Independent sleep EEG slow-wave and spindle band dynamics associated with 4 weeks of continuous application of short-half-life hypnotics in healthy subjects

Abstract

Objectives: Habituation and adverse withdrawal reactions after prolonged medication with benzodiazepine (BZ) hypnotics are believed to play a role in dose escalation and the development of dependence.Methods: In the current sleep EEG study in 43 healthy male subjects, the known property of BZ- and similar hypnotics to change the NREM sleep EEG spectrum is utilized for a detailed quantitative analysis across 4 weeks of continuous medication and a subsequent two-week withdrawal period. The BZ hypnotic triazolam and the non-BZ hypnotics zopiclone and zolpidem, differing in pharmacological properties and reported adverse effects, were examined in parallel to a placebo group.Results: Reliably occurring spectral effects in the sleep stage 2 EEG were found in the 3 frequency bands 0.8–5 Hz, 5–10 Hz and 10–15 Hz. All 3 hypnotics showed the typical ‘benzodiazepine signature’, a 10–15 Hz increase and lower-frequency (<10 Hz) suppression relative to the preceding drug-free night. However, these effects developed differently across the first medication night, across the 4 medication weeks and after withdrawal: While the 5–10 Hz effect covaried with the blood presence of the drugs as estimated from the known plasma half-lifes, showed habituation and a rebound after withdrawal, the 10–15 Hz power increased across medication days and showed no rebound. Effects in the 0.8–5 Hz band in the first medication night correlated with the decrease of sleep efficiency at later withdrawal for triazolam and zolpidem.