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PubMed2005

Modafinil for treatment of residual excessive sleepiness in nasal continuous positive airway pressure-treated obstructive sleep apnea/hypopnea syndrome.

STUDY OBJECTIVES: Nasal continuous positive airway pressure (nCPAP) usually reduces sleepiness in patients with obstructive sleep apnea/hypopnea syndrome. However, even with regular use of nCPAP, some patients experience residual excessive sleepiness. We evaluated the efficacy and safety of the wake-promoting agent modafinil for treating residual excessive sleepiness in nCPAP-treated patients. DESIGN: 12-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial. PATIENTS: Patients aged 18 to 70 years diagnosed with obstructive sleep apnea/hypopnea syndrome and having residual excessive sleepiness during nCPAP therapy were eligible. INTERVENTIONS: Once-daily modafinil, 200 mg or 400 mg, or placebo. MEASUREMENTS AND RESULTS: Assessments included the Maintenance of Wakefulness Test, Epworth Sleepiness Scale, Clinical Global Impression of Change, and Functional Outcomes of Sleep Questionnaire. Both doses of modafinil significantly improved mean (SD) sleep latency on the Maintenance of Wakefulness Test at weeks 4, 8, and 12 compared with placebo (week 12: modafinil 400 mg, 15.0 [5.3] minutes; 200 mg, 14.8 [5.3] minutes; placebo, 12.6 [5.8] 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 [4.3]; 200 mg, -4.5 [4.7]; 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 was generally well tolerated and did not adversely affect nighttime sleep or nCPAP use. CONCLUSIONS: These results confirm previous shorter-term controlled trials, indicating modafinil is a useful adjunct therapy for improving wakefulness in patients with residual excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome who were treated with nCPAP.

Adolescent↗
PubMed2002

Modafinil reduces excessive somnolence and enhances mood in patients with myotonic dystrophy.

OBJECTIVE: To evaluate the potential of modafinil in reducing excessive daytime somnolence (EDS) and enhancing indexes of quality of life and mood in patients with myotonic dystrophy (DM). METHODS: Forty patients with DM were randomized to receive modafinil and placebo for 14 days each, using a double-blind, cross-over design. Before and after each trial, subjects completed handgrip strength testing, spirometry, and quality-of-life measures (RAND). On days 7 and 14, each subject completed the Epworth Sleepiness Scale (ESS), the Stanford Sleepiness Scale (SSS), and the Profile of Mood States (POMS). RESULTS: ESS scores were lower while taking modafinil (mean 248 mm; 95% confidence limit 220 to 276 mm) as compared with placebo (309 mm; 281 to 336 mm) (p < 0.001). Mean SSS scores were also lower during the modafinil trial (3.05; 2.77 to 3.33) than during the placebo trial (3.45; 3.18 to 3.71) (p < 0.05). The POMS indicated that modafinil decreased fatigue-inertia (p < 0.001) and increased vigor-activity and tension-anxiety (p < 0.001) indexes. The total mood disturbance score was also decreased during the modafinil trial as compared with placebo (p < 0.05). The RAND quality-of-life measures of energy (p < 0.001) and health change (p < 0.05) were both significantly enhanced during the modafinil treatment phase. No changes in maximal grip strength or forced expired volume in 1 second were detected over the course of the study. Headache was the most frequently reported adverse event. Four patients withdrew from the study, three because of side effects (two during modafinil ingestion and one during placebo ingestion). CONCLUSION: Modafinil reduces somnolence and improves mood in patients with DM.

Activities of Daily Living↗
PubMed2005

Modafinil influences the pharmacokinetics of intravenous cocaine in healthy cocaine-dependent volunteers.

OBJECTIVE: To determine if modafinil, a putative treatment for cocaine dependence, influences the pharmacokinetics of intravenous cocaine in otherwise healthy cocaine-dependent volunteers. METHODS: Cocaine 20 or 40 mg was administered intravenously on consecutive days over 1 minute at baseline and after modafinil administration at each of two dosages of 400 and 800 mg/day for 7 days. RESULTS: Twelve subjects completed the clinical protocol. Compared with baseline, the cocaine peak plasma concentration was decreased after both the 20 and 40 mg cocaine infusions, but the reduction was only statistically significant after the 40 mg cocaine infusion (p < 0.01 after modafinil 400 mg/day; p < 0.05 after modafinil 800 mg/day). The area under the cocaine plasma concentration-time curve from 0 to 180 minutes (AUC180) was significantly decreased by modafinil administration (p < 0.01 and p < 0.001 for modafinil 400 and 800 mg/day, respectively, for the cocaine 20mg dose; p < 0.001 for the cocaine 40 mg dose at both modafinil levels). There were no significant changes in total AUC, clearance or elimination half-life of cocaine. CONCLUSION: This study did not find evidence for a harmful pharmacokinetic interaction between modafinil and cocaine. In contrast, long-term administration of modafinil significantly decreased systemic exposure to cocaine during the first 180 minutes following intravenous cocaine administration.

Administration, Oral↗
PubMed2000

In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil.

The ability of modafinil to affect human hepatic cytochrome P450 (CYP) activities was examined in vitro. The potential for inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 by modafinil (5-250 microM) was evaluated with pooled human liver microsomes. Modafinil exhibited minimal capacity to inhibit any CYP enzyme, except CYP2C19. Modafinil inhibited the 4'-hydroxylation of S-mephenytoin, a marker substrate for CYP2C19, reversibly and competitively with a K(i) value of 39 microM, which approximates the steady-state C(max) value of modafinil in human plasma at a dosage of 400 mg/day. No irreversible inhibition of any CYP enzyme was observed, and there was no evidence of metabolism-dependent inhibition. The potential for induction of CYP activity was evaluated by exposing primary cultures of human hepatocytes to modafinil (10-300 microM). Microsomes were then prepared and assayed for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 activities. The mean activities of microsomal CYP1A2, CYP2B6, and CYP3A4/5 from modafinil-treated hepatocytes were higher (up to 2-fold) than those in the solvent-treated controls but were less than those produced by reference inducers of these enzymes. At high concentrations of modafinil (>/=100 microM), the mean activity of CYP2C9 was decreased (up to 60%) relative to that in the solvent controls. Overall, modafinil was shown to have effects on human hepatic CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5 activities in vitro. Although effects obtained in vitro are not always predictive of effects in vivo, such results provide a rational basis for understanding drug-drug interactions that are observed clinically and for planning subsequent investigations.

Benzhydryl Compounds↗
PubMed2004

Effect of the wake-promoting agent modafinil on sleep-promoting neurons from the ventrolateral preoptic nucleus: an in vitro pharmacologic study.

STUDY OBJECTIVES: The pharmacologic profile of modafinil, an increasingly popular wake-promoting drug for narcolepsy treatment, differs from those of classic psychostimulants such as amphetamine. However, its brain targets are still a matter of debate. We hypothesized that modafinil could increase waking by inhibiting the sleep-promoting neurons from the ventrolateral preoptic nucleus (VLPO). Such action could be direct or indirect via the potentiation of inhibition mediated by waking neurotransmitters. We thus studied the effect of modafinil on the membrane potential and firing rate of VLPO neurons recorded in rat-brain slices. We further determined whether pretreatment with modafinil modifies the effect of noradrenaline, carbachol, serotonin, histamine, dopamine, or clonidine. MEASUREMENTS AND RESULTS: Pretreatment with modafinil specifically increased the inhibition of VLPO neurons induced by noradrenaline but had no effect when applied alone or in combination with other substances. Pretreatment with nisoxetine, a selective noradrenaline reuptake blocker, similarly increased the noradrenaline-induced inhibition of VLPO cells. Further, the potentiation by modafinil was minimized when modafinil and nisoxetine were applied together. CONCLUSIONS: These results suggest that modafinil blocks the reuptake of noradrenaline by the noradrenergic terminals on sleep-promoting neurons from the VLPO. Such a mechanism could be at least partially responsible for the wake-promoting effect of modafinil.

Animals↗
PubMed2004

Effects of modafinil on cognitive and meta-cognitive performance.

The stimulant modafinil has proved to be an effective treatment modality for narcolepsy and related sleep disorders and is also being studied for use during sustained military operations to ameliorate the effects of fatigue due to sleep loss. However, a previous study reported that a relatively large, single dose of modafinil (300 mg), administered to already sleep-deprived individuals, caused participants to overestimate their cognitive abilities (i.e. 'overconfidence'). Because the predominant application of modafinil is in otherwise healthy, non-sleep-deprived individuals, the present study investigated the generality of modafinil-induced overconfidence in a group of 18 healthy, non sleep-deprived adults. The design involved a double-blind, placebo controlled, fully within-subjects manipulation of placebo and modafinil (4 mg/kg: approximately 300 mg, on average) over three 50-min cognitive testing sessions (i.e. before drug ingestion, and at 90 and 180 min after drug ingestion). The cognitive task battery included subjective assessments of mood, fatigue, affect, vigor and motivation, and cognitive assessments of serial reaction time, logical reasoning, visual comparison, mental addition and vigilance. In addition, trial-by-trial confidence judgements were obtained for two of the cognitive tasks and more global, task level assessments of performance were obtained for four of the cognitive tasks. Relative to placebo, modafinil improved fatigue levels, motivation, reaction time and vigilance. In terms of self-assessments of cognitive performance, both the placebo and modafinil conditions were 'well calibrated' on trial-by-trial confidence judgements, showing neither marked over- nor under-confidence. Of note, the modafinil condition displayed a non-significant tendency towards 'overconfidence' for task-level assessments of performance. The present findings highlight the need for continued research on the many complex interactions involving fatigue states, occasional versus long-term stimulant use, and subjective assessments of fatigue and cognitive performance.

Adolescent↗
PubMed1992

Inhibitory effects of the psychoactive drug modafinil on gamma-aminobutyric acid outflow from the cerebral cortex of the awake freely moving guinea-pig. Possible involvement of 5-hydroxytryptamine mechanisms.

The effects of modafinil on acetylcholine and GABA outflow from the cerebral cortex of awake freely moving guinea pigs provided with an epidural cup were studied. In the dose range of 3-30 mg/kg s.c. modafinil produced a dose dependent significant inhibition of GABA outflow without influencing cortical acetylcholine release. Methysergide (2 mg/kg, i.p.) and ketanserin (0.5 mg/kg, i.p.) but not prazosin (0.14 mg/kg, i.p.) counteracted the inhibitory action of modafinil on cortical GABA outflow. Modafinil both acutely and chronically in the same dose range increased striatal 5-HIAA levels and 5-HT utilization in the rat (acute) and mouse (chronic). The action on cortical GABA release may be dependent on activity at 5-HT2 receptors, since the action of modafinil in this respect is blocked by the non-selective 5-HT antagonist methysergide and the 5-HT2 antagonist ketanserin. The involvement of 5-HT mechanisms in the inhibitory action of modafinil on cortical GABA release is also suggested by the findings that 5-HT metabolism may become increased by modafinil at least in the striatum. The reduction of cortical GABA outflow via 5-HT2 receptors by modafinil is probably related to some of its actions on the central nervous system including behavioural effects.

Acetylcholine↗
PubMed1992

Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat.

Seventeen adult cats were chronically implanted with electrodes for polygraphic recordings in order to assess the role of catecholamines in the arousal effects of oral administrations of modafinil, a presumed noradrenergic agonist, and amphetamine, a well-known catecholamine-releasing agent. Whereas both modafinil (1, 2.5 and 5 mg/kg) and amphetamine (0.25, 0.5 and 1 mg/kg) caused a significant and dose-dependent increase in wakefulness and brain temperature, amphetamine, but not modafinil, elicited marked signs of behavioral excitation. Pretreatments with alpha-methyl-DL-p-tyrosine methyl ester (50 mg/kg, i.p.), an inhibitor of catecholamine synthesis, almost completely prevented the effects of amphetamine (0.25 and 1 mg/kg), but only slightly reduced the duration of the waking effect of modafinil (2.5 and 5 mg/kg). Pretreatments with phentolamine (10 mg/kg, i.p.), prazosin (1.5 mg/kg, per os) and propranolol (5 mg/kg, i.p.), an alpha-, alpha 1- and beta-receptor antagonist, respectively, attenuated significantly the arousal effect of modafinil (1 mg/kg, the same as below) but not of amphetamine (0.25 mg/kg, the same as below). Intraperitoneal injections of haloperidol (0.5 mg/kg), a dopamine-receptor antagonist, blocked significantly the arousal of amphetamine but not of modafinil. The effects of both modafinil and amphetamine were enhanced by a pretreatment with yohimbine (1 mg/kg, i.p.), an alpha 2-receptor antagonist. These results suggest that the arousal effect of modafinil does not depend on the availability of the endogenous catecholamines but results from an enhancement of alpha 1- and beta-receptor activity and that the waking and behavioral effects of amphetamine may be mainly due to an increase in dopamine release.

Amphetamine↗
PubMed1990

On the treatment of the alcoholic organic brain syndrome with an alpha-adrenergic agonist modafinil: double-blind, placebo-controlled clinical, psychometric and neurophysiological studies.

1. In a double-blind study forty abstinent hospitalized male patients with an alcoholic organic brain syndrome (OBS) were treated for 6 weeks with either 200 mg modafinil or placebo. 2. Modafinil (CRL 40476) is a putative central alpha-1 adrenergic agonist. It's pharmacological profile is quite different from that of amphetamine, which can be seen by the lack of peripheral sympathomimetic effects. The vigilance promoting effect of modafinil has been shown previously in pharmaco-EEG and psychometric studies as well as in clinical studies involving treatment of daytime sleepiness in idiopathic hypersomniacs and narcoleptics. 3. The present clinical investigations demonstrated that the spontaneous restitution of the alcoholic OBS was significantly augmented and accelerated by modafinil. 4. Psychometric tests did not show significant intergroup differences. Modafinil- and placebo-treated patients improved continously over the 6-week period. 5. Psychophysiological and autonomous nervous system parameters were affected neither by placebo nor by modafinil. 6. Neurophysiological investigations by means of quantitative pharmaco-EEG showed partly inconsistent findings. However, superimposed dosages of modafinil (on the top of 6 weeks chronic administration) induced a decrease of slow activity and an increase of alpha activity suggesting an improvement of vigilance after the daily drug intake. 7. Considering the beneficial effects of modafinil in abstinent chronic alcoholic patients, it may be said that activation and improvement of adaptive behaviour by an alpha-adrenergic agonist could be regarded as a therapeutic principle in the treatment of the OBS, eventually due to noradrenergic deficits.

Adrenergic alpha-Agonists↗
PubMed1995

Non-amphetaminic mechanism of stimulant locomotor effect of modafinil in mice.

Previously established dose-response curves indicated that modafinil 20-40 mg/kg i.p. elicited in mice an obvious stimulation of locomotor activity roughly similar to that induced by (+)amphetamine 2-4 mg/kg. The effects of various agents modifying dopamine transmission were compared on the locomotor response to both drugs. The preferential D2 dopamine receptor antagonist haloperidol 37.5-150 micrograms/kg i.p. suppressed the stimulant effect of (+)amphetamine in a dose dependent manner, but not that of modafinil. The D1 dopamine receptor antagonist SCH 23390 (7.5-30 micrograms/kg s.c.) reversed the (+)amphetamine but not the modafinil induced hyperactivity. The tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (200 mg/kg) suppressed the hyperactivity induced by 4 mg/kg dexamphetamine but not that induced by 20 mg/kg modafinil. Associating L-DOPA 150 mg/kg and benserazide 37.5 mg/kg with (+)amphetamine 2 mg/kg resulted in stereotyped climbing behavior, that was not observed with modafinil 10-80 mg/kg. The profound akinesia induced by reserpine (4 mg/kg s.c.; 5 h before testing) was reversed by (+)amphetamine 2 mg/kg but not by modafinil 40 mg/kg. Finally, on synaptosomes prepared from mouse striata preloaded with [3H]dopamine, modafinil 10(-5) M did not increase the spontaneous [3H]dopamine release whereas (+)amphetamine, at the same concentration, doubled it. From all these differences between the two drugs, it is concluded that the mechanism underlying the modafinil induced stimulant locomotor effect differs completely from that of (+)amphetamine.

Animals↗
PubMed2006

Absence of mood switch with and tolerance to modafinil: a replication study from a large private practice.

BACKGROUND: Fatigue is a common symptom of depression, especially the bipolar type. Modafinil is a wake-promoting agent that can alleviate fatigue in depressed patients. Many stimulants used to treat fatigue carry the risk of a switch into mania or hypomania in bipolar patients as well as the risk for tolerance or abuse. METHOD: A retrospective chart review was performed on all patients currently being seen in a large outpatient practice who received modafinil at some point during their treatment. Data collected included patient demographics, MiniSCID diagnoses, clinical diagnoses including history of substance abuse, and length and dosage of treatment with modafinil. RESULTS: Of the 191 patients who were given modafinil at some point during their treatment, 105 patients remained on it for 2 months or more and 37% of these patients were bipolar (18 BPI and 21 BPII). In addition, 86 patients were on modafinil for less than 2 months and 31% of these patients were bipolar(16% BPI and 15% BPII). No patients in any group demonstrated a switch into mania or hypomania while on modafinil. There was also no significant difference in final modafinil dosage between patients who had a positive history of chemical abuse/dependence (290 mg/day) and those who did not (258 mg/day). LIMITATIONS: Retrospective chart review. CONCLUSIONS: Adult affective disorder patients, whether unipolar or bipolar, can use modafinil to relieve symptoms of depression, including fatigue and sleepiness, without risking a switch in their mood or developing tolerance or abuse of this medication.

Adult↗
PubMed2005

Modafinil more effectively induces wakefulness in orexin-null mice than in wild-type littermates.

Narcolepsy-cataplexy, a disorder of excessive sleepiness and abnormalities of rapid eye movement (REM) sleep, results from deficiency of the hypothalamic orexin (hypocretin) neuropeptides. Modafinil, an atypical wakefulness-promoting agent with an unknown mechanism of action, is used to treat hypersomnolence in these patients. Fos protein immunohistochemistry has previously demonstrated that orexin neurons are activated after modafinil administration, and it has been hypothesized that the wakefulness-promoting properties of modafinil might therefore be mediated by the neuropeptide. Here we tested this hypothesis by immunohistochemical, electroencephalographic, and behavioral methods using modafinil at doses of 0, 10, 30 and 100 mg/kg i.p. in orexin-/- mice and their wild-type littermates. We found that modafinil produced similar patterns of neuronal activation, as indicated by Fos immunohistochemistry, in both genotypes. Surprisingly, modafinil more effectively increased wakefulness time in orexin-/- mice than in the wild-type mice. This may reflect compensatory facilitation of components of central arousal in the absence of orexin in the null mice. In contrast, the compound did not suppress direct transitions from wakefulness to REM sleep, a sign of narcolepsy-cataplexy in mice. Spectral analysis of the electroencephalogram in awake orexin-/- mice under baseline conditions revealed reduced power in the theta; band frequencies (8-9 Hz), an index of alertness or attention during wakefulness in the rodent. Modafinil administration only partly compensated for this attention deficit in the orexin null mice. We conclude that the presence of orexin is not required for the wakefulness-prolonging action of modafinil, but orexin may mediate some of the alerting effects of the compound.

Animals↗
PubMed2005

Dopaminergic-adrenergic interactions in the wake promoting mechanism of modafinil.

Adrenergic signaling regulates the timing of sleep states and sleep state-dependent changes in muscle tone. Recent studies indicate a possible role for noradrenergic transmission in the wake-promoting action of modafinil, a widely used agent for the treatment of excessive sleepiness. We now report that noradrenergic projections from the locus coeruleus to the forebrain are not necessary for the wake-promoting action of modafinil. The efficacy of modafinil was maintained after treatment of C57BL/6 mice with N-(2-chloroethyl)-N-ethyl 2-bromobenzylamine (DSP-4), which eliminates all noradrenaline transporter-bearing forebrain noradrenergic projections. However, the necessity for adrenergic receptors in the wake-promoting action of modafinil was demonstrated by the observation that the adrenergic antagonist terazosin suppressed the response to modafinil in DSP-4 treated mice. The wake-promoting efficacy of modafinil was also blunted by the dopamine autoreceptor agonist quinpirole. These findings implicate non-noradrenergic, dopamine-dependent adrenergic signaling in the wake-promoting mechanism of modafinil. The anatomical specificity of these dopaminergic-adrenergic interactions, which are present in forebrain areas that regulate sleep timing but not in brain stem areas that regulate sleep state-dependent changes in muscle tone, may explain why modafinil effectively treats excessive daytime sleepiness in narcolepsy but fails to prevent the loss of muscle tone that occurs in narcoleptic patients during cataplexy.

Adrenergic Agents↗
PubMed2002

The central nucleus of the amygdala and the wake-promoting effects of modafinil.

Modafinil, a novel non-amphetamine stimulant recently approved for the treatment of narcolepsy, has been shown to increase waking in both animals and humans. However, its mechanism of action is currently unknown. Earlier research into the brain structures responsible for the wake-producing actions of modafinil implicated the central nucleus of the amygdala (ACe) as a possible site of action [Neuroscience 87 (1998) 905-911; Neurosci. Lett. 241 (1998) 95-98]. The present experiments were designed to test the hypothesis that the ACe is, at least in part, involved in the wake-producing actions of modafinil. In the first experiment, rats with lesions of the ACe were injected systemically with varying doses of modafinil and sleep was recorded. At the highest dose, modafinil significantly increased waking and decreased sleep. However, there was no interaction between the lesion and the effect of the drug. In the second experiment, varying doses of modafinil were injected directly into the ACe and sleep was recorded. Injection of modafinil into the ACe did not affect sleep architecture. Thus, ACe does not play a simple role in modafinil's wake-promoting action. We suggest that more complex testing will be required to elucidate its role.

Amygdala↗
PubMed2000

Effects of amphetamine and modafinil on the sleep/wake cycle during experimental hypersomnia induced by sleep deprivation in the cat.

Modafinil is a newly discovered waking substance now being used in the treatment of hypersomnia and narcolepsy. We have shown previously in the cat that, unlike amphetamine, modafinil induces long-lasting wakefulness (W) without behavioral excitation and subsequent sleep rebound, and that its waking effect does not depend on endogenous catecholamines. To further characterize the awakening properties of modafinil and current psychostimulants in experimental models of hypersomnia, we examined the effect of oral administration of placebo, modafinil (5 mg kg-1) or amphetamine (1 mg kg-1) on the sleep/wake cycle and power spectral density (PSD) in cats after an 18-h water-tank sleep deprivation period. We found that the placebo had no effect on the dynamics of sleep recovery, while both modafinil and amphetamine induced suppression of cortical slow activity and a waking state lasting 6-8 h. After the amphetamine-induced waking period, both deep slow wave sleep (SWS2) and paradoxical sleep (PS) occurred in greater amounts than after placebo and the PSD during SWS was also increased. Thus, the cumulative time spent in W during a 48-h period was similar to that with placebo, indicating enhanced sleep rebound. In contrast, after the modafinil-induced W, the occurrence and evolution of SWS2 or PS, as well as the PSD during SWS, were similar to those seen with placebo during the same period, so that the total time spent in W in a 48-h period remained significantly higher than the control level, indicating no additional sleep rebound. These results indicate that modafinil is effective against somnolence and hypersomnia and does not produce a subsequent increase in sleep and suggest that the pharmacological profile of modafinil is different from that of amphetamine.

Amphetamine↗
PubMed2002

Effect of modafinil on the pharmacokinetics of ethinyl estradiol and triazolam in healthy volunteers.

BACKGROUND: Modafinil has been reported to produce a concentration-related induction of CYP3A4/5 activity in vitro in primary cultures of human hepatocytes. OBJECTIVE: Our objective was to determine whether the pharmacokinetics of steady-state ethinyl estradiol (INN, ethinylestradiol) and single-dose triazolam were altered after 4 weeks of modafinil treatment in volunteers. METHODS: This was a placebo-controlled, single-blind, single-period study in 41 female subjects who were receiving long-term treatment with an oral contraceptive that contained ethinyl estradiol (0.035 mg) and norgestimate (0.180-0.250 mg). Pharmacokinetic profiles for ethinyl estradiol and for a single oral dose of triazolam (0.125 mg) were obtained the day before initiation of treatment with modafinil (200 mg for 7 days, followed by 400 mg for 21 days) or placebo (28 days). A second dose of triazolam was administered with the final dose of modafinil, and pharmacokinetic profiling was repeated. RESULTS: The modafinil treatment group had a marked decrease in maximum observed plasma concentrations and areas under the plasma concentration-time curve for triazolam relative to placebo, with a much smaller decrease in these parameters for ethinyl estradiol. The half-life of triazolam was also decreased, but the half-life of ethinyl estradiol did not appear to be affected by treatment with modafinil. CONCLUSION: Modafinil induced CYP3A4/5 activity in humans in vivo, suggesting that there is potential for metabolic drug-drug interactions between modafinil and substrates of CYP3A4/5. However, the induction appeared to be more gastrointestinal than hepatic in nature. Therefore significant metabolic drug-drug interactions are most likely to occur with compounds (such as triazolam) that undergo significant gastrointestinal CYP3A4/5-mediated first-pass metabolism.

Adult↗
PubMed2006

A randomized, double-blind, placebo-controlled study of modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVE: To evaluate the efficacy and tolerability of modafinil in children and adolescents, ages 7 to 17, with attention-deficit/hyperactivity disorder (ADHD). METHOD: In this 9-week, double-blind, flexible-dose study, patients were randomized to once-daily modafinil (170-425 mg) or placebo. Assessments included ADHD Rating Scale-IV (ADHD-RS-IV) School and Home Versions and Clinical Global Impression of Improvement (CGI-I) scale. RESULTS: Two hundred patients were randomized. Modafinil produced significant reductions in ADHD-RS-IV total scores at school (n = 128; mean change +/- SD: -17.5 +/- 13.1 points) compared with placebo (n = 66; -9.7 +/- 10.3 points; p < .0001). Similarly, modafinil reduced ADHD-RS-IV total scores at home compared with placebo (-17.6 +/- 13.3 versus -7.5 +/- 11.8 points; p < .0001). Fifty-two percent of patients randomized to modafinil and 18% of those randomized to placebo met prestudy criteria for responder on the CGI-I (p < .0001). Randomization to modafinil was associated with significantly more insomnia, headache, decreased appetite, and weight loss than randomization to placebo, but discontinuation attributed to adverse events did not differ statistically between treatment groups (modafinil, 5%; placebo, 6%). CONCLUSION: Modafinil was well tolerated and reduced ADHD symptoms at school and home compared with placebo.

Adolescent↗
PubMed2002

Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study.

OBJECTIVE: To assess the efficacy and safety of modafinil for the treatment of fatigue in multiple sclerosis (MS). METHODS: Patients aged 18-65 years with a diagnosis of MS, a stable disability level < or =6 on the Kurtzke extended disability status scale (EDSS), and a mean score >4 on the fatigue severity scale (FSS) were eligible for the 9 week, single blind, phase 2, two centre study. Exclusion criteria included a diagnosis of narcolepsy, sleep apnoea, or clinically significant major systemic disease and recent use of medications affecting fatigue. All patients, who remained blinded for the treatment regimen, received placebo during weeks 1-2, 200 mg/day modafinil during weeks 3-4, 400 mg/day modafinil during weeks 5-6, and placebo during weeks 7-9. Safety was evaluated by unblinded investigators. Efficacy was evaluated by self rating scales, using the FSS, the modified fatigue impact scale (MFIS), a visual analogue scale for fatigue (VAS-F), and the Epworth sleepiness scale (ESS). Adverse events were recorded. RESULTS: Seventy two patients (MS type: 74% relapsing-remitting; 7% primary progressive; 19% secondary progressive) received treatment. After treatment with 200 mg/day modafinil for 2 weeks, a significant improvement in fatigue versus placebo run in was demonstrated. Mean scores after treatment with 200 mg/day modafinil were: FSS, 4.7 versus 5.5 for placebo (p<0.001); MFIS, 37.7 versus 44.7 (p<0.001); and VAS-F, 5.4 versus 4.5 (p=0.003). Fatigue scores for 400 mg/day modafinil were not significantly improved versus placebo run in. Mean ESS scores were significantly improved (p<0.001) with 200 mg/day modafinil (7.2) and 400 mg/day (7.0) versus the score at baseline (9.5). Serious adverse events were not found at either dose. The most common adverse events were headache, nausea, and aesthenia. Sixty five patients (90%) completed the study. CONCLUSIONS: These data suggest that 200 mg/day modafinil significantly improves fatigue and is well tolerated in patients with MS.

Adolescent↗