Trazodone increases arousal threshold in obstructive sleep apnoea

Abstract

A low arousal threshold is believed to predispose to breathing instability during sleep. The present authors hypothesised that trazodone, a nonmyorelaxant sleep-promoting agent, would increase the effort-related arousal threshold in obstructive sleep apnoea (OSA) patients.In total, nine OSA patients, mean¡SD age 49¡9 yrs, apnoea/hypopnoea index 52¡32 events?h -1 , were studied on 2 nights, one with trazodone at 100 mg and one with a placebo, in a double blind randomised fashion. While receiving continuous positive airway pressure (CPAP), repeated arousals were induced: 1) by increasing inspired CO 2 and 2) by stepwise decreases in CPAP level. Respiratory effort was measured with an oesophageal balloon. End-tidal CO 2 tension (PET,CO 2 ) was monitored with a nasal catheter.During trazodone nights, compared with placebo nights, the arousals occurred at a higher PET,CO 2 level (mean¡SD 7.30¡0.57 versus 6.62¡0.64 kPa (54.9¡4.3 versus 49.8¡4.8 mmHg), respectively). When arousals were triggered by increasing inspired CO 2 level, the maximal oesophageal pressure swing was greater (19.4¡4.0 versus 13.1¡4.9 cmH 2 O) and the oesophageal pressure nadir before the arousals was lower (-5.1¡4.7 versus -0.38¡4.2 cmH 2 O) with trazodone. When arousals were induced by stepwise CPAP drops, the maximal oesophageal pressure swings before the arousals did not differ.Trazodone at 100 mg increased the effort-related arousal threshold in response to hypercapnia in obstructive sleep apnoea patients and allowed them to tolerate higher CO 2 levels.

Trazodone Increases the Respiratory Arousal Threshold in Patients with Obstructive Sleep Apnea and a Low Arousal Threshold

“…18 However, in that same study, a nonsignificant 9% increase in the arousal threshold to CPAP drops was noted during the trazodone night. Several factors may account for the apparent disparity between the current findings and those of the previous study, including patient selection and study design.…”

“…A standard dose of trazodone (100 mg) increases the arousal threshold to chemical (hypercapnia) but not mechanical (transient continuous positive airway pressure [CPAP] reductions) stimuli in unselected patients with OSA (with a wide range of arousal thresholds). 18 In the current detailed physiology study, we targeted the clinically relevant group of patients with OSA with low arousal thresholds, and hypothesized that trazodone would increase the arousal threshold to transient CPAP reductions. Secondary aims were to examine the effects of trazodone on pharyngeal dilator muscle activity and responsiveness, upper airway collapsibility, and breathing during sleep on an individual patient basis to provide mechanistic insight.…”

The Combination of Supplemental Oxygen and a Hypnotic Markedly Improves Obstructive Sleep Apnea in Patients with a Mild to Moderate Upper Airway Collapsibility

“…For instance, the non-anatomical traits can be targeted with oxygen or acetazolamide to reduce loop gain 21,22 or hypnotics to raise the arousal threshold. 23,24 Such monotherapies typically result in an improvement but rarely a complete resolution of OSA, because (1) the anatomical deficiency is too severe (i.e., a highly collapsible airway), (2) the effects of these therapies on individual traits are not large enough, or (3) more likely, manipulation of a single trait is not adequate to overcome the multifactorial nature of this disorder.…”

Defining Phenotypic Causes of Obstructive Sleep Apnea. Identification of Novel Therapeutic Targets

“…After stable non-REM sleep was established, progressive CPAP drops for up to 3 minutes were applied to induce varying degrees of upper-airway collapse using a modified CPAP device capable of delivering 6 20 cm H 2 O (Philips Respironics) for measurement of (1) Pcrit (6), (2) genioglossus muscle responsiveness (7), and (3) the respiratory arousal threshold (32). Steady-state loop gain was measured on a separate night also using CPAP drops (21, 27) as described below.…”