EFFECTS OF BENZODIAZEPINES ON SLEEP AND WAKEFULNESS

Transcription

1 Br. J. clin. Pharmac. (1981), 11, 31S-3S EFFECTS OF BENZODIAZEPINES ON SLEEP AND WAKEFULNESS 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 of sleep and daytime function. Introduction THE evaluation of any drug requires an understanding of the conditions in which it is going to be used clinically. In the case of hypnotics, the most appropriate use is symptomatic relief for the complaint of insomnia. To understand fully the safety and efficacy of these drugs, we must first be aware of the constellation of symptoms associated with the complaint of insomnia, as well as what these drugs do to each of these symptoms. Insomnia is a complaint. Although all of the aetiological factors which give rise to this symptom are not currently well understood, there is an accepted diagnostic system for the various disorders associated with disturbed nocturnal sleep (Association of Sleep Disorder Centers, 1979). Whenever one of these disorders is diagnosed, the specific disorder should be treated directly. However, when no diagnosis can be determined or if the insomnia is situational and/or time-limited, the problem can and should be dealt with symptomatically. An important point in dealing with the symptomatic relief of insomnia is that insomnia is not simply difficulty with sleep or insufficient sleep. Most insomniac patients feel that the quality of their life, as reflected in their ability to work productively and interact effectively, is seriously compromized by their difficulties with sleep. Thus, in treating insomniac patients, a clinician must deal with the patient's daytime functioning as well as their nocturnal sleep. Similarly, in evaluating hypnotic drugs, their effects on sleep as well as on daytime functioning must be determined. In the symptomatic treatment of insomnia, benzodiazepines are currently the drugs of choice. Unlike the barbiturates, benzodiazepines do not produce tolerance with nightly usage, and there is little risk of death associated with overdosing. Most of the benzodiazepines which were first developed, such as flurazepam, are long-acting compounds (Kaplan et al., 1973). Recently, short-acting benzodiazepine hypnotics, with half-lives of less than 12 h, such as estazolam (Nakajima et al., 1971),, temazepam (Roth /81/ $01.00 et al., 1979), and triazolam (Metzler et al., 1977) have come into clinical use. The present report will present the differential effects of short- and long-acting benzodiazepines on sleeping and waking behaviour. Sleep parameters In evaluating the effects of hypnotics on sleep, two types of parameters should be considered. The first set of parameters deal with hypnotic efficacy and include measures such as latency to sleep onset, total sleep time, number and duration of awakenings, and sleep efficiency. The second set of parameters deal with sleep staging and include measures of the amount of time spent in various sleep stages (that is 1, 2, 3-4 and REM), as well as the latency to stages 3-4 and REM from sleep onset. The differential effects of short- and long-acting benzodiazepines on hypnotic efficacy are illustrated by a study comparing estazolam (short-acting) and flurazepam (long-acting). A group of 18 insomniacs were studied in a 14 d protocol. The first night served as an adaptation night, on nights 2-4 baseline recordings were obtained, on nights -11 active drug was administered (nine subjects received estazolam 2 mg and nine received flurazepam 1 mg), and finally, recovery was evaluated on nights On all nonactive drug nights placebo was administered, and the entire study was carried out using a double-blind procedure. The effects of flurazepam and estazolam on total sleep time and number of awakenings are presented in Table 1. As can be seen, both of these compounds significantly decreased the number of awakenings and increased total sleep time with one week of nightly administration. However, only the short-acting compound showed significant hypnotic effects with only a single night of administration. With long-acting compounds, multiple nights of drug administration, and therefore drug accumulation, are necessary to achieve significant hypnotic efficacy. ) Macmillan Publishers Ltd 1981

2 32S Table I The effects of estazolam and flurazepam on total sleep time and number of awakenings Condition: Study night: Flurazepam 1mg Total sleep time Number of awakenings Estazolam 2 mg Total sleep time Number of awakenings Baseline First Drug t t OverallDrug t 9 428t t Significantly different from baseline P<0.0; t significantly different from baseline P<0.01. Recovery t Similarly, drug accumulation is demonstrated by hypnotic efficacy with flurazepam on the withdrawal nights and a return to baseline with estazolam. Thus, longer-acting drugs like flurazepam are characterized by drug build-up for the first couple of active drug nights and a carry-over of drug activity into the recovery period. Short-acting drugs like estazolam produce their maximal effect with a single night of administration and a return to baseline as soon as drug is discontinued. The differential effects of short- and long-acting benzodiazepines on sleep stages are illustrated by two studies carried out in-our laboratory. In the first study, 0. mg of triazolam, a benzodiazepine with a half-life of 4.- h (10) was administered to eight insomniac 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 nights in a second study. Both studies were doubleblind and each had, in addition to the period of drug administration, a baseline (placebo) and recovery (placebo) period. These results are presented in Table 2. Both triazolam and ketazolam significantly increased the latency to REM sleep in comparison with baseline. However, only ketazolam administration was associated with a significant decrease in the percentage of REM. These findings demonstrate that although both compounds affected REM latency, the drug with the longest half-life significantly suppressed the total percentage of REM across the night. It is also of interest to note that although neither compound significantly affected the latency to stage 3-4, the long-acting drug significantly suppressed the total percentage of stage 3-4. Another major difference between the two drugs was their effect on sleep stages during the post-drug recovery period. Ketazolam sinificantly affected the latency to REM, percentage REM and percentage 34 on the first 3 recovery nights. Triazolam, on the other hand, did not have a significant effect on any of these parameters during the recovery period. This indicates that the longer half-life of ketazolam is associated with a build-up of active drug which in turn is associated with a carry-over of sleep suppression for several days after discontinuation of the drug. Performance parameters Since patients who complain of insomnia also complain of disturbed daytime functioning and since sedative hypnotics are known to affect daytime functioning, their proper evaluation requires examination of their daytime effects. The evaluation of daytime functioning should include a battery of several different types of tests. A battery of different tests is desirable as different drugs may affect different waking functions. Also, the myriad of daily activities (for example, driving, problem solving, and so on) routinely performed cannot be evaluated using a single test. An ideal battery should consist of the Table 2 Percentage change from placebo condition using ketazolam and triazolam Percentage REM Latency to REM Percentage stage 3-4 Latency to stage 3-4 Ketazolam Triazolam Drug days Drug days Recovery days Drug days Drug days Recovery days Significantly different from placebo P<

3 BENZODIAZEPINES & SLEEP AND WAKEFULNESS 33S placelbo levfel 0 2:00 am 8:30 am 9:00 pm 3. h after drug 10 h after drug 22. h after drug S -0. ~~~~~~T2 T. F30 l F ~F30 F l T.0lll T.2 = Triazolam.2 mg T.0 = Triazolam.0 mg F30 = Flurazepam 30 mg F1 - Flurazepam 1 mg S = Secobarbital 100 mg Figure 1 Effects of triazolam 0.2 mg (T.2) and 0.0 mg (T.0), fiurazepam 30 mg (F30) and 1 mg (Fl ), and secobarbital 100 mg (S) on performance expressed as Z scores. following types of tasks: simple motor, gross coordination, reaction time, cognitive, vigilance, and memory. This battery of tests should be performed several times in the 24 h following drug ingestion. The first test should be performed at a time when peak blood levels of the drug are expected so as to gain information about the maximum degree of impairment that can be anticipated. The next testing should be performed in the morning to determine if patients taking the medication experience any morning "hang-over". If there is a performance decrement in the morning, additional assessments should be performed to determine how long into the day the decrement persists. A study evaluating the acute effects of triazolam, flurazepam and secobarbital on performance illustrates the difference between short- and long-acting benzodiazepines (Roth, Kramer & Lutz, 1977). Twelve normal, healthy young males experienced each of six experimental conditions for 2 consecutive nights according to a Latin square design. The six drug conditions consisted of triazolam 0.2 mg and 0.0 mg, flurazepam 1 mg and 30 mg, and secobarbital 100 mg. There was a 12 d washout between drug conditions, and the study was carried out on a doubleblind basis. On each experimental night, subjects were given medication 0. h before sleep. The performance evaluations were carried out 0200 (3. h post-drug ingestion), 0830 (10 h post-drug ingestion) and 2100 (22.0 post-drug ingestion). The perfonnance battery consisted of: (1) pursuit rotor, a test of eyehand coordination in which subjects must keep a stylus in contact with a rotating disk; (2) purdue pegboard, another test of eye-hand coordination in which subjects are required to place pegs onto a board; (3) continuous arithmetic, a test of simple arithmetic ability (addition and subtraction problems); (4) digit symbol substitution test, a test of cognitive ability in which subjects are required to substitute a set of symbols for a series of digits; () card sorting, a test of both cognitive and psychomotor ability in which subjects are required to sort cards (by suit and by number) and to deal cards (in packs of four and ten). To get an overall view of how the drug affected performance, each of the performance test scores was converted to a Z score. The mean Z score for each drug condition for each time of testing is presented in Figure 1. In addition, analyses of variance were performed to assess the effects of the drug conditions on performance. The results demonstrate that all the tasks showed a significant main effect due to time of testing. The 2100 testing exhibited better performance than the 0830 and the 0200 testing, and the 0830 testing was significantly better than the 0200 testing. Ihe effects of the drugs on performance were found to be differential as a function of time of test-

4 34S Table 3 Rank ordering of hypnotic potency and performance decrement for the various drug conditions- Hypnotic potency Performance decrement Triazolam Triazolam Flurazepam Flurazepam Secobarbital 0.2mg 0.0mg 1mg 30mg 100mg Placebo 1 = greatest performance decrement across all tasks and most hypnotic potency as measured by sleep latency. 6 6 ing. Typically at the 0200 testing, all of the drug conditions showed impairment in performance compared with placebo. The condition showing the least impairment was flurazepam 1 mg, and the condition showing the most impairment was triazolam 0.0 mg. At the 0830 testing, the only drug condition which consistently showed impaired performance was flurazepam 30 mg. Finally, by the 2100 testing, none of the drugs showed any impairment in performance. The results of this study showed that hypnotics clearly impaired performance. The nature of the impairment is related to two pharmacological properties of the drug. First, the duration of the decrement is related to the half-life of the drug. The longer-acting compounds show morning decrements, whereas the short-acting ones do not. Second, the degree of performance decrement is related to the hypnotic potency of the drug. This can be seen from the fact that the higher dose of each compound produced greater performance decrements than the lower dose of each drug. In addition, a comparison of the 0200 performance decrements with hypnotic efficacy showed that the greater the effectiveness of a hypnotic, the greater the performance decrement 3. h post-drug ingestion (see Table 3). In conclusion, the potency of hypnotics is related to the degree of performance decrement, whereas half-life is related to the duration of performance decrement. Apart from general performance, there is a specific concern with the anterograde amnesia associated with the use of benzodiazepines (Bixler et al., 1979). A study was carried out to evaluate memory aside from any other measures ofperformance (Roth et al., 1980). Eleven normal male volunteers, yr old without a history of sleep disturbance, served as subjects. Each of three experimental drugs (flurazepam 30 mg, lorazepam 4 mg and triazolam 0. mg) and a placebo were administered to every subject for 2 consecutive days in repeated measures, double-blind Latin square design with a d washout period separating each condition. Three hours post-drug, subjects were awakened and presented with a battery of four tasks consisting of a "pill task, a dressing task, a time task and a travel task". The subjects returned to bed 1 min after the awakening. Memory for four details from each of the four tasks was assessed by a questionnaire administered immediately after the night-time task presentation (immediate recall) and following the final morning awakening (morning recall). Immediate recall for the 16 test items was significantly (P<0.0) poorer following lorazepam and triazolam administration than following flurazepam or placebo administration (see Table 4). Morning recall was significantly (P<0.0) decreased in all three drug conditions compared with placebo, and in addition, significantly (P<0.0) fewer test items were recalled in the lorazepam and triazolam conditions than in the flurazepam condition. Analysis of the immediate recall data showed that the morning memory loss may be attributed to failure of information storage at the time of night-time task presenta- Table 4 Effects of triazolam, flurazepam, lorazepam and placebo on memory and sleep latency Immediate recall (mean number of items) Morning recall (mean number of items) Latency to stage 2 after immediate recall P<0.0 in comparison to placebo. Triazolam Flurazepam Lorazepam Placebo

5 BENZODIAZEPINES & SLEEP AND WAKEFULNESS 3S tion. Of the items which were not recalled at morning testing, 71% were not recalled at night. The other 29% of the unrecalled morning items were forgotten between the night-time and morning testing, indicating that the majority of memory loss occurred at night. The inability of subjects to store information at night is probably due to the hypnotic properties of the drugs, indicated by the significantly (P<0.0) shorter latencies to fall back to sleep following drug administration. Within each condition, subjects had significantly (P<0.0) poorer recall when they fell back to sleep within 2. min compared with when they fell back to sleep in more than minutes. This hypothesis is further supported by the finding that the flurazepam condition which was associated with significantly (P<0.0) poorer recall on day 2 than on day 1 was also the only experimental condition which was References ASSOCIATION OF SLEEP DISORDER CENTERS. (1979). Diagnostic classification of sleep and arousal disorders, first edition, prepared by the sleep disorders classification committee. Chairman H.P. Roffwarg. Sleep, 2, BIXLER, E.O., SCHARF, M.B., SOLDATOS, C.R., M1TSKY, D.J. & KALES, A. (1979). Effects of hypnotic drugs on memory. Life Sci., 2, KAPLAN, S.A., de SILVA, J.A.F., JACK, M.L., ALEXANDER, K., STROJNY, N., WEINFELD, R.E., PUGLISI, C.V. & WEISSMAN, L. (1973). Blood level profile in man following chronic oral administration of flurazepam hydrochloride. J. Pharm Sci., 62, METZLER, C.M., KO, H., ROYER, M.E., VELDKAMP, W. & LINET, O.I. (1977). Bioavailability and pharmacokinetics of orally administered triazolam in normal subjects. Clin. Pharmac. Ther., 21, associated with a shorter latency to fall back to sleep on day 2 in comparison to day 1. The various studies presented in this report demonstrate that benzodiazepines have significant effects on both sleep and wakefulness. In understanding these effects, it is critical for the clinician to appreciate the fact that these effects are interrelated to some degree. When benzodiazepines produce sleepiness and we are measuring sleep, we call it hypnotic efficacy. When benzodiazepines produce sleepiness and we are measuring performance, we call it a side-effect. Clearly, the prescription of hypnotics to improve sleep should be tempered. Drugs should be chosen which clear the system by the time the patient must rise and function the next morning. The effectiveness of hypnotics is defined by their ability to improve sleep without hindering daytime functioning. NAKAJIMA, R. etal. (1971). Pharmacological studies on new potent central depressants, 8-chloro-6-phenyl-4H-Striazolo (4,3-a) (1,4) benzodiazepine (D-4OTA) and its 1-methyl analogue (D-6MT). Japan J. Pharmnac., 21, R6TH, T., HARTSE, K., SAAB, P., PICCIONE, P. & KRAMER, M. (1980). The effects of flurazepam, lorazepam and triazolam on sleep and memory. Psychopharmacolgia (in press). ROTH, T., KRAMER, M. & LUTZ, T. (1977). The effects of hypnotics on sleep, performance and subjective state. Drugs exp. Clin. Res., 1, ROTH, T., PICCIONE, P., SALIS, P.J., KRAMER, M. & KAFFEMAN, M.E. (1979). Effects of temazepam, flurazepam and quinalbarbitone on sleep: psychomotor and cognitive function. Br. J. clin. Pharmac., 8(1), 47S-4S.