Download tWallace B. Mendelson, tHerbert Weingartner

Sleep, 5(4)350-360
© 1982 Raven Press, New York
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*,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.
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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
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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
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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
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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
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AM
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TABLE 2. Effect of flurazepam on EEG sleep measures
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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-
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TOTAL SLEEP TIME - EEG
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HOW MUCH TIME 010 YOU SLEEP LAST NIGHT?
Sleep Questionnaire
(7-8 hlS')f:
(6-7 hrs.)
(5-6 hrs.)
(4·5 hrs.)
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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
-
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t
rt'
Not at All:":
_
HOW MANY TIMES 010 YOU AWAKEN
DURING THE NIGHT?
Sleep Questionnaire
~
~p=.019
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(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
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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
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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.
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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.
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