Psychopharmacology (1992) 108:248 255

Psychopharmacology © Springer-Verlag 1992

Review

Rebound insomnia and newer hypnotics M a l c o l m Lader

Professor of Clinical Psychopharmacology,Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK Received October 29, 1991 / Final version April 21, 1992 Abstract. The prescription of hypnotics, mostly benzodiazepines, continues at a high level. One problem with their use is rebound insomnia: upon discontinuation sleep worsens compared with pretreatment levels. Factors influencing rebound include the type of subject, the duration of action of the hypnotic, the dosage and perhaps duration of treatment. The detection of rebound requires both sleep-laboratory and clinical studies with night-by-night analyses of individual patient data. This review concentrates on the newer compounds, (quazepam and zolpidem) which act selectively on subtypes of benzodiazepine receptors or bind atypically (zopiclone). It concludes that present evidence, while limited, is consistent with claims of less rebound potential than older benzodiazepine hypnotics of equivalent duration of action. Nevertheless, further rigorous studies are essential before these claims can be totally accepted.

residual sedative effects and its clinical significance is unclear. New hypnotic compounds are being developed and marketed (Guelfi 1990), often with claims that they are safer than benzodiazepines either with respect to residual effects, or to rebound, or to both. Some of these newer compounds such as zolpidem and zopiclone are claimed to differ pharmacologically from typical benzodiazepines. For example, GABAA receptor subunit assemblies show a different profile of affinities for zolpidem than for diazepam (Costa et al. 1991). However, it is unclear how this relates to clinical properties such as rebound potential. Nevertheless, such correlations might throw light o n rebound mechanisms. This paper will review the available data, after setting the scene with a brief overview of the benzodiazepines.

Key words: R e b o u n d i n s o m n i a -

Definition of rebound insomnia

Benzodiazepines -

Quazepam - Zopiclone - Zolpidem

Hypnotics are frequently prescribed, particularly in the elderly. Chronic usage is common, despite advice to limit courses of treatment to 2 weeks or less. Drug treatment is usually a benzodiazepine hypnotic and these divide o n pharmacokinetic grounds into the short-acting (e.g. triazolam), the medium-acting (e.g. temazepam) and the long-acting (flurazepam and nitrazepam). In several countries the use of long-acting hypnotics has become less popular, especially in the elderly where the risk of accumulation is greatest (Prinz et al. 1990). Long-acting compounds are also associated with residual sedative effects the next morning, effects which are less or absent with shorter-acting compounds. Another element in the risk/benefit equation is rebound insomnia, which comprises a worsening of sleep compared with pretreatment levels upon discontinuation of an hypnotic. However, it is less easy to study than

Rebound insomnia was described in an initial communication (Kales et al. 1978) and later detailed in a full paper (Kales et al. t979). From this and later work, it became apparent that when a hypnotic, especially a short-acting one, was taken for a few nights and then stopped, some patients suffered a night or two of insomnia worse than that experienced before treatment. Sleep latency was prolonged and wakefulness after sleep onset increased. There is no clear agreement on the definition of rebound insomnia. It was defined by Kales' group as a "statistically significant increase or an increase of 40 % or greater in the mean group value for total wake time for a single withdrawal night or the entire withdrawal condition as compared to baseline" (Kales et al. 1983b). Rebound has been generally measured not only in terms of total wake time but also sleep latency and wake time after sleep onset. Definitions above are based on sleep laboratory observations and may be less relevant clinically than subjective (questionnaire) rebound (Schneider-Hetmert 1988). Rebound may be interpreted by the patient as a worsen-

249 ing of his insomnia, and may lead him to resume medication with an increased risk of longterm use and possible physical dependence. Thus, to the insomniac, the contrast between his quality and quantity of sleep before and after stopping his sleeping tablets is more compelling, especially as it may be months or even years since the initial prescription.

Detection of rebound insomnia Rebound insomnia is generally noted as a by-product of efficacy studies. A typical protocol comprises three phases, a baseline period, a drug administration regimen, and a monitored discontinuation phase. Placebo may be given during the first and third phases but not usually during the drug phase. The durations of the phases vary from study to study: baseline measurements may extend from 1 to 7 nights, most typically 3. Drug administration may be short-term (3-7 nights), intermediate (14 nights) or long-term (28 nights). The length of withdrawal varies from 2 to 21 nights. The FDA (US Dept HEW, 1977) recommend at least 3 nights but this must be the minimum, as longer-acting hypnotics may not be cleared from the body for several days. Such protocols have two drawbacks. Firstly sleep, whether in normal subjects or insomniacs, varies from night to night and also tends to improve spontaneously over time (Roth et al. 1977). Therefore a parallel placebotreatment group is needed so that rebound insomnia can be assessed between groups. Available studies, e.g. Mamelak et al. (1989), suggest that improvement in insomnia rather than deterioration occurs over time so that the usual assessments of rebound insomnia underestimate the problem. The second criticism concerns the difficulty of mainmining blindedness with respect to the time of placebo substitution on withdrawal. The subjects and investigators usually know that the treatment lasts 7, 14 or 28 nights, to be followed by placebo. Although the sleep records can be analyzed blind, biasses may be introduced into the conduct of the recordings. Again, a parallel placebo group strengthens the control.

Choice of subjects and milieu Experimenters vary in the way they recruit, screen and choose subjects, with respect to age, sex, history and type of insomnia, previous hypnotic medication and concurrent psychiatric morbidity. The provenance and characteristics of experimental subjects is particularly important in sleep laboratory research because operational and financial exigencies preclude the use of large numbers of subjects. Many sleep researchers have access to insomniacs presenting themselves for diagnosis and treatment. The symptomatic complaints of insomnia are then confirmed by preliminary sleep laboratory recordings. Hypnotics must also be tested in the elderly, who comprise the bulk of long-term users. Sleep latency changes little with age but wake time after sleep onset and total wake

time both increase (Kales and Kales 1984). Some studies have used older subjects (Oswald et al. 1982) but others fail to provide data on age or sex of the subjects.

Pharmacological factors Duration of action The benzodiazepines can be classified on pharmacokinetic grounds into short-acting (plasma elimination half-life of less than 6 h), intermediate-acting (6-24 h) and longacting (over 24 h) drugs (Greenblatt et al. 1990). Gillin et al. (1989) have reviewed in detail the data relating to triazolam, the most widely used of the short-acting hypnotic benzodiazepines. They reported that seven out of nine studies on triazolam 0.5 mg detected rebound insomnia. In two, no evidence for rebound insomnia was found but in one of these studies (Spinweber and Johnson 1982) the design was not optimal for detecting the phenomenon. In the seven "positive studies", the measures showing rebound included total sleep time, sleep latency and wake time after sleep onset. Other short-acting compounds for which rebound insomnia has been reported include midazolam and brotizolam (Lader and Lawson 1987). However, two clinical studies failed to find evidence of rebound from 4 to 12 weeks use of midazolam, 15 mg (Allen et al. 1987; Lamphere et al. 1990). Brotizolam has an elimination half-life of about 5 h and rebound insomnia has been noted in several studies (Langley and Clissold 1988). Intermediate-acting compounds have been less extensively studied. No consistent rebound was found in four studies of temazepam but some consistent trends were apparent (Gillin et al. 1989). On clinical assessments, Oswald's group showed major rebound in their poor sleepers discontinuing lormetazepam (Oswald et al. 1979). Kales et al. (1982a) also found lormetazepam to be associated with rebound, both polysomnographically and subjectively. Rebound with loprazolam was only minor but delayed to the third withdrawal night (Adam et al. 1984; Clark et al. 1986). Although marketed primarily as an anxiolytic drug, lorazepam was evaluated as an hypnotic by Kales et al. (1986a). Six insomniac patients received placebo for 4 nights, lorazepam 2 mg for 7 nights, and placebo again for 5 nights and spent every night in a sleep laboratory. Marked rebound insomnia appeared on the third night followed the next day by significant increases in tension and anxiety. A similar study showed alprazotam I mg to be highly effective in inducing and maintaining sleep for the first 3 nights, although efficacy waned thereafter (Kales et al. 1987). On the third night following drug discontinuation, considerable rebound insomnia ensued. Data for long-acting hypnotics mainly concern flurazepam. Ten sleep laboratory studies were reviewed by Gillin et al. (1989), flurazepam being given for 4-37 consecutive nights. Up to 15 withdrawal nights were monitored. None of the studies showed evidence of full rebound early in withdrawal but there were some suggestions of a delayed rebound insomnia. However, poor

250 sleep a few nights after discontinuation was seen more consistently (Lader and Lawson 1987). Using clinical measures, nitrazepam was associated with definite rebound in two studies (Adam et al. 1976; Oswald et al. 1982). Flunitrazepam has been assessed in several sleep laboratory studies and rebound insomnia was clearly evident in most (Lader and Lawson 1987).

Dosage Dosage is an important determinant of rebound insomnia. Studies on midazolam (Kales et al. 1983a) and lormetazepam (Kales et al. 1982a) show clear dose-effect relationships, although one flunitrazepam study did not (Bixler et al. 1977). A recent study involved giving temazepam, 15 and 30 rag, and triazolam, 0.t25 mg and 0.25 mg, for 14 nights to 32 chronic insomniacs (Scharf et al. 1990). All four treatments seemed effective in inducing and maintaining sleep but the lower dose of triazolam lost its effectiveness over time. During withdrawal clearcut rebound was seen in a dose-related way for triazolam with respect to sleep latency and total sleep time. Temazepam was not associated with sleep latency rebound; the 30 mg but not the 15 mg dose produced rebound insomnia in terms of total sleep time. One study with concurrent placebo control established that 0.5 mg triazolam was no more effective as an hypnotic than 0.25 mg. Rebound, however, was only detectible after the higher dose (Roehrs et al. 1986). Dosage also influences rebound during the withdrawal phase: a tapering schedule reduces the risk of rebound insomnia (Greenblatt et al. t987). Similarly, halving the dose of temazepam for a week before discontinuing it was associated with less subjective rebound than abrupt placebo substitution (Lader and Frcka 1987). However, this finding was not confirmed in elderly hospitalized patients in whom no rebound was seen after either the abrupt or tapered withdrawal of temazepam, 10 mg (Tham et al. 1989).

Individualfactors The Merlotti et al. (1991) study also showed that some individuals show rebound consistently while others do not. Subjects with rebound had poorer sleep efficiencies and longer sleep latencies before drug administration than subjects without rebound; also they improved when taking the drug. Conversely, tolerance to drug effects did not differentiate the groups. Replication of these findings in insomniac patients would be most interesting.

Quazepam Quazepam is a trifluoroethyl benzodiazepine which is metabotised to the active compound 2-oxoquazepam and thence to N-desalkyl-2-oxoquazepam (desalkylflurazepam) which is psychotropically active and of long duration. Quazepam and 2-oxoquazepam bind selectively to the BZ~ (f~l) receptor. The cerebellum possesses predominantly BZ~ receptors, the cerebral cortex a mixed population of BZ~ and BZ2 receptors, and the spinal cord mainly the BZa subtype. By contrast, desalkylflurazepam binds to both subtypes. It has been suggested that the lack of ataxia seen with quazepam in animal studies may reflect this selectivity (Ankier and Goa 1988). It is not clear whether this selectivity confers any clinical advantages over the non-selective benzodiazepines. The half-life of elimination of quazepam is around 36 h, that of desalkylflurazepam about twice this. Thus, rebound insomnia is not likely after discontinuation of quazepam. Of several sleep laboratory studies, none showed evidence for rebound insomnia, even on a delayed basis (Kales 1990). Indeed because of the slow elimination of quazepam, effectiveness persisted for a few nights after withdrawal (Kales et al. 1982b). However, quazepam administration is associated with some daytime drowsiness (Kales et al. 1985, 1986b, c).

Zopielone Duration of treatment Most study protocols administer the test drug for 1, 2 or 4 weeks (Lader and Lawson 1987). Rebound insomnia was detected after only 3 nights of midazolam usage, in one study (Kales et al. 1983a). Only one study has explored the relationship between duration of administration and likelihood or intensity of rebound (Merlotti et at. 1991). Normal subjects were given placebo or 0.5 mg triazolam for 1, 6 or 12 consecutive nights. Rebound was assessed on the following 2 nights and was the same with respect to both intensity and probability of rebound whatever the duration of administration. Two other studies (Mattman et al. 1982; Mamelak et al. 1990) have also detected rebound after a single 0.5 or 1 mg dose of triazolam.

Zopiclone is a cyclopyrrotone derivative and is marketed in many countries as an hypnotic. It is chemically different from the benzodiazepines, but can displace benzodiazepines from their binding sites on the neuronal membrane. A variety of biochemical evidence suggests nonetheless that the cyclopyrrolone recognition site is close to but separate from the benzodiazepine site on the benzodiazepine/GABAA macromolecular complex (Trifiletti and Snyder 1984; Julou et al. 1985). Zopiclone has an elimination half-life of 5-7 h (Goa and Heel t986), somewhat longer in the elderly (Gaillot et al. 1987). Consequently, it is a short- to medium-acting hypnotic and might therefore be expected to induce rebound.

Studies in normal subjects In an early study, six healthy male medical students were given placebo for 4 nights, then zopiclone 7.5 mg for 5

251 nights, followed by a further 3 nights of placebo (Godtlibsen and Dreyfus 1980). Sleep recordings were taken every night and subjective questionnaires completed. Hypnotic effects were only mild with some minimal rebound effect on stage 2 and REM sleep. A longer study involved giving nine male subjects zopiclone 7.5 mg for 21 nights or placebo 21 nights, each followed by 7 nights of placebo (Dorian et al. 1982). Sleep questionnaires were completed on days 1, 2, 4 and 6 of each withdrawal (placebo) week. On the second and fourth days of withdrawal, subjects reported significantly fewer hours of sleep, of lesser quality and with a longer sleep latency, compared to all the other withdrawal days. Inspection of the graphs suggests some rebound on the second night after withdrawal of zopiclone as compared with withdrawal of placebo, but no direct statistical comparison is included. A comparative sleep-laboratory study assessed the effects of zopiclone 7.5 mg and triazolam 0.5 mg over 6 nights, each given in a cross-over design in 12 healthy male volunteers (Tiberge et al. 1988). No significant rebound was detected at the end of either period of drug administration, but the data from 3 successive nights were pooled. Lader and Frcka (1987) investigated possible rebound effects in ten normal volunteers given either: placebo over 4 weeks; zopiclone 7.5 mg nightly for 2 weeks followed by placebo for 2 weeks; zopiclone 7.5 mg for 2 weeks, then 3.75 mg for 1 week and placebo 1 week; temazepam 20 mg for 2 weeks, placebo 2 weeks; and finally temazepam 20 mg 2 weeks, 10 mg 1 week, placebo 1 week. Daily ratings detected some subjective rebound after stopping temazepam which was somewhat reduced by first halving the dosage. Rebound effects were minimal with zopiclone so that tapering the dose seemed unnecessary. Studies in insomniac patients'

A small-scale study involved six patients with chronic insomnia, confirmed by sleep recordings (Mamelak et al. 1982). After 4 nights of placebo, zopiclone 7.5 mg was given for 21 nights followed by placebo again for 4 withdrawal nights. Sleep recordings were obtained on the first 7 and last 8 nights of the study. No rebound beyond baseline levels was detected but several variables worsened significantly as compared with values on the first few nights of treatment. Another small-scale sleep laboratory study compared zopiclone 7.5 mg and nitrazepam 5 mg, each given for 14 nights to three and two insomniacs, respectively (Jovanovic and Dreyfus 1982). No sign of rebound insomnia was detected after discontinuing zopiclone. A longer study involved giving zopiclone 7.5 mg for 54 nights to 11 chronic insomniacs followed by placebo for 14 consecutive nights (Pecknold et al. 1990). Sleep recordings were obtained before treatment, the first drug night, after 4 and 8 weeks of treatment, and on nights 1, 7, 8, 13 and 14 of the final phase. Unfortunately, rebound after the first night might well be missed. Sleep onset

latency increased non-significantly on the first night of withdrawal compared with baseline. Other changes were noted but significant and consistent rebound was not apparent; subjective questionnaire data gave parallel results. Twelve insomniac women, aged 50-59, were studied in a crossover comparison of zopiclone 7.5 mg and flurazepam 30 mg using sleep laboratory recordings (Quadens et al. 1982). The authors report "an unpleasant rebound beyond baseline levels with flurazepam which is not the case with zopiclone". However, recordings were carried out on nights 11-13 after withdrawal which is too belated to detect rebound from shorter-acting compounds. One sleep laboratory study involved ten insomniac patients aged over 60, given either triazolam 0.25 mg or zopiclone, 7.5 mg for 14 nights, preceded and followed by placebo (Mouret et al. 1990). The first 3 nights after active drug withdrawal were monitored polysomnographically. The authors state that no statistically significant rebound was found but inspection of the figure for total sleep time suggests a trend towards rebound for both drugs, lasting 1 night for zopiclone and 2 for triazolam. Subjective questionnaires were used to compare zopiclone 7.5 mg and triazolam 0.25 mg in 48 chronic insomniacs (Fleming et al. 1990). After a 3-day wash-out period, the drug was given for 21 nights followed by 4 placebo nights of withdrawal monitoring. Both drugs proved effective although zopiclone sustained its effect better than did triazolam. On withdrawal, insomnia was complained of by three-quarters of patients on both drugs. On the first withdrawal night, sleep induction, duration and soundness of sleep scores in the triazolamtreated group were significantly worse than those recorded at baseline. For zopiclone-treated patients, quality and soundness of sleep were significantly reduced on the first, second and fourth withdrawal nights. On the fourth night, sleep soundness was significantly poorer in those withdrawn from zopiclone than those who had stopped taking triazolam. The authors interpret this as a recovery of sleep loss following the first withdrawal night's rebound insomnia in the triazolam group. A general-practice study in 99 insomniac patients compared zopiclone 7.5 mg, nitrazepam 5 mg and placebo administered for two weeks and followed by placebo (Anderson 1987). Subjective assessments failed to uncover any rebound relative to baseline, pretreatment values. However, analysis of the daily ratings showed some deterioration of sleep, maximal the first night after discontinuation of zopiclone with sleep patterns normalizing within 2-3 nights. For nitrazepam, the effect was less marked but tended to occur 3 or 4 days after stopping. In another general-practice study of insomniacs (without placebo control), rebound was not apparent after discontinuing either zopiclone 7.5 mg or ftunitrazepam 2 mg (Wickstrom et al. 1983). However, questionnaire responses were averaged over 3 days of withdrawal. Three nights of withdrawal data were analyzed separately in a comparison of zopiclone 7.5 mg and flurazepam 30 mg in 36 insomniacs (Elie et al. 1990b).

252

Upon discontinuation, scores after both treatments returned to baseline but did not overshoot as full rebound. Similar results were obtained in a comparison of zopiclone 7.5 mg and pentobarbitone 100 mg in 60 insomniac outpatients (Mello de Paula 1983). Individual nights were assessed clinically in a comparison of zopiclone (5 or 7.5 mg), triazolam (0.125 or 0.25 mg) and placebo (Elie et al. 1990a). A total of 48 patients was treated double-blind for 3 weeks and then single-blind for 4 days with placebo. The main therapeutic effects were improved sleep latency with zopiclone and triazolam and in sleep soundness with zopiclone, compared to placebo. On withdrawal, the triazolam group reported a significant increase in sleep latency and decreases in sleep soundness and quality in comparison to the placebo group. No significant changes occurred in the zopiclone group. Analysis of daily differences confirmed definite rebound compared with baseline for the triazolam-treated group but not for the zopiclone group. In summary, several studies provide some tentative conclusions. In the usual dose of 7.5 mg, zopiclone is associated with some rebound in some patients. However, taking into account the short half-life of zopiclone and comparing it with short and medium acting benzodiazepines, the evidence for clinically significant rebound seems less. Whether this is related to other aspects of zopiclone's pharmacology (Goa and Heel 1986), remains an open question.

Zolpidem Zolpidem is an imidazopyridine derivative which binds selectively to benzodiazepine recognition sites. Thus, it has high affinity for BZ1 receptors, but tow affinity for BZ2 receptors. Zolpidem also has low affinity for the peripheral receptors. The pharmacological profile of zolpidem is of sedative, sleep-inducing properties, without significant myorelaxation (Langer et al. 1988). Mereu et al. (1990) found that dose-dependent decreases in firing rates of rat substantia nigra neurons produced by intravenous zolpidem could be prevented or reversed by ftumazenil. Zolpidem is rapidly and well absorbed, with C~ax at 2,2 h and with an absolute bioavailability of about 70% (Langtry and Benfield 1990). It has several metabolites, none active. The mean elimination half-life of zolpidem is about 2 h in young adults and somewhat longer in the elderly. Zolpidem has been available in France for over a year and is being introduced into other countries. It has been extensively evaluated in a series of studies both in the sleep laboratory and in specialist and general clinical practice. The early studies concentrated on efficacy and residual effects with few formal assessments of rebound. However, no REM rebound was noted in the sleep laboratory study of Herrmann et al. (1988), nor was rebound reported on either of the two withdrawal nights after zolpidem 20 mg had been given for 5 nights in Maggioni and Frattola's (1988) clinical study. A range of doses of zolpidem (5, 10, 15, 20 mg and placebo) was

explored in a clinical study involving 30 elderly noninsomniac volunteer subjects (Scharf et al. 1991). Subjects were randomised into two groups who received placebo, 5, 15 mg zolpidem or placebo, 10, 20 mg zolpidem, each for 2 nights followed by a placebo for 1 night. No rebound was detected. Sixty insomniac patients were allocated randomly to 7 nights treatment with either t0 mg or 20 mg zolpidem, followed by three nights of placebo (Lorizio et al. 1990). The two doses were equally efficacious with respect to clinical ratings and no withdrawal effects were detected. In a clinical study involving 119 elderly psychiatric inpatients given zolpidem 10 or 20 mg for 3 weeks, followed by a fourth week on placebo, no evidence of rebound insomnia was detected (Shaw 1988). In another study in the elderly (Emeriau et al. 1988) no rebound was noted, but the assessments were made at the end of the placebo withdrawal week which may have missed rebound on the first or second night. Some relapse was noted, however. A polysomnographic study of Monti (1989) evaluated six insomniac patients, who received zolpidem 10 nag o.n. for 14 nights. Three nights of placebo followed. Sleep was recorded in the laboratory for 3 nights at the beginning and end of the drug period and for the 3 succeeding placebo nights. To avoid obscuring any rebound phenomena, the withdrawal nights were analysed individually. No rebound was noted, although some nonsignificant worsening of sleep latency and total wake time is apparent from the data presented. Preliminary polysomnographic data on ten poor sleepers given zolpidem 10 mg for 14 consecutive nights suggested no detectable rebound (Kurtz et al. 1990). Two other studies also failed to detect rebound (Besset et al. t990; Scharf et al. 1991). A placebo-controlled multicentre evaluation of 10 mg and 15 mg zolpidem utilised 35 nights of treatment in 67 insomniac subjects (Vogel et al. 1989). Polysomnographic recordings were made on the first 2 nights of each week, including the 1-week placebo baseline and a 3 day placebo withdrawal period. This large-scale intensive study showed significant drug effects on sleep latency and efficiency for both doses. Apparent rebound in the 10 mg group with respect to sleep latency is difficult to interpret as the mean baseline value for this group is aberrant. No analyses of individual data are presented in the abstract. In a placebo-controlled trial of zolpidem 10 and 20 mg given for 3 weeks in general practice, data were collected during a final placebo week (Wheatley 1988). The data for days 1-3 of the withdrawal week were pooled. Both doses were effective in shortening sleep latency and improving subjective quality of sleep. Inspection of the published data suggests partial worsening after placebo substitution but no full rebound. However, presenting data for each night would have been more informative. In two long-term open trials using flexible dosage (up to 24 or 52 weeks), it was claimed that no withdrawal was seen on discontinuation (Sauvanet et al. 1988). In another general practice study, 107 insomniac patients were treated single-blind with zolpidem in flexible dosage for upto 6 months (Schlich et al. 1991). Assessments were made at baseline, the last day of treatment and 10 days after substitution of placebo at the end.

253 Useful efficacy was established, about 80% of patients showing clinically significant improvement. Improvement was maintained throughout treatment without any tendency to escalate dosage levels. After placebo substitution, some efficacy was lost over all subjects but no definite rebound was detected by retrospective enquiry on an individual basis. Thus, there have been relatively few systematic studies of rebound with zolpidem with patient-by-patient and night-by-night analyses. Conclusions must be even more tentative than with the other newer compounds. Very little rebound has been reported. Nevertheless, few studies have been conducted searching specifically for rebound on a patient-by-patient and night-by-night basis.

commentators believe it to be an indicator of incipient dependence. F o r example: " R e b o u n d insomnia provides cause for concern at two levels: it is a clear sign of iatrogenic physiological dependence and, through the distress caused, it is a frequently cited reason for patients re-starting their hypnotic drugs" (Morgan 1990). Despite such assertions and the apparent clinical logic of such a connection experimental evidence is almost non-existent (Roehrs et al. 1990). The practical implications are that rebound insomnia must be sought and evaluated with both objective and subjective measures. The clinical implication, however, must be the pragmatic one, the answer to the following questions: Does discontinuation o f the hypnotic result in such distress that the patient resumes medication? Does such resumption predispose the patient to long term use with the risk of physical dependence?

Clinical relevance of rebound In the U K 4% of adults (Dunbar et al. t989) and in the USA 2.6% of adults (Mellinger et ai. 1985) take a benzodiazepine hypnotic during a year. Usage is particularly heavy in the elderly, with 16% using during the previous year, most of these (73 %) using regularly for a year or more (Morgan et al. 1988). Indeed, a quarter o f all elderly users, i.e. 4 % o f all in the population over 65, had used them continuously for 10 years or more. That such usage reflects dependence rather than continuing therapeutic need cannot be dismissed. Many serious chronic insomniacs suffer from major depression, generalized anxiety, or somatic symptoms (Mellinger et al. 1985); long-term hypnotic therapy is inappropriate and fails to address the underlying problem (Morgan 1990). An important but limited study has evaluated the relationships between long-term use, efficacy, and rebound insomnia both subjective and objective (Schneider-Helmert t988). Forty middle-aged and elderly chronic insomniacs, long-term benzodiazepine hypnotics users, and 36 chronic drug-free insomniacs were studied. Polysomnographic measures of sleep performance were the same in the two groups, suggesting that the hypnotics were inefficacious. However, both delta and R E M sleep were largely suppressed in the drugtakers. The drug-users were recorded again on the second night without taking their medication. Insomnia did not increase whereas the delta and R E M suppression tended to recover. Subjectively, subjects over-estimated their sleep duration by an average o f 72 rain while on drug but under-estimated it by 61 min on withdrawal. The author attributes this to the amnesiogenic effects o f the benzodiazepine hypnotics, since estimates of sleeping time are derived from perceptions of wakefulness reported retrospectively. Morgan and T o m e n y (t988) criticized the SchneiderHelmert study on several counts such as lack of adaptation night in the sleep laboratory, absence o f placebocontrolled withdrawal, and use of only 1 withdrawal night. Nevertheless, this study is a pointer to the type of evaluation which is urgently needed in chronic hypnotic users. The importance of rebound insomnia is that some

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Rebound insomnia and newer hypnotics.

The prescription of hypnotics, mostly benzodiazepines, continues at a high level. One problem with their use is rebound insomnia: upon discontinuation...
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