Atomoxetine improves sleepiness and global severity of illness but not the respiratory disturbance index in mild to moderate obstructive sleep apnea with sleepiness

Abstract

Background and purpose

Norepinephrine reuptake inhibitors such as protriptyline have been shown to improve sleepiness in sleep apnea, with or without improvement in the respiratory disturbance index (RDI). This study was performed to evaluate whether the selective norepinephrine reuptake inhibitor atomoxetine improves sleepiness, the clinical global impression (CGI) of severity of illness, and the RDI in patients with mild to moderate obstructive sleep apnea with excessive sleepiness.

Methods

Patients aged 18–60 years with RDI (including apneas, hypopneas with desaturations and hypopneas with arousals) > 5/h sleep, apnea–hypopnea index (AHI; including apneas, hypopneas with 4% desaturations, but not apneas with arousals) < 15/h sleep, and excessive sleepiness (Epworth Sleepiness Scale [ESS] ⩾ 10) received open-label treatment with atomoxetine 40–80 mg HS for 4 weeks, with repeat polysomnography at the end of treatment. Of 20 patients screened, 17 started treatment and 15 completed treatment.

Results

ESS improved from 15.3 to 10.5 and CGI improved from 4.3 to 3.1 (both significant at p < 0.01), but there was no significant change in RDI. ESS and CGI improved in a linear fashion across the weeks of treatment. Sleep efficiency and % stage rapid eye movement (REM) sleep were decreased, and % stage 1, awakenings and wake after sleep onset were increased.

Conclusions

Atomoxetine improved sleepiness and the CGI in patients with mild to moderate obstructive sleep apnea with sleepiness. However, it did not improve the RDI.

Introduction

Obstructive sleep apnea (OSA) is a significant and common medical disorder. As defined by an apnea–hypopnea index (AHI) > 5/h sleep (including apneas and hypopneas with 4% desaturations, but not hypopneas with arousals), 9% of women and 24% of men in the 30- to 60-year age group have OSA [1], although different approaches to defining respiratory disturbances [2], different cut-off indices [3], and whether or not hypersomnolence is required [1] can lead to significant variation in prevalence rates. Mild to moderate OSA, unlike severe OSA, probably has no cardiovascular consequences, but can cause excessive daytime sleepiness. Treatment involves continuous positive airway pressure (CPAP), but compliance is lower in patients with milder sleep apnea [4]. Surgical procedures are available but do not work very well. Compliance issues limit the efficacy of oral mandibular repositioning devices [5].

There is some evidence in the literature [6], [7], [8], [9] that biogenic amine reuptake inhibitors, including protriptyline (a non-selective but predominantly norepinephrine reuptake inhibitor) and fluoxetine (a selective serotonin reuptake inhibitor) improve subjective sleepiness in OSA, with or without an improvement in the respiratory disturbance index (RDI). Brownell et al. [6] treated five patients with severe OSA with 20 mg of the norepinephrine reuptake inhibitor protriptyline in a double-blind crossover study. Four of five patients reported subjective improvement in daytime sleepiness, but there were no significant objective changes in the RDI. Brownell et al. [7] reported that improvement in hypersomnolence persisted long-term, but 5 of 9 patients discontinued protriptyline because of adverse effects (urinary retention, dry mouth, constipation, impotence or loss of interest in sex, or hair loss). Smith et al. [8] studied protriptyline in patients with much more severe OSA. Ten of 12 patients reported subjective improvement in daytime hypersomnolence, again with no significant change in RDI. There was a significant reduction in peak desaturation from 16.2% to 9.2%. Most patients were on 20 mg protriptyline. All patients reported dry mouth, and 5 of 12 patients reported other adverse effects such as constipation, hesitancy while voiding, and difficulty maintaining erection. Hanzel et al. [9] performed a crossover unblinded trial in 12 patients using fluoxetine and protriptyline. Improvement in RDI barely reached significance with each medicine (from 57/h of sleep at baseline to 34/h of sleep with fluoxetine and 33/h of sleep with protriptyline, p = 0.05 for each). All patients tolerated fluoxetine 20 mg, and only 9 of 12 tolerated protriptyline 10 mg. Thus, protriptyline was not well tolerated in these studies.

If non-selective norepinephrine reuptake inhibitors such as protriptyline improve sleepiness in OSA, then atomoxetine, a selective norepinephrine reuptake inhibitor shown to be efficacious in the treatment of attention-deficit/hyperactivity disorder [10], [11], [12], [13], may also do so, while possibly being better tolerated than protriptyline. The improvement is probably insufficient in comparison to CPAP in patients with severe obstructive sleep apnea/hypopnea syndrome. However, in patients with mild to moderate OSA, being treated because of concomitant excessive sleepiness, improvement in the daytime sleepiness may be quite beneficial, whether or not there is improvement in RDI.

Atomoxetine is well-absorbed after oral administration [14]. It is eliminated by oxidative metabolism through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway (to 4-hydroxyatomoxetine) and subsequent glucuronidation. It has a half-life of 5 h, except for 22 h in subjects with reduced CYP2D6 pathway activity (7% of whites and 1–2% of other races). Although 4-hydroxyatomoxetine is pharmacologically active, it circulates in plasma at much lower concentrations (0.1–1% of atomoxetine concentration) so that its actual pharmacological effect is minimal.

This study was designed to assess the hypothesis that atomoxetine given at bedtime is useful in the treatment of mild to moderate OSA with hypersomnia. The study objectives were to demonstrate that atomoxetine improved the RDI (apneas, hypopneas with 4% desaturations, and hypopneas with arousals/h sleep), the Epworth Sleepiness Scale (ESS) and the clinical global impression (CGI) of the severity of illness.