Daytime Sleepiness as a Criterion in Hypnotic

Sleep, 6(2):156-163 © 1983 Raven Press, New York

Daytime Sleepiness as a Criterion in Hypnotic Medication Trials: Comparison of Triazolam and Flurazepam *Donald Bliwise, *Wesley Seidel, tIsmet Karacan, *Merrill Mitler, §Thomas Roth, §Frank Zorick, and *William Dement *Sleep Disorders Centers, Stanford University School of Medicine, Stanford, CalzJornia; tDepartment of Psychiatry, Baylor College of Medicine, Houston, Texas; :f:Long Island Research Institute, State University of New York at Stony Brook, Stony Brook, New York; and §Henry Ford Hospital Sleep Disorders and Research Center, Detroit, Michigan, U.S.A.

Summary: Sleep laboratory hypnotic medication trials typically determine efficacy by examining changes in polysomnographically recorded sleep. We introduce the use of daytime sleepiness, as assessed by the Multiple Sleep Latency Test (MSLT), as a criterion for daytime functioning in such trials. Two benzodiazepine hypnotics, triazolam (0.5 mg) and flurazepam (30 mg), with short and long half-lives respectively, were compared in a multicentered, doubleblind crossover study. Results indicated these medications had virtually indistinguishable nocturnal effects, but differed dramatically during the day. Flurazepam decreased sleep latency on the MSLT, whereas triazolam did not. These results could indicate that daytime sleepiness is a concomitant effect of flurazepam. Key Words: Benzodiazepines-Sleeping pills-Carryover-Sleepiness-Insomnia.

Sleep laboratory hypnotic medication trials typically determine efficacy by examining changes in polysomnographically recorded nocturnal sleep. Assessment of subsequent day functioning following hypnotic medication ingestion is also important as a criterion measure (1,2). Subsequent day functioning can reveal potential hazards of a medication, but it is conceivable, at least in insomniacs, that daytime functioning might even improve following a beneficial night of sleep (2), though a recent review found no evidence for this speculation (1). A wide range of tasks have been used to assess daytime functioning following hypnotic medication ingestion. With the exception of psychomotor speed, tests of higher cognitive functioning did not show consistent decrements (1). Without jUdging the validity of these performance measures, it appears to us that the familiar reports of grogginess, fatigue, hangover, and loginess expressed by patients receiving some seAccepted for publication February 1983. Address correspondence and reprint requests to Donald L. Bliwise, Ph.D., Stanford Sleep Research Center, Stanford University Medical School, Stanford, CA 94305, U.S.A.

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TRIAZOLAM AND FLURAZEPAM IN INSOMNIA

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dative-hypnotic medications have been overlooked. Some patients may refer to changes in their daytime functioning in terms of impairment in accuracy or speed of their behaviors. However, it is our beliefthat a far greater number describe their experiences with medications using terms such as those above. These words convey an intrusion of sleep-related phenomena into the waking state. Quantifying feelings of sleepiness presents a psychometric dilemma. A subjective sleepiness scale was introduced (3), but has fallen into disfavor because of inconsistent relationships to polysomnographic measures (4) and state dependency (5).. The Multiple Sleep Latency Test (MSLT), which defines sleepiness as the tendency to fall asleep, as measured polysomnographically at a series of fixed intervals throughout the day (6), can be sensitive to experimental manipulations which could increase daytime sleepiness (e.g., lack of nocturnal sleep (7), total sleep deprivation (8)) or decrease daytime sleepiness (e.g., nocturnal sleep extension (9)). These experimental data do not eliminate the possibility that variables such as anxiety or instructional set (10,11) could affect polysomnographically defined sleep latency. However, they do validate the MSLT as a sensitive measure of sleepiness in some situations. The present double-blind, crossover study assesses polysomnographically defined daytime sleepiness following ingestion of two benzodiazepine hypnotics, triazolam (T) and flurazepam (FLZ). Both medications are known to have significant hypnotic properties (12,13), but differ in pharmacokinetic effects. Triazolam, with a rapid absorption half-life of 1.5 to 5 h (14), contrasts with flurazepam, whose principal metabolite, Ndesalkylflurazepam has a half-life of 40 to 150 h (15). As such, we expected different effects on daytime sleepiness with each. METHODS Subjects Subjects were 24 insomniacs diagnosed as disorders of initiating and maintaining sleep (DIMS), persistent psychophysiological type; DIMS, without objective findings; or DIMS, with symptom and personality disorders, in accordance with the nomenclature and criteria of the Association of Sleep Disorders Centers (16,17). Diagnoses were made from initial interview, medical history, physical examination, and Sequential Multiple Analysis 12. A night of pre study polysomnography ruled out sleep-related seizures, sleep apnea, or nocturnal myoclonus. Pregnant women, nursing mothers, persons with known sensitivity to benzodiazepines or concomitant medications, and persons with a history of drug or alcohol abuse were excluded. In addition, we excluded persons who had taken long-acting psychoactive drugs, such as reserpine, monoamine oxidase inhibitors, or phenothiazines, within 30 days of the start of the study. All hypnotics and anxiolytics were suspended at least 7 days before the start of the study. The four participating institutions (Sleep Disorders Centers at Stanford University, Baylor University, Henry Ford Hospital, State University of New York at Stony Brook) each ran six subjects. All procedures were standardized across institutions. Polysomnograms were scored blind to condition. One of the Stanford subjects was dropped from the study following suicidal ideation and somnolence during the flurazepam administration. The mean age of the remaining 23 subjects was 36.8 years (SD = 12.48), and the sample consisted of 13 women and 10 men. There were no significant age

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Sleep, Vol. 6, No.2, 1983

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D. BLIWISE ET AL.

differences across institutions, nor did sex distribution or diagnostic category vary significantly across institutions. Procedures Bedtime, wake-up time, and time in bed (TIB) were established for each subject from sleep diaries kept prior to the study and were constant from night to night. All subjects were asked to refrain from napping, alcohol, and all social drugs throughout the study. Medications (triazolam 0.5 mg and flurazepam 30 mg) were given 30 min before lights out. The study was run double-blind. Randomization code was provided by The Upjohn Co. following completed data collection by all institutions. All 23 subjects received flurazepam and triazolam in counter-balanced order. Because of the odd number of subjects, however, 12 subjects were scheduled to receive flurazepam initially, whereas 11 were scheduled to received triazolam. As the result of an error in the randomization code given to one institution, only 10 subjects received triazolam first and 13 subjects received flurazepam first. The design of the study is shown in Fig. 1. Week 3 permitted medication "wash out." The nighttime polysomnographic recording consisted of channels for electroencephalogram, electro-oculogram, and surface electromyogram (18). The following variables were obtained from each polysomnographic recording: TIB (min), Total Sleep Time (TST) (min), sleep efficiency (TST/TIB x 100), stage 1 and 2 latencies (min), rapid eye movement (REM) latency (min), and percentage of TST spent in stage 1, stage 2, stages 3 and 4, and REM. Because first-night effects may occur when insomniacs return to the laboratory (19), we eliminated all initial recording nights. First baseline (Bl) thus consisted of data from nights 2 and 3; first drug administration (Dl), from nights 9 and 10; second baseline (B2), from nights 23 and 24; second drug administration (D2), from nights 30 and 31. Week 1

DAY 1 Placebo psg

DAY 2 Placebo psg

DAY 3 Placebo psg day test

DAY 4 Med 1 home day test

DAY 5 Med 1 home

DAY 6 Med 1 home

DAY 7 Med 1 home

Week 2

DAY 8 Med 1 psg

DAY 9 Med 1 psg

DAY 10 Med 1 psg day test

DAY 11 Placebo home day test

DAY 12 Placebo home

DAY 13 Placebo home

DAY 14 Placebo home

Week 3

DAY 15 Placebo home

DAY 16 Placebo home

DAY 17 Placebo home

DAY 18 Placebo home

DAY 19 Placebo home

DAY 20 Placebo home

DAY 21 Placebo home

Week 4

DAY 22 Placebo psg

DAY 23 Placebo psg

DAY 24 Placebo psg day test


DAY 26 Med 2 home

DAY 27 Med 2 home

DAY 28 Med 2 home

Week 5

DAY 29 Med 2 psg

DAY 30 Med 2 psg


DAY 32 Day test END STUDY

FIG. 1. Study design. Psg = Polysomnogram recorded in laboratory; home = no recording, sleep at home; med 1 = first administration of medication; med 2 = second administration of medication.

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The MSLT was performed at 0900, 1100, 1300, 1500, 1700, and 1900 on days 3 and 4 for Bl, days 10 and 11 for Dl, days 24 and 25 for B2, and days 31 and 32 for D2. Data analysis Distributions of all variables were examined for normality with the KolmogorovSmirnov single sample test (20). Our general strategy was to confine parametric analyses to only those variables with normal distributions. Of the 10 nocturnal polys omnographic variables, each measured eight times, only one, stages 3 and 4 percentage, showed a probability of nonnormality at the 0.05 level on more than one occasion. This occurred for three times of measurement, and nonparametric analyses were used for this variable. For each condition, a mean of the two individual night values was used; e.g., data from the nights of days 23 and 24 were averaged for B2. The MSLT, administered 48 times (8 days, 6 times each day), showed significant probabilities of nonnormality at the 0.05 level or higher for 13 times of measurement; hence nonparametric analyses were also employed here. For the MSLT, each condition consisted of the median of the 12 MSLTs given during that 2-day period. Drug effects for normally distributed nocturnal polysomnographic parameters were assessed with repeated-measures analyses of variance (ANOVAs) using the Greenhouse-Geisser df adjustment suggested for heterogeneity of variances (21). Degrees of freedom were 1 (numerator) and 22 (denominator) for all ANOVAs. Neuman-Keuls contrasts were performed on all possible pairwise comparisons. Drug effects for nonnormally distributed parameters (MSLT, stage 3 and 4 percentage) were assessed with Friedman ANOVAs. RESULTS Nocturnal polysomnographic variables Because each drug was tested against the baseline preceding that drug administration, Bland B2, as well as baseline prior to triazolam (BT) and baseline prior to flurazepam (BFLZ), were compared to insure comparability of baselines. Only stage 2 percentage distinguished B 1 from B2, and this difference was only marginally significant (58.9 versus 62.0, paired t = 1.98, P < 0.07). Moreover, when Bland B2 were compared separately for those persons receiving triazolam first and those persons receiving flurazepam first, no differences were seen, except for TIB for persons receiving triazolam first (466.0 versus 459.3, paired t = 2.57, p < 0.05, for Bl and B2 values). Results of repeated measures ANOVAs on night variables are shown in Table 1. Both triazolam and flurazepam significantly increased TST, sleep efficiency, and stage 2 percentage over preceding respective baselines. Stage 1 percentage and REM percentage were lowered by both medications. Although contrasts between baseline and drug conditions (BT versus T, BFLZ versus FLZ) showed different levels of significance for three of the five variables, contrasts between drug conditions (T versus FLZ) were all nonsignificant, suggesting both drugs had identical effects on these variables. Stage 1 and 2 latency tended to decrease and REM latency tended to increase under both conditions, but the changes were not significant. Analyses of drug effects for stages 3 and 4 with Friedman ANOVAs revealed a significant overall condition effect (X 2 = 18.52, P < 0.001). Median stages 3 and 4



160

D. BL1W1SE ET AL. TABLE 1. Summary of repeated measures ANOVAS on nocturnal

polysomnographic variables Variable TIB (min) TST (mins)

T

BFLZ

FLZ

456.3

451.4

452.4

460.1

NS T > BT, P < 0.01 FLZ > BFLZ, P < 0.001

399.3

420.3

402.6

433.4

F = 7.51 P < 0.05

87.0

92.4

88.3

93.8

F = 8.75 p < 0.01

T > BT, P < 0.01 FLZ > BFLZ, P < 0.001

Sleep efficiency (%)

Condition

Significant contrasts

BT

Stage 1 (%)

9.35

7.95

9.47

7.51

F = 3.86 P < 0.10

T < BT, P < 0.01 FLZ < BFLZ, P < 0.001

Stage 2 (%)

60.91

66.07

59.92

69.81

F = 19.81 P < 0.001

T > BT, P < 0.001 FLZ > BFLZ, P < 0.001

REM (%)

22.95

20.32

21.82

19.14

F = 6.51 P < 0.05

T < BT, P < 0.01 FLZ < BFLZ, P < 0.01

Stage 1 latency (min)

13.32

11.99

19.71

11.06

NS

Stage 2 latency (min)

20.08

17.26

27.33

14.69

NS

REM latency (min)

89.17

103.32

84.26

106.85

NS

All p values are two-tailed probabilities. BT-BFLZ and T-FLZ contrasts were all nonsignificant.

percentages were 6.50 and 0.90 for baseline and drug conditions under triazolam (X 2 = 1.57, NS); median stages 3 and 4 percentages were 7.05 and 0.55 for baseline and drug conditions under flurazepam (X 2 = 9.78, P < 0.002). Daytime sleepiness There were no significant differences between Bland B2 or between BT and BFLZ on MSLT sleep latency as assessed by paired t tests. Table 2 presents MSLT data of individual subjects from the two drug and two baseline conditions, and Table 3 summarizes these data across subjects. Flurazepam significantly decreased median sleep latency (i.e., increased daytime sleepiness), whereas triazolam had no effect. When subjects were subdivided by basal levels of daytime sleepiness (Table 3), based on the median of the 24 baseline sleep latency measures (4 days, 6 measures per day), flurazepam tended to increase sleepiness regardless of this basal sleepiness. In the sleepiest subjects, however, triazolam showed a nonsignificant tendency to make subjects more alert. Study site effects Study site effects were assessed with 2-factor repeated measures ANOVAs. To maintain orthogonality, we dropped one subject at random from the Stony Brook, Baylor, and Henry Ford groups. Site effects for baseline/treatment conditions emerged only



161

TABLE 2. MSLT sleep latencies of individual subjects BT

T

BFLZ

FLZ

Subject

Median

Mean

SD

Median

Mean

SD

Median

Mean

SD

Median

Mean

SD

1 2 3 4 5 6 7 8 9 10

8.0 2.3 6.3 13.8 16.8 8.3 20.0 6.5 12.8 19.0 20.0 13.0 17.8 4.8 2.2 20.0 20.0 20.0 20.0 20.0 18.8 18.3 9.0

9.50 3.92 8.67 12.38 14.38 9.08 17.96 8.46 12.67 16.00 15.33 13.54 16.04 6.75 2.46 16.79 16.08 18.13 15.21 15.71 16.88 17.54 11.71

4.74 4.42 7.90 7.34 7.42 4.57 3.80 5.59 6.23 5.01 6.40 5.82 4.78 6.32 2.28 5.60 5.57 3.64 6.40 6.30 3.89 3.11 5.89

20.0 6.5 12.3 10.0 15.8 20.0 20.0 13.3 20.0 19.0 20.0 10.5 7.3 6.3 1.5 20.0 20.0 20.0 20.0 14.5 20.0 20.0 17.8

18.29 10.42 13.04 10.54 12.58 14.13 18.17 13.92 17.79 15.75 15.25 12.42 7.92 8.71 5.58 18.42 18.29 17.20 17.29 13.88 18.42 18.04 15.42

3.78 8.70 8.09 8.42 7.79 7.31 4.08 6.02 3.95 5.65 6.22 6.38 7.04 7.23 7.01 4.17 3.17 4.32 4.68 6.01 2.94 3.45 5.42

10.5 2.3 10.5 6.8 9.8 5.0 20.0 12.8 9.3 16.3 20.0 18.0 20.0 9.0 1.3 20.0 16.3 20.0 18.5 8.8 20.0 20.0 16.3

10.83 4.21 10.17 9.79 10.00 5.83 16.96 13.08 10.25 16.13 17.04 16.17 18.88 9.96 1.42 19.08 13.71 16.92 15.50 12.21 17.13 18.42 14.58

7.40 5.42 6.43 7.83 8.56 3.43 5.68 6.03 4.80 4.10 6.93 4.51 2.65 6.57 1.35 3.18 6.99 5.25 4.89 6.99 5.47 2.65 6.23

4.8 1.8 19.0 8.8 4.3 2.0 7.7 4.3 7.8 12.0 20.0 6.3 7.0 4.3 0.5 20.0 5.5 11.3 9.0 2.8 14.3 3.3 14.5

5.88 2.63 6.21 12.04 6.38 3.00 8.73 4.50 9.38 13.54 16.38 7.63 11.36 6.21 1.54 13.63 8.33 11.54 10.67 4.92 13.88 4.88 13.38

5.68 2.85 5.27 8.86 7.28 2.67 5.61 1.49 5.46 4.75 6.45 4.48 8.49 5.97 3.06 8.24 6.96 7.79 5.92 6.00 6.12 5.25 7.00

11

12 13 14 15 16 17 18 19 20 21 22 23

All values are in minutes and are based on 12 sleep latency measures (2 days, 6 measures per day) in each condition.

for sleep efficiency (F = 2.68, p < 0.05, df = 9,48) and REM latency (F = 2.96, p < 0.01, df = 9,48). Neuman-Keuls contrasts adopting the 0.05 significance level revealed that improvement in sleep efficiency under triazolam was significant only for the Stanford and Stony Brook groups, whereas under flurazepam improvement in sleep efficiency was significant only for the Stony Brook and Baylor groups. Significant increases in REM latency were seen under trizolam only for the Baylor group and under flurazepam for the Stanford, Baylor, and Henry Ford groups.

TABLE 3. Summary of Friedman ANOVAS on MSLT median sleep latency

All Subjects (n = 23) Basal MSLT 17 min (n = 9)

Significant contrasts

BT

T

BFLZ

FLZ

Condition

16.8

19.0

16.3

7.0

BFLZ > FLZ, p < 0.01

6.3

12.3

9.0

4.3

X' = 27.20 (p < 0.001) X' = 9.93 (p < 0.02)

13.8

15.8

9.8

7.80

X' = 10.67 (p < 0.01)


20.0

20.0

20.0

9.0

X' = 9.81 (p < 0.03)


BT < T, p < 0.06 BFLZ > FLZ, p < 0.06

All values are in minutes and are medians of individual subjects' medians.



162

D. BLIWISE ET AL. DISCUSSION

Given our focus on sleep latency measures, it is noteworthy that neither stage latency, stage 2 latency, nor MSL T sleep latency showed significant study site effects. In fact, no study site effects occurred for the majority of the polysomnographic variables. The site effects for sleep efficiency and REM latency might reflect interlaboratory scoring differences, though why the effects should be limited to these two variables is unclear. Moreover, it is difficult to explain how such effects could operate selectively for only the triazolam or flurazepam administration. If identification of the first REM period, for example, was unreliable in one site, we would expect that site to be affected for both flurazepam and triazolam administrations. Only one site (Stony Brook) showed no baseline/drug effects for either administration on REM latency, thus allowing the possibility of unreliable scoring of REM latency in this institution. If we assume unreliable REM latency scoring here, we should logically expect unreliability in scoring of sleep efficiency at Stony Brook as well. Contrasts showed this did not occur. In fact, another institution (Henry Ford) was the only site to show no baseline/drug effects for sleep efficiency. Hence, if lack of scoring reliability had affected these data, we should have to assume that the unreliability was confined to a very small number of distinct variables at different institutions. Parsimony dictates to us that such apparent site differences are random. Analyses of nocturnal polysomnographic variables showed triazolam and flurazepam to have virtually indistinguishable effects on sleep. Only when daytime effects were considered could the two medications be differentiated. The interpretation of these differences remains ambiguous. On one hand, flurazepam's longer half-life suggests that daytime sleepiness could well reflect persistent sedation. Under triazolam, the shorter-acting benzodiazepine, daytime functioning remains unimpaired, and in the sleepiest subjects, alertness may even increase, perhaps the result of a good night's sleep uncontaminated by lingering pharmacological effects. These findings may be interpreted somewhat differently, however, if we characterize optimal daytime functioning by absence of anxiety, rather than by alertness. From this perspective, flurazepam induces sleepiness during the day because of its anxiolytic properties: if subjects are relaxed, they will probably fall asleep easily. On the other hand, in some studies triazolam has been related to anxiety the day after subsequent ingestion (22) and to anxiety during a withdrawal period (23). If subjects are anxious they may be unable to sleep. The present data do not answer this issue definitively, as we have no measures of anxiety. One other recent study employing the Profile of Mood States (POMS), however, found differential daytime sleepiness effects with triazolam and flurazepam, without corresponding changes in the POMS (24). From our perspective, a large body of varied empirical and clinical literature now suggests the MSLT to be a sensitive measure of sleepiness. Other factors may, indeed, be capable of affecting this measure. However, it seems to us that relaxed, quiet wakefulness without anxiety is simply a qualitatively different experience from sleepiness. REFERENCES 1. Johnson LC, Chernick DA. Sedative-hypnotics and human perrormance. Br J Clin Pharmacal, 1982;76: 101-13.



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