Physostigmine May Be a New Therapy for Sleep Apnea

Laurie Barclay, MD

November 19, 2003

Nov. 19, 2003 — The cholinesterase inhibitor physostigmine may offer a new therapy for sleep apnea, according to the results of a double-blind, placebo-controlled, randomized trial published in the November issue of the American Journal of Respiratory and Critical Care Medicine.

"This predominately REM-related reduction of sleep apnea after physostigmine may provide a new treatment option if the effects are maintained in long-term studies," lead author Jan Hedner, MD, PhD, and colleagues from Sahlgrenska University Hospital in Göteborg, Sweden, says in a news release.

In this crossover-design trial, 10 men, aged 35 to 56 years, with moderate to severe obstructive sleep apnea received a seven-hour infusion of physostigmine, 0.12 µg/minute/kg, or placebo. Apnea/hypopnea index (AHI) at baseline ranged from 12 to 73 events per hour.

During physostigmine infusion, mean AHI decreased by 13.6 (95% confidence interval [CI], 2.2 to 25.1) corresponding to 21.4% (95% CI, –5.5 to 47.9), and the minimum SaO2 increased by 8.7% (95% CI, –0.3 to 17.7) corresponding to 23.2% (95% CI, 4.8 to 41.3).

Plasma concentration steady state of physostigmine was thought to be reached during the last third of the night. At that time, non-REM sleep AHI decreased by 19.2 (95% CI, 0.1 to 38.3) or 14.9% (95% CI, -43.6 to 77.7) and REM AHI decreased by 33.8 (95% CI, 13.7 to 54.0) or 67.5% (95% CI, 49.7 to 85.3).

Although mean total sleep time was reduced by 74 minutes (95% CI, 33.9 to 114.9), men with the least shortening of sleep time had the largest reduction in AHI (r = 0.73; P < .02). Physostigmine treatment was associated with a reduced nocturnal decline in heart rate. Heart rate early in the night during placebo infusion was positively correlated with reduction of REM apnea index (r = 0.69; P < .02), while body mass index was negatively correlated (r = 0.77; P < .02).

"The present study investigated sleep and breathing during single nights only, and no attempts were made to evaluate the impact of drug treatment on daytime function," the authors write. "Although REM sleep–dominated apnea is a common phenomenon, many patients will have sleep apnea across all sleep stages. As time spent in REM sleep is usually less than 25% of total sleep time, elimination of apneas during REM sleep will have a proportionately smaller impact on total AHI across the night."

The investigators recommend further studies of other anticholinesterase inhibitors, dose optimization, and whether the effect is maintained with repeated dosing.

Three of the four authors are part owners of a patent addressing the use of physostigmine in sleep-disordered breathing.

Am J Respir Crit Care Med. 2003;168:1246-1251

Reviewed by Gary D. Vogin, MD

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