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Psychiatric Times. Vol. 11 No. 7
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Hypnotics and the Perception of Wakefulness

By Wallace B. Mendelson, M.D.
| July 1, 1994
Dr. Mendelson is director of the Sleep Disorders Center and the Cleveland Clinic Foundation in Ohio.

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."

Subjective Insomnia

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.

Forced Arousals

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.

Hypnotic Medications

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(Drug information on 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(Drug information on 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, 1975).

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, 1988).

A multicenter study of 99 insomniacs receiving 15 or 30 mg flurazepam or 15 mg midazolam(Drug information on 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 two nights.

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).

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