Pharmacotherapy for excessive daytime sleepiness

Abstract

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 side-effect 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.

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 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 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 side-effect 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 above-mentioned 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