from sleep researchers except for the brief report of Kales & Scharf (1973). In particular, its short

Transcription

1 Br. J. clin. Pharmac. (1976), 3, FFT OF DIAZPAM AD FOSAZPAM (A SOLUBL DRIVATIV OF DIAZPAM) O SLP I MA A.. IHOLSO, BARBARA M. STO & ORAL H. LARK Royal Air Force Institute of Aviation Medicine, Farnborough, Hampshire 1 The effect of diazepam (5 mg and 1 mg), and fosazepam (6 mg and 8 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 3 h after ingestion. 2 ffects on total sleep time were limited to the night of ingestion. There were increases with diazepam (1 mg) (P =.5), and with fosazepam (6 mg and 8 mg) (P =.1). 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 (6 mg and 8 mg) (P =.5). 3 The low and high dose of each drug reduced the duration (min) of stage sleep (P =.1), but fosazepam also reduced the duration (min) of stage 1 sleep (P =.1), and there was an increase in stage 2 sleep (P =.1). With fosazepam there were carry over effects to the next night with reduction of stage 1 sleep (P =.5). There were no effects on the duration of stage 3, but there was evidence that stage 4 activity was reduced during the revery night after ingestion of fosazepam (8 mg). o effects were observed on RM 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. orrelations were calculated for sleep measures and subjective assessments. Introduction The suitability of an hypnotic for persons involved in skilled activity requires information which is not usually included in the evaluation of drugs. Individuals involved in skilled activity often work irregular hours, and a suitable hypnotic must be free from residual effects on performance, and effective when used at times which do not incide with usually accepted sleep periods. Little work has been carried out on the effectiveness of hypnotics at unusual times, but several studies have been ncerned with residual effects on performance. Many hypnotics, including the benzodiazepines, lead to impaired performance after overnight ingestion (Malpas, Rowan, Joyce & Stt, 197; Bond & Lader, 1972, 1973; Borland & icholson, 1974, 1975a; Borland, icholson & Wright, 1975), but it would appear that the persistence of impaired performance after diazepam is more limited than that after nitrazepam and flurazepam hydrochloride (Borland & icholson, 1975a & b). 35 may be a particularly useful hypnotic, even though it has received little attention from sleep researchers except for the brief report of Kales & Scharf (1973). In particular, its short elimination half time (De Silva, Koechlin & Bader, 1966), and its limited effects on performance have prompted the present study on the effect of 5 mg and 1 mg on sleep in man. We have also studied the soluble derivative of diazepam, fosazepam, which, like diazepam, has a short elimination half time. Methods The subjects were six healthy male volunteers aged between 19 and 43 years. They were familiar with the laboratory, and with the techniques used in rerding sleep activity. The assessment of each treatment (placebo or dose of a drug) involved 4 days. For two nights the subjects slept at home

2 534 A.. IHOLSO, BARBARA M. STO & ORAL H. LARK b t OH3 a < P H ci H3 H2 Figure 1 The structural formulae of diazepam and fosazepam. The metabolism of diazepam includes demethylation with the formation of -desmethyldiazepam (nordiazepam). A similar process occurs with fosazepam. The dimethyl-phosphinymethyl group is lost and nordiazepam is formed. and retired at a set time between 23. and 23.3 h, and for the next two nights the subjects slept in the sleep laboratory. They were required to refrain from napping and undue exercise, and to abstain from caffeine and alhol after mid-day on the days which involved rerdings. The sleep laboratory was sound attenuated, and the temperature (18 ± 1 ) and humidity (55 ± 2%) were ntrolled. ine to twelve days separated each assessment. The subjects reported to the sleep laboratory 1.5 h before their set time to retire. At.5 h before lights out subjects mpleted an assessment of their well-being related to a 1 mm analogue scale. The assessment (A) was: How did you feel during the day? The extremes of the scale were Tired () and Fresh (1). Drug or placebo was ingested on the third night only i.e. first night in the laboratory. On each occasion the subjects ingested two idientical capsules. They were taken with water at the set time between 23. and 23.3 h (lights out). o capsules were ingested on the fourth night i.e. send night in the sleep laboratory, and this night (revery night) was used to observe any residual effects of the drugs. In the morning the subjects were allowed to wake naturally, and.5 h after awakening mpleted four assessments. The assessments and the extremes of the 1 mm analogue scales were, B: I slept, very poorly - very well, : ow I feel, very sleepy - wide awake, D: I fell asleep, never - immediately, and : After I fell asleep I slept, very badly- very well. In each case a favourable response tended toward the 1 extreme of the scale. Three ingestions of placebo, each a separate 4 day assessment, were included to determine whether any trends in sleep measures occurred during the study. ach subject received three ingestions of placebo, diazepam (5 mg and 1 mg), and fosazepam (6 mg and 8 mg). The study was double blind. (7-chlor (dimethyl - phosphinylmethyl) phenyl - 1, 3 - dihydro - 2H - 1, 4 - benzodiazepin on) is a soluble derivative of diazepam (greater than 5% at 2) with an elimination half time of 1.8 ±.3 h. The formula is 18H18I22P (Figure 1) with a molecular weight of Details of rerding techniques, sring of the electroencephalographic (G) rerds into sleep stages, and statistical analysis of the G measures and analogue scales are given in a previous paper icholson, Stone, larke & Ferres, 1976). Results onsistent trends were not observed in the sleep measures with the three separate ingestions of placebo, and so the values were mbined. The effect of diazepam (5 mg and 1 mg) and fosazepam (6 mg and 8 mg) on total sleep time, number of stage shifts in the first 6 h, latency to stage 3 and the appearance of the first RM period, and the RM/RM ratio are given in Table 1. The effects on total sleep time were limited to the night of ingestion. There were no effects of diazepam (5 mg). With diazepam (1 mg) total sleep time increased to min (P =.5). and with fosazepam (6 mg and 8 mg) the total sleep times were min and min (P=.1). A regression equation (P =.5) was fitted to the fosazepam data-total sleep time = dose (mg), and the dose of fosazepam equivalent to the effect of 1 mg diazepam on total sleep time was 36.4 mg. There were no effects of the drugs on stage shifts, but the latency to stage 3 was reduced with fosazepam (P =.5). The latency to the first RM period, and the RM/RM ratio were not altered by the drugs. The means for sleep onset latency, and number and duration (min) of awakenings are given in Tables 1 and 2, but the data were analysed using the hypothesis that the observations were distributed equally around critical values. For sleep onset latency the critical values were 2, 25 and 3 min. With placebo the hypothesis was supported for each of these values, but with diazepam the hypothesis was rejected at the

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4 536 A.. IHOLSO, BARBARA M. STO & ORAL H. LARK 3 min (P =.1) latency for night of ingestion, and at the 3 and 25 min (P=.1) latencies for the revery night. With fosazepam the hypothesis was rejected at the 3 min (P=.2) latency for night of ingestion and revery night. The analysis for awakenings is given in Tables 3 and 4. For number of awakenings to stage and + 1 the critical values were 9, 12 and 1 5, and for the number of awakenings to stage 1 the values were 6, 9 and 12. For duration (min) of awakenings to and 1 the values were 6, 9 and 12 min, and for + 1 the values were 1 5, 2 and 25 minutes. had little effect on reducing the number of awakenings to, 1 or + 1, except that awakenings to I and + 1 on the revery night were reduced mpared with placebo. reduced the number of awakenings to and + 1 on the night of ingestion, but did not reduce the number of awakenings during the revery night. The effect of diazepam and fosazepam on the duration (min) of awakenings was more marked. and fosazepam reduced the duration of awakenings to activity mpared with placebo, and with fosazepam the Table 3 Levels of significance for deviation from equal distribution around critical values for number of awakenings with placebo, diazepam and fosazepam Awakening (sleep stage) Treatment Placebo 1 Placebo + 1 Placebo ight of ingestion Significance levels: * P=.5; ** P=.1; *** P=.1 Revery night <9 <12 <15 <9 < 12 < 15 * * <6 <9 <12 <6 <9 <12 * <9 <12 <15 <9 < 12 < 15 * * * * * Table 4 Levels of significance for deviation from equal distribution around critical values for duration (min) of awakenings with placebo, diazepam and fosazepam Awakening (sleep stage) Treatment Placebo 1 Placebo + 1 Placebo ight of ingestion <6 <9 < 12 < 15 <2 <25 Revery night <6 <9 < 12 <6 <9 <12 <6 <9 < 12 < 15 <2 <25 Significance levels: * P =.5; ** P =.1; *** P =.1

5 DIAZPAM AD SLP I MA (A._ x en ). Q. -c m c U V Q cm,._ D m o Ul %6-... o.. o. '-- ) t qt (D a) ) D o r- L Lt o L. D 4 ).) e 4 r- LOI li oi cc; c3 - II Lf v- X) sd O-,c c6 - td 4-oIA. o (oo D 64 c4,: r L o! 14 o-( i I-D.c w- _ - 4 U@n u ool) ab 2 ),- o-o- )T- X O 6 r- o X 14 ' x -d 1t %-.1 _ ") + LU *_.2 duration of awakenings to 1 activity was reduced. There were little, if any, effects of the drugs on duration of awakenings on the revery night. The percentage of total sleep time occupied by each sleep stage is given in Table 5. Analysis of variance was used for these measures. o effects uld be demonstrated with diazepam (5 mg and 1 mg) on the night of ingestion or on the revery night. There was a reduction in percentage stage 1 after fosazepam, both 6 mg and 8 mg, (P =.1 ) with carry over effects (P =.5). There were mpensatory increases in stage 2 after fosazepam (6 mg) (P =.1) on the night of ingestion with carry over effects to the next night (P =.5). There were no effects on stage 3, but analysis of the stage showed that there was a reduction during the revery night with fosazepam (P=.1). o effects were observed with RM sleep. The effects of the drugs on duration (min) of sleep stages in the first 6 h of sleep are given in Table 6. The high variability of the data of stage indicated that an analysis of variance was not appropriate, and non-parametric analysis was used. The Friedmann two-way analysis of variance showed a significant effect, and the Wilxon Matched-Pairs Signed-Ranks test showed that diazepam and fosazepam reduced the duration of stage (P=.5), but without carry over effects to the next night. o other effects of diazepam were established. The reduction in the duration of stage 1 during the night of ingestion after fosazepam (6 mg and 8 mg) (P=.1) was carried over to the next night (P =.5). With stage 2 there were increases after fosazepam (6mg, P=.1: 8mg, P=.1, and this change was seen also during the next night (P =.5). o effects were observed with stage 3, but there was a reduction during the revery night in the duration (min) of stage with fosazepam (8 mg). o changes were observed with RM sleep. The two hourly distributions of sleep stages 1, 2 and RM are given in Table 7. o effects were observed with diazepam. With stage 1 the effects of fosazepam were spread throughout the night. An analysis of variance on the mbined data for the first two hourly interval of sleep showed an overall drug effect, and as the effects on stage 1 during the send (P=.1) and third (P=.1) intervals were limited to fosazepam, it was possible to identify that the effect during the first interval was due to this drug. There was evidence of carry over effects of fosazepam to the third interval of the next night. With stage 2 the increases with fosazepam became more pronounced as the night proceeded. o effect uld be demonstrated during the first

6 538 A.. IHOLSO, BARBARA M. STO & ORAL H. LARK (A (A._ U ) ~ D a, ) ẸX DV X LO.. (A 4 -- to g?o6 a u V o 4 au ) D Pro - 4O - Y ) r- a) Lo (6 6c -.SL D(DOO )O ) (D a 7 'IO _r LO - 4 Y _- D '- )D D U) ') ') g (D LuO_ oo (-3 a-.'.) I~ D 'i A ' '4) lq ('t v- L - D ) D 4t V v '- (8 - ',c x a._._i 4- two hourly interval, and the value in the send interval missed the least significant difference for 5% level of significance by the send place of decimals. The reduction in the duration of stage 2 in the third interval was very highly significant (P =.1). There were no changes in RM sleep. The variability of the data for stage, stage 3 and stage was such that it was not reasonable to include means of these measures as they had very little, if any, value. The means of assessments by the subjects are given in Table 8. For the night of ingestion changes in subjective assessments were limited to sleep quality, and were seen only with fosazepam. The subjects reported improved sleep. They fell asleep quicker and slept better. There were no changes in the assessments of sleep quality related to the revery night. A sense of freshness during the day after ingestion of diazepam and fosazepam was reported, but there were no changes in the assessments of wakefulness. orrelations showed that subjectively improved sleep was related to increased total sleep time (P=.1), reduced sleep onset latency (P=.1), less stage (P=.1) and stage 1 (P.1) with increased stage (P=.1). A rrelation of the assessment related to staying asleep (assessment ) emphasized increased stage (P =.1) and included reduction of stage RM (P=.5). A sense of freshness during the day (assessment A) was associated with reduced sleep onset latency (P =.5), increased latency to the first RM period (P =.1) and reduced duration of stage RM (P =.1) and a feeling of wakefulness in the morning (assessment ) was associated with reduced sleep onset latency (P=.1), less stage 1 (P=.5) and stage RM (P=.1). Discussion The present studies show that diazepam within the range 5-1 mg has restricted effects on sleep in man. Total sleep time is increased with the 1 mg dose only, and reduction of sleep onset latencies is limited. Awakenings to are reduced and there is less stage activity, but there are no other effects on sleep. On the other hand the effects of fosazepam within the range 6-8 mg are more pronounced. Though the effect on sleep onset latencies and stage activity is similar to that of diazepam, there is a marked increase in total sleep time, reduced latency to stage 3, and, in particular, reduced stage 1 (drowsy) activity. Stage 1 activity is reduced throughout the night of ingestion and during part of the revery night. There is also reduced stage activity during the revery night, but these effects are not acmpanied by

7 DIAZPAM AD SLP I MA 539 changes in latency to the first RM period or the duration and two hourly distribution of RM sleep. The effects of fosazepam on sleep raise the question whether they are related to the parent drug or to the activity of one of its metabolites, nordiazepam. has an elimination half time of around 2 h, and so effects specific to fosazepam would be seen during the night of ingestion, whereas effects related to nordiazepam, which has a half life of around two days (Tansella, Siciliani, Burti, Schiavon, Zimmermann Tansella, Gerna, Tognoni & Morselli, 1975; Tognoni, Gomeni, Maio, Alberti, Franciosi & Scieghi, 1975), would be seen more clearly during the revery night. In previous studies, icholson et al. (1976) described the carry over effects of nordiazepam to the night after ingestion. The effects were reduced stage 1 in the third 2-hourly interval, increased stage 2 and reduced stage activity. These changes were also observed with fosazepam. It is also of interest that with nordiazepam, but not with diazepam, latency to stage 3 is reduced during the night of ingestion, and this effect was also observed with fosazepam. It is, therefore, likely that the effects of fosazepam, both during the night of ingestion and the revery night, are related to nordiazepam. Substitution of the methyl group weakens the activity of the diazepam molecule (Figure 1), and the higher dose necessary to preserve an hypnotic effect leads to increased formation of the metabolite. The subjective assessments were of particular value. With both diazepam and fosazepam there was an improved sense of freshness during the day after ingestion. There were no other changes related to the ingestion of diazepam, but with fosazepam the subjects reported changes in assessments related to the quality of sleep. On the morning after ingestion they felt they had fallen asleep quicker, and had slept better during the night. The subjects did not report increased sleepiness the morning after ingestion of the drugs, but such assessments related to residual effects Table 7 ffect of diazepam and fosazepam on the 2 hourly distributions (min) from sleep onset latency (means for six subjects) of sleep stages 1, 2 and RM ight of ingestion Revery night Stage Interval /V Placebo Placebo RM oefficient of variability (/V) = s.d. x 1/mean Table 8 ffect of diazepam and fosazepam on assessments of well-being and sleep quality (means for six subjects) (The data refer to mm on a 1 mm scale) Assessment /V Placebo Placebo A B D ight of ingestion 61.6 Morning after ingestion oefficient of variability (/V) = s.d. x 1/mean Revery night Morning after revery night

8 54 A.. IHOLSO, BARBARA M. STO & ORAL H. LARK of drugs may not be reliable (Borland & icholson, 1975a). The residual effects of 5-1 mg diazepam would be limited (Borland & icholson, 1975b), but, as the activity of fosazepam may be related to that of nordiazepam, it is likely that with fosazepam residual effects on performance would be present (Tansella, Zimmermann Tansella & Lader, 1974). It is of interest that subjectively improved sleep was related only to fosazepam, even though with diazepam (1 mg) there was an increase in total sleep time, reduced sleep onset latency and stage activity. This may suggest that a subjective assessment of improved sleep is associated with marked changes in sleep patterns, and that a useful improvement in sleep may not be easily appreciated. Similar nclusions were drawn in the previous study on the effects of nordiazepam on sleep icholson et al., 1976). orrelation of sleep measures and subjective assessments proved to be a more sensitive approach to the use of assessments, and supported the findings of the previous study. Increased freshness during the day (assessment A) was associated with reduced sleep onset latency, increased latency to the first RM period and reduced duration of RM sleep. A feeling of wakefulness in the morning (assessment ) was related to reduced sleep onset latency, reduced stage 1 and RM sleep. In the previous study the rrelates of improved sleep related to falling asleep quicker and staying asleep uld not be separated, but with the present data it was found that staying asleep was related, particularly, with increased stage and reduced RM sleep. It would appear that well-being and improved sleep are associated with less desynchronized (reduced sleep onset latencies, increased latency to first RM period, decreased stage, 1 and RM activity) and more synchronized (increased total sleep time and increased stage 3 + 4) electroencephalographic activity. It is evident that the pharmalogical basis of the effect of diazepam and fosazepam on sleep differ. The hypnotic effect of diazepam in the dose range 5-1 mg depends on the activity of the parent mpound, while that of fosazepam in the dose range 6-8 mg is likely to depend more on the activity of nordiazepam. Using the regression equation for the effect of fosazepam on total sleep time the dose of fosazepam equivalent to the effect of diazepam (1 mg) would be 36.4 mg. However, the effect of diazepam (1 mg) on sleep is limited, and it is suggested that the therapeutic range for fosazepam as an hypnotic for healthy persons may be 4-6 mg. The present study suggests separate clinical indications for the use of diazepam and its soluble derivative, fosazepam. in the dose range 5-1 mg has a limited duration of action and may prove to be particularly useful as an hypnotic for persons involved in skilled activity, whereas fosazepam with its longer duration of action may prove to be useful for persons with disorders of sleep sendary to psychopathology. The single overnight administration of fosazepam uld have beneficial effects during the next day in patients with anxiety. However, the effectiveness of diazepam on sleep is limited. Though the duration of stage (awake) activity is reduced, it has little or no effect on stage 1 (drowsy) activity. and it may be necessary for an effective dose to exceed 1 mg. In this event impaired performance may arise, as though diazepam has a short half life of 2-3 h the increasing formation of nordiazepam, with its half life of around 2 days, is likely to lead to residual effects. The authors are indebted to Miss Helen M. Ferres for statistical advice, and to Mr A.S. Day and Mrs S.M. Robertson for reduction of data. The assistance of Miss P.A. larke and Miss.M. Wright in rerding the sleep electroencephalograms is gratefully acknowledged. The drugs were kindly supplied by Hoechst Pharmaceuticals. References BOD, A.J. & LADR, M.H. (1972). Residual effects of hypnotics. Psychopharmalogia (Berl.), 25, BOD, A.J. & LADR, M.H. (1973). The residual effects of flurazepam. Psychopharmalogia (Berl.), 32, BORLAD, R.G. & IHOLSO, A.. (1974). Human performance after a barbiturate (heptabarbitone). Br. J. clin Pharmac., 1, BORLAD, R.G. & IHOLSO, A.. (1975a). omparison of the residual effects of two benzodiazepines (nitrazepam and flurazepam hydrochloride) and pentobarbitone sodium on human performance. Br. J. clin. Pharmac., 2, BORLAD, R.G. & IHOLSO, A.. (1975b). Immediate effects on human performance of a 1,5-benzodiazepine (clobazam) mpared with the 1,4-benzodiazepines, chlordiazepoxide hydrochloride and diazepam. Br. J. clin. Pharmac., 2, BORLAD, R.G., IHOLSO, A.. & WRIGHT, ATHRI M. (1975). Behavioural sequelae of methaqualone in man and in the monkey (Macaca mulatta). Br. J. clin. Pharmac., 2, D SILVA, J.A.F., KOHLI, B.A. & BADR, G. (1966). Blood level distribution patterns of diazepam and its major metabolite in man. J. pharm. Sci., 55,

9 DIAZPAM AD SLP I MA 541 KALS, A. & SHARF, M.B. (1973). Sleep laboratory and clinical studies of the effects of benzodiazepines on sleep. In The Benzodiazepines, eds Garattini, S., Mussini,. & Randall, L.O. pp ew York: Raven Press. MALPAS, A., ROWA, A.J., JOY,.R.B. & SOTT, D.F. (197). Persistent behavioural and electroencephalographic changes after single doses of nitrazepam and amylobarbitone sodium. Br. med. J., 2, IHOLSO, A.., STO, BARBARA M., LARK, ORAL H. & FRRS, HL M. (1976). ffect of -desmethyldiazepam and a precursor, potassium clorazepate, on sleep in man. Br. J. clin. Pharmac., 3, TALLA, M., ZIMMRMA TALLA, h. & LADR, M. (1974). The residual effects of - desmethyldiazepam in patients. Psychopharmalogia (Berl.), 38, TALLA, M., SIILIAI, O., BURTI, L., SHIAVO, M., ZIMMRMA TALLA, h. GRA, M., TOGOI, G. & MORSLLI, P.L. (1975). -desmethyldiazepam and amylobarbitone sodium as hypnotics in anxious patients. Plasma levels, clinical efficacy and residual effects. Psychopharmalogia (Berl.), 41, TOGOI, G., GOMI, R., MAIO, D.D, ALBRTI, G.G., FRAIOSI, P. & SIGHI, G. (1975). Pharmakinetics of -desmethyldiazepam in patients suffering from insomnia and treated with nortriptyline. Br. J. clin. Pharmac., 2, (Received October 22, 1975)