Hypnotic Drugs and Their Effectiveness
All-night EEG Studies of Insomniac Subjects
Anthony Kales, MD; Clyde Allen, MA; Martin
and Joyce D. Kales, MD, Los Angeles
T
HE results of previous studies with normal subjects in our laboratory suggested
that 1,000 mg of chloral hydrate (Noctec)
and 30 mg of flurazepam (Dalmane) were
effective in enhancing sleep: chloral hydrate
appeared to induce sleep while flurazepam
induced and maintained sleep.1
The aim of the present study was to
further evaluate the effectiveness of 1,000
mg of chloral hydrate and 30 mg of flurazepam by using insomniac subjects and a twoweek drug administration period as part of
a 22-night protocol. This contrasted with
our previous use of normal subjects and a
three-night drug administration period as
part of an eight-night schedule. The use of
insomniac subjects provides a clear-cut way
in which to study the effectiveness of sleep
medications. The two-week drug administration period provides not only a more rigorous evaluation of whether drugs produce
sleep stage alterations, but also allows for
the determination of the length of the
effectiveness of the drugs.
In order to compare the effectiveness of
drugs which do not significantly alter REM
sleep (1,000 mg of chloral hydrate and 30
mg of flurazepam) with one which does
produce marked alterations in this sleep
phase,2 500 mg of glutethimide (Doriden)
was also administered using the 22-night
protocol.
Methods
Insomniac subjects for this experiment were
obtained through two general sources: (1) a
pool of subjects obtained for other studies in
our lab and (2) through public advertisements
for individuals with moderate to severe insom¬
nia. Potential subjects from either source were
screened carefully to eliminate those who were
Accepted for publication April 13, 1970.
From the departments of psychiatry (Dr. A.
Kales, Mr. Allen, and Mr. Scharf), psychology
(Mr. Allen), and anatomy (Dr. J. Kales), Sleep
Research and Treatment Facility, and the Brain
Research Institute (Dr. A. Kales), UCLA School
of Medicine, Los Angeles.
Reprint requests to UCLA Sleep Research and
Treatment Facility, 760 Westwood Plaza, Los
Angeles 90024 (Dr, A, Kales).
B.
Scharf:
not in good general health, used medications of
any type, appeared to have severe psychopathological disturbances, or did not, by history,
seem to have significant insomnia. In these
studies we chose primarily those individuals
who had moderate to severe difficulty falling
asleep—that is, required more than one hour at
least four times per week.
Design of Study.—Flurazepam was studied
initially, using four insomniac subjects. Subse¬
quently chloral hydrate and glutethimide were
studied in four additional subjects who under¬
took the 22 nights of experimental study on
two separate occasions. An interval of four
weeks separated these two series of 22 nights.
During the drug administration period of the
first 22-night study, two of the subjects re¬
ceived 500 mg of glutethimide while the other
two subjects received 1,000 mg of chloral hy¬
drate. In the second series of 22 nights, each
subject received the alternate drug. Thus, each
drug was evaluated with each subject for a
22-night series.
The experimental protocol for each of these
three 22-night series was as follows:
Nights
1-4
Protocol
Substance
Placebo
Administration
Baseline in
laboratory
5-7
Active
8-15
Active
16-18
Active
drug
laboratory
19-22
Placebo
Withdrawal in
drug
drug
Taken in
laboratory
Taken in
home
Taken in
laboratory
The first laboratory night in each series
allowed for adaptation and readaptation,
was
re¬
spectively.
Throughout
every study, the subjects were
instructed not to nap, significantly vary their
level of physical activity, or use any drugs.
During the flurazepam study, one of the sub¬
jects indicated that he had been intermittently
taking glutethimide on his own, thereby com¬
plicating our results. For this reason, data re¬
ported for flurazepam are for three subjects.
On laboratory nights, the subjects were allowed
to sleep for 8V2 hours and were continuously
monitored to obtain
an all-night electroenceph¬
alogram (EEG), electromyograrri (EMG), and
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electrooculogram (EOG). In the laboratory, the
placebo or active drug was given at lights out.
For the home trials, the subjects were instruct¬
ed to take the capsule specified for that night
at bedtime and to set the alarm clock for 8%
hours from the time they went to bed. By these
measures, we attempted to prevent any signif¬
icant excess or limitation of sleep while at
home. Subjects were asked each morning to
briefly assess whether their sleep the previous
night had been better, worse, or "average"
compared to their accustomed pattern prior to
the study.
In each study, the placebo and drug were
administered
on a
double-blind basis. In addi¬
tion, each subject's all-night sleep recordings
were
scored
independently
of
knowledge
of the
experimental conditions.3 The parameters mea¬
sured included those related to sleep induction
(sleep latency) and sleep maintenance (wake
time after sleep onset and total number of
awakenings). Other parameters measured relat¬
ed to possible sleep pattern alterations and
included quantifications of each sleep stage, the
interval between sleep onset and first REM
period (REM latency), and the total number
of REM periods.
Results
Sleep Induction and Maintenance.—Ta¬
ble 1 compares the three hypnotic drugs in
terms of their effects on sleep induction and
maintenance.
One Thousand Milligrams of Chloral Hy¬
drate.—On the first three nights of chloral
hydrate administration (nights 5 to 7) the
mean values for sleep latency showed a sig¬
nificant decrease as compared to baseline
nights 2 to 4 (31.3 vs 52.5 minutes). By
nights 16 to 18, sleep latency had returned
to baseline levels while on withdrawal
nights 19 to 22, sleep latency was slightly
increased above baseline values. In regard to
wake time after sleep onset and the number
of awakenings, there was no change as a
function of initial drug administration
(nights 5 to 7). With continued administra¬
tion, however, a decrease resulted in both
parameters on drug nights 16 to 18. This
effect was also noted through withdrawal
nights 19 to 22. While taking the drug at
home (nights 8 to 15), subjects reported
that sleep effectiveness was diminishing rap¬
idly, and this was associated with their com¬
plaint that falling asleep was becoming pro¬
gressively more difficult.
Five Hundred Milligrams of Glutethi¬
mide,—With glutethimide administration on
nights
5 to
7, the
mean
values for
sleep
latency showed a significant decrease as
compared to baseline nights 2 to 4 (38.0 vs
76.2 minutes). While taking the drug at
home (nights 8 to 15) subjective evaluations
indicated that effectiveness had diminished
quickly, and on laboratory nights 16 to 18
sleep latency was actually observed to be
slightly above baseline values. On withdraw¬
al nights 19 to 22, sleep latency decreased
slightly to below the baseline level. In re¬
gard to wake time after sleep onset and
number of awakenings, there was a slight
increase in both parameters on drug nights 5
to 7. By drug nights 16 to 18, both values
had returned to baseline. Following with¬
drawal (nights 19 to 22), wake time after
sleep onset again increased above baseline;
the number of awakenings after sleep onset
showed, however, no further change. This
meant that although subjects were awaken¬
ing no more often than they were while
taking the drug, they were staying awake
longer.
Thirty Milligrams of Flurazepam.—On
both sets of drug nights, 5 to 7 and 16 to 18,
there was a significant decrease in sleep
latency, wake time after sleep onset, and
number of awakenings as compared to base¬
line nights 2 to 4. In addition, all three
parameters remained moderately decreased
on withdrawal nights 19 to 22. The subject
reports indicated that sleep effectiveness had
continued throughout drug nights 8 to 15;
they felt they were falling asleep and staying
asleep better than was their accustomed prac¬
tice prior to entering the study.
Sleep Stage Alterations.—One Thousand
Milligrams of Chloral Hydrate.—With
chloral hydrate administration (5 to 7 and
17 and 18) and withdrawal (19 to 22)
nights there were only slight changes in the
total nightly amount of REM sleep (Table
2). (Night 16 was not included in the aver¬
ages for the second set of drug nights since
we have found that subjects show readaption to the laboratory consisting of a de¬
crease in REM sleep.4 This readaption
phenomenon occurred with each of the three
groups of subjects when they returned to the
laboratory on night 16.) On the first set of
drug nights, the percentage and absolute
amount of REM sleep was similar to base¬
line levels. On the second set of drug nights,
REM sleep was slightly decreased compared
to baseline levels. Following drug withdraw-
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Table 1.—Effectiveness of Medications
on
Sleep Induction and Maintenance
Drug
Baseline
Withdrawal
(Nights 2-4)
(Nights 5-7)
(Nights 16-18)
(Nights 19-22)
Wake time after sleep onset
Total No. of wakes
Total sleep time
52.5
21.4
9.2
437.8
85.6
31.3
23.6
9.1
455.4
89.3
48.3
12.2
5.7
449.4
88.1
61.2
8.8
5.7
440.0
86.2
Total No. of wakes
36.2
14.3
4.1
459.2
90.0
13.9*
5.0
2.7
491.7
96.4
18.8
5.3
2.4
485.2
95.1
25.4
10.4
3.2
470.4
92.2
76.2
13.7
6.8
421.9
82.7
38.0
19.7
10.9
452.4
88.7
88.3
14.3
6.8
407.4
79.8
62.9
and Dose
Chloral
Drug
Hydrate (1,000 mg)
Sleep latency
Percent sleep time
Flurazepam (30 mg)
Sleep latency
Wake time after sleep onset
Total
sleep
time
Percent sleep time
Glutethimide (500 mg)
Sleep latency
Wake time after sleep onset
Total No. of wakes
Total sleep time
Percent sleep time
* P<0.05.
(All comparisons
related means.)
are
with baseline nights 2 to 4. The statistic used
was
Table 2.—Effect of 1,000 mg of Chloral Hydrate (No.
the Student's f-test for
=
Sleep Parameters
REM
22.6
on
Sleep
(99.4)
Percent sleep stages
REM sleep
No. of REM
latency*
periods
Nights 19-22
Parameters*
22.5
20.8
(102.4)
(94.9)
24.4
(107.6)
7.0
7.0
6.0
6.2
60.4
61.3
62.1
59.8
7.9
3.2
6.8
5.7
3.2
3.5
116.7
129.3
3.7
3.7
Mean REM Minutes
First one-third
Middle one-third
Last one-third
Total
Withdrawal
Nights 17-18
Nights 5-7
cor¬
4)
Drug
Baseline
Nights 2-4
Effects
23.3
6.5
423.9
83.1
by Thirds
138.3
3.3
of
Night
11.7
5.6
5.3
30.1
40.6
29.1
57.6
99.4
56.2
102.4
94.9
60.5
6.3
3.3
107.0
3.7
12.2
34.1
61.3
107.6
* Numbers in
parentheses represent the absolute values in minutes of REM sleep. REM sleep latency is also
expressed in minutes.
al, both the percentage and absolute amount al, but none of these changes was statistical¬
of REM sleep were slightly increased above ly significant.
baseline.
Five Hundred Milligrams of Glutethi¬
When REM sleep was evaluated by com¬ mide.—On drug nights 5 to 7 there was a
paring absolute amounts in each third of the marked decrease in both the percentage and
night to corresponding baseline values, the the absolute amount of REM sleep (Table
slight suppression on nights 17 and 18 and 3). This decrease was maintained through
slight increase on nights 19 to 22 were both the next set of drug nights (17 and 18).
found to occur in the first two thirds of Following drug withdrawal (nights 19 to
those respective nights.
22), there was a marked increase above
Chloral hydrate administration and with¬ baseline levels in both the percentage and
drawal did not produce any changes in other absolute amount of REM sleep. When drug
sleep stages or the total number of REM nights (5 to 7 and 17 and 18) were further
periods. REM sleep latency was slightly evaluated by examining each third of the
increased on both sets of drug nights and night, it was noted that the majority of
slightly decreased following drug withdraw- REM suppression had occurred in the first
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Table 3.—Effect of 500 mg of Glutethimide
Sleep
REM
Effects
21.3
=
4)
Drug
Baseline
Nights 2-4
Parameters
(No.
Withdrawal
Nights
on
Sleep
(88.0)
5-7
Nights 17-18
Nights 19-22
18.3
27.0t
(114.0)
Parameters*
14.4t
(65.5)
6.0
(73.8)
8.7
5.5
6.1
66.3
66.4
56.5
6.6
6.0
7.3
6.3
3.9
4.1
3.2
REM sleep latency*
130.5
138.4
101.4
179.2
No. of REM periods
3.3
3.3
4.1
3.3
Mean REM Minutes by Thirds of Night
First one-third
6.9
6.5
18.0
4.2
Middle one-third
22.0
33.6
33.5
16.4
47.6
Last one-third
62.4
44.9
88.0
114.0
Total
65.5
73.8
* Numbers in parentheses represent the absolute values in minutes of REM
sleep. REM sleep latency is also
expressed in minutes.
2
to
are
with
baseline
P<0.05. (All comparisons
4. The statistic used was the Student's f-test for cor¬
nights
related means.)
Percent sleep stages
62.0
Table 4.—Effect of 30 mg of Flurazepam (No.
Nights 5-7
Nights
REM
Effects
18.2
on
REM sleep latency*
No. of REM periods
First one-third
Middle one-third
Last one-third
Total
Nights 17-18
Withdrawal
19-22
Nights
Sleep Parameters*
(84.0)
Percent sleep stages
3)
Drug
Baseline
2-4
Sleep Parameters
=
3.0
64.0
7.5
7.3
104.1
3.7
Mean REM Minutes
15.4
32.3
36.3
84.0
18.9
18.3
19.6
(93.0)
(88.5)
(91.7)
3.6
64.3
9.1
4.1
95.0
4.0
by Thirds of Night
11.4
30.9
50.7
93.0
2.2
6.6
76.3
3.0
69.9
0.2
3.9
0.0
126.5
3.6
117.3
3.5
7.3
18.9
28.5
44.3
26.5
54.7
88.5
91.7
Numbers in parentheses represent the absolute values in minutes of REM sleep. REM sleep
expressed in minutes.
*
latency is
also
two thirds of the night. Following drug percentage of REM sleep was similar to
withdrawal, increases in REM sleep were baseline levels while the absolute amount
found in the first and last thirds.
Glutethimide administration further re¬
sulted in an increase in REM latency on the
first set of drug nights, while withdrawal of
the drug produced a decrease. The shifts in
REM sleep were accompanied primarily by
a reciprocal change in stage 2 sleep.
Thirty Milligrams of Flurazepam.—The
administration of flurazepam (nights 5 to 7
and 17 and 18) and its withdrawal (19 to
22) resulted in only slight changes in the
total nightly amount of REM sleep (Table
4). On the first set of drug nights, the
was
increased due to
an
increase in total
sleep time. On the second set of drug nights,
both the percentage and absolute REM val¬
essentially the same as baseline.
Following drug withdrawal, both the per¬
centage and absolute amounts of REM sleep
were slightly increased above baseline.
When REM sleep was evaluated by com¬
paring absolute amounts in each third of the
night to corresponding baseline values,
REM sleep was increased in the last third of
both sets of drug nights and the withdrawal
nights. In addition, on the second set of
ues were
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drug nights, REM sleep
was decreased in
the first two thirds.
There were no significant changes be¬
tween conditions in REM latency or in the
total number of REM periods. Flurazepam
administration produced a marked, progres¬
sive decrease in stage 4 sleep which was
maintained through the withdrawal nights
(19 to 22). The percentage of stage 3 sleep
increased slightly on the first set of drug
nights and decreased considerably on the
second set of drug nights, and this decrease
was maintained following drug withdrawal.
On the second set of drug nights and the
withdrawal nights, the decreases in stages 3
sleep stage alterations with chloral hydrate
corresponds to our findings in short-term
studies with normal sleepers.1 The degree of
REM suppression and rebound produced
with glutethimide administration and with¬
drawal, respectively, was also similar to
changes attributed to this drug in our shortterm study.2 In addition, it should be noted
that the level of withdrawal REM rebound
in insomniacs following our two-week drugadministration was only slightly greater
than the REM rebound seen in our eightnight study in normal subjects. This sug¬
gests that there is probably a point at which
increased REM suppression will not pro¬
and 4 sleep were accompanied primarily by duce increased rebound, and further studies
into the implications of this phenomenon
a reciprocal change in stage 2 sleep.
are indicated.
Comment
It has been assumed that when REM
Drug Effectiveness.—The results of this suppressant hypnotics are administered at a
study showed that 30 mg of flurazepam was single clinical dose, the total REM time
effective in insomniac subjects both in in¬ returns to baseline after a few consecutive
ducing and maintaining sleep throughout nights of drug administration. Although this
the two-week administration period and for has been the case with many hypnotic drugs
several withdrawal nights as well. Both 1,- we have studied in our laboratory, we first
000 mg of chloral hydrate and 500 mg of noted an exception in our short-term glu¬
glutethimide significantly decreased sleep la¬ tethimide evaluation where REM suppres¬
tency on the first set of drug nights (5 to 7). sion remained consistent through three
The effectiveness of these drugs, however, nights of drug administration.2 The current
appeared to diminish rapidly when the sub¬ series of experiments indicates that even
jects went home and continued drug admin¬ after two weeks of glutethimide administra¬
istration (8 to 15). This could not have been tion, the REM suppression effected by this
due simply to the fact of sleeping at home drug remains consistently below baseline.
since, with both drugs, sleep latency was at This demonstrates that the REM suppres¬
baseline levels upon return to the laboratory sion produced by a single clinical dose of a
on drug nights 16 to 18. Neither chloral
hypnotic drug can persist long after the first
hydrate nor glutethimide appeared to im¬ night or two of drug administration. Simi¬
sleep maintenance consistently larly, we reported that the long term use of
prove
throughout the drug-administration period either of two hypnotic drugs, in multiple
although it should be noted that difficulty in clinical doses (1,000 mg of glutethimide and
staying asleep was not the primary com¬ 300 mg of pentobarbital) resulted in a per¬
sistent marked suppression of REM sleep.5
plaint in these subjects.
Following withdrawal of flurazepam, Both this and the current studies clearly
there remained a carry-over effect in terms demonstrate that one cannot make the gen¬
of sleep induction and sleep maintenance eralization that REM suppression with hyp¬
through several withdrawal nights. This in notic drugs does not persist beyond the ini¬
itself probably facilitates a smooth transi¬ tial few nights of drug administration.
tion through the withdrawal process and is
The marked decrease in stage 4 sleep
an advantage. However, this also raises the
produced by glutethimide in normal
possibility that, as with any hypnotic drug, sleepers2 was not apparent in the current
there may be a carry-over effect of the drug study where only a minimal decrease was
into the daytime following its use at night. noted. The marked decrease to absent stage
The possibility of the drug carry-over 4 sleep with flurazepam administration was
affecting daytime levels of performance similar to that seen in normal subjects. In
should be evaluated in future studies with contrast to REM sleep rebound following
withdrawal of REM suppressant drugs, no
all hypnotic drugs.
Sleep Stage Alterations.—The minimal rebound in stage 4 sleep was noted following
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withdrawal of flurazepam. Flurazepam pro¬ any claims can be made concerning its use
duced only minimal changes in REM sleep as a hypnotic, either in terms of sleep efficacy
in this study whereas it resulted in slight or a lack of REM sleep alterations.
The present study with 1,000 mg of chlor¬
REM suppression in normal subjects.1 In
neither study was there a REM rebound al hydrate indicates that its effectiveness in
inducing sleep is limited to several nights. If
following withdrawal of flurazepam.
a patient presents only a mild transient
number
of
are
altera¬
There
a
sleep stage
tions in these studies which merit future insomnia either chloral hydrate or fluraze¬
investigation. While the change in REM pam could be used. Since, however, our in¬
sleep distribution by thirds of the night by vestigations with 30 mg of flurazepam show
flurazepam may suggest an initial suppres¬ that it effectively induces and maintains
sion and a later rebound within a given drug sleep for at least two weeks, it would be the
night, it should also be noted that the base¬ more ideal drug if the insomnia were more
line distribution of REM sleep in the flura¬ severe or extended.
While studies involving two-week drug
zepam subjects was not normal. The amount
of REM sleep in the last third for the administration are adequate in most cases
baseline nights for these subjects was much for judging the effectiveness and sleep-alter¬
lower than that usually seen, and may be a ing characteristics of a drug, they do not tell
reflection of their insomnia. We have subse¬ us about the effects of the drug when taken
quently evaluated flurazepam in eight addi¬ over a longer interval, especially on a longtional insomniac subjects. In this study the term basis. In this regard, long-term studies
drug only minimally to slightly supressed of hypnotic drugs are necessary to demon¬
REM sleep, without REM rebound follow¬ strate if extended use produces sleep stage
ing withdrawal, produced a marked decrease alterations not found in shorter term
in stage 4 sleep, and was quite effective both studies. Additionally, it would be possible to
in inducing and in maintaining sleep. Fur¬ determine by such long-term investigations
ther, no suppression or rebound within ac¬ whether the effectiveness of a hypnotic drug
tual drug nights were noted in this study, so is maintained.
In choosing a hypnotic drug, the general
we have concluded that the changes in the
current study were related to a redistribu¬ physician can now rely on data which is
tion of sleep following drug administration. considerably more objective and quantified
We are now in the process of evaluating than was the information previously avail¬
whether the drug affects phasic aspects of able through the traditional methods of clin¬
REM sleep, ie, the number and frequency of ical observation. The evaluation of a hyp¬
the eye movements themselves.
notic drug should include the following
Future studies should evaluate whether considerations: (1) does the drug effectively
long-term use of either chloral hydrate or induce or maintain sleep, and if so for how
flurazepam produces a significant REM sup¬ long; (2) does the drug produce sleep stage
pression or REM rebound following with¬ alterations, particularly REM sleep rebound
drawal. In the current study, a REM re¬ following withdrawal; (3) if the subject is
bound was noted following withdrawal of awakened during the period of drug action,
each drug but this was less than the 10% does the drug significantly affect perfor¬
criterion we arbitrarily feel is significant.1
mance, and (4) are mood and performance
Clinical Implications.—The differential significantly affected the next day following
hypnotic effectiveness of 30 mg of fluraze¬ drug use? We have extensively evaluated the
pam and 1,000 mg of chloral hydrate indi¬ first two aspects, while studies are currently
cates that drugs can selectively induce sleep, in progress relating to the latter two areas.
maintain sleep, or induce and maintain
Technical Considerations and Interpreta¬
sleep while only minimally affecting REM tion of Data.—The sleep laboratory pro¬
sleep. We feel that any hypnotic drug which vides an excellent means for objectively and
in short-term studies appears to be effective rigorously evaluating whether or not a drug
and does not significantly suppress REM alters sleep patterns, and, in addition, par¬
sleep must also be studied, using insomniac ticularly with hypnotic drugs, a means of
subjects and a longer term protocol, before objectively determining their effectiveness.
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In a previous publication,6 we emphasized
that the validity of such sleep laboratory
studies depends on the particular methodol¬
ogy used. In order to allow for proper adap¬
tation (or readaptation if necessary), and to
determine initial and cumulative drug
effects as well as withdrawal changes, we
have recommended recording consecutive
baseline, drug, and withdrawal nights, in¬
cluding at least several nights of drug ad¬
ministration. We also recommended that all
sleep stages be scored, different drug doses
studied, and special protocols and appropri¬
ate patients used when studying drug
effectiveness.
In addition to the methodology of the
sleep-laboratory—drug studies, we feel that
the interpretation of these data, especially
in promotional material for various drugs, is
another area which should be carefully
considered.6 We do not know the spécifie
significance of the presence or absence of a
given sleep stage. Thus, it would be incor¬
rect to state that REM sleep, stage 4 sleep,
etc, are "necessary" unless these claims were
clearly substantiated with new data. The
important correlate of sleep stage al¬
most
terations so far noted relates to the rebound
in REM sleep following hypnotic drug with¬
drawal, which may be associated with unde¬
sirable clinical changes including increased
dreaming, unpleasant dreams and night¬
mares, and insomnia. We recommend, there¬
fore, that the labeling and advertisements
for REM suppressant hypnotic drugs in¬
clude a discussion of the possible clinical
changes consequent to withdrawal of the
suppressant.
Flurazepam (30 mg) was found to be
effective both in inducing and in maintain¬
ing sleep over the entire two-week drug
adnfinistration period. Chloral hydrate (1,
000 mg) and glutethimide (500 mg) signif¬
icantly decreased sleep latency on the first
set of three laboratory drug nights, but this
effectiveness appeared to diminish rapidly
within several days while the subjects slept
at home. This lack of effectiveness was con¬
firmed when the subjects returned to the
laboratory.
Chloral hydrate and flurazepam produced
only minimal changes in REM sleep. Glu¬
tethimide produced a marked REM sup¬
pression which persisted throughout the two
weeks of drug administration. Following
withdrawal, there was a marked REM re¬
bound. Flurazepam administration resulted
in a gradual progressive decrease in stage 4
sleep which was maintained through the
withdrawal nights.
These all night electrophysiological
studies demonstrate that the sleep labora¬
tory allows an accurate and objective deter¬
mination of a drug's effectiveness in induc¬
ing and maintaining sleep, the duration of
its effectiveness, and the type of sleep in¬
duced. This contrasts with traditional
studies evaluating drug effectiveness where
precise measurements of sleep or waking
cannot be made.
This study was supported in part by NINDB
Grant MB-02808, NIMH Training Grant 5 - 6415, and Anatomical Sciences Training Grant 5T01
00616. Computing assistance was obtained from the
Health Sciences Computing Facility, UCLA, and
sponsored by NIH Grant FR-3.
References
Summary
Three drugs, chloral hydrate (1,000 mg),
flurazepam (30 mg), and glutethimide (500
mg), were evaluated in the sleep laboratory
with insomniac subjects to determine their
effectiveness in inducing and maintaining
sleep. A schedule of 22 consecutive nights
was used in each separate drug evaluation.
The first four nights were placebo-labora¬
tory nights and allowed for adapting to the
laboratory and obtaining baseline measure¬
ments. This was followed by two weeks of
drug administration which consisted of three
laboratory, eight home, and another three
laboratory nights. This was in turn followed
by four placebo-laboratory nights which al¬
lowed for evaluating withdrawal changes.
1. Kales A, Kales J, Scharf MB, et al: Hypnotics
and altered sleep-dream patterns: II. All-night EEG
studies of chloral hydrate, flurazepam, and methaqualone. Arch Gen Psychiat, 23:211-218, 1970.
2. Kales A, Preston TA, Tan TL, et al: Hypnotics and altered sleep-dream patterns: I. All-night
EEG studies of glutethimide, methyprylon, and
pentobarbital. Arch Gen Psychiat, 23:219-225, 1970.
3. Rechtschaffen A, Kales A (eds): A Manual of
Standardized Terminology, Techniques, and Scoring
System for Sleep Stages of Human Subjects, Public
Health Service Publication No. 204. US Government
Printing Office, 1968.
4. Scharf M, Kales J, Kales A: Repeated adaptation and "first night" effects of the sleep laboratory.
Psychophysiology 6:263, 1969.
5. Kales A, Preston T, Tal TL, et al: Effects of
chronic hypnotic use. Psychophysiology 6:259, 1969.
6. Kales A, Kales JD: Sleep laboratory evaluation of psychoactive drugs. Pharmacol Physicians,
to be published.
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