Hypnotics and the Perception of Wakefulness

Given such widespread subjective reports of improved sleep with benzodiazepines (e.g., Rickels), and these relatively modest improvements in polygraphically measured sleep, two possible hypotheses come to mind: First, in the future, efficacy will be demonstrated more substantially as subtler polygraphic measures are developed. Second, the benefits of hypnotics on subjective sleep may involve mechanisms other than altering features that can be detected polygraphically. In an effort to explore this latter possibility, we have given various clinically used hypnotics and placebo to insomniacs in the experimental paradigm previously described.

In an early study we gave the benzodiazepine hypnotic triazolam(Drug information on triazolam) (Halcion) 0.25 mg to insomniacs 30 minutes before bedtime (Mendelson and Maczaj, 1990). There was an increase in the auditory arousal threshold five minutes after "lights out," during Stage 2, and intermittent waking time (it seems likely this was not as evident during Stage 4 and REM sleep, due to their higher arousal thresholds with placebo).

Although the only drug effect evident on the polysomnogram was an increase in non-REM sleep, the insomniacs reported in the morning that their sleep was deeper and more restful, that they had fallen asleep more quickly and slept longer than on placebo. During the forced arousals from Stage 4 sleep, they were more likely to report having been asleep on nights with active drug compared to placebo. Thus, in spite of relatively modest improvements in the sleep EEG, their overall impression was that sleep was markedly improved.

In a follow-up study reported in 1993, we gave three doses of triazolam (0.125, 0.25 and 0.375 mg) and placebo to 15 insomniacs, and again awakened them at the same five time points across the night. On the active drug nights, the insomniacs were only half as likely to report that they had been awake compared to placebo nights, at all time points combined. In more recent work (Mendelson, submitted), we have determined that this effect is not unique to triazolam, as it also occurs with 10 mg of zolpidem(Drug information on zolpidem). On placebo nights, insomniacs reported having been asleep in only 30.9 percent of forced arousals, while after zolpidem, this rose to 54.7 percent (p<0.03). This effect seems specific to drug actions on insomniacs, insofar as a similar study with normal volunteers found no drug-induced alterations in the percentage of reports of having been awake or asleep (Mendelson, submitted).

Several interpretations of these studies could be considered. One of these, mentioned earlier, is that insomniacs may suffer from a difficulty in perception of being awake or asleep, and in effect have a dissociation of the experience of being awake or asleep and the traditional polygraphic measures of these states.

If so, one interpretation of the considerable and subjective benefits of these drugs-in the context of relatively modest polygraphic improvement-might be that one aspect of their therapeutic effect (as measured by morning reports of improved sleep) involves drug-induced alterations in the perception of being awake or asleep. In effect, after taking some hypnotics, insomniacs may behave more like normal controls in terms of their ability to perceive wakefulness and sleep. In normal controls a drug effect is not seen because there is not a significant subjective/objective sleep dissociation in baseline conditions.

In closing, I would like to mention one interesting speculation about hypnotic medications. Virtually all benzodiazepine hypnotics have been reported to have various effects on cognition. According to Greenblatt, these can usually be predicted by the kinetics of the particular compound. Traditionally, such actions have been considered undesirable side effects, and much effort is being expended to develop "specific" hypnotics that induce sleep without altering cognition. One possibility that we might consider, however, is whether such an ideal drug would be possible. If indeed one mechanism by which hypnotics improve subjective measures of sleep is by altering perception of wakefulness, it may be that the cognitive "side effects" of these drugs are in actuality a reflection of the therapeutic effect, when the drug's kinetics are such that it is seen in the daytime.

Acknowledgment: The study by Mendelson (1993) and the two studies by Mendelson (submitted) were partially supported by NIMH grant no. 1RO1MH4776901. The study of Mendelson and Maczaj (1990) was partially supported by a grant from the Upjohn Co.