Effects of Benzodiazepines on Sleep and Wakefulness

Br. J. clin. Pharmac. (1981), 11, 31S-35S

EFFECTS OF BENZODIAZEPINES ON SLEEP AND WAKEFULNESS

T. ROTH, F. ZORICK, JEANNE SICKLESTEEL & E. STEPANSKI Sleep Disorders and Research Center, Henry Ford Hospital, Detroit, Michigan

The differential effects of short and long acting benzodiazepines on sleeping and waking behaviour are discussed, with particular reference to hypnotic efficacy, and their effects on the structure ofsleep and daytime function.

Introduction THE evaluation of any drug requires an understand- et al., 1979), and triazolam (Metzler et al., 1977) have ing of the conditions in which it is going to be used come into clinical use. The present report will present clinically. In the case of hypnotics, the most appro- the differential effects of short- and long-acting ben- priate use is symptomatic relief for the complaint of zodiazepines on sleeping and waking behaviour. insomnia. To understand fully the safety and efficacy ofthese drugs, we must first be aware of the constella- tion of symptoms associated with the complaint of Sleep parameters insomnia, as well as what these drugs do to each of these symptoms. In evaluating the effects of hypnotics on sleep, two Insomnia is a complaint. Although all of the types of parameters should be considered. The first aetiological factors which give rise to this symptom set of parameters deal with hypnotic efficacy and are not currently well understood, there is an accepted include measures such as latency to sleep onset, total diagnostic system for the various disorders associated sleep time, number and duration of awakenings, and with disturbed nocturnal sleep (Association of Sleep sleep efficiency. The second set of parameters deal Disorder Centers, 1979). Whenever one of these dis- with sleep staging and include measures of the orders is diagnosed, the specific disorder should be amount of time spent in various sleep stages (that is 1, treated directly. However, when no diagnosis can be 2, 3-4 and REM), as well as the latency to stages 3-4 determined or if the insomnia is situational and/or and REM from sleep onset. time-limited, the problem can and should be dealt The differential effects of short- and long-acting with symptomatically. An important point in dealing benzodiazepines on hypnotic efficacy are illustrated with the symptomatic relief of insomnia is that in- by a study comparing estazolam (short-acting) and somnia is not simply difficulty with sleep or insuf- flurazepam (long-acting). A group of 18 insomniacs ficient sleep. Most insomniac patients feel that the were studied in a 14 d protocol. The first night served quality oftheir life, as reflected in their ability to work as an adaptation night, on nights 2-4 baseline record- productively and interact effectively, is seriously ings were obtained, on nights 5-11 active drug was compromized by their difficulties with sleep. Thus, in administered (nine subjects received estazolam 2 mg treating insomniac patients, a clinician must deal with and nine received flurazepam 15 mg), and finally, the patient's daytime functioning as well as their recovery was evaluated on nights 12-14. On all non- nocturnal sleep. Similarly, in evaluating hypnotic active drug nights placebo was administered, and the drugs, their effects on sleep as well as on daytime entire study was carried out using a double-blind functioning must be determined. procedure. The effects of flurazepam and estazolam In the symptomatic treatment of insomnia, benzo- on total sleep time and number of awakenings are diazepines are currently the drugs of choice. Unlike presented in Table 1. As can be seen, both of these the barbiturates, benzodiazepines do not produce compounds significantly decreased the number of tolerance with nightly usage, and there is little risk of awakenings and increased total sleep time with one death associated with overdosing. Most of the benzo- week of nightly administration. However, only the diazepines which were first developed, such as flura- short-acting compound showed significant hypnotic zepam, are long-acting compounds (Kaplan et effects with only a single night of administration. al., 1973). Recently, short-acting benzodiazepine With long-acting compounds, multiple nights of drug hypnotics, with half-lives of less than 12 h, such as administration, and therefore drug accumulation, are estazolam (Nakajima et al., 1971),, temazepam (Roth necessary to achieve significant hypnotic efficacy. 0306-5251/81/130031-05 $01.00 ) Macmillan Publishers Ltd 1981 32S T. ROTH, F. ZORICK, JEANNE SICKLESTEEL & E. STEPANSKI

Table I The effects of estazolam and flurazepam on total sleep time and number of awakenings Condition: Baseline FirstDrug OverallDrug Recovery Study night: 2-4 5 5-11 12-14 Flurazepam 15mg Total sleep time 397 409 433t 428* Number of awakenings 13 11 9* 8t Estazolam 2 mg Total sleep time 382 436t 428t 372 Number of awakenings 11 5t 5t 7* * Significantly different from baseline P<0.05; t significantly different from baseline P<0.01.

Similarly, drug accumulation is demonstrated by also of interest to note that although neither com- hypnotic efficacy with flurazepam on the withdrawal pound significantly affected the latency to stage 3-4, nights and a return to baseline with estazolam. Thus, the long-acting drug significantly suppressed the total longer-acting drugs like flurazepam are characterized percentage of stage 3-4. by drug build-up for the first couple of active drug Another major difference between the two drugs nights and a carry-over of drug activity into the re- was their effect on sleep stages during the post-drug covery period. Short-acting drugs like estazolam pro- recovery period. Ketazolam sinificantly affected the duce their maximal effect with a single night of latency to REM, percentage REM and percentage administration and a return to baseline as soon as 34 on the first 3 recovery nights. Triazolam, on the drug is discontinued. other hand, did not have a significant effect on any of The differential effects of short- and long-acting these parameters during the recovery period. This benzodiazepines on sleep stages are illustrated by two indicates that the longer half-life ofketazolam is asso- studies carried out in-our laboratory. In the first study, ciated with a build-up of active drug which in turn is 0.5 mg of triazolam, a benzodiazepine with a half-life associated with a carry-over of sleep suppression for of 4.5-5 h (10) was administered to eight insomniac several days after discontinuation of the drug. subjects for 14 consecutive nights. Ketazolam, a benzodiazepine with a half-life of 14 h (4), was administered to eight insomniac subjects for 7 consecutive Performance parameters nights in a second study. Both studies were double- blind and each had, in addition to the period of drug Since patients who complain of insomnia also com- administration, a baseline (placebo) and recovery plain of disturbed daytime functioning and since (placebo) period. These results are presented in sedative hypnotics are known to affect daytime func- Table 2. tioning, their proper evaluation requires examination Both triazolam and ketazolam significantly in- of their daytime effects. The evaluation of daytime creased the latency to REM sleep in comparison with functioning should include a battery of several dif- baseline. However, only ketazolam administration ferent types of tests. A battery of different tests is was associated with a significant decrease in the per- desirable as different drugs may affect different centage of REM. These findings demonstrate that waking functions. Also, the myriad of daily activities although both compounds affected REM latency, the (for example, driving, problem solving, and so on) drug with the longest half-life significantly suppressed routinely performed cannot be evaluated using a the total percentage of REM across the night. It is single test. An ideal battery should consist of the

Table 2 Percentage change from placebo condition using ketazolam and triazolam Ketazolam Triazolam Drug days Drug days Recovery days Drug days Drug days Recovery days 17-3 5-7 1-3 1-3 12-14 1-3 Percentage REM -21 * -22* -11* -13 -09 0 Latency to REM +61 * +64* +30* +56* +72* +04 Percentage stage 3-4 -07 -35* -29* +13 +08 +03 Latency to stage 3-4 +10 +21 +33 +21 +25 +34 * Significantly different from placebo P<0.05. BENZODIAZEPINES & SLEEP AND WAKEFULNESS 33S

+1.0 2:00 am 8:30 am 9:00 pm 3.5 h after drug 10 h after drug 22.5 h after drug +0.5 S placelbo levFel 0

T. F30 l -0.5 ~~~~~~T2 F30

-1.0 | | ~F30 F30

-1.5

-2.0 l T.50lll -2.5

T.25 = Triazolam .25 mg F30 = Flurazepam 30 mg S = Secobarbital 100 mg T.50 = Triazolam .50 mg F15 - Flurazepam 15 mg

Figure 1 Effects oftriazolam 0.25 mg (T.25) and 0.50 mg (T.50), fiurazepam 30 mg (F30) and 15 mg (Fl 5), and secobarbital 100 mg (S) on performance expressed as Z scores. following types of tasks: simple motor, gross co- and 2100 (22.0 post-drug ingestion). The perfonnance ordination, reaction time, cognitive, vigilance, and battery consisted of: (1) pursuit rotor, a test of eye- memory. This battery of tests should be performed hand coordination in which subjects must keep a several times in the 24 h following drug ingestion. The stylus in contact with a rotating disk; (2) purdue first test should be performed at a time when peak pegboard, another test of eye-hand coordination in blood levels of the drug are expected so as to gain which subjects are required to place pegs onto a information about the maximum degree of impair- board; (3) continuous arithmetic, a test of simple ment that can be anticipated. The next testing should arithmetic ability (addition and subtraction be performed in the morning to determine if patients problems); (4) digit symbol substitution test, a test of taking the medication experience any morning cognitive ability in which subjects are required to "hang-over". If there is a performance decrement in substitute a set of symbols for a series of digits; (5) the morning, additional assessments should be per- card sorting, a test ofboth cognitive and psychomotor formed to determine how long into the day the decre- ability in which subjects are required to sort cards (by ment persists. suit and by number) and to deal cards (in packs of A study evaluating the acute effects of triazolam, four and ten). flurazepam and secobarbital on performance illus- To get an overall view of how the drug affected trates the difference between short- and long-acting performance, each ofthe performance test scores was benzodiazepines (Roth, Kramer & Lutz, 1977). converted to a Z score. The mean Z score for each Twelve normal, healthy young males experienced drug condition for each time of testing is presented in each of six experimental conditions for 2 consecutive Figure 1. nights according to a Latin square design. The six In addition, analyses of variance were performed drug conditions consisted of triazolam 0.25 mg and to assess the effects of the drug conditions on per- 0.50 mg, flurazepam 15 mg and 30 mg, and secobar- formance. The results demonstrate that all the tasks bital 100 mg. There was a 12 d washout between drug showed a significant main effect due to time of test- conditions, and the study was carried out on a double- ing. The 2100 testing exhibited better performance blind basis. On each experimental night, subjects than the 0830 and the 0200 testing, and the 0830 were given medication 0.5 h before sleep. The per- testing was significantly better than the 0200 testing. formance evaluations were carried out 0200 (3.5 h Ihe effects of the drugs on performance were post-drug ingestion), 0830 (10 h post-drug ingestion) found to be differential as a function of time of test- 34S T. ROTH, F. ZORICK, JEANNE SICKLESTEEL & E. STEPANSKI

Table 3 Rank ordering* of hypnotic potency and performance decrement for the various drug conditions- Triazolam Triazolam Flurazepam Flurazepam Secobarbital Placebo 0.25mg 0.50mg 15mg 30mg 100mg Hypnotic potency 3 1 5 2 4 6 Performance decrement 3 2 5 1 4 6 * 1 = greatest performance decrement across all tasks and most hypnotic potencyas measured by sleep latency. ing. Typically at the 0200 testing, all of the drug A study was carried out to evaluate memory aside conditions showed impairment in performance com- from any other measures ofperformance (Roth et al., pared with placebo. The condition showing the least 1980). Eleven normal male volunteers, 19-30 yr old impairment was flurazepam 15 mg, and the condition without a history of sleep disturbance, served as sub- showing the most impairment was triazolam 0.50 mg. jects. Each of three experimental drugs (flurazepam At the 0830 testing, the only drug condition which 30 mg, lorazepam 4 mg and triazolam 0.5 mg) and a consistently showed impaired performance was flura- placebo were administered to every subject for 2 zepam 30 mg. Finally, by the 2100 testing, none of the consecutive days in repeated measures, double-blind drugs showed any impairment in performance. Latin square design with a 5 d washout period The results of this study showed that hypnotics separating each condition. Three hours post-drug, clearly impaired performance. The nature of the im- subjects were awakened and presented with a battery pairment is related to two pharmacological properties of four tasks consisting of a "pill task, a dressing task, of the drug. First, the duration of the decrement is a time task and a travel task". The subjects returned related to the half-life of the drug. The longer-acting to bed 15 min after the awakening. Memory for four compounds show morning decrements, whereas the details from each of the four tasks was assessed by a short-acting ones do not. Second, the degree of per- questionnaire administered immediately after the formance decrement is related to the hypnotic potency night-time task presentation (immediate recall) and of the drug. This can be seen from the fact that the following the final morning awakening (morning re- higher dose ofeach compound produced greater per- call). formance decrements than the lower dose of each Immediate recall for the 16 test items was signifi- drug. In addition, a comparison of the 0200 perfor- cantly (P<0.05) poorer following lorazepam and mance decrements with hypnotic efficacy showed that triazolam administration than following flurazepam the greater the effectiveness ofa hypnotic, the greater or placebo administration (see Table 4). Morning the performance decrement 3.5 h post-drug ingestion recall was significantly (P<0.05) decreased in all (see Table 3). In conclusion, the potency ofhypnotics three drug conditions compared with placebo, and in is related to the degree of performance decrement, addition, significantly (P<0.05) fewer test items were whereas half-life is related to the duration of per- recalled in the lorazepam and triazolam conditions formance decrement. than in the flurazepam condition. Analysis of the Apart from general performance, there is a specific immediate recall data showed that the morning concern with the anterograde amnesia associated memory loss may be attributed to failure of informa- with the use of benzodiazepines (Bixler et al., 1979). tion storage at the time of night-time task presenta-

Table 4 Effects of triazolam, flurazepam, lorazepam and placebo on memory and sleep latency Triazolam Flurazepam Lorazepam Placebo Immediate recall 11.8* 13.8 9.7* 14.7 (mean number of items) Morning recall 9.3* 12.7* 8.0* 14.2 (mean number of items) Latency to stage 2 3.2* 5.5* 3.4* 22.2 after immediate recall * P<0.05 in comparison to placebo. BENZODIAZEPINES & SLEEP AND WAKEFULNESS 35S tion. Of the items which were not recalled at morning associated with a shorter latency to fall back to sleep testing, 71% were not recalled at night. The other on day 2 in comparison to day 1. 29% of the unrecalled morning items were forgotten The various studies presented in this report between the night-time and morning testing, indicat- demonstrate that benzodiazepines have significant ing that the majority of memory loss occurred at effects on both sleep and wakefulness. In understand- night. The inability ofsubjects to store information at ing these effects, it is critical for the clinician to night is probably due to the hypnotic properties ofthe appreciate the fact that these effects are interrelated drugs, indicated by the significantly (P<0.05) shorter to some degree. When benzodiazepines produce latencies to fall back to sleep following drug admini- sleepiness and we are measuring sleep, we call it stration. Within each condition, subjects had signifi- hypnotic efficacy. When benzodiazepines produce cantly (P<0.05) poorer recall when they fell back to sleepiness and we are measuring performance, we call sleep within 2.5 min compared with when they fell it a side-effect. Clearly, the prescription of hypnotics back to sleep in more than 5 minutes. This hypothesis to improve sleep should be tempered. Drugs should is further supported by the finding that the flura- be chosen which clear the system by the time the zepam condition which was associated with signifi- patient must rise and function the next morning. The cantly (P<0.05) poorer recall on day 2 than on day 1 effectiveness ofhypnotics is defined by their ability to was also the only experimental condition which was improve sleep without hindering daytime functioning.

References

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