TID versus HS dosing of lorazepam in chronic insomniacs

Abstract:
Insomniacs have both nocturnal and daytime symptoms from their sleep disorder. It is normally assumed that daytime symptoms such as fatigue and dysphoria are secondary to poor nocturnal sleep. However, it is difficult to understand how other symptoms such as increased MSLT latencies and increased metabolic rate can be secondary to poor sleep on the previous night. These symptoms, in agreement with the results of stimulation from chronic caffeine use, suggest that the daytime symptoms of primary insomniacs reflect hyperarousal. If insomniacs are actually hyperaroused throughout the 24 hours, it could be hypothesized that the maximal treatment benefit would be a 24-hour treatment strategy. In this study, it was hypothesized that TID treatment with lorazepam (0.5 mg, TID) would be more efficacious in improving both sleep and daytime function that HS treatment with lorazepam (1.5 mg HS). Insomniacs were identified based upon a history of insomnia for at least 2 years plus demonstration of sleep latencies of greater than 30 min and or sleep efficiency of less that 85% on two consecutive screening nights. Subjects meeting these criteria without other sleep disorders, drug use or significant psychopathology were invited to spend nine additional nights in the laboratory over a 2-week time span. On each week, a baseline night (placebo administration) was followed by a day of MSLT and performance tests. On the following night, Ss received either 0.5 or 1.5 mg of lorazepam 30 min prior to bedtime in a double blind manner. MSLT and daytime tests were repeated on the following day, and pills, either placebo or lorazepam 0.5 mg were administered after awakening and 8 hours later. In the lorazepam 0.5 mg condition, Ss received six consecutive doses of lorazepam (over 2 24-hour periods). In the lorazepam 1.5 mg condition, Ss received lorazepam 1.5 mg on two consecutive nights prior to going to bed. Both conditons were followed by a withdrawal night (placebo). Baseline Loraz. 0.5 Loraz. 1.5 Recovery F P Differences Total Sleep (Min) 380. 412. 424. 380. 2.603 0.1 % Stage 1 18.6 15.5 15.6 15.8 1.50 NS % Stage2 42.5 43.5 49.0 41.8 6.060 0.001 1.5 > ALL %StageSWS 8.0 13.4 12.4 10.0 4.00 0.025 BL<.5= 1.5 % Stage REM 14.6 17.7 16.8 18.6 2.554 0.1 Sleep Latency 29 26 30 56 3.172 0.1 Latency to REM 85 78 82 11 0 1.84 NS Wake Time (Min) 72 42 28 58 5.440 0.005 BL>.5=1.5, 1.5<R Sleep Efficiency 84 91 94 86 5.488 0.005 BL<.5=1.5, 1.5>R Arousal Index 16.8 11.9 11.4 12.5 5.529 0.005 BL < ALL Both doses of medication were effective in improving objective and subjective measures of sleep and in reducing nocturnal whole body metabolic rate. Latencies on daytime nap testing were significantly reduced from a 14-min average to an average of 10 and 12 min respectively in the lorazepam 0.5 and 1.5 mg conditions (see fig.). Significant differences were not found on psychomotor performance. Subjective reports of anxiety and confusion were increased in the morning after receiving lorazepam 0.5 mg in the evening but tension was reduced and subjective alertness was improved in the evening after daytime administration of lorazepam 0.5 mg (see fig.). It was concluded that daytime symptoms in insomniacs can be measured and treated; but that rebounds in anxiety near the end of metabolic activity of lorazepam may make it a poor treatment choice. However, as daytime symptoms in insomniacs become apparent, use of longer acting medications such as flurazepam or quazepam HS may be considered in patients with primary insomnia. __________________________ Supported by a Merit Review Grant from the Department of Veterans Affairs and the Sleep-Wake Disorders Research Institute.