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Sleep, 5(4)350-360 © 1982 Raven Press, New York • _..... .. A ClInIcal ~.... ~tuay r- or ~"1 ~lurazepam *,tWallace B. Mendelson, tHerbert Weingartner, §David J. Greenblatt, *Debra Garnett, and * J. Christian Gillin *Unit on Sleep Studies, Biological Psychiatry Brunch, National Institute of A1ental Health, NIH, Bethesda, Maryland; tAdult Psychiatry Branch, Division of Special Mental Health Research, IRP, National Institute of Mental Health, St. Elizabeths Hospital, Washington, D.C.; +Laboratory of Psychology and Psychopathology, National Institute of Mental Health, NIH, Bethesda, Maryland; and §Division of Clinical Pharmacology, New England Medical Center Hospital, Boston, Massachusetts Summary: Eleven patients suffering from chronic insomnia were given 30 mg flurazepam for 28 nights. While EEG measures of total sleep time and sleep efficiency were improved, changes in sleep latency and intermittent waking time were small and nonsignificant. Subjective benefits in sleep were confined to the first 2 nights. There was neither increased nor decreased daytime sleepiness. Cognitive functioning was significantly decreased during the first 2 days, and patients were unaware of these changes. Simple motor tasks were relatively unaffected. Desalkylflurazepam concentrations showed significant accumulation over time, but were not predictive of sleep measures or daytime performance in individual subjects. The withdrawal period was characterized by subjectively disturbed sleep and daytime dysphoria. Key Words: Flurazepam-Insomnia-Sleep-Hypnotics. Considerable controversy surrounds the clinical use of hypnotic medications. The indications for prescribing them are uncertain, and the nature and nosology of the disorder for which they are most commonly prescribed-insomnia-are unclear. The relative benefits and liabilities of the various available hypnotics have not been well established. It is generally agreed that benzodiazepine hypnotics are less lethal in overdose, less addicting, and possibly less likely to lose their hypnotic effectiveness with repeated use than barbiturate and nonbenzodiazepine - nonbarbiturate hypnotics. Nevertheless, there has recently been increased concern about other more subtle side effects of the benzodiazapines, especially those with long half-lives, such as diazepam and flurazepam. These include impairment of daytime cognitive and psychomotor functioning, possibly associated with the accumulation of active metabolites. Moreover, there is considerable evidence that many insomniacs have Address correspondence and reprint requests to Wallace B. Mendelson, M.D., Unit on Sleep Studies, BPB, Building 10, Room 4S239, NIH, Bethesda, Maryland 20205. Accepted for pUblication July 1982. 350 FLURAZEPAM AND INSOMNIA 351 minimal objective (i.e., EEG) disturbances of sleep, and that the objective and subjective sleep changes induced by hypnotics tend to be quantitatively small (I - 3). Thus far there have been very few clinical studies which have attempted to combine objective and subjective measures of sleep and daytime functioning before, during, and after chronic treatment with any hypnotic. Fewer yet have administered the hypnotic for as great a duration as the average prescription, roughly 1 month in the case of flurazepam (4). The literature on flurazepam contains only two polygraphic studies of 28 nights' duration, with a total combined population of nine subjects, and only one of these studies evaluated both subjective and objective measures (5,6). In this paper we are presenting the results of a study of 11 subjects given flurazepam for 28 nights, as part of an effort to answer the following questions. Is this popular agent effective in improving sleep for a 4-week trial as measured by the EEG and by the subjective reports? Does it alter daytime sleepiness and fatigue (a common complaint among insomniacs) as determined by EEG and subjective criteria? Are daytime performance measures of cognition impaired by administration of this agent, and, if so, are the patients aware of these effects? Do blood concentrations of the active metabolite, desalkylflurazepam, increase over time, and if so does this relate to daytime performance or sleep-inducing properties? METHODS The design of this study included 2 days of practice on the various test batteries to reduce learning effects; the study itself was comprised of 4 nights of placebo (supplied by Hoffmann-La Roche, Inc.), 28 nights of 30 mg flurazepam given at bedtime, and 7 nights of placebo during a withdrawal condition. During the study there were 14 nights of sleep recordings in the laboratory, 9 days in which a battery of psychomotor performance tests, cognitive tasks, and mood and sideeffect ratings were done upon awakening, and a daily questionnaire of duration and quality of sleep (Fig. 1). The cognitive tasks, designed to measure psychobiologically discrete components of cognitive processes, and which had been pretested and validated in a variety of previous studies of normal volunteers and psychiatric patients (7-9), involved free recall of related words, serial learning, and a selective reminding task. Other special procedures included the Multiple Sleep Latency Test, a daytime objective measure of sleepiness in which a person goes to bed for 20 min four times over the course of the day (10:00 AM, noon, 2:00 PM, and 4:00 PM), and the Minnesota MUltiphasic Personality Inventory (MMPI), each done once before receiving active medication and once on the fourth week of drug treatment. Venous blood samples were obtained on the morning after drug-administration nights 1 and 13 and throughout the 26th night of drug treatment. (Because of the possibility that such a procedure might disturb sleep slightly, EEG data from this night are not included in the efficacy material.) Plasma was separated and frozen until the time of assay. Concentrations of desal- Sleep, Vol. 5, No.4, 1982 352 W. B. MENDELSON ET AL. INN ~:;;~ - M ~ ~ ~ -: i !~~ .... ~- .. ~·5 c;) -a _ ~~;;~ ~~=~~~~f~~ -:::.:=.::=_--- __ €!€~ INM .... 0 ;§:.~ In\D ..... dO<;nO ..... NM ... e !:!._N __ i~!~~~ii;; It'IDr- CCl ........... ... ~~g~~J~ijiijiii~i~iiiiiiijjiiiiiiilllllll I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 Start Placebo Start Active Drug Day of Study (1) Psychomotor Tests (2) Cognttive Tests (3) EEG Sleep Study (4) Multiple Sleep latency Test FIG. 1. Schedule of study. kylflurazepam, the major metabolite of flurazepam, were determined by electron capture gas-liquid chromatography (10). The subjects were eight women and three men ranging in age from 23 to 44, who called in response to a newspaper advertisement, and whose characteristic sleep habits and complaints are summarized in Table 1. Inclusion criteria for this study were complaint of inadequate quantity or quality of sleep of at least three years' duration, and which the subject believes affects his daytime life; absence of significant medical or psychiatric disturbance as determined by a physical exam, laboratory tests, and an extensive interview with a psychiatrist; absence of sleep disorders such as sleep apnea syndrome or nocturnal myoclonus as examined on a night of sleep for screening purposes. In terms of the Association of Sleep Disorder Centers nosology of sleep disturbance, these subjects had a persistent psychophysiological disorder of initiating and maintaining sleep (A 1 b). No specific duration of reported sleep latency or total sleep was required. All subjects were free of all forms of medication for at least 1 month before the start of the study. MMPI data for the group as a whole were relatively normal, differing more than 1 SD from the statistical norm only by a decrement in the femininity scale. Eleven subjects started the study; one subject's therapy (no. 2) was discontinued after he developed extensive daytime sedation and increased apneic episodes during sleep on the second night of flurazepam administration, as reported separately (11). Therefore, the data presented here are for the remaining 10. RESULTS EEG measures of sleep As seen in Table 2, the analysis of variance (ANOVA) indicated a significant (p < 0.05) effect of flurazepam treatment on total sleep time. More detailed analysis Sleep, Vol. 5, No.4, 1982 t _i, ---3- ~~ TABLE 1. Characteristics of subjects 2 3 4 5 6 7 8 9 10 11 38 M 4 42 F 7 36 F 7 42 F 4 23 M 4 44 M 3 36 F 6 36 F 4 30 F 7 40 F 7 Patient number '"" ~ ~ Age 38 Sex F How many nights per 2 week do you have disturbed sleep? For how many years 15 has this occurred? Trouble going to 4 sleep?a A wakenings during the night?a Early morning 3 awakening?" Daytime tiredness?" 3 Do you feel refreshed No when you awaken? What time do you go II PM to bed? What time do you get up? 7 AM How long do you take 1\6 to get to sleep? (h) How many hours do you 6-7 sleep on the average? a I = not a problem; 5 30 3 7 5 5 5 4 4 4 4 5 No No 15 8 10 8 5 3 3 3 3 5 4 5 5 2 5 No 2 No 4 No 5 No 10 8 §3 15 17 5 5 3.4 5 5 ~ ~ 4 4 4 4 :.:.. 3 No 5 Yes 3 No 4 No :.:.. ~ ~ S2 Col) 12 AM 5:30-6 AM 1/10 5 1 AM 10-11 PM 9:30 10 AM 5:30-7 IY2 AM I 5:30-7 Y2 7 3-4 PM 5-6 AM 12-2 AM 8-10 AM I 6 10-11 5 PM AM \6 3-4 10-11 PM 6 AM Y2-1 6 10 PM 4 AM Y<! 5 10 PM 7 AM 1-2 4-5 8-8:30 5:30 PM AM I 0 ~ s: 6 = major difficulty. ':;.::0"" !'- ~ v., i:; ~ ~ v." V. -I::.. '<: ~ ::--. <: TABLE 2. Effect of flurazepam on EEG sleep measures " ..... ~ Sleep parameter Total recording Sleep latency Rem latency Intermittent awake time Total sleep time Non-REM time REM time REM index REM density Stage 1 time Stage 2 time Stage 3 time Stage 4 time Slow-wave sleep Stage 1% Stage 2% Stage 3% Stage 4% Slow-wave sleep(%) REM(%) Sleep efficiency Withdrawal Flurazepam Placebo Nights 1-3 Nights 1-2 Nights 13, 15 Nights 27, 28 460.1 30.4 68.2 3.0 465.1 22.5 77.3 2.2 508.4 19.1 96.0 4.2 ± 12.1 ± 4.2 ± 6.4 ± 0.7 382.0 ± 280.9 ± 101.1 ± 154.7 ± 1.5± 16.1 ± 178.7 ± 26.3 ± 59.6 ± 86.0 ± 16.1 ± 46.4 ± 7.0 ± 15.6 ± 22.7 ± 18.3 14.2 8.6 10.2 0.1 2.5 14.8 3.3 9.7 11.5 2.5 2.7 0.9 2.3 2.8 26.4 ± 1.7 82.6 ± 2.4 ± ± ± ± 14.8 3.6 7.6 0.4 498.2 18.9 93.5 3.2 ± ± ± ± 428.3 ± 333.2 ± 96.0 ± 132.2 ± 1.4 ± 10.3 ± 321.4 ± 23.3 ± 68.1 ± 91.4 ± 10.3 ± 53.8 ± 5.5 ± 16.0 ± 21.6 ± 14.7 11.8 5.1 12.5 0.1 2.1 14.3 2.4 10.0 11.2 2.1 2.6 0.5 2.4 2.7 453.9 361.8 92.0 137.7 1.5 15.5 276.0 25.2 45.0 70.2 3.4 60.0 5.7 10.5 16.3 ± 18.6 ± 13.2 ± 8.1 ± 13.9 ± 0.0 ± 2.2 ± 19.4 ± 1.6 ± 8.7 ± 9.8 ± 0.3 ± 2.7 ± 0.5 ± 1.9 ± 2.3 22.2 ± 0.7 92.1 ± 1.3 19.0 2.1 7.4 0.3 20.1 ± 1.1 90.9 ± 0.0 ± 17.4 ± 2.2 ± 7.4 ± 1.2 458.8 ± 359.1 ± 99.6 ± 150.1 ± 1.4 ± 15.6 ± 280.9 ± 27.5 ± 35.1 ± 62.6 ± 3.4 ± 60.5 ± 6.0 ± 8.0 ± 14.0 ± Nights 1,2 451.0 25.0 78.5 3.2 ± 10.6 ± 2.0 ± 5.2 ± 0.5 17.9 15.2 4.8 11.7 0.0 1.8 20.4 1.7 7.4 8.0 0.3 2.4 0.3 1.7 1.9 393.4 ± 301.6 ± 91.8 ± 145.4 ± 1.5± 11.2 ± 222.6 ± 21.7 ± 46.0 ± 67.8 ± 2.8 ± 56.5 ± 5.5 ± 11.8 ± 17.4 ± 8.8 7.9 4.2 10.8 0.0 1.9 13.6 0.9 9.4 9.6 0.4 2.6 0.3 2.5 2.7 21.8 ± 0.9 90.2 ± 1.0 23.1 ± 87.4 ± 1.0 1.6 Nights 6, 7 464.0 34.9 62.8 4.0 393.7 292.4 101.2 188.3 1.8 17.9 205.1 20.8 48.6 69.3 4.6 12.0 5.4 13.0 18.4 ± 17.6 6.1 ± 4.0 :±: 1.3 Significance ± 16.8 15.9 6.7 17.7 0.1 2.5 :!: 22.0 :!: 2.3 ± 8.8 :!: 8.4 ± 0.7 :!: 3.8 ± 0.6 :!: 2.5 :!: 2.4 ± ±: ±: :±: :±: :±: 25.9 ± 84.8 ± 1.8 1.7 <0.05 ~ ~ <0.05 <0.01 ~ ~ ~ CoIl <0.01 a :<; ~ ~ ~ <0.05 <0.05 <0.05 <0.05 All values except percentages represent mean ± SE in minutes. '''- ~ 355 FLURAZEPAM AND INSOMNIA with the Scheffe test revealed that sleep time was increased, but reached significance compared to baseline only on drug-administration nights 13, 15, and 27, 28 (Fig. 2). This was largely due to an increase in Stage 2 sleep. Sleep efficiency (the proportion of sleep in the total recording) was increased (p < 0.05) on all drugadministration nights. Sleep latency decreased by about 30%, and was maintained throughout the 28 nights of treatment. On drug withdrawal nights 6 and 7, latency "rebounded" and became longer than the pretreatment baseline. However, these overall changes in sleep latency did not reach significance as tested by ANOV A. Waking time after sleep onset did not change significantly over time. Stage 4 percentage appeared to decrease across all drug nights, but this reached significance only on drug-administration nights 27 and 28 (p < 0.05). REM per- / v :i "... TOTAL SLEEP TIME - EEG 'E ;:500 -;;: I- p=.05 of I I I I I I I I HOW MUCH TIME 010 YOU SLEEP LAST NIGHT? Sleep Questionnaire (7-8 hlS')f: (6-7 hrs.) (5-6 hrs.) (4·5 hrs.) ~ rAN~:A) .~ ~ 40,~ 30 3 20 I 4 z O( I I I I I I I 0'< 0 I I I I I E p=.10 (ANOYA) I I " I ! I I ! I aUf 140 ~ rA~O~A) I I I I I I ! J MODO RATING SCALE - EUPHORIA Sleep Questionnaire I HOW LONG 010 IT TAKE TO FALL ASLEEP? Sleep Questionnaire 2 (30 min.-l hr.) I 1M"" ~60 01 I I p=.OO3 lDDMM UNE SCALE ALMOST ASLEEP (O)-EXTREMELY ALERT (100) Sleep Questionnaire SLEEP LATENCY - EEG - !:fv t rt' Not at All:": _ HOW MANY TIMES 010 YOU AWAKEN DURING THE NIGHT? Sleep Questionnaire ~ ~p=.019 ~ _ (ANoYA) Maximum 11 10 9 ~ 8 -g.7 1 «30 min.) W 6 p=.OO02 (ANOYA) 5 HOW GOOD A NIGHTS SLEEP COMPARED WITH A TYPICAL NIGHT? Sleep Questionnaire (Excellent4~1 ~ 3 (Usual QUal~ Minimum L-f---+---+-+-+--+-+---+- p=.OO4 (ANOYA) Placebo Drug Withdrawal Day 1,2,3 !lay Day Day Day Day Day Day 1 2 13 26 1 2 6 (Poor) Of I I I I I Withdrawal I I I Placebo Drug ""'.2.3 Day "" "" 1 "" 2 "" 1326 1 "" 2 "" 6 FIG. 2. Objective and SUbjective measures of sleep of insomniacs. Sleep. Vol. 5. No.4, 1982 356 W. B. MENDELSON ET AL. centage began to decrease with the initiation of drug treatment, and was significandy decreased on drug-administration nights 13 and is (p < 0.05); this actually reflected a smaller proportion (due to the increase in non-REM sleep) rather than a significant decrease in minutes of REM. Subjective reports of sleep There was a trend toward a reported shorter time to fall asleep during drug treatment, but this did not reach statistical significance compared to the placebo period. The number of reported awakenings decreased significantly relative to placebo only on drug-administration day 2. The night with the single most awakenings was drug withdrawal night 6 (three to four awakenings compared to two to three awakenings on placebo). There was a tendency toward less difficulty falling asleep, although this reached significance compared to placebo only on drug-administration night 2. Subjects found that depth of sleep was significantly improved compared to placebo only on drug-administration night 2. On a question of quality of sleep, there were no drug-administration nights significantly better than the placebo period. For depth and quality of sleep and difficulty getting to sleep, drug withdrawal night 6 tended to be poorer and reached significance compared to drug-administration night 2, but not compared to placebo. The subjective report of duration of sleep showed a nonsignificant trend toward increased sleep on drug. In sum, the subjects perceived improvements in a variety of aspects of sleep only on the first 2 nights compared to placebo and many aspects of sleep were considered worse in the drug withdrawal period than on these first 2 drug nights. Daytime sleepiness Sleepiness was assessed several different ways. The mUltiple sleep latency test did not show statistically significant evidence of increased tendency to sleep during the fourth week of treatment. The Mood Rating Scale and IOO-mm scale for sleepiness did not indicate substantial daytime sleepiness throughout the drug period. In sum, the multiple sleep latency test and several subjective measures of sleepiness suggested little evidence of daytime sleepiness. Daytime performance-Cognitive functioning Many aspects of cognitive performance were impaired on the first 2 days following onset of drug administration. Free recall of words was impaired an average of 25% on drug-administration days 2 and 3 (F(8,72) = 6.73, p < 0.001). This was particularly evident in the consistency with which subjects would recall words they had remembered before in list learning (F(8,56) = 5.34, p < 0.001). In fact the recall consistency in learning and memory of 0.46 (words recalled that were remembered on a previous test trial) on drug-administration day 2 was a level of impairment evident in previous studies of cognitively impaired depressed patients, or subjects treated with at least moderate doses of drugs that impair learning and memory in man, such as alcohol (8). Serial learning performance was also reduced by an average of 25% compared to baseline values (F(8,72) = 6.95, p < 0.001) on Sleep, Vol. 5, No.4, 1982 FLURAZEPAM AND INSOMNIA 357 drug-administration days 2 and 3, and this effect was evident in both short-term and long-term memory functions. On the other hand, on the sixth day of drug withdrawal, subjects' performance on serial learning was slightly but significantly better than baseline. Daytime performance-Psychomotor tests The finger tapping test indicated a mild decrement in rate with the right hand, which was significant on drug-administration day 13 and the first drug withdrawal day. There was no increase in mistakes on the letter cancellation task, nor was there any decrement in performance on the pegboard task. Thus, flurazepam treatment was associated with some marked cognitive deficits, but relatively little change in simple motor task performance. Interestingly, the daily sleep questionnaire revealed no significant alteration in the subjects' perceptions of their ability to function throughout the study. Daytime mood and feelings The Daily Sleep Questionnaire showed no significant change throughout the study in the responses to a question on how rested the subjects felt in the morning. Similarly, 100-mm line scales for anxiety and energy were unaffected. The Mood Rating Scale indicated an overall decrease in the euphoria scale, a measure of the sense of well-being (p < 0.02); drug withdrawal days 2 and 6 were significantly (p < 0.02) worse than the placebo period. Similarly, the ANOV A revealed changes approaching significance (p < 0.06) on the dysphoria scale, particularly on drug withdrawal day 2, which as an individual comparison was significantly worse than placebo. In sum, relatively little change in mood was seen in the study except for a decrement in the overall sense of well-being in the drug withdrawal period. Blood levels As seen in Fig. 3, desalkylflurazepam concentrations showed substantial accumulation over the 28 days. Blood concentrations on the morning after drug180 E 150 C, c: z 0 ;::: 120 <{ a:: I- zw FIG. 3. Concentrations of desalkylflurazepam in insomniacs. Samples were drawn on morning following drug-administration days 1, 13, and 26. 90 U Z 0 U <{ 60 ::2: <J) <{ ~ Q. 30 0 DAYl DAY 13 DAY 26 Sleep, Vol. 5. No.4, 1982 358 W. B. MENDELSON ET AL. administration nights 1, 13, and 26 were compared to psychomotor and cognitive performance measures that day as weB as subjective and objective measures of sleep the previous night. Blood levels immediately before sleep on drugadministration night 26 were also tested against sleep measures of that night. These calculations involved performing 192 Pearson Correlation Coefficients, of which only 3 (2%) were significant at the p < 0.05 level and thus were probably due to chance. There was no evidence, then, that desalkylflurazepam blood concentrations have predictive value for determining effect of flurazepam on sleep or performance. DISCUSSION These data may be summarized as follows: Nightly use offlurazepam increased EEG measures of total sleep and sleep efficiency over 28 nights, and produced a nonsignificant trend toward decreased sleep latency. Waking time after sleep onset was basically unaffected. Subjectively, the patients reported some decreased difficulty in getting to sleep and in the number of awakenings and depth of sleep, but these reached significance only on the second drug-administration night. There was a tendency to experience sleep onset as being quicker, but no clear effect on quality of sleep was perceived. There was little evidence of increased daytime sleepiness by either EEG or subjective criteria; on the other hand, there was no evidence of improvement in a variety of measures of sleepiness, anxiety, and energy. There were significant deficits in cognitive function, of which the subjects were unaware, on the first 2 days, and relatively little change in simple motor skills. The drug withdrawal period was characterized by subjectively disturbed sleep and daytime dysphoria. Withdrawal phenomena were most marked on day 6 after drug discontinuation. The delayed onset of rebound symptoms has been reported previously (10), and is consistent with the slow disappearance of desalkylflurazepam after the termination of treatment. Basically, nighttime benefits from flurazepam as seen in this study were both brief and modest, and daytime benefits were not observed. Two previous studies, with four and five subjects, respectively (5,6), have reported on 28 nights of administration of flurazepam. The former found a significant reduction in sleep latency only on nights 11- 13, and the latter found no change, which was the finding in our lO-patient study. All studies, however, found a significant effect on total sleep. In the Dement study, subjective reports of improvement in sleep latency and duration were significant only when measured by an analysis of variance but not by the more conservative Greenhouse-Geiser test, and both measures were close to baseline by the fourth week. That relatively modest finding is more positive than the data reported here, in which reported sleep latency and total sleep estimates were not significantly altered at all, and other subjective effects seemed beneficial for only the first 2 nights. This study, in agreement with preceding work (10,12) indicates that desalkylflurazepam, which has been reported to share many pharmacologic properties with the parent compound (13), accumulates significantly during administration. However, blood concentrations did not correlate with subjective or objective Sleep. Vol. 5, No.4, 1982 FLURAZEPAM AND INSOMNIA 359 measures of sleep or with daytime performance, in either acute or chronic administration. The initial but not persistent impairment of daytime performance found in this study appears to be at variance with the findings of Oswald et al. (14), who found a progressive degree of performance deficits and a high incidence of" major crises" in a group of middle-aged "poor sleepers" participating in a double-blind crossover comparison of placebo and flurazepam (30 mg h) for 3 weeks. This discrepancy may reflect differences in age, our patients' being younger. One patient who had normal respiratory status during waking and mild respiratory changes during sleep developed a full sle~p apnea syndrome, including over 100 apneas at night and severe daytime sleepiness (11). This would seem to confirm another report of respiratory suppression by benzodiazepines in patients with other borderline conditions (15) and emphasizes the need for caution in the use of these agents, especially in view of the relatively modest improvement in sleep described here. The clinical benefits and risks of benzodiazepine hypnotic therapy for the complaint of insomnia have received considerable scrutiny in recent years (1,2,3,16,17). The importance of differential diagnosis has been emphasized, especially in identifying underlying conditions which may be treatable or which may be relative contraindications to hypnotic therapy, such as sleep apnea, nocturnal myoclonus, depression, alcoholism and other drug abuse, and hepatic, renal, or pulmonary insufficiency. The potential risks of hypnotic therapy in the elderly have also been publicized since the elderly may run an increased risk of drowsiness, ataxia, and respiratory impairment during sleep. Because of the accumulation of slowly excreted metabolites with medium to long-term nightly therapy with flurazepam, it has been suggested (but not proven) that the risk of side effects increases with time, and that, from this point of view, short-term therapy is preferred. The present study was designed to study some of these issues in a group of chronic insomniac patients who might, in some ways, be considered most suitable candidates for long-term hypnotic treatment. They were relatively young and free of medical and psychiatric complications. Several observations of clinical importance were made. (a) The greatest incidence of side effects occurred early in treatment (the first 2 days) rather than later. In fact, in contrast to some other studies, there was little daytime impairment after the first few days of treatment. It is possible that initial treatment with a dose of 15 mg rather than 30 mg flurazepam would reduce the incidence of side effects early in treatment. (b) The clinical benefits of treatment were not obvious. While total sleep time and other objective measures of sleep did improve, these changes were not associated with any major long-term subjective benefits. It is probably not accurate, therefore, to assert that "all the insomniac needs is more sleep." This latter point, incidentally, was emphasized once again by a related project in the laboratory. The sleep recordings of the insomniacs were compared to those of 10 age- and sex-matched normal control volunteers. It was found that there were no significant differences in sleep latency, total sleep time, or waking time after sleep onset. Sleep, Vol, 5, No.4, 1982 360 W. B. MENDELSON ET AL. Thus the key to insomnia would seem to lie in a realm different from that of decreased EEG sleep time. (c) Withdrawal symptoms do occur upon discontinuing flurazepam, but do not appear for several days. The delayed appearance of withdrawal symptoms is consistent with the slow excretion of desalkylflurazepam. In summary, it appears advisable to evaluate carefully the insomniac patient to identify underlying disorders whenever possible and to assess other conditions, such as age, use of drugs, and medical and psychiatric conditions which may affect treatment. Moreover, if hypnotic therapy were used, it would be important to monitor patients carefully during and after treatment and to recognize that, in most cases, the expected benefits are modest. REFERENCES J. Mendelson WB. The use and misuse of sleeping pills. New.York:Plenum Press, 1980:1-220. 2. Gillin JC, Mendelson WB. In: Palmer GC; ed. Neuropharmacology 0/ central nervous system and behavioral disorders. New York; Academic Press, 1981;285-316. 3. Institute of Medicine. Sleeping pills, insomnia and medical practice. Report of a study by a Committee of the Institute of Medicine. 1979; 1-198. 4. National Prescription Audit. Conducted by IMS America, Ltd., 1977, as cited in NIDA Capsules: Top 26 problem drugs in the U.S., May 1978. 5. Dement, WC, Carskadon MA, Mitler MM, Phillips RL, Zarcone VP. Prolonged use of flurazepam: a sleep laboratory study. Behav Med 1978;(October):25-3J. 6. Kales A, Kales JD, Bixler EO, Scharf, MB. Effectiveness of hypnotic drugs with prolonged use: Flurazepam and pentobarbital. Clin Pharmacol Ther 1978;18:356-63. 7. Weingartner H, Kaye W, Smallberg S, Ebert MH, Gillin JC, Sitaram N. Memory failures in progressive idiopathic dementia. J Abnorm Psycho I 1981;90(3):187-96. 8. Weingartner H, Cohen RM, Murphy D, MastelJo J, Gerdt C. Cognitive processes in depression. Arch Gen Psychiatry 1981 ;38:42-7. 9. Sitaram N, Weingartner H, Gillin JC. Human serial learning: Enhancement with arecoline and choline; impairment with scopolamine. Science 1978;101(4352):274-6. 10. Greenblatt DJ, Divoll M, MacLaughlin DS, Harmatz JS, Shader Rl. Kinetics and clinical effects of flurazepam in young and elderly non-insomniacs. Clin Pharmacol Ther 1981 ;30:475-86. 11. Mendelson WB, Garnett D, Gillin JC. Flurazepam-induced sleep apnea syndrome in a patient with insomnia and mild sleep-related respiratory changes. J Nerv Ment Dis 1981 ;169:261-4. 12. Kaplan SA, de SilvaJAF, Jack ML, Alexander K, Strojny J, Weinfeld RE, Puglisi CV, Weissman L. Blood level profile in man following chronic oral administration offlurazepam hydrochloride. J Pharm Sci 1973;62:1932-5. 13. Randall LO, Kappell B. Pharmacological activity of some benzodiazepines and their metabolites. In: Grattini S, Mussini E, Randall LO, eds. The benzodiazepines. New York: Raven Press, 1973:27- 51. 14. Oswald I, Adam K, Borrow S, Idzikowski C. The effects of two hypnotics on sleep, subjective feelings and skilled performance. In: Passouant P, Oswald I, eds. Pharmacology of the states of alertness. Oxford: Pergamon Press, 1979:51-63. 15. Rudolf M, Geddis DM, Turner JAM, Saunders KB. Depression of central respiratory drive by nitrazepam. Thorax 1978;97-100. 16. Clift AD. A general practice study of dependence on some non-barbiturate hypnotic drugs. In: Clift AD, eds. Sleep disturbance and hypnotic drug dependence. New York: Excerpta Medica, 1975:97-105. 17. Solomon F, White CC, Barron DL, Mendelson WB. Sleeping pills, insomnia and medical practice. New Engl J Med 1979;300:803-8. Sleep, Vol. 5. No.4, 1982