Independent sleep EEG slow-wave and spindle band dynamics associated with 4 weeks of continuous application of short-half-life hypnotics in healthy subjects.
OBJECTIVE
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.
Feige
B
B
Department of Psychiatry and Psychotherapy, Albert-Ludwigs-University, Freiburg, Germany. bernd.feige@gmx.net
Voderholzer
U
U
Riemann
D
D
Hohagen
F
F
Berger
M
M
D000328:Adult; D053961:Azabicyclo Compounds; D004311:Double-Blind Method; D004569:Electroencephalography / Q000187:drug effects*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D017286:Polysomnography; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D012890:Sleep / Q000187:drug effects*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology; D014229:Triazolam / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D000077334:Zolpidem
D053961:Azabicyclo Compounds; D006993:Hypnotics and Sedatives; D010879:Piperazines; D011725:Pyridines; C515050:zopiclone; D014229:Triazolam; D000077334:Zolpidem