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PubMedDate not supplied

Evaluation of the abuse liability of modafinil and other drugs for excessive daytime sleepiness associated with narcolepsy.

Psychostimulants have been used routinely for the treatment of the disabling daytime sleepiness associated with narcolepsy. However, the perceived and real potential for abuse of amphetamine and amphetaminelike stimulants prompted a search for new wake-promoting compounds with lower dependency and abuse liabilities. Modafinil is a novel wake-promoting agent with a mechanism of action that differs markedly from that of amphetamine and amphetamine-like stimulants. In controlled clinical trials, modafinil has been shown to be an effective and well-tolerated treatment for excessive daytime sleepiness (EDS) in patients with narcolepsy. With a benzhydrylsulfinylacetamide structure, modafinil has a low level of solubility in water (< 1 mg/mL) and is unstable at temperatures > or = 180 degrees C, physicochemical properties that reduce the potential for its abuse via intravenous injection and smoking, respectively. Available preclinical and clinical data on the abuse liability of modafinil suggest a much lower potential for abuse and dependency than amphetaminelike stimulants commonly used for treating EDS in patients with narcolepsy. Therefore, modafinil represents a valuable therapeutic option for the treatment of EDS associated with narcolepsy.

Benzhydryl Compounds↗
PubMedDate not supplied

Dosing regimen effects of modafinil for improving daytime wakefulness in patients with narcolepsy.

In a multicenter, randomized, double-blind study the authors compared the efficacy of modafinil 400 mg once daily, 400 mg given in a split dose, or 200 mg once daily for maintaining wakefulness throughout the day in patients (N = 32) with narcolepsy reporting a positive daytime response to modafinil but late-afternoon/evening sleepiness. Efficacy evaluations included an extended Maintenance of Wakefulness Test (9:00 am to 9:00 pm), the Clinical Global Impression of Change scale, and the Epworth Sleepiness Scale. Modafinil demonstrated significant improvement in wakefulness as assessed by the Epworth Sleepiness Scale compared with placebo at baseline (all P < 0.001). Modafinil significantly improved patients' ability to sustain wakefulness, as demonstrated by mean sleep latency at week 3 compared with placebo at baseline (all P < 0.001). The 400-mg split-dose regimen improved wakefulness significantly in the evening compared with the 200-mg and 400-mg once-daily regimen (both P < 0.05). The percentage of patients rated as "much improved" or "very much improved" with respect to evening sleepiness was 27%, 82%, and 80% in the 200-mg, 400-mg once-daily, and 400-mg split-dose groups, respectively. Adverse events were mild to moderate in nature and included headache, nausea, nervousness, dyspepsia, pain, and vomiting (all 6%). Some patients may benefit from 400-mg doses of modafinil taken once daily compared with 200-mg doses. A split-dose 400-mg regimen may be superior to once-daily dosing for sustaining wakefulness throughout the entire waking day.

Adult↗
PubMed2004

A prospective trial of modafinil as an adjunctive treatment of major depression.

Modafinil is a wake-promoting agent approved by the Federal Drug Administration for the treatment of narcolepsy. Preliminary evidence indicates that modafinil may improve fatigue and excessive sleepiness associated with a variety of conditions. The purpose of this study was to investigate the utility of modafinil as an adjunctive treatment of depressed patients. Subjects with a history of major depression with partial response on a stable therapeutic dose of an antidepressant were eligible to participate. All subjects endorsed complaints of significant fatigue and/or excessive sleepiness on clinical assessment. Modafinil was added to their existing regimen at a dose of 100 to 400 mg/d for 4 weeks. Subjects were assessed at 2-week intervals for improvement using the standard depression scales (HDRS, BDI, CGI), fatigue scales (VASF, FSI), and a neuropsychologic battery. Thirty-five subjects were entered and 31 subjects completed the 4-week trial. Significant improvements were seen across all 3 measures of depression (HDRS, BDI, CGIS) and both measures of fatigue (VASF, FSI). On the neurocognitive battery, significant gains in the Stroop Interference Test were seen at 4 weeks, whereas the other cognitive tests showed no change. Modafinil may be a useful and a well-tolerated adjunctive agent to standard antidepressants in the treatment of major depression.

Adult↗
PubMed2005

Performance and alertness effects of caffeine, dextroamphetamine, and modafinil during sleep deprivation.

Stimulants may provide short-term performance and alertness enhancement during sleep loss. Caffeine 600 mg, d-amphetamine 20 mg, and modafinil 400 mg were compared during 85 h of total sleep deprivation to determine the extent to which the three agents restored performance on simple psychomotor tasks, objective alertness and tasks of executive functions. Forty-eight healthy young adults remained awake for 85 h. Performance and alertness tests were administered bi-hourly from 8:00 hours day 2 to 19:00 hours day 5. At 23:50 hours on day 4 (after 64 h awake), subjects ingested placebo, caffeine 600 mg, dextroamphetamine 20 mg, or modafinil 400 mg (n=12 per group). Performance and alertness testing continued, and probe tasks of executive function were administered intermittently until the recovery sleep period (20:00 hours day 5 to 8:00 hours day 5). Bi-hourly postrecovery sleep testing occurred from 10:00 hours to 16:00 hours day 6. All three agents improved psychomotor vigilance speed and objectively measured alertness relative to placebo. Drugs did not affect recovery sleep, and postrecovery sleep performance for all drug groups was at presleep deprivation levels. Effects on executive function tasks were mixed, with improvement on some tasks with caffeine and modafinil, and apparent decrements with dextroamphetamine on others. At the doses tested, caffeine, dextroamphetamine, and modafinil are equally effective for approximately 2-4 h in restoring simple psychomotor performance and objective alertness. The duration of these benefits vary in accordance with the different elimination rates of the drugs. Whether caffeine, dextroamphetamine, and modafinil differentially restore executive functions during sleep deprivation remains unclear.

Adult↗
PubMed1987

Effect of modafinil on pancreatic exocrine secretion in rats. A comparison with adrafinil and related drugs.

The effects of modafinil and adrafinil, 2 drugs that induce locomotor hyperactivity, and those of the parent compounds CRL 40467 and CRL 40385, were studied on the external pancreatic secretion of anaesthetized and conscious rats. In anaesthetized rats modafinil, adrafinil, and CRL 40385 antagonized the central vagal stimulation of protein output induced by 2-deoxy-D-glucose in the pancreatic juice. In conscious rats, modafinil and adrafinil inhibited the output of protein in the basal interdigestive pancreatic secretion. Modafinil was more active than adrafinil as an inhibitor of pancreatic secretion. The effects of modafinil and adrafinil were different from those of sympathetic amines and dopamine: they did not stimulate the output of bicarbonate in anaesthetized rats, and pancreatic inhibition observed in conscious rats was not inhibited by either yohimbine or prazosin.

Anesthesia↗
PubMed2006

Impact of modafinil on prefrontal executive function in schizophrenia.

OBJECTIVE: The purpose of this study was to investigate the acute effects of modafinil on prefrontal activation and cognitive control of motor activity in people with schizophrenia and prominent negative symptoms. METHOD: In a crossover design, 12 subjects with schizophrenia were studied twice, receiving either modafinil or placebo prior to functional magnetic resonance imaging (fMRI). Inside the scanner, they performed a task probing cognitive control that required deliberate variation of motor activity in time. RESULTS: Modafinil administration was associated with significantly greater activation of the dorsolateral prefrontal cortex during fMRI. Its physiological and behavioral effects were correlated. This was most evident in individuals with worse baseline executive function. Focal response to modafinil in the left dorsolateral prefrontal cortex and baseline letter fluency scores predicted most of the variance in the drug's effect on cognitive control. CONCLUSIONS: Modafinil did not improve cognitive control in all schizophrenia patients. Increased activation in the dorsolateral prefrontal cortex and in neuropsychological performance were observed in patients with suboptimal baseline function.

Adult↗
PubMed2006

Comparison of pramipexole and modafinil on arousal, autonomic, and endocrine functions in healthy volunteers.

The noradrenergic locus coeruleus is a major wakefulness-promoting nucleus of the brain, which is also involved in the regulation of autonomic and endocrine functions. The activity of the locus coeruleus is believed to be tonically enhanced by a mesocoerulear dopaminergic pathway arising from the ventral tegmental area of the midbrain. Both modafinil, a wakefulness-promoting drug, and pramipexole, a D(2)/D(3)receptor agonist with sedative properties, may act on this pathway, with modafinil increasing and pramipexole decreasing locus coeruleus activity. The aim of this study was to compare the two drugs on alertness, autonomic and endocrine functions in healthy volunteers. Pramipexole (0.5mg), modafinil (200mg), and their combination were administered to 16 healthy males in a double-blind, placebo-controlled design. Methods included tests of alertness (pupillographic sleepiness test, critical flicker fusion frequency, visual analogue scales), autonomic functions (resting pupil diameter, light and darkness reflex responses, heart rate, blood pressure, salivation, core temperature), and endocrine functions (blood concentrations of prolactin, growth hormone, and thyroid stimulating hormone). Data were analysed by ANOVA. Pramipexole reduced alertness, caused pupil dilatation, increased heart rate, reduced prolactin and thyroid stimulating hormone, and increased growth hormone level. Modafinil caused small increases in blood pressure and core temperature, and reduced prolactin levels. The sedative effect of pramipexole and the autonomic effects of modafinil are consistent with altered activity in the mesocoerulear pathway; the pupil dilatation following pramipexole suggests reduced dopaminergic excitation of the Edinger-Westphal nucleus.

Adolescent↗
PubMed2005

Modafinil modulates anterior cingulate function in chronic schizophrenia.

BACKGROUND: Schizophrenia is associated with widespread cognitive deficits that have an impact on social function. Modafinil promotes wakefulness and is reported to enhance cognition. AIMS: To study the acute effects of modafinil administration upon brain activity and cognitive performance in people with chronic schizophrenia. METHOD: In a randomised double-blind placebo-controlled crossover design, 19 patients received either modafinil (100 mg) or placebo prior to undertaking a working memory task with functional magnetic resonance imaging. RESULTS: Seventeen patients completed the study and another underwent acute relapse 4 days post-drug. Modafinil administration was associated with significantly greater activation in the anterior cingulate cortex during the working memory task. The anterior cingulate cortex signal correlated with cognitive performance, although only a subset of patients exhibited 'enhancement'. CONCLUSIONS: Modafinil modulates anterior cingulate cortex function in chronic schizophrenia but its beneficial cognitive effects may be restricted to a subset of patients requiring further characterisation.

Adolescent↗
PubMed2003

Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea: a 12-week, open-label study.

STUDY OBJECTIVES: The purpose of this 12-week study was to evaluate the efficacy and safety of adjunct modafinil to treat excessive sleepiness in patients with obstructive sleep apnea (OSA) who experience residual sleepiness despite regular nasal continuous positive airway pressure (nCPAP) use. DESIGN: Twelve-week, open-label trial. SETTING: Twenty-two centers in the United States. PATIENTS: We studied 125 patients with moderate-to-severe OSA (ie, respiratory disturbance index > or =15) before nCPAP therapy and residual daytime sleepiness (Epworth sleepiness scale [ESS] score > or =10) despite effective and regular nCPAP therapy. Patients were studied after completing a 4-week, double-blind, placebo-controlled trial of nCPAP plus modafinil for the treatment of residual daytime sleepiness. INTERVENTIONS AND MEASUREMENTS: Patients received individually titrated doses of modafinil (200 to 400 mg qd). Sleepiness was assessed using the ESS, quality of life was evaluated using the Functional Outcomes of Sleep Questionnaire (FOSQ), and the overall clinical effect was indexed using the clinical global impression of change scale. Adverse events, nCPAP use, and vital sign measurements were also recorded. RESULTS: The significant improvements in daytime wakefulness and sleep-related functional status observed with modafinil treatment during the 4-week, double-blind study were maintained throughout 12 weeks of open-label treatment: week 12 ESS, 7.8 (4.7) vs 14.4 (3.1) at double-blind baseline; week 12 FOSQ, 3.3 (0.6) vs 14.4 (2.7) at double-blind baseline (mean [SD]). The percentage of patients rated as clinically improved increased from 83% after 1 week to > or =93% after 2 to 12 weeks of open-label treatment. Mean (SD) nCPAP use decreased from 6.3 (1.3) h/night at baseline to 5.9 (1.4) h/night (p = 0.004) during open-label treatment. The most common adverse events were headache (28%), anxiety (16%), and nervousness (14%). CONCLUSIONS: Modafinil remained effective and well tolerated as an adjunct therapy for residual daytime sleepiness even after 12 weeks of daily dosing in patients with OSA receiving nCPAP therapy.

Adult↗
PubMed2005

Modafinil : a review of its use in excessive sleepiness associated with obstructive sleep apnoea/hypopnoea syndrome and shift work sleep disorder.

Modafinil (Provigil is a wake-promoting agent that is pharmacologically distinct from CNS stimulants, such as amfetamine, dexamfetamine and methylphenidate. Modafinil is approved for use in the US and certain European countries for use in patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnoea/hypopnoea syndrome (OSA/HS) or shift work sleep disorder (SWSD). Oral modafinil promotes wakefulness in patients with OSA/HS and SWSD. It is an effective adjunctive therapy in patients with residual excessive sleepiness associated with OSA/HS who are receiving nasal continuous positive airway pressure (nCPAP) therapy. In SWSD, the drug improves night-time wakefulness without disrupting daytime sleep. Modafinil is generally well tolerated in patients with OSA/HS or SWSD and has a low abuse potential. Thus, modafinil is a valuable new treatment option for use in patients with excessive sleepiness associated with OSA/HS (as an adjunct to nCPAP) or SWSD.

Animals↗
PubMed2000

Modafinil augmentation of antidepressant treatment in depression.

BACKGROUND: Despite a relative lack of controlled data, stimulants are often used to augment antidepressant treatment in patients who have had only a partial response to first-line therapy. Modafinil is a novel psychostimulant that has shown efficacy in, and was recently marketed for, treating excessive daytime sleepiness associated with narcolepsy. The mechanism of action of modafinil is unknown, but, unlike other stimulants, the drug is highly selective for the central nervous system, has little effect on dopaminergic activity in the striatum, and appears to have a lower abuse potential. METHOD: In this retrospective case series, we describe 7 patients with DSM-IV depression (4 with major depression and 3 with bipolar depression) for whom we used modafinil to augment a partial or nonresponse to an antidepressant. The Hamilton Rating Scale for Depression was administered as part of routine clinical practice prior to treatment and at each subsequent visit. RESULTS: At doses of 100 to 200 mg/day, all 7 patients achieved full or partial remission, generally within 1 to 2 weeks. All patients had some residual tiredness or fatigue prior to starting modafinil, and this symptom was particularly responsive to augmentation. Side effects were minimal and did not lead to discontinuation of the drug in any of the patients. CONCLUSION: Modafinil appears to be a drug with promise as an augmenter of antidepressants, especially in patients with residual tiredness or fatigue. It is a particularly attractive alternative to other stimulants because of its low abuse potential and Schedule IV status.

Adult↗
PubMed1999

Naps and modafinil as countermeasures for the effects of sleep deprivation on cognitive performance.

Disruptions in wake-sleep rhythms, particularly induced by sleep deprivation are limiting factors for military personnel in operations. The role of sleep and naps in the recovery of performance is generally accepted. Pharmacological aids, for example hypnotic or stimulant substances can also be effective countermeasures. Recently, a new stimulant compound, modafinil (MODIODAL) has also proven effective. Considering the excellent results obtained with napping and modafinil, we have studied the combined effect of these two countermeasures on psychomotor performance under conditions simulating an operational situation. Beneficial effects of a few hours' nap on performance were confirmed. Consequently naps should be encouraged, even if limited and diurnal. Modafinil, which combines wakening and stimulating properties without any known side effects, was useful for longer periods of sleep deprivation and when there was no real possibility of sleep recovery. Modafinil did not prevent sleep if sleep opportunities were available. The combination of naps and modafinil demonstrated the best cognitive performance during sleep deprivation.

Adult↗
PubMed2002

Effect of modafinil on core temperature during sustained wakefulness and exercise in a warm environment.

BACKGROUND: Previous studies have revealed that modafinil elevates resting core temperature during periods of sustained wakefulness. The purpose of this study was to examine the effects of modafinil on core temperature during rest and exercise throughout 40 h of sustained wakefulness in a warm environment. METHODS: Ten males performed a drug session (three 100 mg doses per day) and a placebo session that involved a control day, 40 h of sustained wakefulness, and a recovery sleep. For 38 h of the sustained wakefulness, subjects were exposed to 30 degrees C with 50% relative humidity. During the afternoon of both days of wakefulness and during the early morning of the second day, subjects performed 2 h of exercise at 60% VO2max while exposed to the warm environment. RESULTS: The data revealed that rectal temperature (Tre) was elevated at rest 0.15-0.2 degrees C following modafinil ingestion throughout the period of sustained wakefulness. This increase in body temperature at rest was due to an increase in heat production during the first day of wakefulness followed by a lower evaporative heat loss during the second day. During exercise, an inconsistent effect of the drug on Tre was observed throughout the 38-h period. On the first afternoon, the impact of modafinil on Tre was no longer evident after 20 min of exercise. In contrast, during the early morning and afternoon of the second day, the effects of the drug on Tre at rest remained during exercise. For seven subjects who had Tre data for 80 min during all exercise periods, Tre during the placebo session was 38.9, 38.4, and 38.7 degrees C after 80 min of exercise for periods one, two and three, respectively, whereas the corresponding values during the modafinil session were 38.8, 38.7, and 38.9 degrees C. CONCLUSION: With a greater cumulative dose of the drug, Tre remained elevated throughout the exercise period to an extent similar to the increase observed under resting conditions when compared with the placebo condition.

Adult↗
PubMed2004

Neuroprotective mechanism of modafinil on Parkinson disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

AIM: To observe the neuroprotective mechanism of modafinil on Parkinson disease (PD) models induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). METHODS: The model of PD was induced by intraperitoneally injecting MPTP into C57BL/6J mice for 4 d. Modafinil (i.p., 50 or 100 mg/kg(-1)/d(-1)) was administered at 30 min following MPTP for 4 d and for another 10 d continuously. The contents of dopamine (DA), noradrenaline (NA), 5-hydroxytryptamine (5-HT), gamma-aminobutyric acid (GABA), glutamine (Glu) in the striatum, and the contents of GABA, Glu, malondialdehyde (MDA), and glutathione (GSH) in the substantia nigra (SN) of model mice were determined. RESULTS: Modafinil (50 and 100 mg/kg) prevented against the decrease of the contents of DA, 5-HT, and NA in the striatum and GSH, GABA in the SN induced by MPTP, but reduced the increase of MDA in the SN and GABA in the striatum induced by MPTP. Modafinil preferentially inhibited striatal GABA release, but it did not change the increase of nigrostriatal Glu release induced by MPTP. CONCLUSION: The anti-oxidation and the modulation of nigrostriatal GABA and striatal NA and 5-HT release contributed to the neuroprotective effects of modafinil on PD induced by MPTP.

Animals↗
PubMed2004

[Modafinil and fatigue in multiple sclerosis].

Fatigue is one of the most frequent and disabling symptoms in multiple sclerosis (MS) patients. This symptom's etiopathogenic mechanism, though not known, seems complex and multifactorial, and its therapeutic management is difficult. Different treatments have been tested in recent years, but a weak efficacy that may be limited in time has been observed. Recently, modafinil has been suggested as a possible treatment for fatigue in MS patients, although nowadays, the only use of modafinil approved by the Food and Drug Administration is narcolepsy. Modafinil, 2-([difenilmetil]sulfinil), acetamide is a state of wakeness promoter, and although its exact action mechanism is not known, it differs from other central nervous system stimulants because no dopaminergic activation is observed, and its action take place at the hypothalamic level. It is known that modafinil increases the proportion of high-frequency alpha waves and reduces delta and theta waves, increasing vigilance. Although few studies exist on modafinil in MS patients with fatigue, the results suggest this drug as a promising treatment, because of its efficacy and safety, and should encourage us to continue working in this area.

Benzhydryl Compounds↗
PubMed1995

Comparative effects of modafinil and amphetamine on daytime sleepiness and cataplexy of narcoleptic dogs.

The effects of modafinil and amphetamine on daytime sleep (polysomnographic recordings) and cataplexy (the food-elicited cataplexy test) were compared using the narcoleptic canine model. Results indicate that both modafinil (5 and 10 mg/kg body weight i.v.) and amphetamine (100 and 200 micrograms/kg i.v.) increase wakefulness and reduce slow-wave sleep in control and narcoleptic dogs. In contrast, the results of cataplexy testing demonstrate that amphetamine (2.5-160 micrograms/kg i.v.), but not modafinil (0.125-8.0 mg/kg i.v.) significantly suppresses canine cataplexy. These results suggest that the pharmacological property of modafinil is distinct from amphetamine. Results of polysomnographic recordings also demonstrate that narcoleptic dogs slept significantly more during the daytime than control dogs and required very high doses (10 mg/kg i.v. modafinil; 200 micrograms/kg i.v. amphetamine) of stimulants to reduce their level of sleepiness to that of control dogs. This finding is consistent with the data collected in human narcolepsy and validates the use of this canine model for the screening of stimulant compounds.

Amphetamine↗
PubMed2006

Randomized controlled trial of modafinil for the treatment of fatigue in postpolio patients.

The purpose of this study was to test whether modafinil is effective in alleviating the symptoms of fatigue in postpolio patients, because it has been helpful for such symptoms in other neurologic disorders. Using a double-blind, randomized, placebo-controlled cross-over design, 14 postpolio patients with moderate to severe fatigue were assigned to receive modafinil or placebo first. Piper Fatigue Scale, Epworth Sleepiness Scale, digit span, and reaction time tests were done at baseline and then at weekly intervals. The Piper Fatigue Scale scores improved by 27 +/- 40% (mean +/- SD) following modafinil and by 43 +/- 36% following placebo. Scores for most of the other tests did not change during the study. Therefore, we conclude that modafinil was not effective in alleviating the symptoms of fatigue in postpolio patients.

Benzhydryl Compounds↗
PubMed1994

The stimulant effect of modafinil on wakefulness is not associated with an increase in anxiety in mice. A comparison with dexamphetamine.

Modafinil is a new drug used in the treatment of narcolepsy. Its administration in mice induced a dose-dependent increase in locomotor activity. The effects of modafinil were compared with those of dexamphetamine on three tests that assessed the anxiety level (drugs were used at doses which induced a roughly similar stimulation of locomotor activity). Dexamphetamine increased the latency of exploration of a white compartment, increased thigmotaxis in an open-field and decreased the time spent in the open arms of an elevated plus-maze. None of these responses was significantly modified by modafinil. We conclude that modafinil does not share the anxiogenic effects of dexamphetamine.

Animals↗