Modafinil: Stimulant Drug in Sheep's Clothing

Modafinil (Provigil) was unwisely approved by the FDA as an "orphan drug" for narcolepsy.  The orphan drug status meant that the manufacturer was given regulatory breaks enabling less money to be spent on its development because it was aimed at helping a rare disease, narcolepsy.  Since then, the manufacturer has been promoting this stimulant drug for a very wide range of diseases, as well as for healthy people.  Some doctors have been prescribing it very frequently and at a very high cost ($450-$600/month in below studies).  It is also easily bought over the internet by lying to the internet doctor.  Sales have boomed to $575 million in 2005 with it likely to reach $1 billion in 2006.  It is a very expensive drug with very limited usefulness and many drawbacks in my opinion.  It's another part of our stimulant/sedative drug obsessed culture.

The manufacturer goes to great lengths to say that provigil is not like amphetamines.  However, the truth is that it is simply a new, slightly milder stimulant with few significant benefits, certainly none worth its high cost.  The manufacturer is waging a worldwide campaign to portray modafinil as great for everyone, allowing everyone to sleep less and to be more productive. 

In a highly sensationalistic cover story in Britain's New Scientist, authors say modafinil has a "near-mythical reputation" for keeping people awake without side-effects. They feature a young Seattle software programmer who fraudulently obtains modafinil on the internet so that he "can go out partying Friday night and still go skiing early on Saturday."  He gives his unquestioned testimonial that modafinil is "tremendously useful," and that it makes him "very productive at work."  The authors claim modafinil makes it possible to have 48 hours of continuous wakefulness with few, if any, ill effects.  The authors promise sleeping pills on the horizon that are faster and better than natural sleep and a drug-induced world where 2 hours of sleep a night is all that is needed.

Jeffrey Vaught, President of R&D at Cephalon, is quoted promoting it for 48 hours of awake time.  The manufacturer claims that there is no sleep debt built up.  Like other stimulants, modafinil prevents nerve cells from reabsorbing the excitatory dopamine.  It does have other differences, but is clearly no miracle drug.  Authors call modafinil a new "lifestyle drug," and claim that hardly anyone has a bad word about modafinil.  The Pennsylvania company is already developing, with the help of the University of Pennsylvania, the look-alike armodafinil for when modafinil's patent runs out.  Vaught and the authors say we are already in a stimulant-sedative society, "so why not make it as clean and safe as possible?"  

In fact, modafinil causes psychosis and many other side-effects, just as one would expect from a stimulant.  The manufacturer has funded many irresponsible one and two day studies proclaiming beneficial effects.  Numerous, unresponsible "open trials" and single case reports of proclaimed benefits have been published.  Undoubtedly, the manufacturer has had a hand in many.  As expected, modafinil does much less well in double-blind research, especially independent double-blind research, than in open-label studies.  It is being pushed for children for ADHD, and for anything that makes you fatigued or tired in adults.

Heroin, when first introduced by Bayer Pharmaceuticals, was proclaimed a non-addictive medication good for diarrhea and morphine addiction.  Cocaine was widely claimed in the early 1970s to be a harmless stimulant.  Some users still sing praises to cocaine, methamphetamine, and narcotics as wonder drugs.  Modafinil is just another stimulant, only one that is a little more mild, and slightly different from methylphenidate or amphetamines.  It's extremely high cost, very modest benefits, and significant side-effect profile makes it  very undesirable for the clinical practice of medicine.

High Dose Coffee Just as Good as Modafinil: In a DB study to determine whether modafinil should replace caffeine for restoring performance and alertness during total sleep deprivation in otherwise healthy adults, 50 healthy young adults remained awake for 54.5 hours. After 41.5 hours, they received placebo; modafinil 100, 200, or 400 mg; or caffeine 600 mg, followed by hourly testing. Performance and alertness were significantly improved by modafinil 200 and 400 mg relative to placebo, and effects were comparable to those obtained with caffeine 600 mg. The authors conclude, "Modafinil does not appear to offer advantages over caffeine for improving performance and alertness during sleep loss in otherwise normal, healthy adults. Maintaining alertness and performance during sleep deprivation: modafinil versus caffeine. Wesensten NJ, et al. Walter Reed Army Institute of Research. . Psychopharm (Berlin) 2002 Jan;159(3):238-47.

Harvard, Pittsburgh, Stanford Push Modafinil for Drug Company Despite Study Documenting Very Little Benefit: In a multicenter 8-week DB PC study of 311 patients with major depression and only partial responses to SSRI therapy after at least 8 weeks, half were given the expensive brandname stimulant modafinil 200 mg/day, an "orphan" drug approved only for the treatment of narcolepsy. There was no significant improvement in 31-item or 17-item HAM-D depression scores, Epworth Sleepiness scores, Fatigue Severity scores, Brief Fatigue Inventory scores, or MADRS depression scores. More side-effects occurred with modafinil (nausea and jitteriness).  The only weakly significant finding favoring modafinil and only at the final visit was that modafinil improved patients' overall clinical condition compared with placebo on the basis of Clinical Global Impressions-Improvement scores (p = .02). The authors claim, that based on their study, "these findings suggest that modafinil is a well-tolerated and potentially effective augmenting agent for SSRI partial responders with fatigue and sleepiness." A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. Fava M, Thase ME, DeBattista C. MGH-Harvard, University of Pittsburgh, and Stanford. Ed: The company manufacturing modanifil has a long history of funding very brief, even single dose studies, to irresponsibly push its drug.  This study actually has a good research design and found nothing. The CGI is the most unreliable of all research measures. It could easily be influenced just by the fact that patients like the little amphetamine like surge you get after taking modafinil.  That doesn't mean its good for you.  Harvard and the University of Pittsburgh have long histories of cranking out studies for drug companies. These particular authors are among the worst offenders.

Modafinil (Provigil) Helps Fatigue Barely and Briefly at Great Cost: In a 136-patient DB PC of Major Depression, modafanil or placebo was added to standard anti-depressants during the daytime at 100-400 mg once a day.  While researchers from Stanford claim that modafanil "rapidly improved" fatigue and daytime sleepiness by the second week, in fact, despite the relatively large size of the study, its superiority over placebo was only at p<.05!  Any advantage over placebo had totally disappeared by week 6.  Modafanil had no beneficial effect on depression scores. The study was financed by the manufacturer! 

Modafinil Failed to Help ER Docs: Modafinil has recently been approved for the treatment of shift work sleep disorder, making it potentially available for shift-working emergency physicians. In a DB PC crossover single-dose study of ER physicians using it to stay awake the day after working all night, modafinil facilitated sustained attention, cognitive control, and working memory, as well as performance on the coding task at the first session. It increased perceived alertness during the simulated patient care sessions, but worsened sleep onset when opportunities for sleep arose. Cognitive performance following modafinil versus placebo in sleep-deprived emergency physicians: a double-blind randomized crossover study. Gill M, et al. Loma Linda University. . Acad Emerg Med 2006 Feb;13(2):158-65.

ADHD: Modafinil (Provigil) Better than Placebo, But Extremely Expensive with Stimulant Type Side-Effects: In a 9-week DB PC study of 248 children with ADHD, ADHD symptoms decreased by 15.0 points vs 7.3 for placebo (effect size: 0.69). Significant improvements were observed with modafinil on the ADHD-RS-IV School and on Home Versions at week 1, with improvements maintained throughout the study. Modafinil reduced inattention and hyperactivity-impulsivity. 48% of modafinil-treated patients were rated as "much" or "very much" improved vs. 17% for placebo. Modafinil caused insomnia (29%), headache (20%), and decreased appetite (16%). Efficacy and safety of modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, flexible-dose study Biederman J, et al. Massachusetts General Hospital. . Pediatrics 2005 Dec;116(6):e777-84.

ADHD: Modafinil Helped Compared to Placebo at Extremely High Cost: In a 7-week DB PC study of 190 ADHD patients aged 6 to 17 with an abrupt discontinuation of modafinil and a 2-week, double-blind observation period in which half were switched to placebo without tapering and half continued to receive modafinil, the daily doses were 340 mg for patients < 30 kg or 425 mg for patients > or = 30 kg. Reductions in ADHD-RS-IV School Version total scores compared with placebo occurred at all visits (p < or = .009), including the final visit of the double-blind phase (p < .0001). With modafinil, ADHD-RS-IV School Version mean total scores changed from 37.8 at baseline to 29.3 at week 1 and 20.7 at final visit; corresponding placebo values were 36.6, 32.8, and 28.4, respectively; effect size at final visit was 0.76. Total scores on the ADHD-RS-IV Home Version were also significantly reduced at all visits (p < or = .022) and final visit (p = .001) in patients receiving modafinil compared with those receiving placebo. No withdrawal symptoms were observed when modafinil was abruptly discontinued at the beginning of the final 2-week observation period. Modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, fixed-dose study followed by abrupt discontinuation. Swanson JM, et al. University of California at Irvine. . J Clin Psychiatry 2006 Jan;67(1):137-47. Ed: The medication cost in this study were $480-600 based on Walgreen prices on March 11, 2006. That's $7200 per year per child over 66 pounds. Considerable benefits are obtainable with structured classrooms and non-stimulant medications. Even for stimulants, generic ritalin costs only $600 per year.

Chronic Fatigue Syndrome: Modafinil Appears Worthless: In a 20-day/phase DB PC crossover study of 14 chronic fatigue syndrome patients without concurrent major depression, modafinil (200 and 400mg/day) improved sustained attention at 200 mg, but 400 mg increased the number of missed targets. In a test of spatial planning, the 200 mg dose resulted in a slower initial thinking time for the easiest part of the task, whereas 400 mg reduced the initial thinking time for the hardest part of the test. Lastly, in a test of mental flexibility and one of motor speed, patients performed worse while on modafinil (400mg), compared with the placebo period. No effects were observed on the performance of other psychometric tests or on self-ratings of fatigue, quality of life or mood. Chronic treatment with modafinil may not be beneficial in patients with chronic fatigue syndrome. Randall DC, et al. King's College London. J Psychopharm 2005 Nov;19(6):647-60.

Cocaine Dependence: Some Short-Term Benefit: Modafinil is a glutamate-enhancing agent that blunts cocaine euphoria under controlled conditions. In an 8-week DB PC study of 62 cocaine-dependent adults, all receiving twice weekly cognitive behavior therapy, modafinil (400 mg) somewhat increase the number of BE-negative urine samples (p=0.03). A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Dackis CA, et al. University of Pennsylvania. . Neuropsychopharm 2005 Jan;30(1):205-11. Ed: Other short-term studies have reported modest benefits with stimulants. No long-term studies have been done and long-term research with medications for nicotine dependence suggest that any benefit is likely to disappear.

Depression: Another Trash Study From Stanford: In the unethical publication of a drug-industry sponsored "open trial," 35 patients with major depression under treatment with an anti-depressant were also given modafinil 100 to 400 mg/d for 4 weeks. Patients had significant decreases in depression, but there were no controls and the study had numerous sources of potential bias.  Despite this, the authors conclude, "Modafinil may be a useful and a well-tolerated adjunctive agent to standard antidepressants in the treatment of major depression." A prospective trial of modafinil as an adjunctive treatment of major depression. DeBattista C, et al. Stanford University. . Ed: DeBattista is a consultant for the manufacturer, receives many grants from drug companies, and is on six different drug company speakers bureaus, receiving handsome stipends for giving positive talks praising the manufacturers' drugs. The publication of open trials is clearly unethical since the authors and the drug companies know that they prove absolutely nothing and yet mislead physicians into prescribing the drug in question. Of course, that is the sole reason that they are published.

Depression: Modafinil Minor, Brief Benefit for Fatigue and Sleepiness Which Quickly Disappears: In a 6-week DB PC study of 136 Major Depression patients with partial response to anti-depressant therapy, modafinil 100-400 mg/day "rapidly" (sic) improved fatigue and daytime wakefulness, with somewhat less fatigue only at week 2 (p < .05) and less sleepiness only at week 1 (p < .01); the differences between modafinil and placebo at week 6 were not statistically significant. Modafinil had no benefit on depression, clinical global improvement or general health. Despite this dismal performance for a very expensive drug with occasionally serious side-effects, the authors proclaim, "Modafinil may be a useful adjunct therapy for the short-term management of residual fatigue and sleepiness in patients who are partial responders to antidepressant therapy." Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind, placebo-controlled study. DeBattista C, et al. Stanford University. . J Clin Psychiatry 2003 Sep;64(9):1057-64.

Multiple Sclerosis: No Benefit: In a 5-week DB PC study of 115 MS patients with fatigue, modafinil 400 mg was of no benefit for fatigue. Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study. Stankoff B, et al. Hopital de la Salpetriere, Paris, France. . Neurol 2005 Apr 12;64(7):1139-43.

Normals: No Help With Mental Performance: In a DB PC study of 60 healthy students of 100 or 200 mg modafinil, there were no treatment-associated changes in these or in mood ratings during the tests. Modafinil was without effect in several tests of reaction time and attention, but the 200-mg group was faster at simple color naming of dots and performed better than placebo in the Rapid Visual Information Processing test of sustained attention. Modafinil was without effect on spatial working memory, but the 100-mg group performed better in the backward part of the digit span test. Modafinil was without effect on verbal short-term memory (story recall), but 100 mg improved digit span forward, and both doses improved pattern recognition, although this was accompanied by a slowing of response latency in the 200-mg group. There were no significant effects of modafinil compared with placebo in tests of long-term memory, executive function, visuospatial and constructional ability, or category fluency. Modanifil cannot be considered as a cognitive enhancer in non-sleep-deprived individuals. Does modafinil enhance cognitive performance in young volunteers who are not sleep-deprived? Randall DC, et al. King's College London, UK. . J Clin Psychopharm 2005 Apr;25(2):175-9.

Parkinson's Disease: Modafinil Worthless: In a DB PC study of 40 Parkinson's Diseased adults, modafinil (200-400 mg/day) had no benefit on the Epworth Sleepiness (ES) scale scores, Unified Parkinson's Disease Rating Scale, the Fatigue Severity Scale, the Hamilton Depression Scale, or the multiple sleep latency test. Modafinil for daytime somnolence in Parkinson's disease: double blind, placebo controlled parallel trial. Ondo WG, et al. . J Neurol Neurosurg Psychiatry 2005 Dec;76(12):1636-9.

Post-Polio Fatigue: Modafinil Worthless: In a DB PC cross-over study of 14 postpolio patients with moderate to severe fatigue, modafinil was of no benefit for testing on the Piper Fatigue Scale, Epworth Sleepiness Scale, digit span, and reaction time tests. The Piper Fatigue Scale scores improved by 27% following modafinil and by 43% following placebo. Randomized controlled trial of modafinil for the treatment of fatigue in postpolio patients. Chan KM, et al. University of Alberta. . Muscle Nerve 2006 Jan;33(1):138-41.

Schizophrenia: No Benefit and One of 13 Had Increased Psychosis: In an 8-week DB PC study of 24 patients with schizophrenia, modafinil up to 200 mg a day had no beneficial effect. One out of 13 had a worsening of psychosis. There were no differences between groups on changes in fatigue, symptoms, attention, working memory, or executive functioning. Double-blind, placebo-controlled study of modafinil for fatigue and cognition in schizophrenia patients treated with psychotropic medications. Sevy S, et al. North Shore-Long Island Jewish Health System. .

Shift Work Drowsiness Helped Slightly: Sleepiness in adult doing shift-work has been declared a disease: the dreaded shift-work sleep disorder, instead of an unethical work schedule. In a three-month, DB PC study of 209 adults with shift-work sleep disorder, modafinil 200 mg, as compared with placebo, taken just before work resulted in a modest improvement in the time a person attempts to fall asleep and the onset of sleep (1.7 vs. 0.3 minutes; P=0.002). Modafinil reduced sleepiness (74% vs. 36%; P<0.001). There was a small, but significant improvement in performance, and fewer patients reported near accidents while commuting home (29% vs. 54%; P<0.001). However, those on modafinil continued to have excessive sleepiness and impaired performance at night. Headache was the most common adverse event. Modafinil for excessive sleepiness associated with shift-work sleep disorder. Czeisler CA, et al. Harvard. . New Eng J Med 2005 Aug 4;353(5):476-86.

Sleep Apnea: Statistically Significant But Minimal Clinical Benefit: In a 12-week, DB PC study of sleep apnea adults aged 18 to 70 using nCPAP, modafinil, 200 mg or 400 mg improved sleep latency on the Maintenance of Wakefulness Test at weeks 4, 8, and 12 compared with placebo (week 12: modafinil 400 mg, 15.0 minutes; 200 mg, 14.8 minutes; placebo, 12.6 minutes; P < .0001). The Epworth Sleepiness Scale score decreased more in patients taking modafinil compared with those in the placebo group (week 12: modafinil 400 mg, -4.5; 200 mg, -4.5; placebo, -1.8 [3.5]; P < .0001). At week 12, overall clinical condition improved for 61% and 68% of patients treated with modafinil 200 mg and 400 mg, respectively, versus 37% of placebo-treated patients (P < .001). Modafinil for treatment of residual excessive sleepiness in nasal continuous positive airway pressure-treated obstructive sleep apnea/hypopnea syndrome. Black JE, et al. Stanford University. . Sleep 2005 Apr 1;28(4):464-71. Ed: The sleep apnea patients I see do not mention daytime sleepiness very often and rarely as a significant complaint. Some like their CPAP machines, while others don't. A 3 minute improvement on sleep latency doesn't seem like much to me.

Stimulant Given to Fight Normal Sleep: Armodafinil Joins Modafinil: In a DB PC study of 107 healthy male volunteers receiving a single oral dose of armodafinil (100, 150, 200, or 300 mg), modafinil (200 mg), or placebo at 19:25 h, all four doses of armodafinil, and the dose of 200 mg modafinil, improved wakefulness as measured by increased MWT latencies (treatment effect, p < 0.0001) and reduced PVT lapses of attention (treatment effect, p < 0.0001). Armodafinil at 200 mg resulted in comparable C(max), a later t(max), and higher plasma concentrations 6-14 hours post-drug administration than with 200 mg modafinil. Pharmacodynamic effects on alertness of single doses of armodafinil in healthy subjects during a nocturnal period of acute sleep loss. Dinges DF, et al. University of Pennsylvania. . Curr Med Res Opinion 2006 Jan;22(1):159-67.

Side-Effects

Irritability and Aggression Increased: Modafinil-induced irritability and aggression? A report of 2 bipolar patients. Ranjan S, et al. J Clin Psychopharm 2005 Dec;25(6):628-9.

Acute Hepatic Failure in Mice Increased: Zhu HP, et al. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2005 Jun;30(3):344-8.

Hypertension and Heart Rate Increased: In a 3-day DB PC cross-over study of 12 healthy adults, modafinil (400 mg/day) increased resting heart rate (9.2; P=0.001), resting systolic blood pressure (7.3 mm Hg; P=0.044), and resting diastolic blood pressure (5.3 mm Hg; P<0.012). Modafinil elicited a 42% higher orthostatic increase in plasma norepinephrine (0.8 nmol/L; P=0.01), and caused a 33% increase in urine norepinephrine (5.1 nmol/L creatinine per day; P=0.001), and an 81% increase in urine epinephrine (1.3 nmol/L creatinine per day; P<0.001). The peroneal microneurographic sympathetic activity was attenuated by modafinil during orthostatic tilt (P<0.001). alpha1-Adrenoreceptor function was maintained. Modafinil substantially perturbs autonomic cardiovascular regulation by increase in heart rate and blood pressure. Modafinil elicits sympathomedullary activation. Taneja I, et al. Vanderbilt University. Hypertension 2005 Apr;45(4):612-8.