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PubMed2006

A systematic review of modafinil: Potential clinical uses and mechanisms of action.

BACKGROUND: Modafinil is a novel wake-promoting agent that has U.S. Food and Drug Administration approval for narcolepsy and shift work sleep disorder and as adjunctive treatment of obstructive sleep apnea/hypopnea syndrome. Modafinil has a novel mechanism and is theorized to work in a localized manner, utilizing hypocretin, histamine, epinephrine, gamma-aminobutyric acid, and glutamate. It is a well-tolerated medication with low propensity for abuse and is frequently used for off-label indications. The objective of this study was to systematically review the available evidence supporting the clinical use of modafinil. DATA SOURCES: The search term modafinil OR Provigil was searched on PubMed. Selected articles were mined for further potential sources of data. Abstracts from major scientific conferences were reviewed. Lastly, the manufacturer of modafinil in the United States was asked to provide all publications, abstracts, and unpublished data regarding studies of modafinil. DATA SYNTHESIS: There have been 33 double-blind, placebo-controlled trials of modafinil. Additionally, numerous smaller studies have been performed, and case reports of modafinil's use abound in the literature. CONCLUSIONS: Modafinil is a promising drug with a large potential for many uses in psychiatry and general medicine. Treating daytime sleepiness is complex, and determining the precise nature of the sleep disorder is vital. Modafinil may be an effective agent in many sleep conditions. To date, the strongest evidence among off-label uses exists for the use of modafinil in attention-deficit disorder, postanesthetic sedation, and cocaine dependence and withdrawal and as an adjunct to antidepressants for depression.

Animals↗

PubMed2003

Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind, placebo-controlled study.

BACKGROUND: Fatigue and sleepiness are primary symptoms of depression that may not resolve with antidepressant therapy. Modafinil is a novel agent that has been shown to improve wakefulness and lessen fatigue in a variety of conditions. In this study, we examined the utility of modafinil as an adjunct therapy to treat fatigue and sleepiness in patients with major depression who are partial responders to antidepressants. METHOD: Patients with partial response to anti-depressant therapy given for at least a 6-week period for a current major depressive episode (DSM-IV criteria) were enrolled in this 6-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Patients received once-daily doses (100-400 mg) of modafinil or matching placebo as adjunct treatment to ongoing antidepressant therapy. The effects of modafinil were evaluated using the Hamilton Rating Scale for Depression (HAM-D), the Fatigue Severity Scale (FSS), the Epworth Sleepiness Scale (ESS), the Clinical Global Impression of Change (CGI-C), and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). Adverse events were monitored throughout the study. RESULTS: One hundred thirty-six patients were randomized to treatment, with 118 patients (87%) completing the study. Most patients (82%) were fatigued, and one half of patients (51%) were sleepy. Modafinil rapidly improved fatigue and daytime wakefulness, with significantly greater mean improvements from baseline than placebo in fatigue (FSS) scores at week 2 (p < .05) and sleepiness (ESS) scores at week 1 (p < .01); the differences between modafinil and placebo at week 6 were not statistically significant. Assessment of the augmentation effects of modafinil (HAM-D, CGI-C, and SF-36) did not significantly distinguish modafinil from placebo. Modafinil was well tolerated in combination with a variety of antidepressants. CONCLUSION: 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.

Adult↗

PubMed2006

A comparison of once-daily and divided doses of modafinil in children with attention-deficit/hyperactivity disorder: a randomized, double-blind, and placebo-controlled study.

OBJECTIVE: This randomized, double-blind, placebo-controlled study assessed the efficacy and tolerability of several modafinil dosing regimens in children with attention-deficit/hyperactivity disorder (ADHD) to determine whether modafinil can be given once daily in pediatric ADHD. METHOD: Children and adolescents (age range, 6-13 years) (N = 248) with DSM-IV-defined ADHD were enrolled in a 4-week, double-blind, placebo-controlled study, conducted February-May 2002. The group was assigned to receive oral (100-mg tablets) modafinil 300 mg once daily (300 mg in the morning followed by placebo at midday), modafinil 300 mg as a divided dose (100/200 mg or 200/100 mg), or matching placebo. In children weighing > or = 30 kg, a higher dose of 400 mg (200/200 mg) was evaluated. Efficacy measures included the teacher-rated School Version and clinician-rated Home Version of the ADHD Rating Scale-IV and the parent-completed Conners' ADHD/DSM-IV Scales. RESULTS: 223 children completed the study. Those who received modafinil 300 mg once daily showed a significantly greater improvement (change from baseline) than those who received placebo in symptoms of ADHD across all rating scales and subscales (all p < .05). Divided 300-mg doses of modafinil provided some significant but inconsistent improvements in ADHD symptoms. In children weighing > or = 30 kg, modafinil 400 mg (200/200 mg) was significantly superior to placebo on clinician- and parent-completed scales (all p < .05). Insomnia was the only adverse event to occur with significantly greater frequency in a modafinil group (200/100) than in the placebo group (14% vs. 2%) (p = .03). CONCLUSION: Modafinil significantly improved ADHD symptoms in children. Once-daily dosing (300 mg) provided the most consistent improvement in symptoms. All dosing regimens of modafinil were well tolerated.

Adolescent↗

PubMed2005

A retrospective chart review of the effects of modafinil on depression as monotherapy and as adjunctive therapy.

Major depression is often refractory to antidepressants, and it is important to explore alternative medication treatments. Among the symptoms common with depression are energy loss/fatigue and anxiety. Modafinil has a novel mechanism of action and may have antidepressant properties. In a single outpatient clinic, data were systematically collected on all patients including those who began modafinil treatment for major depression. This clinician (C.P.) had used modafinil to treat major depression in patients who failed one or more adequate antidepressant treatments. To monitor changes during treatment, charting had included four rating scales: the Beck Depression Inventory, the Zung Self-Rating Depression Scale, and the Hamilton Depression and Hamilton Anxiety Rating Scales. A follow-up chart review identified 45 patients whose major depression was treated with modafinil over a 9-month period. The mean dose of modafinil was 184.3+/-100.0 mg/day (range=50-450 mg/day). For these 45 patients, all four rating scales showed significant improvement following 2 weeks and following 3 months of modafinil treatment. Fifteen of these patients were on modafinil monotherapy, and the remaining 30 on modafinil as an augmenting agent. For both subgroups, all three depression rating scales showed a significant improvement following 2 weeks and 3 months of modafinil treatment. This chart review provides preliminary evidence that modafinil treatment may be beneficial to those with major depression, even when unresponsive to other treatments.

Adult↗

PubMed2006

Behavioral effects of modafinil in marmoset monkeys.

RATIONALE: Modafinil is increasingly used in sleep disturbances in general and in neurodegenerative diseases and is recently being used in healthy people for attention control. However, the application of modafinil is possibly not only restricted to alertness enhancing effects. More insight in this compound may lead to new applications. Not all behavioral aspects have been studied sufficiently; therefore, more detailed investigations on modafinil's positive and aversive behavioral effects are addressed in this paper. OBJECTIVES: Determination of effects of modafinil in marmoset monkeys with observational methods and with behavioral tests measuring locomotor activity, hand-eye coordination, response to a threat situation and startle response. MATERIALS AND METHODS: Two hours after oral administration of modafinil in doses of 50, 100, 150, and 225 mg/kg, animals were observed and tested in the behavioral test systems. RESULTS: Locomotor activity was increased after 100 mg/kg modafinil in the Bungalow test and after 100, 150, and 225 mg/kg, as found in the movement parameters of the human threat test. Moreover, modafinil showed anxiolytic-like effects in the human threat test. No other side effects were observed, nor were the hand-eye coordination and startle response affected. CONCLUSIONS: Besides psychostimulation, modafinil has no aversive effects in the doses used in the domains measured. The potential anxiolytic-like effects of modafinil may create new possibilities for the therapeutic use of modafinil.

Acoustic Stimulation↗

PubMed2001

Maintaining alertness and performance during sleep deprivation: modafinil versus caffeine.

RATIONALE: The performance and alertness effects of modafinil were evaluated to determine whether modafinil should replace caffeine for restoring performance and alertness during total sleep deprivation in otherwise healthy adults. OBJECTIVES: Study objectives were to determine (a) the relative efficacy of three doses of modafinil versus an active control dose of caffeine 600 mg; (b) whether modafinil effects are dose-dependent; and (c) the extent to which both agents maintain performance and alertness during the circadian trough. METHODS: Fifty healthy young adults remained awake for 54.5 h (from 6:30 a.m. day 1 to 1:00 p.m. on day 3) and performance and alertness tests were administered bi-hourly from 8:00 a.m. day 1 until 10:00 p.m. day 2. At 11:55 p.m. on day 2 (after 41.5 h awake), subjects received double blind administration of one of five drug doses: placebo; modafinil 100, 200, or 400 mg; or caffeine 600 mg ( n=10 per group), followed by hourly testing from midnight through 12:00 p.m. on day 3. RESULTS: 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. Although a trend toward better performance at higher modafinil doses suggested a dose-dependent effect, differences between modafinil doses were not significant. Performance enhancing effects were especially salient during the circadian nadir (6:00 a.m. through 10:00 a.m.). Few instances of adverse subjective side effects (nausea, heart pounding) were reported. CONCLUSIONS: Like caffeine, modafinil maintained performance and alertness during the early morning hours, when the combined effects of sleep loss and the circadian trough of performance and alertness trough were manifest. Thus, equivalent performance- and alertness-enhancing effects were obtained with drugs possessing different mechanisms of action. However, modafinil does not appear to offer advantages over caffeine (which is more readily available and less expensive) for improving performance and alertness during sleep loss in otherwise normal, healthy adults.

Administration, Oral↗

PubMed2003

Chiral analysis of d- and l-modafinil in human serum: application to human pharmacokinetic studies.

Modafinil is a novel stimulant approved by the FDA for use in the management of excessive sleepiness associated with narcolepsy. Utility for other indications includes attention deficit-hyperactivity disorder (ADHD), depression, and management of cocaine dependence. To investigate the pharmacokinetics of modafinil in these patients, the authors improved and validated an HPLC method to separate and quantitate the separate enantiomers of modafinil in human serum. d- and l-Modafinil and the internal standard 3,3-diphenylpropylamine were extracted from serum, separated by gradient elution on a beta-cyclodextrin column, and then detected by UV absorbance at 225 nm. The elution gradient was developed to eliminate interferences by other drugs used to manage narcolepsy, ADHD, and stimulants of abuse, and endogenous substances in human serum. Validation studies included determination of stability, selectivity, precision, accuracy, and recovery. The method was used to investigate the pharmacokinetics of d- and l-modafinil in a volunteer after receiving 400 mg twice daily of racemic modafinil for 5 days. Interday and intraday assay variability (CV) typically ranged from 3% to 4%. The limits of detection (0.01 microg/mL) and quantitation (0.5 microg/mL) were well below the concentration expected in serum from patients receiving therapeutic doses of modafinil. The method was free from interference by methylphenidate, cocaine, commonly used antidepressants, and amphetamines. An example of apparent stereoselective disposition is presented as d-modafinil was eliminated more rapidly than l-modafinil from human serum. The validation data support the use of this method for human pharmacokinetic studies of modafinil in patients with known or suspected use of common antidepressants, psychostimulants, and drugs of abuse.

Benzhydryl Compounds↗

PubMed2006

Use of modafinil for the treatment of attention deficit/hyperactivity disorder.

OBJECTIVE: To review the evidence for the use of modafinil in the treatment of attention deficit/hyperactivity disorder (ADHD). DATA SOURCES: A MEDLINE search (January 1990-May 2006) was conducted using MeSH terms ADHD and modafinil. The search was limited to English-language articles on clinical trials in humans. The Cochrane Database was also searched. STUDY SELECTION AND DATA EXTRACTION: The literature search yielded 4 randomized clinical trials. DATA SYNTHESIS: The use of modafinil in the treatment of ADHD is associated with significant improvements in primary outcome measures used to assess the status of patients diagnosed with ADHD. Several aspects of cognitive function in ADHD patients also appear to improve following modafinil treatment. Modafinil shows a favorable adverse effect profile. Insomnia and headache were the most common adverse effects, seen in approximately 20% of treated individuals. However, it has not been demonstrated that the beneficial effects of modafinil are maintained with chronic administration. CONCLUSIONS: Modafinil may be a viable option for some patients in the treatment of ADHD, perhaps those for whom standard ADHD therapies have not been successful or tolerated. There remains a need for additional large, long-term studies using flexible titration methods to optimize the dose of modafinil to establish safety and efficacy, as well as head-to-head comparisons between modafinil and both long- and short-acting stimulants to determine the role of modafinil in the treatment of ADHD.

Attention Deficit Disorder with Hyperactivity↗

PubMed2000

Hypothalamic arousal regions are activated during modafinil-induced wakefulness.

Modafinil is an increasingly popular wake-promoting drug used for the treatment of narcolepsy, but its precise mechanism of action is unknown. To determine potential pathways via which modafinil acts, we administered a range of doses of modafinil to rats, recorded sleep/wake activity, and studied the pattern of neuronal activation using Fos immunohistochemistry. To contrast modafinil-induced wakefulness with spontaneous wakefulness, we administered modafinil at midnight, during the normal waking period of rats. To determine the influence of circadian phase or ambient light, we also injected modafinil at noon on a normal light/dark cycle or in constant darkness. We found that 75 mg/kg modafinil increased Fos immunoreactivity in the tuberomammillary nucleus (TMN) and in orexin (hypocretin) neurons of the perifornical area, two cell groups implicated in the regulation of wakefulness. This low dose of modafinil also increased the number of Fos-immunoreactive (Fos-IR) neurons in the lateral subdivision of the central nucleus of the amygdala. Higher doses increased the number of Fos-IR neurons in the striatum and cingulate cortex. In contrast to previous studies, modafinil did not produce statistically significant increases in Fos expression in either the suprachiasmatic nucleus or the anterior hypothalamic area. These observations suggest that modafinil may promote waking via activation of TMN and orexin neurons, two regions implicated in the promotion of normal wakefulness. Selective pharmacological activation of these hypothalamic regions may represent a novel approach to inducing wakefulness.

Animals↗

PubMed2004

Modafinil's effects on simulator performance and mood in pilots during 37 h without sleep.

INTRODUCTION: Modafinil is a relatively new alertness-enhancing compound of interest to the military aviation community. Although modafinil has been well-tested in clinical settings, additional studies are required to establish its safety and efficacy for use in pilots. OBJECTIVE: The purpose of this study was to determine whether modafinil (100 mg after 17, 22, and 27 h without sleep) would attenuate the effects of fatigue on fighter-pilot mood and performance during 37 h of continuous wakefulness. METHODS: A quasi-experimental, single-blind, counterbalanced design tested the effects of modafinil in 10 Air Force F-117 pilots. RESULTS: Modafinil attenuated flight performance decrements on six of eight simulator maneuvers. Overall, modafinil maintained flight accuracy within approximately 15-30% of baseline levels, whereas performance under the no-treatment/placebo condition declined by as much as 60-100%. Modafinil decreased self-ratings of depression and anger, while improving ratings of vigor, alertness, and confidence. Benefits were most noticeable after 24 to 32 h of continuous wakefulness. One potential drawback of modafinil was that, at least at the 100-mg dose level, the drug's effects were not subjectively salient. Since this may lead personnel to escalate the dose without flight surgeon approval, personnel should be cautioned regarding this particular drug characteristic. CONCLUSION: Although modafinil did not sustain performance at predeprivation levels, the present study suggests that modafinil should be considered for the military's armament of short-term fatigue countermeasures. Future research will evaluate whether 200-mg doses are more beneficial than the 100-mg doses used here.

Adult↗

PubMed1997

Modafinil induces wakefulness without intensifying motor activity or subsequent rebound hypersomnolence in the rat.

Modafinil, a novel compound for treating excessive sleepiness, potently increases wakefulness in laboratory rodents, cats, monkeys and humans. Although its mechanism of action is unknown, modafinil appears to be unlike classic stimulants. We investigated this generality by testing the selectivity of this compound for wake-promoting effects (e.g., relative to locomotor effects) and homeostatic sleep responses after drug-induced waking relative to the prototypical stimulant methamphetamine (METH). Continuous measures of electroencephalogram (EEG) sleep-wakefulness, locomotor activity (LMA) and body temperature (Tb) were obtained from adult male Wistar rats 3 days before and after treatment with modafinil (30, 100 and 300 mg/kg i.p.), 0.25% methylcellulose (vehicle) or METH (0.5 and 1.0 mg/kg i.p.). Individually housed rats in a 24-h light-dark cycle (LD 12:12) were treated 5 h after lights-on (CT-5). LMA and Tb were monitored via intraperitoneal telemetry. Sleep-wake stages and LMA were recorded every 10 s, Tb every minute. During the first 3 h post-treatment, modafinil and METH significantly and dose-dependently increased EEG wake time (P < .01 for 30 mg/kg modafinil, all other P < .0001) and wake episode duration. Although the cumulative increases in wakefulness were statistically equivalent, METH, but not modafinil, produced subsequent rebound hypersomnolence. At these equipotent wake-promoting doses, modafinil produced the same total amount of REM sleep inhibition but during a longer time than METH. Modafinil also increased LMA amount (counts/h, P < .001) and LMA intensity (counts/min awake, P < .001) less than METH. Both rebound hypersomnolence and increased LMA intensity, which are undesirable features in wake-promoting drugs, were not observed after modafinil treatment, and thus further differentiated modafinil from amphetamine-like stimulants.

Animals↗

PubMed1993

The vigilance-promoting drug modafinil counteracts the reduction of tyrosine hydroxylase immunoreactivity and of dopamine stores in nigrostriatal dopamine neurons in the male rat after a partial transection of the dopamine pathway.

We studied the ability of the vigilance-promoting drug modafinil to modulate the anterograde and retrograde changes in tyrosine hydroxylase (TH) immunoreactivity and in dopamine (DA) stores in the nigro-neostriatal DA neurons, following a partial hemitransection of this ascending DA system, using a combined morphometrical, biochemical and behavioural analysis. Modafinil was given daily i.p. in doses of 10-100 mg/kg, starting 15 min after the lesion, and the partially hemitransected rats were killed 2 weeks later. Changes in TH-immunoreactive nerve cell bodies and nerve terminals induced by the partial hemitransection were studied in the substantia nigra and neostriatum in combination with image analysis. The substantia nigra and neostriatum were also subjected to biochemical analysis of DA, 3,4-dihydroxyphenylacetic acid and homovanillic acid levels. Modafinil treatment dose-dependently (10-100 mg/kg) counteracted the hemitransection-induced disappearance of nigral TH-immunoreactive nerve cell body profiles and neostriatal TH-immunoreactive nerve terminal profiles. A 2-week treatment with 100 mg/kg of modafinil also counteracted the hemitransection-induced depletion of DA stores in the neostriatum and the ventral midbrain. Moreover, the repeated daily treatment with modafinil (100 mg/kg) protected against the hemitransection-induced disappearance of striatal 5-hydroxytryptamine, 5-hydroxyindoleacetic acid and noradrenaline levels. Striatal DA function was analysed by studying apomorphine-induced (1 mg/kg, s.c.) ipsilateral rotational behaviour 4 and 11 days after the operation. A marked dose-dependent reduction of ipsilateral rotational behaviour was demonstrated after the daily modafinil treatment in the partially hemitransected rats. In another model involving unilateral nigral microinjections of 6-hydroxydopamine, acute (one single dose) modafinil (100 mg/kg) did not affect the contralateral rotational behaviour induced by apomorphine (0.05 mg/kg s.c.), when given 30 min before the apomorphine. Taken together, morphological, neurochemical and behavioural evidence has been obtained that anterograde and retrograde changes induced in the DA stores and TH immunoreactivity of the nigro-neostriatal DA neurons by a partial hemistransection are counteracted by modafinil in a dose dependent way with 100 mg/kg producing a significant protective action against impairment of DA transmission. The results of this study open up the possibility that modafinil may protect against the anterograde and retrograde degeneration of nigrostriatal DA neurons seen after mechanically induced injury.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2000

Antiparkinsonian and neuroprotective effects of modafinil in the mptp-treated common marmoset.

The psychostimulant drug, modafinil, protects rodents against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity, striatal ischemia and partial transection of the nigro-striatal pathway. We now report on the ability of modafinil to reverse motor disability in MPTP-treated common marmosets and to prevent MPTP-induced nigral cell death in this species. In the initial experiments, adult common marmosets were treated with MPTP to produce stable motor deficits. The subsequent administration of modafinil (10, 30 or 100 mg/kg/day, p.o.) produced a dose-dependent reversal of motor disability. In a subsequent experiment, normal common marmosets were concurrently treated with 10, 30 or 100 mg/kg of modafinil once daily by gavage during acute MPTP administration (daily for 5 days), continuing for 2 weeks after the last dose of MPTP. Modafinil dose-dependently prevented the decline in motor activity normally produced by MPTP treatment. MPTP treatment caused a 76% loss of nigral tyrosine-hydroxylase-immunoreactive cells in placebo-treated animals, and this was dose-dependently prevented by modafinil. At the highest dose (100 mg/kg/day) of modafinil, there was no significant loss of tyrosine-hydroxylase-immunoreactive cells in the substantia nigra compared with normal animals. MPTP treatment also reduced striatal dopamine uptake sites by 95%, as measured by specific [3H]-mazindol binding, compared with normal controls. Modafinil treatment dose-dependently reduced the loss of specific [3H]-mazindol binding. Behavioural and morphological evidence in the present study indicate a potential antiparkinsonian and neuroprotective role for modafinil, which may form a new pharmacological approach to the treatment of Parkinson's disease.

Animals↗

PubMed2005

Cognitive effects of modafinil in student volunteers may depend on IQ.

The results of two previous studies on the effects of modafinil, a selective wakefulness-promoting agent, in healthy university students were combined in a retrospective analysis. This allowed determination of whether the effects of modafinil were dependent on IQ and whether the larger sample size (n=89) would reveal more cognitive benefits. A battery of cognitive tests was completed 2-3 h after dosing. In the whole sample, modafinil (200 mg) significantly reduced the number of missed targets in a test of sustained attention (RVIP). However, interestingly, several interactions between modafinil and IQ emerged. Modafinil (100 and 200 mg) significantly improved target sensitivity in the RVIP test, but only in the group of 'lower' IQ (mean+/-sem=106+/-0.6), not in the 'higher' IQ group (mean+/-sem=115.5+/-0.5). Furthermore, there were significant modafinil x IQ interactions in two further tests. Modafinil significantly reduced speed of responding in a colour naming of dots, and in clock drawing, but only in the 'lower' IQ group. Thus, the cognitive benefits of modafinil seem particularly marked in tests of vigilance and speed, in which sleepiness would be an important factor. Furthermore, the results indicate that high IQ may limit detection of modafinil's positive effects.

Adult↗

PubMed2000

Amplification of cortical serotonin release: a further neurochemical action of the vigilance-promoting drug modafinil.

The present in vitro and in vivo studies examined the effects of modafinil on serotonergic transmission in the rat frontal cortex. In the in vitro study modafinil (0.3-30 microM) increased electrically-evoked, but not spontaneous, serotonin ([(3)H]5-HT) efflux from cortical slices in a concentration-dependent manner while the indirect serotonin agonist dl-fenfluramine (1-15 microM) enhanced both spontaneous and evoked [(3)H]5-HT efflux. The effects of modafinil were more pronounced when the 5-HT reuptake was blocked by paroxetine. Contrary to paroxetine (0.3-3 microM) and dl-fenfluramine (1-5 microM), modafinil failed to influence the [(3)H]5-HT uptake. In the in vivo study modafinil (3-100 mg/kg i.p.) increased 5-HT dialysate levels, the maximal effect being already reached at the 30 mg/kg dose. dl-fenfluramine (5 mg/kg) induced an increase in 5-HT levels which was significantly higher than that displayed by modafinil at 30 mg/kg. In the presence of paroxetine (3 microM), the effect of modafinil at 30 mg/kg was higher than that observed in the absence of 5-HT reuptake inhibition. Finally, in the presence of the selective 5-HT(1A) receptor agonist 8-OH-DPAT, modafinil at 100 mg/kg failed to affect 5-HT dialysate levels. These results demonstrate that modafinil regulates cortical serotonergic transmission and suggest that the drug preferentially acts by amplifying the electro-neurosecretory coupling mechanisms and via mechanisms which do not involve the reuptake process.

Animals↗

PubMed2003

Modafinil and cocaine: a double-blind, placebo-controlled drug interaction study.

Modafinil is a novel compound that is approved for the treatment of narcolepsy. It is now being studied as a potential treatment for cocaine dependence. Cocaine withdrawal symptoms are associated with poor clinical outcome and are likely to be reversed by modafinil. In addition, the neurotransmitter actions of modafinil are opposite to cocaine-induced neuroadaptations affecting dopamine and glutamate reward circuits. Since cocaine-dependent subjects might use cocaine during a clinical trial with modafinil, this study tested the safety of intravenous cocaine (30 mg) in combination with modafinil. Each of seven subjects received a baseline (open-label) cocaine infusion. Three subsequent cocaine infusions were administered after subjects received 4 days of low dose modafinil (200 mg/day), high dose modafinil (400 mg/day), or placebo in randomized double-blind sequences. One subject received placebo prior to all infusions. Our results indicate that co-administering modafinil and a single dose of intravenous cocaine is not associated with medical risk in terms of blood pressure, pulse, temperature, or electrocardiogram measures. Furthermore, pretreatment with modafinil did not intensify cocaine euphoria or cocaine-induced craving. In fact, cocaine euphoria was significantly blunted (P=0.02) in one of our subjective measures.

Adult↗

PubMed2003

Efficacy and safety of modafinil for improving daytime wakefulness in patients treated previously with psychostimulants.

OBJECTIVES: To assess the efficacy and safety of modafinil for improving wakefulness in narcolepsy patients treated previously with psychostimulants. BACKGROUND: Modafinil has become a standard therapy for improving daytime wakefulness in narcolepsy patients and may be a useful therapeutic alternative to psychostimulants used to improve waking function in other medical conditions. Modafinil is chemically dissimilar to and has a pharmacological profile that differs from the psychostimulants. Modafinil has a low abuse potential and is well tolerated. METHODS: Patients (N=151) with narcolepsy who had been unsatisfactorily treated with dextroamphetamine (N=48), methylphenidate (N=66), or pemoline (N=37) were enrolled in this 6-week, open-label, multicenter study. Following a 2-week washout period, patients received modafinil once daily (Week 1, 200 mg; Weeks 2-6, 200 or 400 mg). Efficacy was evaluated at Weeks 1, 2, and 6 using the Epworth Sleepiness Scale and the Clinical Global Impression of Change. Adverse events were monitored throughout the study. RESULTS: Treatment with modafinil improved daytime wakefulness versus baseline regardless of which psychostimulant was taken previously. Mean ESS scores were improved after 1 week of treatment with modafinil. Improvements were maintained throughout the 6 weeks of treatment (all P<0.001 versus baseline after washout). At Week 6, 79% of all patients were considered to be clinically improved relative to post-washout baseline. The most frequent adverse events were headache, nausea, and insomnia; the majority of adverse events were mild or moderate in nature. Approximately 70% of patients were receiving 400 mg of modafinil once daily at the end of the study. CONCLUSION: During this 6-week, open-label study, modafinil was an effective and well-tolerated treatment for improving daytime wakefulness in narcolepsy patients previously treated with psychostimulants.

Adolescent↗

PubMed2003

Modafinil in the treatment of excessive daytime sleepiness in children.

BACKGROUND: Modafinil is an alerting agent approved for the treatment of narcolepsy in adults. There are no studies examining the long-term effects and safety profile of modafinil in children with excessive daytime somnolence (EDS). OBJECTIVES: To determine the effects of modafinil on clinical manifestations of narcolepsy and idiopathic hypersomnia. METHODS: A systematic chart review was conducted for 13 children (mean age 11.0+/-5.3 years, six males, 10 with narcolepsy and three with idiopathic hypersomnia) receiving modafinil. RESULTS: The mean modafinil dose was 346+/-119 mg/day, with a mean treatment duration of 15.6+/-7.8 months. For approximately 90% of the children treated, parents reported a favorable response with the reduction in sudden sleep attacks, as documented by sleep-wake diaries. One child failed to improve on 400 mg/day modafinil and was switched to methylphenidate. Two other children showed only partial improvement and required additional stimulant medication to control EDS symptoms. Seven children underwent repeated nocturnal polysomnography and multiple sleep latency tests (MSLT). Compared to baseline MSLT measures (mean sleep latency: 6.6+/-3.7 min), modafinil prolonged mean sleep latency (10.2+/-4.8 min, p=0.02) without significant alteration in nocturnal polysomnographic measures. However, a trend towards REM sleep reduction was noted (16.8+/-5.1%TST vs. 11.8+/-6.2%TST). Exacerbation of seizures and psychotic symptoms was reported with modafinil therapy in two children with preexisting conditions. Hematological and hepatic functions assessed every 3 months remained unaltered. CONCLUSION: Modafinil has a modest, yet significant effect on EDS in children and appears to be safe and well tolerated.

Adolescent↗