Pharmacotherapy for excessive daytime sleepiness

Sleep Medicine Reviews (2004) 8, 339–354

www.elsevier.com/locate/smrv

CLINICAL REVIEW

Pharmacotherapy for excessive daytime sleepiness Dev Banerjeea,c, Michael V. Vitiellob, Ronald R. Grunsteinc,* a

Sleep and Ventilation Unit, Department of Respiratory Medicine, Birmingham Heartlands Hospital, Bordesley Green East, Birmingham B9 5SS, UK b Psychiatry and Behavioral Sciences, University of Washington, 98195-6560 Seattle, WA, USA c Sleep Research Group, Woolcock Institute of Medical Research, Royal Prince Alfred Hospital and University of Sydney, Missenden Road, Camperdown, Sydney, NSW 2050, Australia KEYWORDS Excessive daytime sleepiness; Psychostimulants; Dexamphetamine

Summary Excessive daytime sleepiness (EDS) has recognized detrimental consequences such as road traffic accidents, impaired psychological functioning and reduced work performance. EDS can result from multiple causes such as sleep deprivation, sleep fragmentation, neurological, psychiatric and circadian rhythm disorders. Treating the underlying cause of EDS remains the mainstay of therapy but in those who continue to be excessively sleepy, further treatment may be warranted. Traditionally, the amphetamine derivatives, methylphenidate and pemoline (collectively sympathomimetic) psychostimulants were the commonest form of therapy for EDS, particularly in conditions such as narcolepsy. More recently, the advent of modafinil has broadened the range of therapeutic options. Modafinil has a safer sideeffect profile and as a result, interest in this drug for the management of EDS in other disorders, as well as narcolepsy, has increased considerably. There is a growing school of thought that modafinil may have a role to play in other indications such as obstructive sleep apnea/hypopnea syndrome already treated by nasal continuous positive airway pressure but persisting EDS, shift work sleep disorders, neurological causes of sleepiness, and healthy adults performing sustained operations, particularly those in the military. However, until adequately powered randomised-controlled trials confirm long-term efficacy and safety, the recommendation of wakefulness promoters in healthy adults cannot be justified. q 2004 Elsevier Ltd. All rights reserved.

Introduction Excessive daytime sleepiness (EDS) has recognized detrimental consequences such as road traffic accidents, impaired psychosocial functioning and reduced work performance.1 Causes for EDS are numerous and include intrinsic sleep disorders (e.g. narcolepsy, obstructive sleep apnea/hypopnea syndrome (OSAHS), idopathic hypersomnia), extrinsic *Corresponding author. Tel.: þ 61-2-95158630; fax: þ61-295158196. E-mail address: [email protected] (R.R. Grunstein).

sleep disorders (e.g. inadequate sleep hygiene, insufficient sleep syndrome, toxin-induced sleep disorder), circadian rhythm sleep disorders (e.g. delayed sleep phase syndrome, time-zone change (jet lag) syndrome, shift work sleep disorder), sleep disorders associated with medical disorders (e.g. dementia, Parkinsonism) and sleep disorders associated with mental disorders (e.g. psychoses, mood disorders, anxiety disorders). Full assessment should include a detailed history, physical examination and relevant investigations to evaluate a possible causation. Treating the underlying cause is the mainstay of treatment. Addressing

1087-0792/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.smrv.2004.03.002

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the cause may be enough to counter EDS but in other cases patients may continue to be symptomatic. In such cases, the consideration for psychostimulant drugs that increase alertness may be considered. Psychostimulants can be regarded as drugs that produce a behavioral activation accompanied by an increase in arousal, motor activity, and alertness. Psychostimulants may be sympathomimetic (i.e. mimicking the action of the sympathetic nervous system when activated) such as amphetamine, methylphenidate, and pemoline, or non-sympathomimetic such as caffeine and modafinil. Traditionally, sympathomimetic drugs have been popular options to treat EDS. Amphetamine was first synthesized in 1927 and used to treat narcolepsy in 1935.2 The D-isomer (dexamphetamine) is more efficacious and is currently the second most frequently prescribed stimulant for narcolepsy in US after methylphenidate which was first used in 1959. Pemoline is a milder stimulant with a lower potency compared to the amphetamines, but due to reported liver toxicity it is presently not as commonly used as the other sympathomimetic drugs. Caffeine is also commonly used as a wakefulness agent and may have advantages over other wake-promoting drugs particularly with regard to its relatively mild sideeffect profile. Modafinil (or 2-phenyl methylsulfinylacetamide) is a relatively new synthetic compound with novel wake-promoting properties, and is increasingly a popular alternative to the abovementioned psychostimulants. A potential advantage of a drug like modafinil is that it seems to promote wakefulness in the absence of the other arousing effects typically seen with the sympathomimetic drugs. That is, it increases wakefulness without causing autonomic arousal and psychomotor agitation. This article reviews the therapeutic role of sympathomimetic drugs, caffeine and modafinil in the management of certain conditions characterised by EDS. In this review, sympathomimetic psychostimulants broadly covers amphetamine based compounds and methylphenidate. The role of others such as mazindol and selegiline are not discussed. The conditions covered in this review are narcolepsy, idiopathic hypersomnia, OSAHS and shift work sleep disorders. Readers are recommended to refer to a recent review of EDS in neuromuscular disorders.3

Mechanism of action of drugs treating EDS Sympathomimetic psychostimulants promote wakefulness by enhancing mono-aminergic

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transmission (particularly dopamine, noradrenaline and serotonin neurotransmission); by increasing the release and inhibiting the reuptake of these neurotransmitters.2,4 Studies of control and narcoleptic Doberman dogs suggested that dopaminergic activation is the key to mediating wakefulness promotion.5 However, amphetamines also cause the release of noradrenaline from the peripheral nerve terminals leading to enhanced sympathetic activity which may cause intolerable side-effects. Caffeine is an adenosine receptor antagonist and promotes wakefulness.6,7 There is evidence that activation of a subgroup of adenosine receptors causes an inhibition of cortical acetylcholine release which may contribute to promoting wakefulness.8 The specific mechanism of action for modafinil remains unclear despite research which has focussed on the effect on various neurotransmitters involved in sleep –wake regulation. In contrast to amphetamines, the effects of modafinil are unlikely to be mediated via adrenergic neurons,9 although another study suggests a possible role for a1adrenoreceptor activity in the brain.10 The exact mechanism is not totally clear but is thought to be dopamine related. Studies in dopamine knockout mice have shown that modafinil has a reduced effect.11 Modafinil may also have an indirect effect on the histaminergic system within the hypothalamus12 and possibly also reduces the release of GABA, particularly in areas such as the cortex and posterior hypothalamus. 13,14 Some evidence suggests that modafinil may also affect cortical15 and hypothalamic16 serotonin release. Compared with amphetamine, modafinil has been shown to cause selective neuronal activation as seen by an increase in the expression of the transcription factor Fos (an indicator of neuronal activation) in the suprachiasmatic nucleus (SCN) and the anterior hypothalamus.17,18 More recently, however, there is evidence in rats that modafinil inhibits the sleep-promoting neurons of the ventrolateral preoptic nucleus (VLPO) by blocking the noradrenaline reuptake transporter.19 This effect, therefore, enhances the inhibitory effects of noradrenaline on the VLPO neurons. Alertness requires inhibition of the VLPO, and this local effect may be mediated by noradrenaline.

Pharmacokinetics The pharmacology of sympathomimetic psychostimulants has been described more fully elsewhere.20 – 23 Both the L - and D - dimers of amphetamine have been used as treatment but

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the D -isomer (dexamphetamine) is generally more potent. The addition of a methyl group produces methamphetamine. This compound is the most potent amphetamine as a result of its lipophilic properties and greater central nervous system penetration. The molecular weight of methamphetamine hydrochloride (185 Da) is half that of dexamphetamine (d-alpha-methylphenethylamine) sulfate (368 Da). The half-life of amphetamine is 12 h and hence multiple doses are desirable for a sustained wakefulness effect. It is readily absorbed enterally and largely eliminated unchanged in the urine. Urinary excretion is pH-dependent, therefore, being a basic substance, elimination will be greater in acidic urine. Hence, concomitant therapy with products that alkalinize urine (e.g. bicarbonates) will reduce elimination. Methylphenidate (methyla-phenyl-2-piperidineacetate) is a piperidine derivative and is the most popular prescribed psychostimulant in clinical practice.22 Methylphenidate is a racemic compound. Its more potent (þ ) enantiomer has a halflife of 6 h and the less potent (2 ) enantiomer has a half-life of between 3 and 4 h. It is rapidly metabolised and excreted in urine, primarily as the inactive metabolite ritalinic acid, which accounts for 80% of the dose. Introduced in 1959 for narcolepsy, its popularity emanates from its shorter half-life compared with dexamphetamine. The shorter duration of action allows some subjects with narcolepsy to use methylphenidate as a ‘when needed’ preparation, and allows napping in between dosing. The long acting version, however, may be taken once a day to promote better compliance. Methylphenidate also has the advantage of a better therapeutic index, i.e. the risk of adverse effects is less when taken at the doses, which provide a therapeutic benefit. Pemoline is a milder stimulant with less sympathomimetic effects than the amphetamine compounds. It is pharmacologically similar to the amphetamines. It has a slower onset of action, better tolerated than the amphetamines, but is less potent. The half-life is 16 – 18 h. The long duration of action may encourage better compliance. Due to reports of liver toxicity, its popularity has waned. Caffeine24,25 (1,3,7-trimethylxanthine) is a natural alkaloid, rapidly absorbed through the gastrointestinal tract and reaching peak plasma levels between 30 and 75 min. Six cups of coffee per day would equate to plasma levels between 2 and 6 mg/l. Caffeine capsules at doses up to 150 mg (equivalent to two cups of coffee) would result in plasma levels of about 3 mg/l. It is primarily metabolised in the liver, by demethylation, to 1,7-dimethylxanthine via cytochrome P-450 1A2.

The half-life varies between 3 and 7 h and is dependent on numerous factors such as pregnancy, smoking, age, gender and oral contraceptive usage; the latter increasing the half-life. Only 1 –5% of caffeine is excreted unchanged in the urine, the majority metabolized to 1-methylxanthine and 1-methyluric acid derivatives. The variable effect of caffeine within a population maybe explained by differing cytochrome P450 activities between individuals.26 The pharmacokinetics of modafinil have been investigated in detail in healthy volunteers.27 – 32 Modafinil is a racemic compound, whose enantiomers have approximately equipotent pharmacological effects but act differently pharmacokinetically. In humans, the half-life of the L -isomer is approximately three times that of the D -isomer. The effective elimination half-life of modafinil after multiple dosing is about 15 h. The enantiomers exhibit linear kinetics upon multiple dosing of 200 – 600 mg once daily in healthy volunteers. Steady states of total modafinil and L -modafinil are reached after 2 – 4 days of dosing. Therefore, intermittent usage of modafinil may not allow the attainment of an adequate steady-state blood level. The absorption of modafinil is rapid (although not as rapid as caffeine), with a peak plasma concentration of around 2 – 4 h. The bioavailability is not affected by food although absorption ðtmax Þ maybe delayed by approximately 1 h when taken with food. Modafinil is well distributed in body tissue with an approximate volume of distribution around 0.9 l/kg. In plasma (in vitro) modafinil is moderately bound to protein; approximately 60% to mainly albumin. Only two metabolites reach appreciable concentrations in plasma; modafinil acid and modafinil sulfone. The major route of elimination is metabolism primarily by the liver with subsequent renal elimination of its metabolites. Patients with severe hepatic impairment should have the modafinil administered at lower doses. Doses of 200 mg do not lead to increased modafinil exposure in patients with severe renal impairment although higher levels of modafinil acid have been found; the significance of this is unclear. Less than 10% of the administered dose is excreted unchanged. The potential for drug interactions have been examined both in vivo and in vitro. Reversible inhibition of the cytochrome P450 enzyme CYP2C19 in human liver microsomes have been observed as well as an induction of the CYP3A4, CYP1A2 and CYP2B6 enzymes.33 As a consequence, co-administration of modafinil with diazepam, phenytoin, and propanolol, which are eliminated through the CYP2C19 enzyme, may increase the levels of these

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drugs. Induction of CYP3A4 may reduce levels of steroidal contraceptives.34 It is recommended that alternative or concomitant methods of contraception should be considered during treatment with modafinil and 1 month after the cessation of any modafinil therapy.35 Concomitant administration of modafinil (200 –400 mg daily) with dexamphetamine (10 – 20 mg daily)27,32 or methylphenidate (20 – 40 mg)28,31 did not significantly change the steady-state pharmacokinetics for tolerability profiles of modafinil. These studies suggest a low probability of drug-to-drug interactions pharmacokinetically between modafinil and dexamphetamine or methylphenidate.

Effect of stimulants in normal human volunteers Wakefulness and cognitive function In a trial of sleep deprived healthy males, 20 mg of dexamphetamine led to a better cognitive performance when compared with placebo.36 Increased alertness and a marked reduction in the drive to sleep was also noted when compared with caffeine.37 Methamphetamine was shown to prevent the deterioration of cognitive functioning during one night (without sleep) with the 10 mg dose outlasting the 5 mg dose with regard to continued effect.38 The effect of caffeine on mood, cognitive performance and sleep has been reviewed in more detail elsewhere.24 The dose-effect relationship of caffeine on sleep is wide and variable but evidence suggests that caffeine will increase the time taken to fall asleep if taken prior to sleep and that individuals will control caffeine consumption to prevent sleep disturbance. One cup of instant coffee may contain between 40 and 105 mg of caffeine, espresso 30 – 50 mg, percolated coffee 60 – 125 mg, decaffeinated coffee 1 – 4 mg and one cup of tea has between 20 and 100 mg. Studies have also looked at the effect of caffeine on cognitive and psychomotor functioning after sleep deprivation. Two double-blinded placebo trials using 600 mg caffeine found some improvement in cognitive and psychomotor performance as well as vigilance.39,40 Another two trials assessing the effect of caffeine on driving performance suggest some improvement in steering accuracy41 and lane drifting.42 The latter study was conducted as a placebo controlled vs caffeine slow release 300 mg trial after partial sleep deprivation. In another trial, after a period of extended wakefulness, volunteers were permitted to undertake seven 2-h naps, but

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after each 2-hour nap, were abruptly awoken and followed by psychomotor performance testing.43 Caffeine was effective in counteracting sleep inertia (i.e. cognitive impairment on wakening) compared with placebo. A slow release preparation of caffeine which aims to keep effective plasma levels for between 4 and 6 h, has also shown to maintain a good level of vigilance and performance testing after sleep deprivation.44 Interestingly, the 300 mg dose in this trial was reported to have the most optimum effect with minimal side-effects compared with the 600 mg dose. In another study, meanwhile, no change in subjective alertness was seen when 600 mg of slow release caffeine was compared with placebo.45 There has been a growing number of studies looking at the effect of modafinil on sleepiness, psychomotor and cognitive functioning with some studies comparing this agent with other psychostimulants in normal human volunteers. In one placebo controlled trial, eight-hourly 200 mg of modafinil after 60 h of sleep deprivation improved subjective and objective vigilance when compared to placebo.46 Modafinil (three tablets of 300 mg during 60 h of sleep deprivation) showed comparable improvements in fatigue, sleepiness and objective measures of reaction time, logical reasoning and short-term memory compared with 20 mg of dexamphetamine (also taken three times) in military subjects.47 A trial comparing the effect of modafinil (100, 200 or 400 mg single dose), caffeine (600 mg single dose) and placebo on vigilance and cognitive performance in sleep deprived healthy adults found that modafinil had similar improvements in these parameters as caffeine but significantly better when compared to placebo.48 The effect of modafinil on cognitive function in healthy non-sleep deprived adults is uncertain. Once daily modafinil (100 or 200 mg), when compared to placebo, improved cognitive memory and attention testing in one study49 but not in another.50

Field studies Dexamphetamine at doses of 10 mg compared with placebo sustained helicopter aviation performance during periods of sleep deprivation and sustained wakefulness.51 Caffeine of doses up to 300 mg has also been shown to improve cognitive function and marksmanship in military personnel, whilst sleep deprived.52,53 The role of caffeine (150 and 200 mg doses) in counteracting driving impairment during sleep deprivation has been tested in two trials.54,55

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One study54 found that 150 mg and taking a nap both reduced driving impairment during a car simulator test in sleep deprived adults. In the other trial,55 driving simulator performance (2 h of computer generated dull monotonous drive) was tested after 5 h of sleep and on another occasion after no sleep; the test taking place between 0600 and 0800 h. Caffeine (200 mg) reduced the number of driving incidents in the post sleep test, whereas in the ‘nil-sleep’ test, caffeine reduced the number of driving incidents for the first 30 min only, but was still profoundly abnormal compared to the post 5-h sleep results. The simulated drive after nil-sleep was terminated after 1 h. The authors conclude that caffeine may improve early morning driver sleepiness, but for only 30 min and that caffeine is no substitute for an adequate sleep period. The potential importance of modafinil as a means of maintaining wakefulness in emergency and military personnel is being recognised.56 Two studies on helicopter pilots57 and army reservists58 showed improved alertness after sleep deprivation using modafinil. In the former study,57 when compared with placebo, modafinil also maintained performance levels in some of the simulated helicopter precision maneuvers carried out by the pilots.

latency time during MSLT assessment.46 Comparing modafinil (200 or 400 mg) and caffeine to placebo, there were no differences between the two active groups and the authors comment that modafinil did not offer any advantages over caffeine.48 The effect of modafinil and dexamphetamine on EEG recordings during sleep has suggested a reduction in slow wave sleep by both57 but an increase in alpha activity by only modafinil and not dexamphetamine.58 This differential effect on EEG activity may suggest a different mode of mechanism between the two drugs to maintain wakefulness. Modafinil was shown not to affect the natural circadian rhythm when compared to dexamphetamine.58 Another double-blind study compared modafinil (100 and 200 mg doses) with dexamphetamine (10 and 20 mg doses) and placebo taken on a nightly basis for five nights and determined their effect on sleep architecture.63 Modafinil showed no difference in total sleep time (TST) and sleep efficiency when compared to placebo, but these parameters were reduced with dexamphetamine. There was no change in sleep stage architecture in the placebo and modafinil groups whereas dexamphetamine caused a reduction in Non-REM stage 2 and REM sleep duration times. The effect of modafinil and dexamphetamine on recovery sleep architecture after 64 h of wakefulness was determined in healthy volunteers in another study.64 Modafinil showed that there was less sleep disturbance and less rebound sleep in comparison with dexamphetamine during the first recovery night. REM rebound was detectable during the second night in the dexamphetamine group but only seen during the first REM period of the first recovery night in the modafinil group.

Objective sleep measures A number of trials has determined the effects of psychostimulants on objective measures of sleep, particularly total sleep time and sleep onset latency time during Maintenance of Wakefulness (MWT) and Multiple Sleep Latency Test (MSLT) assessments. A number of trials has compared one active therapy with another. Methylphenidate (10 mg) compared with placebo has shown to increase MSLT sleep onset latency times.59 Caffeine increased MSLT sleep onset latency time in healthy adults.60 Another study compared the effect of caffeine (250 mg per day) and placebo on sleep onset latency time after 64 h sleep deprivation during MSLT and MWT assessments.61 The mean sleep onset latency time for caffeine in the MWT test was 12 min compared to 5 min for placebo in this study. There was no difference in sleep onset latency time in MSLT assessment between caffeine and placebo. The authors conclude that caffeine may be more effective in keeping individuals awake than reduce the ability to go to sleep. Caffeine has also been shown to reduce total sleep time.62 Modafinil, compared with placebo, given after 60 h of sleep deprivation has shown to suppress brief sleep episodes and improve sleep onset

Tolerability, safety and abuse potential Sympathomimetic psychostimulant drugs have common adverse effects including nervousness, irritability, headaches insomnia, anorexia, tachycardia, gastrointestinal disturbances, mood changes, and tremor.2,65,66 Liver toxicity has been reported with the usage of pemoline, especially in children, where this agent was used to treat attention deficit hyperactivity disorder (ADHD).67 There have also been concerns with the potential of psychiatric complications particularly psychotic episodes, persecutory delusions, and visual hallucinations. Between 0.3 and 2% may have this complication with amphetamine treatment.2 Caffeine is generally well tolerated although habitual consumption of over 600 mg/day may

344 represent a health risk.68 Caffeine toxicity may present with symptoms of nervousness, irritability, tachycardia, insomnia, diuresis, and gastrointestinal disturbances.68 The tolerability and safety of modafinil have been studied in normal volunteers and subjects with sleep disorders, particularly narcolepsy. Generally, modafinil is well tolerated and the commonest symptoms occurring include headache, nausea, hyperactivity, dry mouth, palpitations, and insomnia.27,28,30 – 32 Headache was reported in between 19 and 63% of normal volunteers taking modafinil. Comparing those taking modafinil and those taking modafinil with dexamphetamine, both groups had comparable side-effects, particularly headache and insomnia.32 Comparing modafinil with a combination of modafinil and methylphenidate, a similar adverse effect profile was seen for both groups. The majority of adverse events were regarded as being mild in severity. There were no clinically relevant changes in blood pressure reported in these studies although there was one report of hypertension (when taking once daily modafinil 800 mg) and another with significant ECG changes (modafinil 400 mg) in one study.30 In the same study, doses of 200, 400, 600 and 800 mg of modafinil were compared. Although the numbers in each group were small (eight in each), there was a suggestion that there may be a dose-adverse event relationship.30 The US modafinil in narcolepsy multicentre study group (the total number of subjects enrolled was 478) has reported on the long-term safety of modafinil (once daily 200, 300 and 400 mg) in 341 (71% of total) subjects with narcolepsy who had completed a 40-week course.69 The majority of adverse events (95%) were rated as mild to moderate and transient in nature. The commonest adverse events thought to be related to modafinil were headache (13%), nervousness (8%) and nausea (5%). Treatment-related cardiovascular events were uncommon but included palpitations (1.5%), hypertension (1%) and tachycardia (1%). Elevated liver enzymes (gamma-glutamyl transferase, aspartate aminotransferase and alanine aminotransferase) were reported in 5%. Only one subject withdrew as a result of liver enzyme derangement. The study group did not report any direct relationship between the incidence of adverse events and the dose of modafinil. There was a 29% drop-out rate during the 40-week open label modafinil course of which 30% of the drop-outs withdrew because of an adverse effect and over half of these events were regarded as being related to treatment. The commonest three adverse effects leading to treatment related withdrawal were nervousness, nausea

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and anxiety. Headache, nausea and irritability have also been reported as the commonest side-effect elsewhere.70,71 In those subjects with OSAHS, modafinil did not cause any clinically significant increase in blood pressure.71

Stimulants in sleep disorders Narcolepsy Narcolepsy is characterised by uncontrollable sleepiness and the initiation of REM sleep during times when a person would normally be awake. Other REM-related manifestations of narcolepsy, along with EDS, include cataplexy, sleep paralysis, and hypnagogic hallucinations. Naps have been shown to temporarily reduce sleepiness72 but sympathomimetic drugs, such as dexamphetamine, methamphetamine and methylphenidate have been the traditional mainstay of therapy for the EDS in this disorder. These drugs have a long record of efficacy with improved sleepiness symptoms in up to 85% of those taking this form of treatment.20,73 Two early open studies in the 1950’s looked at the effect of methylphenidate (doses between 15 and 300 mg once daily) on subjective sleepiness.74,75 Both trials included 29 and 68 patients, respectively, and found that methylphenidate improved subjective sleepiness. There are, however, few placebo controlled trials that have evaluated the efficacy of sympathomimetic psychostimulants in subjects with narcolepsy. Mitler et al. undertook a placebo controlled trial (eight subjects with narcolepsy and eight controls) looking at the effect of successive incremental doses of methamphetamine (from 0 mg, i.e. placebo, to 60 mg) for 4 days with each dose followed by 3 days of washout and then 4 days of an increasing dose.76 Controls were given a maximum dose of 10 mg dexamphetamine and not 60 mg. Mean MSLT sleep onset latency time for those with narcolepsy increased from 4.3 min on placebo to 9.3 min on high dose, compared with an increase from 10.4 to 17.1 min for controls. The error rate on the driving task decreased from 2.53% on placebo to 0.33% on high dose, compared with a decrease from 0.22 to 0.16% for controls. Mitler et al. also reviewed 109 patients from six trials looking at the use of different sympathomimetic psychostimulants on MWT assessments of objective sleepiness.77 Drugs used included methylphenidate (doses up to 60 mg), pemoline (up to 112.5 mg), and dexamphetamine (up to 60 mg). The authors conclude that methylphenidate and

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dexamphetamine at higher doses were effective in reducing sleepiness but pemoline at 112.5 mg in comparison was less effective. The issues of treating EDS with acceptable sideeffects is a common clinical dilemma. Some patients will need higher doses of amphetamines to gain effective treatment of EDS. Due to concerns of the potential development of tolerance and addiction,65 trials of modafinil as an alternative treatment option have been undertaken. As yet, there have been no comparative trials between modafinil and sympathomimetic psychostimulants in human narcolepsy. There is little trial data on the effect of caffeine on sleepiness in subjects with narcolepsy. Data on 530 subjects with narcolepsy from two large trials suggested that those with moderate caffeine usage had the lowest MWT sleep onset latency time relative to those patients with heavy and light use.78 It may be possible that some individuals are taking caffeine as an additional stimulant to improve wakefulness but those with heavy usage may be those with more severe sleepiness and have therefore characteristic shorter MSLT sleep onset latency times. The two US modafinil in narcolepsy multicenter study group trials have been the largest controlled trials looking at the effect of modafinil in subjects with narcolepsy.79,80 In the earlier of the two trials,79 92, 96 and 95 subjects with narcolepsy received 9 weeks of once daily placebo, modafinil 200 mg and modafinil 400 mg respectively. Twelve subjects did not complete the course. Modafinil improved subjective (Epworth sleepiness scale— ESS) and objective (MSLT and MWT sleep onset latency time assessments) scores of sleepiness compared with placebo. There were no differences between the two modafinil dose groups. The ESS score improved from a mean of 17.1 at baseline to 13.0 after 9 weeks of modafinil 400 mg. In the MWT assessment, 20% of those taking 400 mg of modafinil remained awake for at least three sleep onset latency time testing compared to 3% at baseline. In the second trial,80 the same research group repeated this protocol; 93, 89 and 89 subjects with narcolepsy received 9 weeks of once daily placebo, modafinil 200 mg and modafinil 400 mg, respectively. This second trial also investigated the incidence of rebound sleepiness and withdrawal symptoms with discontinuation of therapy and whether the gradual increase of dosing reduces the number of adverse events (100 mg for 7 days, then 200 mg for 1 day, then randomized to continue on 200 mg or increase to 400 mg). Again, improvements were found in ESS, MWT and MSLT assessments with modafinil but no differences between

the modafinil groups were detected. On discontinuation, there was a greater incidence of rebound sleepiness in the modafinil 200 mg group compared to placebo but not compared to the 400 mg group. The number of adverse events did not differ between the active and placebo groups and the authors speculate that a gradual increase in modafinil dose may lead to a better side-effect profile; although no direct comparisons with the previous trial can be made. Two important earlier placebo controlled trials also confirmed the potential use of modafinil in narcolepsy.81,82 A crossover trial in 50 patients taking once daily 300 mg modafinil found improvements in MWT sleep latency times and subjective assessments of daytime sleepiness but no improvement in cataplectic symptoms nor night time sleep parameters on polysomnography (PSG).81 In the other trial,82 6 weeks of once daily placebo, 200 or 400 mg modafinil in a total of 75 subjects with narcolepsy found that modafinil improved MWT and ESS mean sleep onset latency times; there was no added benefit with the larger modafinil dose. There was no improvement in the number of cataplexy events during therapy as evidenced from sleep diaries.

Long term efficacy of modafinil in narcolepsy A study of 63 patients undergoing treatment with modafinil (mean daily dosage 330 mg) followed up for a total of 24 weeks, showed that improvements in mean MWT sleep onset latency time, number of ‘sleep attacks’ and ESS scores can be maintained throughout the course with minimal drop-outs.70 This study group randomly allocated half of the subjects to continue modafinil and half to change to placebo on the 22nd week for 2 weeks. Noticeable worsening in mean MWT sleep onset latency time (from 15.3 to 9.7 min), and mean ESS scores (from 12.9 to 15.4) were seen in the placebo group compared to the modafinil group. This group did not report a decrease in modafinil efficacy over time without an increase in the dosing necessary. At the Montpellier sleep center, 140 subjects with narcolepsy underwent therapy with modafinil for a mean duration of 22 months (range 1 –114 months).83 The long-term improvement in daytime sleepiness was regarded as being ‘good’ or ‘excellent’ in 64% of all subjects. This study, however, also reported that nearly 40% were not totally compliant and took modafinil on an intermittent basis. By 2 years, nearly half of these patients had discontinued therapy. The authors comment that the lack of efficacy was the main cause of the modafinil discontinuation.

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The US modafinil in narcolepsy multicenter study group followed up the subjects enrolled into their previous two trials79,80 over a total of 40 weeks as an open labelled extension study.69 The total number of subjects followed up were 478, of which 75% received 400 mg modafinil daily with 341 (71%) completing the study. The study found that the improvement in ESS scores and subjective assessment of disease severity continued at the level found after 2 weeks of therapy. Nearly 60% of all subjects enrolled reported that their illness was ‘much improved’ or ‘very much improved’. Around 40%, (11% of the total study sample) of those discontinuing therapy did so due to insufficient efficacy. There is recent evidence that splitting the 400 mg dose during the day may improve sustained wakefulness in some individuals.84 At present, modafinil has been approved for the treatment of narcolepsy in France since 1992, in US and UK since 1998, Italy since 2000 and Australia and New Zealand since 2002.

The risk of abuse In the treatment of narcolepsy, modafinil is regarded as having a favorable benefit-risk ratio.85 The abuse liability of sympathomimetic psychostimulant drugs has received considerable attention. Even in low doses, amphetamine, methamphetamine, and methylphenidate produce affective states characterized by intensified feelings of contentment, relaxation and euphoria. Clinicians are encouraged to be wary of the potential risk of dependency and abuse. The potential for abuse, however, in subjects with narcolepsy has shown to be low where such subjects are unlikely to escalate their dosing regimens.86 One study showed that 22 out of 43 subjects with narcolepsy took a reduced dosage of their stimulant medication or none at all in the preceding 24 h of review. Modafinil has been studied in male volunteers previously known to be substance abusers (including cocaine).87 Comparing to methylphenidate, modafinil showed reduced stimulant effect based on addiction questionnaire scores. Modafinil and pemoline are listed as a schedule IV drug (i.e. low potential for abuse with the possibility of limited physical or psychological dependence) compared to the sympathomimetic drugs which are classed as schedule II (i.e. high potential for abuse which may lead to severe psychological or physical dependence).88 There have been suggestions that drug holidays, i.e. period of time without stimulant therapy, may prevent or reduce the incidence of tolerance and/or dependence. However, there is no evidence

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in the literature to suggest this and withdrawing medication may lead to the risk of rebound sleepiness and hence life-threatening motor vehicle accidents if the subject is not totally made aware of these risks. The discontinuation of psychostimulants during pregnancy, for the fear of potential teratogenic effects, also needs to be carefully balanced with the risks that are inherent with EDS as a result of untreated narcolepsy.

Changing therapy The data, therefore, suggest that modafinil may have numerous advantages over sympathomimetic psychostimulants in the treatment of narcolepsy. As amphetamines have been the traditional first choice of therapy, it is more frequent that some subjects with narcolepsy may wish to transfer over from a sympathomimetic psychostimulant to modafinil, particularly where intolerance has developed. This change over may be a challenge and some studies have assessed the feasibility of this. One study followed 14 subjects taking amphetamine who underwent a gradual withdrawal (10 mg every 5 days and when down to 10 mg daily, withdrawing by 5 mg every 5 days) over to modafinil (with increments of 100 mg every 3 days to 400 mg in divided doses).89 Eight of the 14 subjects went back onto amphetamines as subjective symptoms of sleepiness were worse whilst on modafinil. None of the patients had reported cataplectic attacks previously for a number of years but whilst on modafinil, all developed an increase in cataplexy episodes. Those remaining on modafinil had their cataplexy adequately controlled by venlaflaxine hydrochloride. The authors warn about the reemergence of cataplexy symptoms that may have been masked by the anti-cataplectic properties of amphetamines but not treated by modafinil. More recently, in a study of 40 subjects with narcolepsy on methylphenidate, three ways of change over were tested;90 (1) a direct change over to 200 mg modafinil per day (and subsequently to 400 mg daily) without a washout; (2) a change over but with a 2-day washout in between and; (3) a taper down of methylphenidate dosage with a concurrent commencement of an increasing dose of modafinil. All three methods were well tolerated and 95% of all subjects managed to change over successfully. There were no differences between any of the protocols with regard to adverse events. Another recent study91 looked at the gradual withdrawal of dexamphetamine (48 subjects), methylphenidate (66 subjects) and pemoline (37 subjects) followed by a 2-week washout and then 6 weeks of once daily modafinil. All 151 successfully

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completed the 2-week washout and 82% completed the 6 weeks course of modafinil. Insufficient efficacy accounted for eight drop-outs and nine discontinued modafinil therapy as a result of adverse events. No new troublesome cataplectic symptoms were reported in this study. Therefore, these two recent studies suggest that a change over to modafinil from the sympathomimetic psychostimulants is possible without major adverse effects.

other sleep disorders or coexisting medical comorbidities.71,99 – 101 The US modafinil in obstructive sleep apnea study group71 enrolled a total of 157 subjects to continue nCPAP and receive 4 weeks of once daily modafinil (200 mg during the first week and then 400 mg for 3 weeks) or placebo; 91% completing the course. All subjects were established on nCPAP but suffered from continual sleepiness (mean ESS score of 14 in both groups). Modafinil improved ESS scores and mean MSLT sleep onset latency time compared with placebo. At the end of the trial over half of the patients receiving modafinil had an ESS score of below 10 compared to 27% in the placebo group ðp , 0:01Þ: There was no change in the amount of nCPAP usage in both groups (above 6 h per night) or any change in the sleep stage architecture. The authors hypothesize that the causes of residual sleepiness in their group may be either due to chronic alterations in sleep promotion or residual upper airway abnormalities not detected by the apnea/hypopnea scoring. Kingshott et al.99 assessed 32 patients who were randomised to receive once daily modafinil (200 mg for 5 days then 400 mg for 9 days) or placebo. Thirty completed the trial. Mean ESS score was 15 for the whole group and mean baseline sleep onset latency time for MSLT and MWT were 6.9 and 16.5 min, respectively. There were no significant improvements in ESS score or MSLT sleep onset latency time but there was a marginal improvement ðp ¼ 0:02Þ in sleep onset latency time for MWT. This study therefore shows that modafinil improves the ability to stay awake although no improvements in subjective daytime sleepiness were detected. Schwartz et al. 100 found that 4 weeks of modafinil when compared to placebo produced significant improvements in sleep-related functional health status (Functional Outcomes of Sleep Questionnaire (FOSQ) scores) and subjective ESS scores. The trial continued for another 12 weeks as an open label study and there was a small but significant reduction in the nocturnal nCPAP usage time per night in the modafinil group; from 6.3 to 5.9 h ðp ¼ 0:004Þ; the clinical significance of this is unclear. In a placebo-controlled trial by Dinges et al.101 4 weeks of modafinil (maximum dose 400 mg) significantly improved the frequency of lapses of attention during psychomotor vigilance performance testing and reaction times as well as total FOSQ scores. These trials in OSAHS pose interesting questions in the management of this condition and have aroused controversy. Some argue that modafinil should not be considered as adjunct therapy in those on nCPAP complaining of continued EDS until

Idiopathic hypersomnia The role of the psychostimulants in idiopathic hypersomnia is uncertain. The diagnosis of idiopathic hypersomnia relies on the elimination of other sleep disorders and the pathogenesis and pathophysiology of this condition remains relatively unknown.92 The debate on the diagnostic criteria for idiopathic hypersomnia and the difficulties in differentiating this condition from hypersomnia secondary to other sleep disorders has been raised elsewhere.92,93 In one small trial, modafinil was shown to improve daytime sleepiness94 and elsewhere amphetamines have also been shown to have a potential role in its treatment.95 As yet, there have been no double-blind randomised-controlled trials assessing the effect of modafinil on idiopathic hypersomnia compared to placebo. Although there have been few controlled studies determining the use of modafinil in this condition, there may still be a role for this drug in the management of this condition, as experienced in clinical practice. There are two forms of idiopathic hypersomnia; a polysymptomatic and a monosymptomatic and the effect of wake-promoting agents in these two subgroups may well be different.

Obstructive sleep apnea/hypopnea syndrome Nasal continuous positive airway pressure (nCPAP) therapy is the treatment of choice in the management of subjects with clinically significant OSAHS and when used effectively improves EDS, oxygen desaturations, quality of life as well as apneas and hypopneas. However, there have been studies that have shown that EDS can still persist despite therapy with nCPAP.96 – 98 Reasons for persisting EDS may include non-compliance, other medical comorbidities and other coexisting sleep disorders such as narcolepsy.96 The possibility of using sympathomimetic psychostimulants for treating EDS in subjects with OSAHS has been explored.96 Recent trials have investigated the potential use of modafinil as adjunct therapy in subjects with treated OSAHS but no evidence of

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Table 1 Trials in narcolepsy. First author (ref)

Study design Sample size Drugs used (dose range/day) Outcome measures

Daly et al.74 Yoss et al.75 Mitler et al.76

Case series Case series RCT CO

Billiard et al.81 Broughton et al.82 US modafinil in narcolepsy group79 US modafinil in narcolepsy group80

RCT CO RCT CO RCT RCT

29 68 16 50 75 283 271

MP (20-240 mg) MP (15–300 mg) Pl vs MA (5–60 mg) Pl vs Pl vs Pl vs Pl vs

MOD (300 mg) MOD (200–400 mg) MOD (200–400 mg) MOD (200–400 mg)

Conclusions

Patient opinion Relieves sleepiness Self-reporting of symptoms Good relief of EDS in 75% MSLT, driving simulator MA reduces SOL time and improves error rate on driving simulator MWT, subjective MOD improve SOL times and EDS MWT, subjective MOD improves SOL times and EDS MWT, MSLT, subjective MOD improves SOL times for MWT and MSLT and improves EDS MWT, MSLT, subjective MOD improves SOL times for MWT and MSLT and improves EDS

Ref, reference; EDS, excessive daytime sleepiness; MP, methylphenidate; MA, methamphetamine; MOD, modafinil; Pl, placebo; RCT, randomised-control trial; CO, crossover; SOL, sleep onset latency.

Table 2 Trials in obstructive sleep apnea/hypopnea syndrome (OSASH), treated with CPAP but continuing daytime sleepiness. First author (ref)

Study design

Sample size

Drugs used (dose range/day)

Outcome measures

Conclusions

Pack et al.71 Kingshott et al.99 Schwartz et al.100 Dinges et al.101

RCT RCT RCT then open label continuation study RCT

157 32 125 157

Pl vs MOD (200–400 mg) Pl vs MOD (200–400 mg) Pl vs MOD (200–400 mg) Pl vs MOD (200–400 mg)

MSLT, subjective MSLT, MWT, subjective Subjective Subjective, PVT

MOD improved MOD improved MOD improved MOD improved

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For abbreviations, See Table 1; PVT, psychomotor vigilance testing; CPAP, continuous positive airway pressure.

SOL times and EDS MWT SOL times only EDS EDS and PVT parameters

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they are fully investigated for other potential treatable causes.102 Others say that symptom control and quality of life are a priority with potential secondary gains (e.g. a reduction in sociologic and economic burden caused by compromised daytime function), but with the recognition that nCPAP should still remain as the mainstay of therapy.103 At present, modafinil is licensed in UK for the use in subjects with OSAHS treated with nCPAP but with persisting EDS (since December 2002). Approval (November 2003) has been granted in US and other countries such as Ireland, Germany and France have either filed an application or are in the process of doing so. The legitimate concerns of a gradual escalation in the prescription of wakefulness promoters for sleepiness, tiredness, fatigue and lack of energy has been highlighted in a recent editorial.104

application in US to the US Food and Drug administration for the usage of modafinil in shift work disorders. Although modafinil may have a potential role in this population, until adequately powered placebo-controlled trials have confirmed long-term efficacy and safety, the routine prescribing of modafinil in this group cannot be recommended ( see Tables 1 and 2 for trial data).

Shift work sleep disorders Night shift workers can experience sleepiness and potential impairment in work performance. Low doses of methamphetamine (up to 10 mg) have been shown to reduce psychomotor dysfunction as a result of shift work.105 Similarly, caffeine when compared to placebo may improve functioning during a night shift.106 As a result of the potential advantages of modafinil over sympathomimetic psychostimulants with regard to tolerance and side-effects, the role of modafinil in improving wakefulness and vigilance in shift work sleep disorders has recently been explored. Two randomized placebo-controlled trials in healthy adults,107,108 published in abstract format, have looked at the effect of 200 mg modafinil when sleep was displaced by 12 h for four consecutive day and nights. Modafinil improved alertness and neurobehavioral performance during those four nights compared to placebo. Modafinil did not affect total sleep duration or sleep architecture during the daytime sleep periods. More recently data, also in abstract form, have shown that compared to placebo, modafinil at up to 300 mg per day improved nocturnal psychomotor vigilance performance,109 reduced night-time objective and subjective sleepiness, 110 and improved quality of life111 in those subjects with chronic shift work sleep disorder. These trials are particularly important, as yet there is unresolved debate on the potential role of modafinil in healthy adults with altered sleep patterns and EDS not caused by sleep disorders such as OSAHS and narcolepsy. Cephalon, Inc has presently submitted a supplemental drug

Practice points: mechanism of action 1. Sympathomimetic drugs, such as dexamphetamine and methylphenidate, enhance monoamine neurotransmission (dopamine, noradrenaline and serotonin) by increasing release and inhibiting reuptake. 2. Caffeine is a adenosine receptor antagonist. 3. The specific mechanism of modafinil remains unclear; most likely affecting dopamine and noradrenaline neurotransmission but may involve other neurotransmitters such as histamine and serotonin.

Practice points: pharmacokinetics 1. D -isomer of amphetamine (dexamphetamine) is more potent than the L -isomer. Methamphetamine is the most potent amphetamine due to lipophilic properties and greater central nervous system penetration. The half-life of amphetamine is 12 h and is excreted unchanged in the urine. Methylphenidate is a piperidine derivative, has a shorter halflife than amphetamine (3 – 6 h) and is rapidly metabolised and excreted in the urine. It has a better therapeutic index than amphetamine. Amphetamine based drugs and methylphenidate have sympathomimetic effects and may be potentially abused or develop dependence. 2. Caffeine is a natural alkaloid. One cup of instant coffee may contain between 40 and 105 mg of caffeine; decaffeinated drinks have between 1 and 4 mg per cup. Primarily metabolised in the liver. Half-life is between 3 and 7 h.

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3. Modafinil has a half-life of 15 h and is rapidly absorbed with peak plasma concentrations reached by 4 h. Primarily metabolised by the liver, with renal elimination of metabolites. Modafinil may interact with other drugs due to its effect on the cytochrome P450 enzymes. 2. 3.

Practice points: stimulants in normal volunteers 1. Few trials have assessed the effect of amphetamines on alertness and cognitive function in normal adults. These drugs may increase sleep onset latency times but its routine use cannot be presently recommended. 2. Caffeine delays the onset of sleep and reduces total sleep time. Sleep onset latency times are prolonged. Caffeine may improve vigilance and performance testing after sleep deprivation but it is no substitute for inadequate sleep. Caffeine may be a safer and more cost-effective alternative to other psychostimulant drugs but head-to-head comparisons in well conducted trials are necessary. 3. The effect of modafinil on psychomotor function and vigilance in normal healthy volunteers is mixed. Modafinil is generally well tolerated with mild adverse effects and may improve sleep onset latency times. There may be a potential role of modafinil in emergency and military personnel but not until adequately powered trials confirm long-term safety and efficacy, can routine treatment in this group be recommended. Prescribing control is necessary as quite easily a drug such as modafinil may become promoted widely to the normal population as an ‘energy booster’ without full and proper evaluation.

Practice points: narcolepsy 1. Traditionally sympathomimetic psychostimulants have been the mainstay of treatment. There have been few

4.

5.

6.

randomised placebo-cotrolled trials, however, in this group. These drugs do improve symptoms of sleepiness and sleep onset latency times. The effect of dexamphetamine and methylphenidate are comparable. Abuse with sympathomimetic drugs is uncommon in subjects with narcolepsy. There have been no placebo-controlled trials of caffeine therapy in narcolepsy. Modafinil has shown to improve objective and subjective measures of daytime sleepiness in narcolepsy. There have been no head-to-head trials between modafinil, caffeine and/or sympathomimetic drugs looking at efficacy and long-term safety in narcolepsy. There have been reports of insufficient efficacy and discontinuation of therapy in some subjects when taking modafinil for narcolepsy. Changing therapy from sympathomimetic drugs to modafinil has been reported to be safe and feasible.

Practice points: idiopathic hypersomnia, obstructive sleep apnea, shift work sleep disorders 1. No well-conducted randomised-control data exist for the treatment of idiopathic hypersomnia with wakefulness promoting drugs. Clinical practice, however, suggests that there may still, however, be a role for such agents in this condition. 2. Growing evidence suggests that modafinil may play a role in treating persisting EDS in OSAHS. However, it is imperative that initial management of such subjects should include a mechanism to rule out poor compliance and other co-existing sleep disorders particularly sleep deprivation and narcolepsy. 3. There is also growing evidence that modafinil may have a role to play in improving vigilance and wakefulness in subjects who have shift work related sleep disorders. Well-conducted trials should confirm long-term efficacy and safety before such treatment is recommended.

Pharmacotherapy for excessive daytime sleepiness

Research agenda 1. Ongoing research in the neuroimmunohistochemisty of modafinil aims to fully elucidate the exact mechanisms of the agent as a wakefulness promoter. 2. Further adequately powered trials comparing sympathomimetic drugs, caffeine, and modafinil with each other in normal healthy adults are necessary to determine which agent is more efficacious in wakefulness promotion and enhancement of cognitive function. An advantageous long-term safety profile is necessary before any of these agents is recommended in the normal healthy population. 3. Caffeine may have a role to play in narcolepsy, particularly in maintaining wakefulness between the daily dosing of other wakefulness promoters. Trials testing this may be useful to determine this. 4. Head-to-head trials which are adequately powered are important to test which wakefulness promoter is the best agent in narcolepsy with the best safety profile and efficacy. 5. Randomised-controlled trials of wakefulness promoters are necessary in idiopathic hypersomnia to test long term safety and efficacy. 6. Large long-term studies assessing efficacy and safety are required to evaluate the use of modafinil in treating subjects with OSAHS with continual EDS despite adequate therapeutic CPAP therapy. 7. Trials of modafinil in individuals with OSAHS undergoing temporary clinically-warranted cessation of CPAP therapy may ascertain if wakefulness promoters have a role to play in such a situation. 8. On going trials with new pharmaceutical products, as wakefulness promoters, are required to determine which agents are the most efficacious and safe in treating EDS. The ‘superior’ psychostimulant should (a) effectively promote wakefulness; (b) have minimum impact on sleep; and (c) show minimal tolerance, dependence and withdrawal/rebound effect.

Acknowledgements Drs Vitiello and Grunstein have been recipients of travel education grants from Cephalon, Inc, the US

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distributor of modafinil. Dr Grunstein has been a consultant to CSL, the Australian distributor of modafinil. Dr Vitiello’s work is supported by USA PHS grants RO1-MH45186, RO1-MH53575 and KO2MH01158 to MVV. Dr Grunstein is the recipient of an NHMRC practitioner fellowship.

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