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APPENDIX
ASSESSING HAZARDS AND BENEFITS OF HYPNOTIC DRUGS
There are many complexities in evaluating the presumed benefits of
hypnotic drugs. Some of these emerge when one considers the question:
"What is at stake in not prescribing sleeping pills for a patient's com-
plaints of insomnia?" The risk seems to be chiefly one of subjecting
the patient to anticipatory distress while lying awake at night and/or
dysphoria during the day after a poor night's sleep. Though there may
also be the fear that loss of sleep will cause impaired cognitive and
motor skills in the daytime, as yet no published reports have documented
such deficits in various types of insomniac patients. In studies of
experimentally induced sleep deprivation of normal volunteers, two
full nights of sleeplessness are required in order to produce appreciable
impairment of psychomotor skills such as tracking (a visual-motor skill
related to driving). 1/-2/ Certain changes may be detected in the
performance of very monotonous tasks by volunteers who have been acutely
deprived of 2 1/2 hours or more of sleep for the two previous nights,
but if the deprivation has been only two hours or less, even these
subtle effects on psychomotor performance are absent. 3/ Thus, from
a strictly objective point of view, the daytime benefits of hypnotic
drugs would seem dubious, as their typical maximum effect is a shortening
of sleep latency by 10-20 minutes and a lengthening of total sleep time
by only 30-40 minutes. From a subjective point of view, of course,
relief of daytime sleepiness by means of a nocturnal hypnotic would
be valuable. Yet even daytime sleepiness is extremely variable among
insomniacs and not directly correlated with their objective deficiencies
in nocturnal sleep measures. 4/
Although there is little doubt that most hypnotic drugs promote
drowsiness and have some effect on sleep, documentation of the benefits
or efficacy of hypnotic drugs is meager and laden with difficulties
in interpretation. For example, a series of studies in general medical
hospital settings reveal that most hypnotic drugs are judged "satis-
factory" by a majority of patients and their doctors, 5/-7/ but the
basis of this satisfaction is not specified. Perhaps the hypnotic drug
is providing a tranquilizing effect on the anxious patient sleeping
in a strange and frightening place; or perhaps it provides some chemical
insulation from intrusive noises during the night. In any case, it
seems unwise to extrapolate to the presumed benefits for ambulatory
insomniacs who actually complain of poor sleep. Studies of such
patients reveal that hypnotic drugs usually do alter objective charac-
teristics of their sleep, but to what extent these effects (on sleep
latency, etc.) are clinically significant is not known. Unfortunately,
reports of technologically advanced monitoring of drug effects in the
sleep laboratory typically omit details of patients' subjective com-
plaints, before, during or after treatment. From many of these reports
a reader might get the impression that drug treatment is directed at
sleep laboratory measures and not at insomnia problems.
—155—
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At the present time, the use of hypnotics is often intended to pro-
vide symptomatic relief in many cases of insomnia of unknown etiology.
How these drugs work is not understood. But even without explica-
tion of specific mechanisms of action, efficacy studies could at least
establish whether or not a hypnotic drug reliably alleviates the com-
plaints of certain types of patients without increasing their risks.
Unfortunately, until now objectively measured sleep parameters have
not been related precisely to the complaint of the patient. Future
studies which simultaneously monitor the effects of a drug upon sleep
measures and any concomitant changes in the complaints of patients
(both nocturnal and daytime) would have the greatest potential for
accurately describing the drug's hypnotic efficacy.
A. Approaches to the Study of the Effects of Hypnotic Drugs
The following is a general framework for research on the hypnotics
which includes various types of studies, questions that should be
addressed in each, and measurements that could be taken to try to
answer the questions.
The "ideal hypnotic'' would be safe and effective. Evaluation of
this drug would demonstrate that it would cause neither coma nor
death when taken in overdose; it would not be attractive for abuse;
it would not interact adversely with other medications; it would be
free from such side effects as allergic reactions, respiratory depres-
sion, and cardiovascular complications; it would be free of hangover
effects, such as daytime drowsiness, memory and cognitive impairment,
incoordination, and adverse mood changes; it would be safe for such
special population groups as pregnant women, the elderly, and patients
with pulmonary, renal, or liver insufficiency; it would not disrupt
the order of natural sleep, including waveform characteristics; its
onset and duration of action would be consistent with clinical use
and need -- that is, it would enable patients to fall asleep quickly,
to sleep through the night, and to wake at the desired time; although
it would promote sleep, it would not anesthetize the patient so as
to render him unresponsive to a full bladder, pain, telephone calls,
fire alarms, a crying baby, or the smell of smoke; if needed for pro-
longed use, neither tolerance nor dependence would develop, and upon
cessation of treatment rebound insomnia would not occur; it would be
inexpensive; it would not disrupt the normal physiological process
associated with sleep or with circadian rhythms, such as changes in
temperature and neuroendocrine responses; and it would effectively
treat the problems of a wide variety of patients. No currently avail-
able hypnotic fulfills all these criteria.
The efficacy of hypnotic agents is particularly difficult to judge
at this time. To say that a medical treatment is effective indicates
that it cures or at least ameliorates some aspects of a specific disorder
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in a certain proportion of afflicted patients. This implies that the
disorder -- even if its etiology is unknown -- can be defined, that the
important measures of change in the patient's condition are known and
that there are appropriate controls against which to compare this
treatment (such as the natural history of the untreated disease, placebo
treatment, or an established conventional treatment.) These criteria
have not been met in the assessment of hypnotic drug treatment of
insomnia. Little data is available which convincingly demonstrates
that drug "X" is effective according to specific criteria in, say,
80 percent of patients with insomnia of type "Y" when treated under
conditions "Z't. These types of specifications would be more useful
than global statements that drug "X" is the best hypnotic.
These issues are not merely academic, but are important ir guiding
the physician in the clinical management of the complaint of insomnia.
Hypnotic agents are administered to many different types of patients,
under widely different co~ditio~s, and for varying periods of time.
The executive flying from Washington to Tokyo, the enfeebled retiree
living in a nursing home, the anxious spouse of an alcoholic, the hospi-
talized preoperative patient, the agitated depressive, and the "chronic
insomniac" all share the complaint of poor sleep but differ in their
therapeutic needs. In short, the physician needs to know what he is
treating when he decides to prescribe a hypnotic and needs relevant
outcome measures with which to judge clinical effectiveness.
Target Populations and Sample Selection
Most of the research reported in the literature has been performed
with normal young adult male subjects. Even when sleep-disturbed
patients have been studied, the tendency has been to use relatively
young patients.
Future research with hypnotic drugs should take into account the
different effects drugs may have on various populations that will use
them. Such differences may be related to age, sex, ethnic background,
pregnancy, and medical, psychiatric, or surgical problems. For example,
hypnotic drugs are often taken by people who do not normally suffer from
sleep disturbance, such as shift workers and travelers. Their responses
are probably different from those with a chronic sleep disturbance.
It would be unreasonable to expect a single drug to serve patients
of all types. Therefore, when studying a particular drug, it is
important to study subjects comparable to those who will use that drug.
One potentially misleading aspect of hypnotic' efficacy studies has been
the custom of establishing arbitrary sleep laboratory criteria for
"insomnia," such as greater than 30 minutes sleep latency, less than six
or 6 1/2 hours total sleep time, or greater than 30 minutes wake time
after sleep onset. In early studies such criteria seemed reasonable in
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view of the fact that patients' complaints were often far worse than the
objective findings. However, the sleep laboratory evaluations of insom-
niacs reviewed for this study* clearly indicate that most persons who
complain of insomnia do not meet these arbitrary criteria. In the only
available hypnotic drug efficacy study that reported on details of its
selection process, 330 "insomniac" volunteers were screened to obtain
seven patients (less than 37) who met the objective criteria. 8/ Many
hypnotic drug evaluations reviewed appear to have ignored such relevant
characteristics of sample individuals as age and sex. Another important
variable, weight, is also typically omitted from consideration, even
though, for example, preliminary evidence suggests that flurazepam
30 mg may be an excessive dose for patients weighing less than 120
pounds. 8/ Because the drug testing is generally performed using
standard dosages rather than on a mg/kg basis, a given compound would
be expected to have a much greater effect when given to a 100-pound
subject than a 200-pound subject. Since obesity may be a factor in
pharmacokinetics, height should also be reported, but almost never is.
Nighttime Measures of Hypnotic Effects and Adverse Effects
The simplest subjective measures for each night of sleep include
the subjects' own estimates of sleep latency, number and duration of
awakenings, total sleep time, and restfulness of sleep. However,
patients with sleep disturbance are known to be poor judges of their
actual sleep. During periods of relatively disturbed sleep, they
tend to exaggerate the disturbance, and during periods of drug induced
sleep they correspondingly tend to exaggerate the improvement.
Complementary to subjective impressions are the objective measures
produced by all-night EEO tracings. In addition to recording intervals
of sleep and wakefulness during the night, the EEG is also analyzed in
30-second or one-minute periods for each of five separate sleep stages
(REM and stages 1, 2, 3 and 4 of Non-REM) and these are further analyzed
to define various patterns for the entire night, such as percentages
of the stages, latencies to the onset of the stages, duration of each
sleep cycle and number of shifts among sleep stages during the night.
Hypnotic drugs all produce disruptions in these phenomena, with possible
(but far from certain) implications as to efficacy and safety. A hypnotic
drug that affects sleep stages 3 or 4 may have implications for elderly
people since these sleep stages normally decrease with age. Most
hypnotics decrease REM sleep during one or more consecutive nights of
*These are tabulated in the technical supplement to this report
and summarized in Chapter 4.
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medication, and this is often followed by REM rebound upon discontin-
uation of the drug. Although the full implications of these effects
are not known, there is no question but that the normal mechanisms
of sleep are upset in the process.*
Unfortunately, in many study reports, the definition of such
terms as "total wake time" or "sleep efficiency" is unclear. Similarly,
there is no standardization of laboratory procedures at bedtime, or
whether the subjects are awakened after eight hours or allowed to sleep
ad libitum. Results from different laboratories are often not comparable
because of these omissions.
Adverse effects of a hypnotic drug on respiratory, cardiovascular,
and neuro-endocrine physiology should be determined during nighttime
monitoring. Effects on respiration are particularly important because
a depression of respiratory function could have lethal consequences in
patients suffering from sleep apnea or other respiratory difficulties.
Artificial awakenings of the subjects should be included to
evaluate the subjects' ability to become reoriented, reasonably alert,
and capable of good mobility should these be necessary in real life
situations when hypnotics are used. As stated earlier, the effect
of a hypnotic should not be that of temporary anesthesia, nor should
there be disorienting and amnesiac effects as a result of the drug.
There is one recent report suggesting that flurazepam may cause such
a sound sleep that the noise of home fire alarms might not awaken people
in time to attend to their safety. This was not a problem with pento-
barbital. 9/ There are reports that flunitrazepam (not yet marketed
in this country) has powerful amnesia-inducing effects that could pose
practical hazards in clinical use. 10/
Because people commonly mix alcohol with sleeping pills at bedtime,
despite medical warnings, it could be useful to test combinations of
new hypnotics with low doses of alcohol to see if especially deleteri-
ous effects on nighttime physiology or psychomotor performance are
demonstrable.
Daytime Measures of Hypnotic Effects and Residual Adverse Effects
There are two reasons why assessments of daytime functions should
be included in the clinical evaluations of hypnotic agents. First is
the necessity to determine the safety and side-effects of drugs. At
*Even more highly sensitive reflections of drug activity may be
obtained through the examination of EEG waveform activity. Waveforms
of particular current interest are sigma spindles (which occur through-
out non-REM sleep but are especially associated with stage 2) and
delta waves (which are used to define stages 3 and 4~.
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present, such evaluations are commonly limited to monitoring a few
variables in subjects' moods and physiological functions. The standard
evaluation procedures should be expanded to include measures of addi-
tional subjective effects and measures of certain behavioral functions.
The subjective measures can contribute information on both the abuse
potential of the drug and the mechanisms of the subjects' response
to the drug. For example, it may be that a drug that produces subjec-
tive euphoria has a greater abuse potential than a drug that does not
have this effect, or that euphoria contributes significantly to a
subject's retrospective positive assessment of the drug's effectiveness
the night before. Measures of behavior such as cognition, memory,
coordination, automobile driving skill, and alertness are necessary
to determine whether important waking functions are impaired.
The second reason for including assessments of non-sleep functions,
and particularly behavioral functions, is the potential they offer for
demonstrating heretofore undetected benefits of the drug. For example,
increased sleep in insomniacs ought to lead to better daytime function-
ing, although no study has ever demonstrated this.
An appropriate battery of tests for the assessment of non-sleep
functions would include measures of mood, psychomotor and cognitive
functions, and daytime alertness. Since substantial psychopathology
is found in many insomniacs, it would be interesting to determine the
effect of hypnotic treatment on measures of emotional disturbance.
Because daytime sleepiness is one of the most common side effects
of hypnotic agents, daytime alertness requires special evaluation
procedures. Both subjective and objective measures should be used.
An instrument such as the Stanford Sleepiness Scale can provide subjec-
tive ratings, while polygraphic monitoring during multiple daytime
sleep-latency tests can provide objective measures. 11/
Assessing daytime psychomotor performance is of special concern
because of potential hazards in driving or in operating heavy machinery.
In recent years it has been recognized that there are several different
paths to impaired psychomotor performance, each of which could result
in potentially hazardous decrements in ability to drive automobiles
or handle complex machinery. The following recommendations are offered
with this potential public health issue in mind - especially since
the hypnotics most commonly prescribed in North America and Europe
(flurazepam and nitrazepam) produce active metabolites that, when taken
nightly, remain present all day long at high levels.
A battery of standard performance tests would include measures of
gross motor coordination (balance board), fine motor coordination
(Purdue Pegboard, symbol copying test), cognition (Digit Symbol Sub-
stitution Test), perception (critical flicker-fusion threshold),
short-se con memory and long-term memory.
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In the past decade, however, several tests have evolved from traffic
safety oriented research that also should be included in the laboratory
protocols for testing the residual effects of hypnotics. Ideally, a
driving simulator should be included. 12/ In addition there should be
difficult tasks requiring eye-hand coordination and tracking ability, as
well as information processing tasks requiring divided attention. 13/-14/
Reaction time should be measured under various conditions -- especially
in monotonous tests of vigilance versus drowsiness. 15/ Substantial
impairment in any of these tests, even in the presence of adequate per-
formance on other tests, could be indicative of a deficit with practical
significance for traffic and industrial safety. 16/ Obviously, standard
measures of mood and overall alertness should be included, 17/ as well
as the subjects' own estimates of their daytime performance.
An especially hazardous combination is the presence of impaired
performance along with a subjective assessment of normal performance.
Some authors have suggested there might actually be a small benefit
to experiencing daytime sleepiness or other hangover effects of
hypnotics -- these symptoms may serve to warn the subject that his
body is still being influenced by these drugs. In two studies,
subjects did not report a significant sense of impairment after noctur-
nal use of nitrazepam, although their motor and attention skills were
indeed decreased. 18/-19/ Subjects who had received a barbiturate --
butabarbital or amobarbital -- and subjects who had received flurazepam
acknowledged their impaired performance as they were still somewhat
sleepy during the test periods. 18/-19/-20/
Testing should be done at different times of the day, especially
when it is known that a hypnotic or its active metabolites is long-lived.
Blood samples to test for the hypnotic and its metabolites should
accompany the testing to add further confirmation that drug effects
are indeed related to pharmacokinetics. 19/-20/
All drugs should be tested for daytime interaction with alcohol.
On some tests nitrazepam, flurazepam and diazepam have remarkable
additive effects with alcohol, and in this dimension present potential
problems greater than those posed by nightly consumption of barbi-
turate hypnotics. 19/-20J-21/-22/
Assessments must be made of hypnotics not only in acute studies
that would resemble the clinical situation of use for only one to
three nights in a row, but also in situations that resemble chronic
nightly use (7-14 days or more). Certain assessments of comparative
safety made after one or two nights' administration might be reversed
in the more chronic situation once the hypnotic with the long-lived
metabolites has accumulated in the body (and indeed this appears to
be the case in comparisons of flurazepam with barbiturate hyp-
notics). 20/,23/
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It has been learned in recent years that well-trained subjects, who
have learned to perform well on the difficult coordination and attention
tasks referred to above, are the ones in whom the investigation of
potentially deleterious drug effects will be most productive. Inter-
estingly, untrained (and presumably anxious) subjects will sometimes
improve their performance if given sedative or anxiolytic medication,
which helps them learn the task more rapidly than if their anxiety
remains high. It is the well-trained subjects upon whom the deleter-
ious effects of drugs can be most clearly seen; and, of course, the
variable of practice on the complex task has already been accounted
for. 22/
Drugs should be tested both in middle-aged and elderly volunteers
and insomniac patients. Drugs deemed to have little or no residual
effect at low doses in 20 year aids may have considerable effects
at those doses in 40 year olds. 18/ As noted elsewhere in this report,
most hypnotic medication is prescribed for middle-aged and elderly
people, and yet most research is conducted on young adult student
volunteers. Barbiturates seem to have a fairly constant level of ad-
verse residual reactions with age (mainly, unacceptable daytime drow-
siness), but benzodiazepines have an increasing level of adverse
reactions with age. It has been estimated that the half-life of
benzodiazepines is twice as long in someone over 70 as it is in some-
one 20 years old. 24/
Overall Study Design
Assessment of a hypnotic drug's effects would logically include
four different types of studies described by Kay, et al: 25/
(1) pilot studies, in which potential drug effects are described;
(2) dose-effect studies which establish minimum effective dosage,
maximum tolerated dosage, therapeutic range, and relative potency
in comparison to a standard drug; (3) short-term studies, in
which acute tolerance, if any, is characterized and optimal dosage
and characterization of the recovery from accumulated drug is
established; and (4) long-term studies, in which maximum tolerance
can be assessed, along with the nature of chronic toxicity, if any.
Such studies will also reveal syndromes that may appear after the
drug is withdrawn.
In evaluating hypnotic drugs it would be useful to compare
standardized measurements for each in relation to certain standard
drugs. Distinctive patterns characteristic of each drug could then
be obtained. Likewise, determination of approximately equivalent
dosages of various drugs facilitates realistic comparisons in further
studies. (Many studies have been biased in favor of one drug over
another by using dosages which are grossly unequal in hypnotic
potency.)
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Animal pharmacology, including sleep pattern analysis, obviously
would precede the testing of drugs in man. Such animal testing should
include comparisons with standard drugs. A broad range of effects should
be evaluated in several species, including measures of anti-wakefulness,
specific sleep mode promotion, toxicity and drug dependence. This might
allow investigation of mechanisms of sleep induction or maintenance and
allow distinctions to be made among the effects of different drugs.The
pharmacokinetics of drugs in relation to such effects should be included
and pursued in subsequent human studies.
B. Daytime Residual Effects of Hypnotic Drugs
Overview
There is a growing body of evidence that hypnotics may continue to
influence the nervous system throughout the day following nocturnal
administration. This is manifested in changed performance on psycho-
motor testing and in altered EEG patterns. The practical significance
of these changes is as yet unclear. However, they point to the possi-
bility that persons taking hypnotics may perform their daily tasks
with diminished skill, and may potentially be more likely to suffer
harm from accidents. The potential for adverse drug interaction with
alcohol is also present, at least with flurazepam and nitrazepam, all
day long.
Particularly troublesome is the observation that subjects may be
unaware of their decreased performance following hypnotic use. This
would seem to put them at a potentially greater risk of harm when
engaging in tasks requiring alertness and coordination such as opera-
ting an automobile, airplane or industrial machinery. It is not
clear from the available evidence that getting a good night's sleep
is essential to maintaining skilled performance of psychomotor tasks,
and there is some evidence to suggest that the residual deleterious
effects of some hypnotic drugs on daytime functioning could outweigh
any benefits which may be derived from a feeling of having slept well.
More research is needed testing normals and insomniac patients
at various times of the day with various doses of nocturnal hypnotics,
as well as epidemiological studies of drivers and machinery opera-
tors* who may be either insomniac or taking hypnotic drugs or both.
*A prospective study of Israeli industrial accidents in relation
to workers' sleep problems and/or hypnotic drug use was begun in 1978,
under the direction of Dr. P. Lavie of Haifa University.
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Findings
The half-lives of the commonly used hypnotics vary widely, but
typically are much longer than the few hours needed to aid sleep.
This may have implications for daytime functioning of persons who take
this medication. After a single nocturnal dose of flurazepam, for
example, its powerful metabolite, N-desalkylflurazepam remains in the
body with a half-life of 50 to 100 hours. The following day it may
have undesired effects on the person's alertness or coordination.
If the drug is taken for several consecutive nights, there will be an
accumulation of the drug in the body which potentially increases the
risk of untoward effects during the day. 26/,24/ Alcohol ingestion
during the day could also prove hazardous because of additive
effects. _/
A variety of studies have examined the influence of hypnotics on
daytime performance measures, including tests that measure finger
tapping rate, simple auditory reaction time, complex visual reaction
time, adaptive tracking tests, card sorting speed, and the digit-symbol
substitution test. The latter two tests may be divided into different
components intended to parse out drug effects on motor skills and on
cognitive functions. A few laboratories have investigated coordina-
tion skills directly with simulated driving.
Most of the laboratory studies have examined the effects of the
benzodiazepines or barbiturates on psychomotor tasks, compared to
placebo, other hypnotics, alcohol, and combinations of the drugs
with alcohol. No pharmacologic class of hypnotic has been shown to
be benign in this regard. In one study, the changes in performance
following single doses of hypnotics lasted in the range of 10 to 16
hours 27/ and in another 34 hours. 28/ There is also evidence
that cumulative effects can occure One study found that following
one night of administration of N-desmethyldiazepam (an active
metabolite of diazepam) there were no performance decrements,
but after seven nights there was decreased daytime performance
in tests of visual-motor coordination. 29/ The benzodiazepines
appear to impair motor skills particularly, while barbiturates
mainly affect cognitive functions. 30/
Occasionally performance will be improved on some tasks.
Such improvements are usually isolated findings, however, and not
evidence of generally improved functioning. In one simulated
driving test chronic administration of diazepam was associated
with improved reaction time and slightly improved coordination
when the simulated vehicle was going at a fixed speed. 21/ This
may have been related to an anti-anxiety effect upon the untrained
subjects. In the same study, however, the diazepam subjects
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drove faster and made more mistakes when they were allowed to control
the speed themselves a manifestation, perhaps, of poorer self-
control.
Because of the widespread prescribing of flurazepam, it is
particularly important to closely examine those studies which have
measured its effects on daytime functioning. Four research groups,
three in Great Britain and one in Finland, have established signifi-
cant patterns of impairment, especially of eye-hand coordination,
as a daytime residual effect from nocturnal doses of flurazepam.*
In the first report, normal subjects received single doses of
either 15 mg or 30 mg of flurazepam and were tested the next day with
an assortment of psychological tests as well as an electroencephalogram.
The electroencephalogram showed changes up to 18 hours following the
administration of the drug; impairment on the symbol copying test was
observed up to 12 hours following the dose of the drug. 30/ The symbol
copying test is essentially a test of visual-motor coordination and
speed, not requiring coding or complex cognitive skills. 31/,32/
Both doses of flurazepam significantly impaired performance on this
test. The subjects also did poorly on the digit symbol substitution
test that requires both motor function and cognitive skills. In the
view of the authors, it was a motor impairment that flurazepam had
induced.
Anxious, insomniac patients who were tested in a British medical
office practice on the eighth day after they had been receiving nightly
doses of 30 mg of flurazepam manifested definite impairment of visual-
motor coordination. Patients in the same study who received only 15 mg
doses did not exhibit such impairment. 34/
At the Royal Air Force Institute of Aviation Medicine, volunteers'
perfo~ance on reaction time and on an "adaptive tracking" test (similar
to eye-hand coordination skills used by airplane crews) was impaired
by one 30 mg dose of flurazepam until the early afternoon of the next
day. _/
In later research, the R.A.F. researchers tested the hypnotic
efficacy and residual effects of several drugs. They reported that
a single 10 mg dose of diazepam was an effective hypnotic whose
*In the United States, one small preliminary study revealed that
both flurazepam and secobarbital adversely affected cognitive-associa-
tion tasks and visual-motor performance. Secobarbital's daytime effects
wore off with continued nightly administration. Flurazepam's daytime
effects were not studied during prolonged treatment, nor were they
followed up in subsequent reports. 33/
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30
32
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~ ~_J a_ ~ ~ eA&C&~11] ~ ~ ~~ ~ &1C ~
Clinical Pharmacology and Therapeu-
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—198—
Representative terms from entire chapter:
clinical pharmacology
