Description of the condition
Excessive daytime sleepiness (EDS) is characterised by an increase in fatigue during the day despite adequate rest at night. EDS affects approximately 20% of the US population (Pagel 2009); in those affected, EDS is a cause of significant morbidity and decreased health-related quality of life (Briones 1996; Vignatelli 2004; Wu 2012). Daytime sleepiness can be particularly hazardous for professional drivers (Masa 2000). It also impairs physicians' performance (Chen 2008). EDS is a manifestation of many different aetiologies including insufficient sleep, sleep-related breathing disorders, periodic limb movements, primary disorders of alertness such as narcolepsy and idiopathic hypersomnia, and general medical conditions including diabetes, dementia, parkinsonism, depression. Increased daytime sleepiness can also be a consequence of consuming other drugs including, sedatives, antihistaminics and neuroleptics (Guilleminault 2001; Harris 2012).
Over the years, scholars have developed various tools to measure sleepiness, though each tool suffers from its own limitations. These include subjective outcome measures such as the Stanford Sleepiness Scale and the Epworth Sleepiness Scale (ESS) (Hoddes 1972; Johns 1991), and the more objective tests such as the Multiple Sleep Latency Test (MSLT) and the Maintenance of Wakefulness Test (MWT) (Carskadon 1986; Doghramji 1997).
Treatment of EDS depends upon the underlying aetiology. For example, there is strong evidence that treatments such as continuous positive airway pressure can reduce fatigue caused by moderate and severe obstructive sleep apnoea (Giles 2006). Other treatments target the sleepiness itself. Classically, psychostimulants such as amphetamines and methylphenidate have been used to relieve symptoms of daytime sleepiness; however, these drugs have a high potential for abuse (Harris 2012).
Description of the intervention
Modafinil (2-[(diphenylmethyl)sulfinyl]acetamide) is a novel eugeroic drug that acts as a 'wakefulness-promoting agent'. Chemically, modafinil is a racemate comprising of 50:50 mixture of the R- and S-enantiomers of which the R-enantiomer (armodafinil) is the longer lived enantiomer. Armodafinil and adrafinil (prodrug of modafinil) are separately available commercial congeners. The usual dosage range for oral administration is 200 to 400 mg/day.The clinical pharmacokinetics is dose independent over a dose range of 200 mg/day to 800 mg/day (Wong 1999).The maximum plasma concentration is reached in two to four hours and the steady state concentration in two to four days after oral administration (Robertson 2003). The elimination half-life of modafinil is 10 to 15 hours, which is similar to its R-enantiomer, while the S-enantiomer has a much shorter half-life. The drug is metabolised mainly in the liver and the metabolites are excreted in urine (Wong 1999; Robertson 2003).
Modafinil is currently approved by the US Food and Drug Administration (FDA) for use in excessive sleepiness associated with narcolepsy, shift work disorder and obstructive sleep apnoea (Valentino 2007). However, the 2010 recommendations of the European Medicines Agency (EMA) advise its use only in the treatment of narcolepsy (EMA 2011).
Its efficacy has been investigated in a wide variety of conditions, including Parkinson's disease (Högl 2002; Ondo 2005; Van Vliet 2006), cocaine dependence (Dackis 2005), schizophrenia (Turner 2004b), Huntington's disease (Blackwell 2008), attention-deficit/hyperactivity disorder (Turner 2004a; Boellner 2006; Lindsay 2006), fatigue (Rammohan 2002; Zifko 2002; Fava 2005), spastic cerebral palsy (Hurst 2002), and myotonic dystrophy (MacDonald 2002; Orlikowski 2009).
Modafinil has been shown to decrease food intake and has been reported to cause weight loss ((Makris 2004; Henderson 2005; Perez 2008). Several studies also report that modafinil enhances cognition in healthy volunteers and in people with chronic schizophrenia (Turner 2003; Turner 2004b; Müller 2013), attention deficit hyperactivity disorder (Turner 2004a), and Huntington's disease (Blackwell 2008).
In comparison to alternative medications such as amphetamines, modafinil is generally considered as a safe drug with minimal or negligible adverse effects. However, study participants have discontinued its use due to serious adverse consequences such as headache, nausea, anxiety, dizziness, insomnia, chest pain, and nervousness. Other commonly reported harmful effects include, rhinitis, diarrhoea, back pain, anxiety, dizziness and dyspepsia. In people with psychiatric history, some have developed mania, delusions, hallucinations, and suicidal ideation. Post marketing surveillance has reported cases of multi-organ hypersensitivity reactions, life-threatening rashes and Stevens-Johnson Syndrome (EMA 2011; Modafinil 2013).
Modafinil is relatively affordable and is available in different brand names (such as Provigil® and Modalert®) from different manufacturers. The retail price ranges from about USD$2 to USD$10 per pill, depending upon the country and manufacturer (Everydayhealth 2011).
How the intervention might work
Though the exact mechanism of action remains unclear, modafinil is known to act in ways, and at sites, which are distinct from the classical 'stimulants' such as amphetamines (Lin 1996; Engber 1998). Modafinil has been shown to act through a variety neurotransmitters (dopamine, histamine, noradrenaline, gamma-aminobutyric acid (GABA), serotonin) at various locations especially in the hypothalamus (Tanganelli 1995; Ferraro 2000; Scammell 2000; De Saint 2001; Gallopin 2004; Dopheide 2007; Ishizuka 2010). In recent years, researchers have explored modafinil's neuroprotective actions. These properties might be relevant to its wakefulness-promoting activity (Xiao 2004; Gerrard 2007).
Modafinil may produce age-dependent effects, especially in relation to neurological outcomes, probably due to differences in baseline activity levels, metabolism and other age-related changes (McFadden 2010). Underlying causative conditions and point of follow-up also may cause differences in outcomes.
In comparison to other stimulants, modafinil appears to be free from most of the undesirable effects. It is of limited abuse potential as individuals are unlikely to become dependent on it. However, it induces hepatic enzymes and as a result it can interact with several other drugs including contraceptives, antiepileptic drugs, and antidepressants. Furthermore, it has the potential to harm to the foetus when taken during pregnancy (Valentino 2007).
Why it is important to do this review
Studies suggest that modafinil (1) has specific use in sleep disorders, (2) may potentially have several neurological benefits and (3) be of use in several neurological disorders (Valentino 2007; Repantis 2010). It is considered to be a safe drug, but concrete information regarding this is limited, especially with harms and long-term outcomes. A Cochrane systematic review evaluated the use of modafinil to relieve EDS in people with myotonic dystrophy (Annane 2009). The review concluded that there is low quality evidence available that suggests modafinil does not significantly improve results from MWT but that it does significantly improve the results from ESS. A non-Cochrane systematic review evaluated the role of modafinil in narcolepsy and concluded that it is effective in terms of reducing daytime sleepiness (Golicki 2010). We wish to undertake this review in order to estimate the effect of modafinil from randomised controlled trials, including quasi-randomised trials in people with EDS, across underlying disease conditions.