Hypnotics and the Perception of Wakefulness
Hypnotics and the Perception of Wakefulness
Insomnia, the subjective sense of having inadequate quantity or
quality of sleep, may result from a variety of causes. In its
chronic form, such etiologies may include psychiatric disorders
such as depression or anxiety, medical illnesses, medications,
substance abuse, circadian dysrhythmias and pathophysiologies
intrinsic to sleep such as sleep apnea or periodic movement disorder.
When these conditions have been ruled out, however, there remain
two very interesting groups that at this time are best understood
in psychophysiological terms.
In the first form, conditioned insomnia ("chronic psychophysiologic
insomnia"), sleep is disrupted because the act of going to
sleep has become associated with anxiety-related behaviors incompatible
with sleep, and excessive efforts are made to try to fall asleep
that are counterproductive (Mendelson, 1987).
The second form is subjective insomnia, characterized by a disparity
between the degree of sleep disturbance reported by the patient
and that seen by a sleep study (polysomnography). Typically, such
a patient will come to the clinic complaining of taking an hour
to fall asleep and then sleeping only three hours. The sleep study,
however, might reveal that in physiologic terms he or she fell
asleep in 30 minutes and slept six hours.
If the unwary physician should later meet with the patient and
report that he or she "in fact" did sleep adequately,
the patient is unlikely to believe such report. Also, the patient
may feel that the doctor doesn't believe him or her. Such intriguing
and difficult patients are the subject of this paper, and for
shorthand they will be referred to as "insomniacs."
One of the first insights into subjective insomnia came from the
classic study by Rechtschaffen (1968), in which he reported that
when poor sleepers were awakened 10 minutes after the first sleep
spindle, they were more likely to report that they had been awake;
in contrast, good sleepers were more likely to report that they
had been asleep.
Moore and colleagues, Coates and colleagues, and Mendelson and
colleagues subsequently described a similar phenomenon. The model
which we used involved awakening the subject with a 500 Hz electronic
tone of progressively increasing amplitude (two dB every three
seconds) at five time points across the night:
- 5 minutes after "lights out," at which time subjects
have empirically been found to be awake;
- 10 minutes after the first sleep spindle (in all studies subjects
have been in Stage 2 sleep at that point);
- 10 minutes after the onset of Stage 4 sleep;
- 5 minutes after the onset of rapid eye movement (REM) sleep;
- during the first period of spontaneous waking time after the
first REM period.
During these events, which we shall refer to as "forced arousals,"
an investigator enters the room and asks each subject a series
of questions, including whether he or she was awake or asleep
and whether the subject had been dreaming. The investigator also
administers a brief rating scale, the Dream Complexity Scale (Foulkes
and Vogel), which helps determine the subject's perception of
state of consciousness. These data, combined with the polygraphic
sleep stage and a measure of the amplitude of the electronic tone,
provide the basic observations which we shall discuss.
In our 1986 study that contrasted insomniacs and age- and sex-matched
controls, the amplitude of the electronic tone needed to awaken
the insomniacs and good sleepers was similar, suggesting that
subjectively poor sleep may not necessarily be the same as "light"
sleep (as determined by the amplitude of a stimulus needed to
induce an arousal). It was found, though, that insomniacs reported
having been awake in 71 percent of the forced arousals across
all time points; this was significantly (p<0.05) more often
than the 44.6 percent found in the normal controls. The consistency
of this observation suggests its incorporation into any theory
of the mechanism of insomnia, and the implication to us has been
that insomniacs may suffer from a dissociation between the perception
of being awake or asleep and the physiologic measures of waking
and sleep, at least as we know how to assess them at this point.
A second insight into insomnia may come by studying medications
used to treat it: clinically used hypnotics such as the
benzodiazepines and newer nonbenzodiazepine hypnotics such as
zolpidem (Ambien). There seems little doubt that in a short-term
sense, i.e., measured in terms of a few nights, they provide substantial
relief from insomnia, as measured by the patient's report in the
morning (although in chronic nightly use their benefits are less
clear due to issues of tolerance). Indeed their acceptance by
patients is striking. Although hypnotics are substantially less
widely used than antidepressants, nonetheless approximately 2
percent to 3 percent of the population has taken them sometime
in the past year, according to Mellinger and Balter. Shader and
colleagues found that approximately 20 million prescriptions are
written annually for this purpose.
One interpretation would seem to be that many patients get relief
from these agents. Such a view would be supported by the observation
of Balter and Uhlenhuth that approximately 70 percent to 80 percent
of people who have taken the most common benzodiazepine hypnotics
in the past year say that they would want to take the medication
again should the need arise.
In contrast to this relatively high rate of acceptance of clinical
hypnotics, at least for short-term use, is what I believe to be
relatively modest improvement in polygraphic measures of sleep.
To give but a few examples:
In one of the major studies of the efficacy of flurazepam (Dalmane),
a 30 mg dose led to an increase in total sleep of only 6 percent
to 8 percent during one month of administration; sleep onset time
was improved only on nights 11 through 13 (Kales and associates,
When 30 mg flurazepam was given to insomniacs for five weeks,
total sleep rose by only 21 minutes (Mitler et al., 1984).
A one-week trial of 15 mg flurazepam given to insomniacs for
one week increased sleep by a mean of only 29 minutes (Roehrs
and colleagues, 1982).
Patients on chronic low doses of benzodiazepines have similar
sleep to nonmedicated insomniacs in terms of total sleep, sleep
onset time and waking time after initial sleep onset (Schneider-Helmert,
A multicenter study of 99 insomniacs receiving 15 or 30 mg flurazepam
or 15 mg midazolam (Versed) for two weeks found no polygraphic
improvement of sleep on the first night with flurazepam, although
patients reported in the morning that they believed that they
had slept longer (Kripke et al., 1990). The few significant polygraphic
improvements in sleep with either drug were only on the first
A literature review of all studies of hypnotics that achieved
basic standards of quality found that they increased sleep by
a mean of only 35 minutes (Gillin and Mendelson, 1981).