Chronic benzodiazepine usage and withdrawal in insomnia patients

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Abstract

We studied the sleep of patients with insomnia during continuous and very long-term use of benzodiazepines (BZDs), and after withdrawal. A group of 25 patients (mean age 44.3±11.8 years) with persistent insomnia, who had been taking BZDs nightly for 6.8±5.4 years was selected. The control group was comprised of 18 age-matched healthy individuals. Sleep stage parameters were analyzed during Night 1 (while taking BZDs), Night 2 (first night after completing BZD withdrawal), and Night 3 (15 days after gradual BZD withdrawal). Sleep data for control subjects was monitored in parallel. Sleep EEGs of the patients were analyzed using Period Amplitude Analysis (PAA), during Nights 1 and 3 only. During BZD use, a significant reduction of Total Sleep Time (TST) and increased sleep latency were found in the insomniac group when compared to controls. We found an increase in stage 2 non-REM (NREM) sleep, and a reduction in Slow Wave Sleep (SWS) when comparing to night 3 (after withdrawal). Sleep EEGs analysis showed an increase in sigma band and decrease in delta count in stages 2, 3, 4 NREM and REM sleep in the BZD group when comparing to night 3 (after withdrawal). During the BZD withdrawal period, six out of nine subjects taking lorazepam failed withdrawal. In the remaining 19 subjects, gradual withdrawal of BZDs was associated with immediate worsening of nocturnal sleep, as indicated by sleep parameters. However, 15 days after withdrawal (Night 3), some of the sleep structure parameters of patients were not significantly different from baseline (while taking BZDs), except for a significant increase in SWS and in delta count throughout most sleep stages, and a decrease in stage 2 NREM sleep. These values were not different from those shown by control subjects. REM sleep parameters showed no significant variation across the experimental conditions. Subjective sleep quality was significantly improved on Night 3 compared with Night 1. Conclusions: Chronic intake of BZDs may be associated with poor sleep in this population. A progressive 15-day withdrawal did not avoid an immediate worsening of sleep parameters. But at the end of the protocol, SWS, delta count, and sleep quality were improved compared to those recorded during the chronic BZD intake, despite the lack of change in sleep efficiency.

Introduction

Benzodiazepines are among the most widely prescribed of all psychoactive drugs. Problems resulting from their chronic use, such as dependence, tolerance, long-term memory impairment, and altered sleep structure, are documented in the literature (Busto et al., 1986, Gorenstein et al., 1994, Griffiths and Weerts, 1997, Lader and Russell, 1993, Murphy and Tyrer, 1991). Increased mortality risk has also been found to be associated to BZD consumption (Kripke et al., 1998) and chronic use of BZDs results in a decreased number of GABA-A receptors in the brains of animals (Chiu and Rosenberg, 1978, Miller et al., 1988, Sher et al., 1983). On the other hand, a part of chronic BZD users expressed some continued efficacy of the BZD (Ohayon et al., 1998, Ohayon et al., 1999).

Short-term use of BZDs alters both sleep structure and sleep EEG. An increase in stage 2 NREM sleep, a decrease in SWS, and a prolonged REM sleep latency are most commonly reported. BZDs also increase fast EEG frequencies and sigma activity (which includes sleep spindles) and reduce delta frequencies as shown by spectral analysis of the EEG during sleep (Borbély and Achermann, 1991, Borbély et al., 1985, Uchida et al., 1996). Interestingly, GABA agonists like muscimol have the opposite effect, increasing slow frequencies (delta power) in the EEG and reducing fast frequencies (above 12 Hz) (Lancel et al., 1997). There is limited data available in relation to the effects on sleep of chronic (defined as over one year) and uninterrupted use of BZDs for insomnia, or the consequences of BZD withdrawal after long-term use (Schneider-Helmert, 1988). Nonetheless, efforts have been made to obtain successful withdrawal from BZD use (Genton et al., 1994, Lemoine and Ohayon, 1997, Pailhous et al., 1994, Rickels et al., 1990, Ries et al., 1989, Schweizer et al., 1991, Shapiro, 1994, Smits et al., 1996).

We addressed the following question: What are the sleep structure and sleep EEG of “primary insomnia patients” who continue to complain of poor sleep after ingesting BZDs for over a year, and how do they compare to those of age-matched normal controls? Does gradual drug withdrawal over 15 days have an impact on these sleep variables?

Section snippets

Subjects

Sixty patients were seen for the complaint of chronic insomnia, despite the use of BZDs, at the Sleep Disorders Clinic and the Psychiatry Ambulatory Clinic at the Federal University of São Paulo over a 4-month period. They were then recruited to participate in the study according to the following inclusion criteria: complaint of poor sleep for over a year associated with chronic and uninterrupted use of BZDs.

All insomnia subjects were submitted to clinical interviews and clinical evaluation

General results

The average duration of the continuous BZD intake was 6.8±5.4 years, with a minimum of 2.2 years, and maximum of 14 years.

Sleep diaries showed no report of regular napping during the day or intake of caffeine or alcohol over the course of the study. The urine samples from Night 3 did not show evidence of BDZ relapse.

Withdrawal failures

Six patients dropped out of the study before the end of the withdrawal period due to difficulties associated with benzodiazepine withdrawal. The symptoms were: significant increase

Discussion

We performed a non-blind clinical study on a group of patients seen in clinical practice and rarely studied polysomnographically: chronic users of benzodiazepines with regular drug intake who still complain of insomnia. We defined “chronic” as nightly BDZ usage for more than one year, aimed at sleep induction and sleep maintenance. Our sample reported much longer regular usage periods, with a mean of nearly 7 years and a minimum of 2.2 years. These patients consulted sleep specialists because

Summary

An altered sleep structure is associated with chronic BZD intake. Significant improvement of sleep is observed after withdrawal, on Night 3, in this group of insomnia subjects. Interestingly, 15 days after BZD withdrawal, SWS percentage of TST and delta count on most sleep stages were similar to control subjects. These were considered the most consistent alterations associated with chronic BZD ingestion and its withdrawal. GABAergic mechanisms may underlie these SWS changes.

The difficulties

Acknowledgments

This work was supported by Associação Fundo de Incentivo à Psicofarmacologia (AFIP). Christian Guilleminault was supported by an Academic Award from the Sleep Research Center at the National Heart, Lung and Blood Institute of the National Institutes of Health.

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