Progress in Neuro-Psychopharmacology and Biological Psychiatry
Placebo and modafinil effect on sleepiness in obstructive sleep apnea☆
Introduction
Obstructive sleep apnea syndrome (OSAS) is a relatively common condition and is estimated to affect 2 to 4% of middle-aged adults (Young et al., 2002). OSAS is a chronic disorder characterized by repeated episodes of complete or partial collapse of the upper airway during sleep. In most instances these episodes result in hypoxia and microarousals from sleep that last only seconds and patients are rarely aware of. The consequent sleep fragmentation leads to excessive daytime sleepiness (EDS) (AASM, 1999). Patients also complain of unrefreshing sleep and impairment in cognitive tasks such as concentration and memory (Endeshaw, 2006, Heitman and Flemons, 2001). The EDS caused by OSAS is one of the main features responsible for occupational and automobile accidents and also contributes to social engagement impairment (Krieger et al., 2002).
Continuous positive airway pressure (CPAP) is the treatment of choice for patients with OSAS and the most effective method to reduce EDS (Heitman and Flemons, 2001). However, some patients who are regular CPAP users continue to complain of residual EDS even when other causes of somnolence are ruled out (sleep deprivation, other sleep disorders, alcoohol and hypnotic drugs use) (Guilleminault and Philip, 1996).
Modafinil, a [2-(diphenyl-methyl)-sulfinyl-2 acetamide] derivative, is a central stimulant of post-synaptic alpha-1 adrenergic receptors (Ferraro et al., 1996a, Ferraro et al., 1996b). Differently from amphetamines, this medication acts in more specific brain areas (Ferraro et al., 2000, Ferraro et al., 1999, Ferraro et al., 1996a, Ferraro et al., 1996b, Scammell et al., 2000) and promotes an increase in the alertness in a selective way. Mood changes are infrequent and modafinil does not lead to sleep rebound seen with amphetamines after withdrawal. Treatment with modafinil has not shown development of dependence and tolerance (Jasinski, 2000, Jasinski and Kovacevic-Ristanovic, 2000).
The use of modafinil is currently established for narcolepsy and idiopathic hypersomnia (Beusterien et al., 1999, Guilleminault et al., 2000, Jasinski and Kovacevic-Ristanovic, 2000, Schwartz et al., 2003, US Modafinil In Narcolepsy Multicenter Study Group, 2000). In addition, studies involving patients with neurological, psychiatric and other disorders associated with fatigue and hypersomnolence also show benefits with this drug (Damian et al., 2001, Hogl et al., 2002, Rammohan et al., 2005, Talbot et al., 2003).
Studies with both animals (Panckeri et al., 1996) and humans with OSAS (Arnulf et al., 1997) using modafinil have demonstrated increase in vigilance without changes in the sleep pattern (US Modafinil in Narcolepsy Multicenter study group, 2000). One of the main concerns regarding the chronic use of amphetamine is the increase of cardiovascular side effects. The use of 300 mg modafinil in OSAS patients has shown only a discrete increase of blood pressure measurement after mental stress and physical exercise (Heitmann et al., 1999).
Previous studies have evaluated the effect of modafinil on residual EDS in OSAS patients under effective CPAP treatment (Black and Hirshkowitz, 2005, Dinges and Weaver, 2003, Kingshott et al., 2001, Pack et al., 2001, Schwartz et al., 2003).
Some of them have found reduction of EDS only with objective tests (Kingshott et al., 2001), others with subjective tests (Schwartz et al., 2003) and others still with both tests (Black and Hirshkowitz, 2005, Pack et al., 2001, Roth et al., 2006). In spite of the use of placebo in parallel groups in these trials, we suppose that placebo effect could have persisted in modafinil groups after randomization and be responsible for these different results. In order to test our hypothesis, that is, the placebo effect during the use of modafinil, we submitted all patients to a placebo period before randomization (to drug and placebo groups).
Section snippets
Study design
This was a prospective, randomized, double-blind, parallel groups and placebo-controlled study conducted at the Universidade Federal de São Paulo (UNIFESP) with the approval of the local Ethical Committee. All participants provided written informed consent. The study included a 30-day screening period with CPAP therapy, a 7-day screening and baseline evaluation (T1). Following baseline evaluation, all subjects were instructed to take two placebo capsules at 8 AM and one placebo capsule at noon
Results
Out of the final sample of 22 patients, two dropped-out: one of them because he had lost weight and the other because of headaches (both of them belonged to modafinil group). Twenty patients completed the study, 9 in the modafinil group and 11 in the placebo group. Their characteristics are presented in Table 1. The polysomnographic results (with CPAP) and the CPAP use in the inclusion period (T1) are shown in Table 2.
After all the patients had been screened and the regular and appropriate CPAP
Discussion
This study replicates many but not all of the findings reported in previous double-blind modafinil/placebo trials in OSA (Black and Hirshkowitz, 2005, Dinges and Weaver, 2003, Kingshott et al., 2001, Pack et al., 2001, Schwartz et al., 2003). We used a different design from all other trials. At the end of the recruitment period, all subjects participating in the trial were submitted to a single blinded 7 day placebo period. The existence of the placebo effect with any intervention is well
Conclusion
In summary, our study confirms that modafinil used adjunctively with CPAP therapy improves subjective daytime sleepiness in patients with OSAS who were regular users of CPAP therapy but still experienced sleepiness. Moreover, it could help in the improvement of objective measures of behavioral alertness and reduce functional impairments. The usefulness of a blinded placebo period for systematic investigation of placebo role in studies based on subjective response is a point that should be
Acknowledgements
This study was supported by a grant from Laboratoire Lafon (France) (Dr. Serge Lubin) to Christian Guilleminault.
The Associação Fundo de Incentivo à Psicofarmacologia (AFIP) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)-CEPID supported by financial funds to conduct this study.
References (38)
- et al.
Effects of modafinil on sustained attention performance and quality of life in OSA patients with residual sleepiness while being treated with nCPAP
Sleep Med
(2003) - et al.
The vigilance promoting drug modafinil decreases GABA release in the medial preoptic area and in the posterior hypothalamus of the awake rat: possible involvement of the serotonergic 5-HT3 receptor
Neurosci Lett
(1996) - et al.
The vigilance promoting drug modafinil increases dopamine release in the rat nucleus accumbens via the involvement of a local GABAergic mechanism
Eur J Pharmacol
(1996) - et al.
The vigilance promoting drug modafinil increased extracellular glutamate levels in the medial preoptic area and the posterior hypothalamus of the conscious rat: prevention by local GABAA receptor blockade
Neuropsychopharmacology
(1999) - et al.
Amplification of cortical serotonin release: a further neurochemical action of the vigilance-promoting drug modafinil
Neuropharmacology
(2000) - et al.
Comparison of therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised prospective parallel trial
Lancet
(1999) - et al.
Megestrol acetate in a moderate dose for the treatment of malnutrition-inflammation complex in maintenance dialysis patients
J Ren Nutr
(2005) - et al.
Effects of armodafinil in the treatment of residual excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome: a 12-week, multicenter, double-blind, randomized, placebo-controlled study in nCPAP-adherent adults
Clin Ther
(2006) - et al.
Maintenance of wakefulness test and multiple sleep latency test. Measurement of different abilities in patients with sleep disorders
Chest
(1992) - et al.
Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea: a 12-week, open-label study
Chest
(2003)
Reduction in excess daytime sleepiness by modafinil in patients with myotonic dystrophy
Neuromuscul Disord
Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research
Sleep
Atlas Task Force — EEG arousals: scoring rules and examples
Sleep
Atlas Task Force — recording and scoring leg movements
Sleep
Modafinil in obstructive sleep apnea–hypopnea syndrome: a pilot study in 6 patients
Respiration
Health-related quality of life effects of modafinil for treatment of narcolepsy
Sleep
Modafinil for treatment of residual excessive sleepiness in nasal continuous positive airway pressure-treated obstructive sleep apnea/hypopnea syndrome
Sleep
Modafinil for excessive daytime sleepiness in myotonic dystrophy
Neurology
Clinical characteristics of obstructive sleep apnea in community-dwelling older adults
J Am Geriatr Soc
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Supported/Funding: Associação Fundo de Incentivo à Psicofarmacologia (AFIP); Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)-CEPID; Laboratoire Lafon.