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Generic name Onset of action Half-life (h) Active metabolites Benzodiazepine anxiolytics Alprazolam Fast to intermediate 12 15 No Chlordiazepoxide Intermediate 8 28 Yes Clonazepam Slow 18 50 No Dipotassium clorazepate Fast 48 Yes Diazepam Fast 20 50 Yes Estazolam Fast 10 24 No Lorazepam Intermediate 10 20 No Oxazepam Intermediate to slow 5 20 No Prazepam Slow 70 Yes Temazepam Intermediate to slow 9.5 12 No Benzodiazepine hypnotics Triazolam Fast 1.7 5 No Midazolam Fast 1 4 No Brotizolam Fast 5 Yes Loprazolam Fast 5 8 Yes Lormetazepam Fast 12 20 No Flunitrazepam Fast 19 22 Yes Flurazepam Fast 40 114 Yes Nitrazepam Fast 24 Yes Quazepam Fast 25 41 Yes Non-benzodiazepine hypnotics Zolpidem Fast 1.5 4.5 No Zopiclone Fast 3 6 Yes Zaleplon Fast 1 No
Drug Half-life PSG in healthy individuals ACP effectsa Rebound and residual effectsb Latency Total sleep time Delta sleep REM Sleep quality Comments Benzodiazepine hypnotics Triazolam Short c <pathol. ACP rate Rebound insomnia ! ! ! ! ! ! stage 2 Midazolam Short c c Rebound insomnia ! ! ! ! ! !stage 2 Brotizolam Short c c Rebound insomnia ! ! ! ! ! ! stage 2 Loprazolam Intermediate c c Rebound insomnia ! ! ! ! ! ! stage 2 Lormetazepam Intermediate c c Rebound insomnia ! ! ! ! ! !stage 2 Flunitrazepam Intermediate ! slow waves c < latencies in MSLT. No rebound ! ! ! ! ! !stage 2 Flurazepam Long ! slow waves c < latencies in MSLT. No rebound ! ! ! ! ! ! stage 2 Nitrazepam Long c c < latencies in MSLT. No rebound ! ! ! ! ! !stage 2 Quazepam Long c c < latencies in MSLT. No rebound ! ! ! ! ! ! stage 2 Non-benzodiazepine hypnotics Zolpidem Short No or few changes <pathol. ACP rate No rebound or residual effects ! ! ! !! !! ! waking Zopiclone Short No or few changes <pathol. ACP rate No rebound ! ! ! !! !! ! waking Zaleplon Short No changes c No rebound or adverse effects ! ! ! ! c c
a Alternating cyclic pattern: pseudo-periodic activation phenomenon of slow sleep characterised in the EEG by limited duration waves that can appear spontaneously or after waking stimuli. <ACP means that these compounds decrease the ACP index. b Confirmed by the multiple sleep latency test ( MSLT). < = decreases. c No conclusive data.
Drug/chemical class (half-life) Hangover effect Rebound insomnia Tolerance Dependence/ abuse Comment Benzodiazepine hypnotics Triazolam/Benzodiazepine (short: <6h) 0 +++ +++ ++ Triazolam may have fewer respiratory depressive effects than other benzodiazepines. No more than 0.25mg should be administered to avoid increasing adverse CNS effects Midazolam 0 +++ +++ ++ Brotizolam 0 +++ +++ ++ Loprazolam/Benzodiazepine (medium: 6 24h) +/++ ++/+++ ++/+++ ++ More marked hangover effect at higher doses Lormetazepam +/++ ++/+++ ++/+++ ++ Flunitrazepam +/++ ++/+++ ++/+++ ++ Flurazepam/Benzodiazepine (long: >24h) +++ 0b + ++ Avoid in elderly, since increased risk of falls and fractures Nitrazepam +++ 0b + ++ Quazepam +++ 0b + ++ Non-benzodiazepine hypnotics Zolpidem/Imidazopyridine (short) 0 + 0 0 Hangover effect and tolerance can occur with supratherapeutic doses and/or very long-term treatment Zopiclone/Cyclopyrrolone (short) ++ ++ ++ + Doses >7.5mg increase adverse effects without improving efficacy Zaleplon/Pyrazolopyrimidine (short) c 0 after 5 wks c No sedation seen on following day, 5 6.5h after 10mg taken at midnight, with no significant psychomotor changes
a Refer also to tableIV and section 4.6. b With long half-life benzodiazepines, rebound insomnia is uncommon and appears late. c No conclusive data are available in the consulted literature.
0 = no effect; + = mild effect; = no tolerance observed until that time; ++ = moderate effect; +++ = severe effect.
Drug Memory Psychomotor performance Night of administration Following day Short-acting benzodiazepine hypnotics[76] ! !! ! Intermediate-acting benzodiazepine hypnotics[76] ! ! or !! ! Long-acting benzodiazepine hypnotics[76] ! ! ! Zolpidem[51] !! or ! !! !! Zopiclone[50,51,66] ! !! !! or ! Zaleplon[40] !! !! !!
! = worsening; !! = no significant effects.
Drug COPD and compensated restrictive pulmonary diseases Treated OSAS Cardiac function Short-acting benzodiazepine hypnoticsa ! ! ? Intermediate-acting benzodiazepine hypnotics ! ! ? Long-acting benzodiazepine hypnotics ! ! ? Zolpidem !! !! !! Zopliclone !! !! ? Zaleplon ?!! ?!! ?
a In mild to moderate stable diseases, triazolam does not impair oxygen saturation
COPD = chronic obstructive pulmonary disease; OSAS = obstructive sleep apnoea syndrome; ! = Worsening; ? = inconclusive or missing data; !! = no changes.
Drug Efficacy Untoward effects or complications Tolerability Benzodiazepine hypnotics Good ! Good Zolpidem Good !! Good Zopiclone Good !! or ! Good Zaleplon Good !! Good
! = increased; !! = no significant effects.
ICSD ICD-9 ICD-10 DSM-IV name code name code name code name code 1a. Adjustment sleep disorder 307.41-0 Transient disorder of initiating or maintaining sleep 307.41 Non-organic insomnia F51.0 1b. Psychophysiological insomnia 307.42-0 Persistent disorder of initiating or maintaining sleep 307.42 Non-organic insomnia F51.0 Primary insomnia 307.4 Other insomnia 780.52 Disorder of initiating or maintaining sleep G47.0 5b. Central sleep apnoea syndrome 780.51-0 Insomnia with sleep apnoea 780.53 Sleep apnoea G47.3 Breathing-related sleep disorder 780.5 5c. Central alveolar hypoventilation syndrome 780.51-1 5f. Altitude insomnia 289 Altitude insomnia 289 Other altitude effects T20.2 7a. Short sleeper 307.49.0 8e. Fatal familial insomnia 337.9 Fatal familial insomnia 337.9 Other degenerative diseases G31 Insomnia due to ...indicate medical pathology 780.X 11. Idiopathic insomnia 780.52.7 Other insomnia 780.52 Disorder of initiating or maintaining sleep G47.0 Primary insomnia 307.4