fetal risks have been observed in animals, though human studies are lacking.
Embryotoxicity was observed in rats at doses approximately 5–10 times the maximal recommended human dose. The extent of excretion in breast milk remains unknown.
Women of childbearing potential should be counseled about potential teratogenic risks associated with stimulant medications. In general, these drugs should be discontinued prior to conception unless the risk of stopping—such as in severe narcolepsy—outweighs potential fetal risks.