Effect of Diazepam and Fosazepam (A Soluble Derivative of Diazepam) on Sleep in Man A.N

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Effect of Diazepam and Fosazepam (A Soluble Derivative of Diazepam) on Sleep in Man A.N Br. J. clin. Pharmac. (1976), 3, 533-541 EFFECT OF DIAZEPAM AND FOSAZEPAM (A SOLUBLE DERIVATIVE OF DIAZEPAM) ON SLEEP IN MAN A.N. NICHOLSON, BARBARA M. STONE & CORAL H. CLARKE Royal Air Force Institute of Aviation Medicine, Farnborough, Hampshire 1 The effect of diazepam (5 mg and 10 mg), and fosazepam (60 mg and 80 mg), a soluble derivative of diazepam, on sleep was studied in six healthy adult males using electroencephalography for sleep measures, and analogue scales for subjective assessments of well-being and sleep quality. The effect of diazepam was limited to the night of ingestion, but the effect of fosazepam was carried over to the next night and so modified sleep for about 30 h after ingestion. 2 Effects on total sleep time were limited to the night of ingestion. There were increases with diazepam (10 mg) (P = 0.05), and with fosazepam (60 mg and 80 mg) (P = 0.001). For the night of ingestion sleep onset latencies were shortened, and awakenings were reduced by both drugs. The latency to stage 3 was shortened by fosazepam (60 mg and 80 mg) (P = 0.05). 3 The low and high dose of each drug reduced the duration (min) of stage 0 sleep (P = 0.01), but fosazepam also reduced the duration (min) of stage 1 sleep (P = 0.001), and there was an increase in stage 2 sleep (P = 0.01). With fosazepam there were carry over effects to the next night with reduction of stage 1 sleep (P = 0.05). There were no effects on the duration of stage 3, but there was evidence that stage 4 activity was reduced during the recovery night after ingestion of fosazepam (80 mg). No effects were observed on REM sleep. 4 Subjects reported an improved sense of well-being during the day after ingestion of diazepam and fosazepam, and with fosazepam they reported improved sleep. Correlations were calculated for sleep measures and subjective assessments. Introduction The suitability of an hypnotic for persons involved Diazepam may be a particularly useful hyp- in skilled activity requires information which is notic, even though it has received little attention not usually included in the evaluation of drugs. from sleep researchers except for the brief report Individuals involved in skilled activity often work of Kales & Scharf (1973). In particular, its short irregular hours, and a suitable hypnotic must be elimination half time (De Silva, Koechlin & Bader, free from residual effects on performance, and 1966), and its limited effects on performance have effective when used at times which do not prompted the present study on the effect of 5 mg coincide with usually accepted sleep periods. Little and 10 mg on sleep in man. We have also studied work has been carried out on the effectiveness of the soluble derivative of diazepam, fosazepam, hypnotics at unusual times, but several studies which, like diazepam, has a short elimination half have been concerned with residual effects on time. performance. Many hypnotics, including the benzodiazepines, lead to impaired performance after overnight ingestion (Malpas, Rowan, Joyce & Methods Scott, 1970; Bond & Lader, 1972, 1973; Borland & Nicholson, 1974, 1975a; Borland, Nicholson & The subjects were six healthy male volunteers aged Wright, 1975), but it would appear that the between 19 and 43 years. They were familiar with persistence of impaired performance after the laboratory, and with the techniques used in diazepam is more limited than that after recording sleep activity. The assessment of each nitrazepam and flurazepam hydrochloride (Bor- treatment (placebo or dose of a drug) involved 4 land & Nicholson, 1975a & b). days. For two nights the subjects slept at home 35 534 A.N. NICHOLSON, BARBARA M. STONE & CORAL H. CLARKE badly- very well. In each case a favourable a b 0t < OH3 response tended toward the 100 extreme of the P scale. CH Three ingestions of placebo, each a separate 4 day assessment, were included to determine CH3 CH2 whether any trends in sleep measures occurred during the study. Each subject received three ingestions of placebo, diazepam (5 mg and 10 mg), and fosazepam (60 mg and 80 mg). The study was double blind. Fosazepam (7-chlor - 1 - (dimethyl - phosphinylmethyl) - 5 - phenyl - 1, 3 - dihydro - 2H - ci N 1, 4 - benzodiazepin - 2 - on) is a soluble derivative of diazepam (greater than 50% at 200C) with an elimination half time of 1.8 ± 0.3 h. The formula is C18H18CIN202P (Figure 1) with a molecular weight of 360.5. Details of recording techniques, scoring of the electroencephalographic (EEG) records into sleep Figure 1 The structural formulae of diazepam and stages, and statistical analysis of the EEG measures fosazepam. The metabolism of diazepam includes and analogue scales are given in a previous paper demethylation with the formation of N-desmethyl- (Nicholson, Stone, Clarke & Ferres, 1976). diazepam (nordiazepam). A similar process occurs with fosazepam. The dimethyl-phosphinymethyl group is lost and nordiazepam is formed. Results Consistent trends were not observed in the sleep and retired at a set time between 23.00 and measures with the three separate ingestions of 23.30 h, and for the next two nights the subjects placebo, and so the values were combined. slept in the sleep laboratory. They were required The effect of diazepam (5 mg and 10 mg) and to refrain from napping and undue exercise, and to fosazepam (60 mg and 80 mg) on total sleep time, abstain from caffeine and alcohol after mid-day on number of stage shifts in the first 6 h, latency to the days which involved recordings. The sleep stage 3 and the appearance of the first REM laboratory was sound attenuated, and the period, and the REM/NREM ratio are given in temperature (18 ± 1°C) and humidity (55 ± 2%) Table 1. The effects on total sleep time were were controlled. Nine to twelve days separated limited to the night of ingestion. There were no each assessment. effects of diazepam (5 mg). With diazepam The subjects reported to the sleep laboratory (10 mg) total sleep time increased to 457.8 min 1.5 h before their set time to retire. At 0.5 h (P = 0.05). and with fosazepam (60 mg and 80 mg) before lights out subjects completed an assessment the total sleep times were 484.4 min and of their well-being related to a 100 mm analogue 514.2 min (P= 0.001). A regression equation scale. The assessment (A) was: How did you feel (P = 0.05) was fitted to the fosazepam data-total during the day? The extremes of the scale were sleep time = 412.5 + 1.245 dose (mg), and the Tired (00) and Fresh (100). Drug or placebo was dose of fosazepam equivalent to the effect of ingested on the third night only i.e. first night in 10 mg diazepam on total sleep time was 36.4 mg. the laboratory. On each occasion the subjects There were no effects of the drugs on stage shifts, ingested two idientical capsules. They were taken but the latency to stage 3 was reduced with with water at the set time between 23.00 and fosazepam (P = 0.05). The latency to the first 23.30 h (lights out). No capsules were ingested on REM period, and the REM/NREM ratio were not the fourth night i.e. second night in the sleep altered by the drugs. laboratory, and this night (recovery night) was The means for sleep onset latency, and number used to observe any residual effects of the drugs. and duration (min) of awakenings are given in In the morning the subjects were allowed to wake Tables 1 and 2, but the data were analysed using naturally, and 0.5 h after awakening completed the hypothesis that the observations were four assessments. The assessments and the distributed equally around critical values. For extremes of the 100 mm analogue scales were, B: I sleep onset latency the critical values were 20, 25 slept, very poorly - very well, C: Now I feel, very and 30 min. With placebo the hypothesis was sleepy - wide awake, D: I fell asleep, never - supported for each of these values, but with immediately, and E: After I fell asleep I slept, very diazepam the hypothesis was rejected at the DIAZEPAM AND SLEEP IN MAN 535 co C U)LOL I* ) CN N oo-- qq L r- oo00 _t CD Li.(oCu 4.) T co C) a(LO N Cuz c" (6 r- _: ( O 0- N T-- Tco (3 0 E "lb, C Cu QL 00CO) CD- 0 0 6oaco6cir- Cu LL) _(N VZ co 0 Cu'4. C.) -0 ID LO (D00 00 (N C')(N C') fiD (N r-: 00 4.0 Q (N 0 00 (N LO 00 0. *0 ._ CY N CVI lq to CN UD C) 00 CN 0 CY) LO CD 0 C'- ai c4k6 ( (-N E L _ - 0w E C.S co LID E vCu0 E ql - -0 Lc Ecn a CY 00 N1 CN a) CY OOr'-.(N'-OO6 cC i 0. (6q IL6 la U- (N o t31 00 C') C.D '-(.N -11 P. L6 Ci -: d cO itI 0 CO 0) *_*t;t (N C') 0 4. 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