Download Pharmacological and Medical Considerations in Hypnotic Use

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© 1982 Raven Press, New York
Pharmacological and Medical
Considerations in Hypnotic Use
T. Roth, F. Zorick, R. Wittig, and T, Roehrs
Sleep Disorders and Research Center, Henry Ford Hospital, Detroit, Michigan
The purpose of this presentation is to provide a survey of the clinical use of
hypnotics. To this end, we shall first discuss the relation of pharmacokinetic
properties and the clinical effects of hypnotics. The second part will present some
guidelines for hypnotic use based on current knowledge of sleep disorders
medicine.
There is much confusion over the definition of a sedative/hypnotic. For the
purpose of the present overview, a sedative/hypnotic is defined as any compound
that promotes sleep (sleepiness-drowsiness, falling asleep, and staying asleep) and
inhibits wakefulness (awakening, maintaining wakefulness, and functioning while
awake).
Many different groups of drugs (e.g., barbiturates, tricyclics, antihistamines,
benzodiazepines) can be and are used as hypnotics. Of the various drug classes,
benzodiazepines are the most commonly used compounds (1) and, therefore, will
be discussed more extensively than other classes.
To understand the effects of hypnotics, one must first recognize that hypnotic
drugs do not simply affect rapidity of falling asleep and time of waking. In fact,
they have multiple effects. Those biological processes currently known to be
affected by hypnotics are: (a) sleep architecture, (b) sleep physiology, (c) sleep
pathophysiology, and (d) sleep efficiency.
Effects on Sleep Architecture. Virtually all psychotropic drugs affect sleep
stages, suppressing stage 3-4, the rapid eye movement (REM) stage, or both. A
thorough review of the effects of psychotropics on sleep stages is beyond the
scope of this paper, and can be found in an article by Kay et aL (2). Benzodiazepines were once thought to have no effect on REM sleep; however, it is
well documented that benzodiazepines, like all other sedative hypnotics, suppress
REM sleep. Overall, benzodiazepines have dose-related effects on virtually all
sleep stages (3). They decrease stages 1,3 -4, and REM. In comparison with other
psychotropics, they suppress delta sleep (stage 3-4) as much as any other drug
group. On the other hand, they are mild REM suppressants as compared with
tricyclic antidepressants (4). Although the clinical effect of increasing or decreasing sleep stages is currently not well understood, the effect of drugs on sleep
Address correspondence and reprint requests to Thomas Roth, Ph.D., Sleep Center, 512 NCP,
Henry Ford Hospital, 2799 w. Grand Boulevard, Detroit, Michigan 48202.
Key Words: Hypnotics-Sleep disorders-Pharmacokinetics.
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stages needs to be documented and further investigated. Certain sleep
disorders-night terrors, enuresis, somnambulism, and sleep apnea-have been
associated with different stages of sleep (5). Clearly, drugs that affect sleep stages
have the potential to affect these disorders.
Effects on sleep physiology. Determining the effects of psychotropic drugs on
physiological function is a major factor in the assessment of drug safety. Typically, their effects on cardio-respiratory functioning are emphasized. Although
there is increasing evidence that sleeping physiology and waking physiology are in
some cases quite different, little work has been done on the effects of hypnotics on
physiology during sleep (6). This is important, because hypnotics have the greater
part of their effect on sleeping physiology. One of the few studies done on this
topic was reported recently (7). The authors evaluated the effects of two benzodiazepines (triazolam 0.5 mg and flurazepam 30 mg) on heart rate during sleep in
healthy volunteers and found that both of these benzodiazepines produced small,
but statistically reliable, increases (4- 5 bpm) in heart rate during both REM and
non rapid eye movement (NREM) sleep. In contrast, waking heart rate after oral
administration of benzodiazepines is not affected, according to previous reports.
Although these increases in heart rate are not clinically significant, this study
suggests that hypnotic drugs may affect sleep physiology differently from waking
physiology. Therefore, inferences from studies of waking physiology may be quite
misleading.
Effects on sleep pathophysiology. In referring to effects on pathophysiology,
we mean the effects of hypnotics on physiological function characteristic of specific sleep disorders. Much is said about the effects of various drugs on nocturnal
myoclonus and sleep apnea. However, there are no systematic data demonstrating
differential effects of hypnotics on sleep disorders. Recent work on the effects of
central nervous system suppressants has shown that they increase the frequency
and the duration of apnea episodes in sleep. This has been demonstrated for
alcohol (8) as well as benzodiazepines (9). Although these data are of critical
importance in using hypnotics, there are several limitations to these data, which
must be understood. First, it is essential to understand that central nervous system (CNS) suppressants have only been shown to exacerbate apnea, not create it.
There are no data to suggest that a patient with normal respiration during sleep
will develop apnea if given a hypnotic. The question arises as to whether a patient
with compromised respiration (i.e., snoring) may become fully obstructed if given
a hypnotic. Second, the consistency of this effect is unclear. Reports on the
effects of benzodiazepines on apnea are all single case studies. No statistical data
on a large group of patients have been reported to date. In fact, anecdotal reports
have been presented showing that some patients actually show a decrease in the
number ofapneas when given benzodiazepines. This inconsistency of results may
be due to (a) the night-to-night variability of infrequent apneas (10), (b) differences
among patients with different types of apnea (central versus upper airwaY-ll),
and (c) differences among patients with regard to severity of apnea. Finally, it is
unclear how benzodiazepines affect apnea. One hypothesis is that they are suppressants of respiration during sleep. An alternative explanation is that they
aggravate apneas by increasing hypoxic and hypercapnic arousal thresholds.
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This latter explanation is more appealing, as benzodiazepines do not actually
create apnea, but only make it worse. Further, benzodiazepines are known to
increase other sensory thresholds (e.g., auditory awakening thresholds). Since
apneas are a relatively common occurrence in sleep, especially in the elderly (12),
it is critical that research be carried out to clarify the relation between hypnotics
and disturbed breathing during sleep. Further, there is no systematic research on
the effect of hypnotics on other specific sleep disorders, such as restless legs
syndrome, periodic leg movements during sleep, circadian dysrhythmias, or
parasomnias.
Effects on sleep efficiency. Sleep efficiency is an index of the time in bed spent
asleep, and is reflective of both sleep induction and sleep maintenance. Sleep
induction refers to the ability of a hypnotic to induce sleep, and is usually measured by latency to stage 2 or latency to persistent sleep (first 10 min of continuous
sleep). Sleep maintenance refers to the drug's ability to keep a patient asleep after
sleep onset. This is usually measured by the number of awakenings and total time
awake after sleep onset. Virtually all hypnotics studied, if given in adequate
dosages, improve at least sleep maintenance and typically produce more rapid
sleep induction as well. It is most important to recognize that all effective hypnotics also impair waking functioning as long as they are pharmacologically active.
Measures of psychomotor functioning show significant decreases when subjects
are awake (13). These drugs also decrease the patients' ability to respond to the
external environment, as shown by increases in auditory awakening threshold
(14). Overall, it is difficult to select a hypnotic solely on the basis of efficacy.
The mqjor differences lie in their side effects and safety.
Pharmacological properties. To understand the reciprocal relationship between efficacy and safety, it is important to review the various pharmacological
and clinical characteristics of hypnotics, as well as their interrelation. Those
pharmacological properties that are clinically important include toxicity, rate of
absorption, rate of elimination, and potential for interaction with other drugs.
No drug is free of toxic effects. An index referred to as the therapeutic index, or
the margin of safety, is used to describe the relative safety of drugs. Therapeutic
index is defined as the ratio of the dose producing lethal effects in 50% of the
population to the dose producing therapeutic effects in 50% of the population. In
other words, the larger the index the safer the drug is. The benzodiazepines, as
compared with all other sedative hypnotics, have larger therapeutic indices (IS),
which is one reason they have become the preferred hypnotic. But it should be
noted that these indices have not been determined in studies on patients with
insomnia or with regard to combination with other drugs. The indices may be quite
different under these varying conditions.
Another important characteristic is rate of absorption. A drug that is rapidly
absorbed and thus becomes effective with a minimum of delay is less likely to
encourage increased dosing when the patient is not sufficiently sedated after administration. Drugs taken by mouth are absorbed for the most part from the
gastrointestinal tract. When in solid form, the dissolution of a drug becomes the
limiting factor in its absorption. Studies have assessed the effect of pharmaceutical
formulation (e.g., soft capsule versus hard-shelled capsule) on blood levels. Dif-
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ferent formulations have been shown to produce differences in blood levels within
20 to 30 min of administration, which then disappear within 60 min (16). The
critical question is, what is the clinical significance of that difference in rate of
absorption, particularly for patients with complaints of difficulty in falling asleep?
In addition to rate of initiation, the duration of drug action is also of clinical
importance. Metabolism and elimination rates are thought to control the termination of drug effect; however, the distribution of a drug is also important, particularly with single doses and highly lipid-soluble agents (17). This whole process, by
which the activity of a drug is terminated (distribution, metabolism, and elimination), is described in terms of various half-lives. Half-life, in simple terms, can be
defined as the time in which half of the drug is eliminated from the body. With the
various benzodiazepines there are great differences in half-life, which varies from
3 to 100 h (18). The clinical significance of half-life, with respect to both effects
on sleep following a single dose or repeated doses and functioning the next day,
has been documented. In general, hypnotics with longer half-lives (greater than 24
h) show increased efficacy with two or three nights of administration (19) and
increased daytime residual effects. Shorter-acting hypnotics have consistent effects on sleep with multiple administration and little or no daytime residual effects.
A final pharmacological consideration is the extent of drug interaction. It is
recognized that the activity of a drug may be modified by the presence of other
drugs. Drug interactions can arise from an alteration of the absorption, distribution, metabolism, or elimination of one drug by another. For example, when two
drugs compete for plasma protein binding sites, one is displaced, making it available in greater concentration to receptors, which then may produce a more intense
effect. On the other hand, a drug that induces metabolizing enzymes can increase
the rate of metabolism of other drugs, which then decrease in their effect. Since
ethanol is often combined with benzodiazepines, whether intentionally to improve
sleep or inadvertently, when an individual with residual blood levels after nighttime use drinks the following day, their interaction has been investigated extensively. Generally, when combined with ethanol, sedative effects of benzodiazepines are increased both at night and during the next day. Long-acting
benzodiazepines, which remain in the body for up to 100 h, may present a particular risk in this regard.
Clinical properties. The clinical properties that are important in comparing the
various hypnotics include (a) sleep induction, (b) sleep maintenance, (c) production of daytime residual amounts, (d) tolerance development, and (e) withdrawal
effects. By and large, the pharmacological properties of the various hypnotics
determine these clinical characteristics.
Sleep induction capacity is the ability of the medication to reduce the latency to
sleep. This clinical effect is determined largely by the absorption characteristics of
the drug.
The capacity of a hypnotic to maintain sleep refers to its ability to reduce the
number of awakenings from sleep and the time spent awake and to increase the
total time spent asleep. The half-life of a drug primarily determines this clinical
effect. Obviously, if a drug is cleared from the system quickly, its sleep mainte-
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nance capacity is minimal. For patients with a sleep induction problem only, this
is nut a criticai issue. On the other hand, for patients with sleep maintenance
problems this is an important question.
A daytime residual effect is present when there is disruption of a patient's
ability to function during the day following nighttime use of a hypnotic. As noted
earlier, effective hypnotics also impair waking function while pharmacologically
active. Thus the presence of a residual effect of a hypnotic is related to the half-life
of the drug. A number of studies have shown that drugs, or their active metabolites, with long half-lives (greater than 24 h) compared with shorter-acting drugs
produce decrements on a variety of performance tests and increase the probability
of falling asleep on daytime nap tests (20).
Tolerance development is simply the decline in efficacy with repeated administration of a given dose of a drug. Tolerance is related to a drug's capacity to induce
drug-metabolizing enzymes or to produce changes in receptor sensitivity; it occurs with repeated use of all nonbenzodiazepine hypnotics. The benzodiazepine
hypnotics remain effective with repeated administration-a second reason for
their popularity (21).
A final clinical issue is that of withdrawal effects (22). There is considerable
confusion regarding the use of the term withdrawal. In using this term we mean
those changes in sleep and daytime function which occur following discontinuation of the drug. Research has shown that discontinuation after repeated use of
alcohol, barbiturates, and related hypnotics is associated with a rebound effect.
That is, sleep is more disturbed after drug discontinuation than it was before
administration. Whether such a rebound effect follows the discontinuation uf
benzodiazepine hypnotics is unclear. Studies have shown some disturbed sleep
following withdrawal, and some reports have maintained that such a recurrence of
symptoms is unique to short-acting benzodiazepines. Adequate studies have not
been carried out to resolve these issues.
/
Indications for use of hypnotics. Clinically effective use of hypnotics requires
not only selecting the most appropriate medication but also understanding the
nature of insomnia. Given the current understanding of insomnia, it becomes clear
that hypnotics are appropriate for selected patients (23), and patients using them
should be carefully monitored. The single most appropriate use of hypnotics is for
transient situational insomnia. Situations such as acute stress, environmental
change, and jet lag often result in sleep disturbance. The short-term use of hypnotics in these situations is clearly indicated. Some clinicians even argue that the
acute use of hypnotics may, in some cases, prevent the development of a persistent problem of initiating and maintaining sleep. The chronic use of hypnotics is a
more complicated issue. There currently exists little or no information on the
efficacy and safety of hypnotics when taken for over one month. Despite this lack,
some speculations can be made. First, it must be recognized that chronic use of
hypnotics should not be undertaken until a thorough sleep evaluation (including
polysomnography) has been done. After an evaluation has been performed and the
degree of sleep disruption has been documented, a clinical trial with hypnotics can
be undertaken with certain patients. Specifically, patients with the diagnoses of
persistent psychophysiological insomnia, nocturnal myoclonus, and insomnia as-
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sociated with selected psychiatric problems often may benefit from a trial with
hypnotics.
Contraindications for use of hypnotics. There are four situations in which
hypnutics are clearly contraindicated. Patients with disturbed sleep associated
with sleep apnea should not be given hypnotics. Despite the fact that the precise
relationship between sleep apnea and hypnotics is not well understood, there are
sufficient data to indicate that hypnotics have a potentially negative effect on
patients with sleep apnea.
Patients who are known to use alcohol excessively should never be given hypnotics. It is well known that alcohol potentiates the effects of hypnotics. Even the
high safety margin associated with benzodiazepines is reduced when they are used
in combination with alcohol. The teratogenic effects of psychotropics are always a
major concern. Clearly, pregnant women should avoid the use of hypnotics. This
is especially critical in the first trimester. Finally, people who are subject to being
aroused and required to function in the middle of the night should avoid hypnotics.
As mentioned previously, all hypnotics that promote sleep increase awakening
thresholds and impair the ability to function adequately when awake.
Special situations. In certain situations, hypnotics are not clearly contraindicated, but should be prescribed with caution. Hypnotic use in elderly patients
always requires careful monitoring. Elderly patients present potential problems
because of their high incidence of sleep apnea (12). Furthermore, these patients
metabolize certain hypnotics more slowly, placing them at a greater risk of drug
toxicity. As the elderly also awaken more frequently during the night, having
hypnotics in their systems increases the likelihood of accidents.
Heavy snoring is frequently associated with sleep apnea. Any patient, regardless of age, who reports loud snoring should receive a followup evaluation soon
after hypnotics are initiated. Similarly, patients with lung disease often show
disturbed respirations during sleep. Evaluation of the effects of hypnotics on
respiration during sleep is necessary with these patients.
Normal drug metabolism and elimination is necessary for safe and effective use
of hypnotics. Patients with kidney or liver disease should be carefully monitored
for drug toxicity.
Misuse of medications is also a concern for the clinician. This is especially
important when medications are used chronically. Patients who are a suicidal risk
or have a tendency to abuse drugs should be carefully monitored. Finally, some
hypnotics remain pharmacologically active after the patient gets out of bed. Patients who have skilled jobs (e.g., pilots, drivers, air traffic controllers) should be
carefully monitored for morning "carry-over" effects.
Survey data on hypnotic use indicate that the majority of patients with insomnia
do not take any medications to help them sleep. In fact, hypnotic prescriptions
have decreased dramatically from 1971 to 1980. Despite this, many people continue to write about the overuse of these drugs. The seeming contradiction between these two observations reflects the fact that hypnotics are not so much
overused as they are misused. They are probably underused for transient situational insomnia and overused in treating patients with chronic insomnia of undetermined origin. The rational use of hypnotics is dependent upon the increasing
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T. ROTH ET AL.
sophistication of clinicians in the differential diagnosis of the insomnia complaint.
Only when the cause of the sleep problem is unmasked wiU ciinicians be able to
develop a rational treatment plan and to use hypnotics in a way that will be of
maximum benefit to the patient.
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