Placebo and modafinil effect on sleepiness in obstructive sleep apnea.
BACKGROUND
Previous studies have evaluated the effect of modafinil on residual excessive daytime sleepiness (EDS) in patients with obstructive sleep apnea syndrome (OSAS) under effective CPAP treatment. Even though those trials also used placebo groups, we suppose that the placebo effect might influence the patients' response to modafinil.


METHODS
Twenty sleepy patients with OSAS under CPAP treatment were selected. All of them had Epworth Sleepiness Scale (ESS) >10. Following baseline evaluation (T1), all subjects were instructed to take placebo for 7 days. After this single-blind placebo phase and second evaluation (T2), patients were randomly allocated to placebo or modafinil treatment for 21 days in a double-blind protocol. Patients underwent a final evaluation (T3) on the last day of drug intake. The evaluations at T1, T2 and T3 consisted of: medical and laboratory examinations, nocturnal polysomnography, ESS, maintenance of wakefulness test (MWT) and complex reaction time (CRT-NY). In addition, in T2 and T3 the change of illness severity scale (CGI-C) and the evaluation of quality of life (SF-36) were applied.


RESULTS
The comparison between the two groups during the three periods studied, showed the following results: in the modafinil group, ESS score did not change during the initial placebo period, but there was a significant reduction during the modafinil treatment period (p=0.0006); in the placebo group a significant reduction occurred during the initial placebo period (p=0.05), and no further change was observed in the treatment (placebo) period. A significant difference was found between the two groups after the placebo period (T2) (p=0.02). Three patients (33%) of the modafinil group and 9 patients (81%) of the placebo group were classified as placebo-responsive (X2: p=0.039). In the treatment period, reaction time was significantly reduced in the modafinil group compared to the placebo group (p<0.02). There was a trend toward improvement in overall clinical condition and also in some domains of SF-36 in the modafinil group.


CONCLUSIONS
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 considered in this type of drug trial.
Bittencourt
Lia Rita A
LR
Sleep Medicine and Biology Discipline, Psychobiology Department, Universidade Federal de São Paulo, Napoleão de Barros 925, São Paulo 04024-002, SP Brazil. lia@psicobio.epm.br
Lucchesi
Ligia M
LM
Rueda
Adriana D
AD
Garbuio
Silvério A
SA
Palombini
Luciana O
LO
Guilleminault
Christian
C
Tufik
Sergio
S
D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D015897:Comorbidity; D045422:Continuous Positive Airway Pressure / Q000379:methods; D006970:Disorders of Excessive Somnolence / Q000188:drug therapy* / Q000453:epidemiology / Q000628:therapy; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006304:Health Status; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077408:Modafinil; D015990:Placebo Effect; D010919:Placebos; D017286:Polysomnography; D011446:Prospective Studies; D011788:Quality of Life / Q000523:psychology; D011930:Reaction Time; D016037:Single-Blind Method; D020181:Sleep Apnea, Obstructive / Q000188:drug therapy / Q000453:epidemiology* / Q000628:therapy; D011795:Surveys and Questionnaires; D016896:Treatment Outcome
D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D010919:Placebos; D000077408:Modafinil