Judith A. Jacoby

Nocturnal Sleep and Wakefulness: Effects of Age and Sex in Normal Sleepers

Sleep patterns were evaluated in 100 normal men and women who did not have any complaints of a sleep disorder and who were divided into three broad age groups: 19-29, 30-49, and 50-80 years. Total laboratory recording time was held constant across all four study nights. The amount of nightly wakefulness was positively correlated with age; total wake time for the oldest age group was about two times that of the youngest group, due primarily to an increase in wake time after sleep onset, because sleep latency did not change with age. Within each of the three age groups, especially the two oldest groups, the greatest amount of wakefulness following sleep onset occurred in the final hours of the recording period. Sleep in men was characterized by a higher number of nocturnal awakenings, and in elderly men by a longer final awakening; however, other parameters of sleep efficiency did not differ considerably between the sexes.

Quazepam and flurazepam: Long‐term use and extended withdrawal

Two investigational benzodiazepine hypnotics with long half‐lifes, (30 and 15 mg quazepam and 30 mg flurazepam) were evaluated in 47‐night sleep laboratory studies. The effectiveness and side effects of these benzodiazepines were assessed during short‐, intermediate‐, and long‐term use. Subjects were also assessed for presence of rebound insomnia during the 15 days following abrupt withdrawal. Quazepam, 15 and 30 mg, and flurazepam, 30 mg, each were effective in sleep induction and maintenance after short‐ and intermediate‐term use. Some loss of effectiveness was noted during long‐term use of both doses of quazepam and, to a lesser extent, of flurazepam. Subjective reports of improvement in sleep latency and total sleep time were in general agreement with the objective data. During the 15 nights after abrupt withdrawal of these two long‐half‐life drugs there was no rebound insomnia, either immediate or delayed. Both drugs exerted carry‐over effectiveness on the first 2 to 3 nights after withdrawal; with quazepam this effect persisted throughout the withdrawal period. Quazepam, 30 mg, induced frequent side effects related to sleepiness. Side effects noted with 30 mg flurazepam were less frequent and severe, while the side effects with 15 mg quazepam were minimal. These data suggest that the optimal dose of quazepam is 15 mg.

Lorazepam—Efficacy, side effects, and rebound phenomena

Lorazepam, 4 mg, was evaluated in an 18‐night sleep‐laboratory study involving five insomniac subjects. Hypnotic effectiveness and effects on sleep stages and related parameters were assessed. Placebo was given on baseline nights 1 to 4, lorazepam on nights 5 to 11, and placebo was given again on withdrawal nights 12 to 18. Subjective and objective data clearly demonstrated that lorazepam was effective for both inducing and maintaining sleep. Sleep latency was reduced from a baseline value of 34.6 min to 17.9 min (P < 0.01) and total wake time was reduced from 75.9 to 38.5 min (P < 0.01). On the third and fifth nights of drug withdrawal total wake time rose above baseline levels (termed rebound insomnia) and sleep latency increased by 77% and 60% over baseline (P < 0.01). Subjective estimates of daytime anxiety also increased above baseline (rebound anxiety) during the withdrawal period. All subjects experienced severe hangover and varying degrees of impaired functioning during the first 3 days on drug. Three subjects also experienced anterograde amnesia during the day after the first drug night. These side effects diminished in intensity over the course of the study. Our results suggest that while 4 mg lorazepam may be effective in inducing and maintaining sleep, this dose induces clinically significant side effects that are followed by consistent rebound phenomena after withdrawal.

Rebound Insomnia and Elimination Half‐Life: Assessment of Individual Subject Response

Following abrupt withdrawal of five benzodiazepine hypnotics, the presence of rebound insomnia on individual subject nights was evaluated in comparison to a placebo group. During the first three nights of withdrawal, the frequency of occurrence of rebound insomnia for drugs with relatively rapid rates of elimination (triazolam, midazolam, and lormetazepam) was significantly higher than that for the placebo control group. In contrast, the frequency of withdrawal sleep difficulty for two slowly eliminated hypnotics (flurazepam and quazepam) was similar to that of the placebo control group during each of five successive three‐night segments of a 15‐night withdrawal period. These findings, based on individual subject‐night data, confirm and extend previous reports using group mean values that demonstrate a frequent, immediate, and intense degree of rebound insomnia following abrupt withdrawal of relatively rapidly eliminated hypnotic drugs and an infrequent, delayed, and milder degree of sleep difficulty following withdrawal of slowly eliminated drugs.

Quazepam and temazepam: Effects of short‐ and intermediate‐term use and withdrawal

Two benzodiazepine hypnotics, one with an intermediate elimination t½ (temazepam, 15 mg) and the other with a long t½ (quazepam, 15 mg), were evaluated in 22‐ night sleep laboratory studies. The effectiveness and side effects of these benzodiazepines were assessed during short‐ and intermediate term use. Subjects were also assessed for the presence of rebound insomnia after abrupt withdrawal. Quazepam, 15 mg, was significantly effective in improving sleep both with short‐ and intermediate‐term use, but the effectiveness of temazepam was considerably less. Although temazepam was effective for maintaining sleep with short‐term use, there was rapid development of tolerance for this effect with intermediate‐term use. Temazepam did not produce any behavioral side effects during either drug condition. The only side effect associated with quazepam was a significant degree of daytime sleepiness. After its withdrawal, temazepam was associated with some sleep and mood disturbance on the first withdrawal night, whereas quazepam had carryover effectiveness.

Lorazepam: Effects on Sleep and Withdrawal Phenomena

Lorazepam, an anxiolytic drug, was evaluated in a 2-mg dose using a 16-night protocol including 7 nights of drug trial. Initially and with continued use the drug was moderately effective in inducing and maintaining sleep. Side effects included episodes of memory impairment and confusion in 2 subjects and group mean increases in daytime anxiety and tension with continued drug use. Following drug withdrawal, there was a marked and significant worsening of sleep above baseline levels (rebound insomnia) on the third night as well as significant increases in tension and anxiety the next day. The peak degree of withdrawal sleep disturbance was several times the peak degree of sleep improvement with drug administration.

Dose‐response studies of quazepam

Quazepam, an investigational benzodiazepine, was evaluated in doses of 7.5, 15, and 30 mg in a 12‐night protocol including four nights of drug trial. All three doses were effective in inducing and maintaining sleep, with the highest degree of effectiveness after the first drug night. Carry‐over effectiveness, which was seen after withdrawal of all three doses, persisted throughout the withdrawal period after the 30‐mg dose. Quazepams effects during both drug use and withdrawal appeared to be dose related; 15 mg induced a greater reduction in wake time after sleep onset than the 7.5‐mg dose, and 30 mg induced even greater differences in both wake time after sleep onset and total wake time. Subjective reports of improved sleep were in general agreement with the objective data at each dose level. Side effects appeared to be dose related in terms of severity. The efficacy and comparatively less severe side effects of the 7.5‐and 15‐mg doses of quazepam suggest that these doses may be optimal when the drug is considered for the adjunctive treatment of insomnia.

Narcolepsy/Cataplexy III: Nocturnal Sleep and Wakefulness Patterns

Nocturnal sleep and wakefulness patterns of 50 patients with narcolepsy and cataplexy were compared to those of 50 control subjects. A sleep onset REM period (SOREM) occurred in 22 (44%) of the patients but in none of the controls. Comparisons among patients showing a SOREM, patients without this abnormality, and controls demonstrated that the timing, number and duration of the remaining REM periods did not differ across the three groups. Thus, the basic REM sleep disturbance in narcolepsy appears to relate to the timing of onset of the initial REM period. This finding lends further support to the theory of dual control of REM-NREM cycling. While narcoleptics took significantly less time to fall asleep, they had significantly more awakenings, wake time after sleep onset and total wake time. The disturbed sleep experienced by patients could not be accounted for by the presence of a sleep onset REM period or the use of medication. Nocturnal wakefulness appeared to be distributed in a regular oscillating manner throughout the recording period similar to the pattern of daytime vigilance previously reported in normal subjects. Thus, typical nocturnal dampening of daytime ultradian vigilance rhythms may be lost in the narcoleptic patient.