Sleep and Sleep Disorders in Chronic Users of Zopiclone and Drug-Free Insomniacs
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SCIENTIFIC INVESTIGATIONS
Sleep and Sleep Disorders in Chronic Users of Zopiclone and
Drug-Free Insomniacs
Børge Sivertsen, Ph.D.1; Siri Omvik, Ph.D.1; Ståle Pallesen, Ph.D.2,4; Inger Hilde Nordhus, Ph.D.1,4; Bjørn Bjorvatn, M.D., Ph.D.3,4
Department of Clinical Psychology, 2Department of Psychosocial Science, and 3Department of Public Health and Primary Health Care,
1
University of Bergen, Bergen, Norway; 4Norwegian Competence Center for Sleep Disorders, Haukeland University Hospital, Bergen, Norway
Study Objectives: To examine polysomnographic parameters and the polysomnography parameters. A similar pattern was found for data
sleep diary data, as well as the prevalence of sleep apnea and peri- based on sleep diaries. The frequency of sleep apnea (apnea-hypo-
odic limb movement disorder (PLMD) in older chronic users of zopi- pnea index > 10) were 41% to 42% in both the zopiclone and insom-
clone compared with aged-matched drug-free patients with insomnia nia groups, compared with 12% in the good sleepers group, whereas
and good sleepers. there were no significant group differences in the frequency of PLMD.
Methods: Polysomnographic data were collected at a university- The zopiclone group reported higher levels of anxiety and depression
based outpatient clinic for adults and elderly. Seventeen patients us- compared with the other groups.
ing zopiclone on a daily basis for at least 1 year were compared with Conclusions: This study suggests that the sleep of chronic users of
64 drug-free patients with insomnia and 26 good sleepers. Mean (SD) zopiclone is no better than that of drug-free patients with insomnia.
age was 63.8 (7.0) years. Outcome measures were polysomnographic It is disturbing that 41% of the patients treated pharmacologically for
sleep parameters, sleep diary data, and psychological symptoms, as insomnia also had sleep apnea. We suggest careful sleep assessment
well as prevalence estimates of sleep apnea and PLMD. as a prerequisite for long-term prescription of sleep medications.
Results: The zopiclone users spent more time awake, had longer Keywords: Sleep disorders, sleep medications, sleep apnea, periodic
sleep latencies, and reduced sleep efficiency compared with the good limb movement disorder, PLMD
sleepers. The amount of slow-wave sleep was also significantly lower Citation: Sivertsen B; Omvik S; Pallesen S; Nordhus IH; Bjorvatn B.
in the zopiclone group compared with the good sleepers. There were Sleep and sleep disorders in chronic users of zopiclone and drug-free
no differences between the zopiclone and insomnia group on any of insomniacs. J Clin Sleep Med 2009;5(4):349-354.
T here is growing public concern about the increasing use of
sleeping pills, which increased nearly 60% from 2000 to
2006.1 While $2 billion were spent on sleep remedies in 2006,
sleep medications have been found to be only small and, for
some individuals, outweighed by the adverse effects.9 Although
sleep architecture is largely believed to remain unaltered when
American consumers now spend more than $4.5 billion a year patients are treated with the newer nonbenzodiazepine sleeping
on hypnotics.2 Findings from both the US and Europe show that aids (such as zopiclone and zolpidem),10 the literature on slow-
more than 50% of all sleep medications are prescribed to older wave sleep (SWS) is mixed with regard to different age cohorts.
adults (60+ years of age),3,4 making this age group by far the Whereas zopiclone has been shown to increase SWS in younger
most common consumers. adults,11 studies on older adults indicate that zopiclone has no
The majority of sleep medications is used over longer periods effect on SWS.12 In contrast, a recent trial demonstrated a sig-
of time, usually on a nightly basis for several years.4-6 Still, with nificant reduction of SWS after both 6 weeks’ and 6 months’
the exception of a recent study showing sustainable effects of use of zopiclone.13 There is also recent evidence linking traffic
eszopiclone on self-reported sleep parameters after 6 months,7 collisions to daytime drowsiness caused by both benzodiaze-
long-term benefits from sleep medications have yet to be dem- phines14 and nonbenzodiazephines,15 and several studies have
onstrated. It is still widely recognized that sleep medications demonstrated increased mortality in individuals with chronic
should be used with caution and preferably avoided in patients use of sleep medications, even after controlling for a range of
with chronic insomnia,8 as clinical benefits associated with possible confounders.16-18 Moreover, there is recent evidence
showing a possible link between nonbenzodiazepine hypnotics
and increased risk of skin cancer.19
Submitted for publication November, 2008
Still, physicians continue to prescribe pharmacotherapy as
Submitted in final revised form March, 2009
their treatment of choice for most patients with insomnia. This
Accepted for publication March, 2009
Address correspondence to: Børge Sivertsen, PhD, Department of Clini-
may be particularly problematic for older adult patients, who
cal Psychology, University of Bergen, Christiesgt 12, 5015 Bergen, Nor- are more likely to be taking multiple medications. This age co-
way; Tel: 47 55 58 88 76; Fax: 47 55 58 98 77; E-mail: borge.sivertsen@ hort is also more likely to suffer from other sleep disorders,
psykp.uib.no including sleep apnea and periodic limb movement disorder
Journal of Clinical Sleep Medicine, Vol.5, No. 4, 2009 349B Sivertsen, S Omvik, S Pallesen et al
(PLMD).20 Only a small portion of these sleep disorders are GROUP 3 – GOOD SLEEPERS
properly diagnosed, which often relates to insufficient aware-
ness of sleep disorders among physicians and the public at Twenty-six healthy participants (19 women and 7 men) aged
large.21 One important reason for this may be that symptoms of 55 years or older with self-reported good sleep were recruited
both sleep apnea and PLMD are rarely experienced by the pa- through newspaper advertisements. The participants underwent
tients themselves. Rather, symptoms are attributed to more gen- a short screening to ensure that they did not fulfil the diagnostic
eral sleep problems, including insomnia, which also increases criteria for insomnia. Mean age was 68.2 years (SD = 7.2).
significantly with advancing age.22-26
Based on the above considerations, the aims of the present Polysomnography
study were (1) to explore objective (polysomnographic) and
subjective (sleep diary) sleep parameters in individuals with Participants in all 3 groups were assessed using ambulatory
chronic use of zopiclone and to compare these parameters with clinical polysomnography for 2 consecutive nights. Data from
those of age-matched drug-free patients with chronic insomnia the first night were not used to control for the first-night ef-
and good sleepers, (2) to examine subjective data on daytime fect31; hence, the design allowed for patient adaptation to the
functioning and psychological symptoms in these 3 groups, and polysomnography recording and equipment. Data collected
(3) to estimate the frequency of sleep apnea and PLMD. during the polysomnography recordings included electroen-
cephalogram, electromyogram, and electrooculogram. The 4
METHODS electroencephalographic derivations used for recording were
C4-A1, C3-A2, O1-A2, and O2-A1. Respiratory flow was re-
Participants corded by both a nasal pressure cannula and a thermistor. Res-
piratory effort was assessed by means of a piezo thorax and
GROUP 1—CHRONIC ZOPICLONE USERS abdominal belt. Limb movements were recorded from ante-
rior tibialis. In addition, measures of pulse and heart function
Participants were recruited through newspaper advertise- (electrocardiogram), body position, and snoring were includ-
ments. Inclusion criteria were 55 years of age or older and daily ed. Sleep stages in all 3 groups were scored according to Re-
usage (5-7 days per week) of sleep medications for at least 1 chtschaffen and Kales criteria32 in 30-second epochs, employ-
year. Of a total of 51 respondents, 32 were excluded due to too ing the Somnologica® 5.1 software package (Flaga-Medcare
infrequent use of sleep medications, unwillingness to undergo Somnologica® 5.1, Reykjavik, Iceland). The criteria for sleep
polysomnographic recordings, or serious psychopathology (se- apnea were defined as more than 50% reduction of air flow at
vere depression) or physical handicap precluding transport to the nose and mouth associated with fall in oxygen saturation
the university clinic. In all, 19 persons fulfilled the criteria, of of at least 3%. The duration of the apnea or hypopnea must
which 17 persons used zopiclone. The most common daily dos- be a minimum 10 seconds. Sleep apnea was defined as an ap-
age was 7.5 mg (range = 3.75-22.5 mg). The 2 remaining per- nea-hypopnea index (AHI) of greater than 10, which has been
sons used zolpidem and nitrazepam, but these were omitted for suggested as a more appropriate cut-off in this age cohort.33,34
purposes of the present study. In total, the sample comprised 10 Periodic limb movements of sleep were defined according to
women and 7 men with a mean age of 64.0 years (SD = 6.5).27 standard criteria;35 leg movements were scored only if they
Patients’ adherence to the sleep medications were estimated by were part of a series of 4 or more successive movements last-
2 weeks of sleep diaries. ing at least 0.5 seconds, separated by intervals between 4 to
90 seconds. PLMD was defined as a periodic limb movement
GROUP 2—DRUG-FREE PATIENTS WITH CHRONIC INSOMNIA index greater than 15.
Participants in this group were recruited through newspaper SUBJECTIVE DATA
advertisements for a treatment study of chronic insomnia.13,28 In-
clusion criteria were (1) age 55 years or older; (2) fulfilment of All participants completed sleep diaries36 every morning
the DSM-IV criteria for insomnia, including difficulties initiating for 2 weeks. The sleep diary provided self-reported informa-
sleep, maintaining sleep, and/or early morning awakenings with tion about the same sleep parameters as collected from the
no ability of return to sleep; (3) insomnia duration of at least 3 polysomnography recordings. To increase the reliability, data-
months; and (4) complaints of impaired daytime functioning. The analysis were based on the average scores of the 2-week pe-
following exclusion criteria were used: (1) use of sleep medica- riod.
tion the last 4 weeks before the polysomnographic assessment, The Beck Depression Inventory37 is a 21-item questionnaire
(2) use of antidepressant or antipsychotic medications, (3) signs measuring depressive symptoms along a 4-point scale (range =
of dementia or other serious cognitive impairment defined by a 0-3). A score of 10 or above is considered to be an indication of
score below 23 on the Mini-Mental State Examination,29 (4) pres- mild depressive symptoms.38
ence of a major depressive disorder or other severe mental disor- The State-Trait Anxiety Inventory39 is a self-report instru-
der as identified by a clinical assessment based on The Structured ment. It includes 20 items measuring state anxiety (State-Trait
Clinical Interview for DSM-IV,30 or (5) having a physical handi- Anxiety Inventory-state) and 20 items measuring trait anxiety
cap precluding transport to the university clinic. A total of 64 pa- (State-Trait Anxiety Inventory-trait). Each item is rated on a
tients (29 women and 35 men) were included for the purpose of 4-point
-point scale (range = 1-4). On the trait measure, 39 is recom-
the present study (mean age 61.8 years, SD = 6.0). mended as a clinical cutoff value.39
Journal of Clinical Sleep Medicine, Vol.5, No. 4, 2009 350Sleep Disorders in Users of Zopiclone and Drug-free Insomniacs
Table 1—Sleep, Sleep Disorders, and Psychological Functioning in Chronic Zopiclone Users, Drug-Free Patients with Insomnia, and Good
Sleepers
Chronic zopiclone Drug-free patients Good sleepers
users (n = 17) with insomnia (n = 64) (n = 26)
Polysomnographic data
TST, min 372.6 ± 64.8a,b 366.4 ± 64.0a 396.0 ± 49.2b
WASO, min 114.5 ± 57.4a 93.0 ± 58.0a 44.3 ± 23.3b
SOL, min 37.9 ± 54.9a 28.2 ± 41.3a 7.7 ± 6.5b
SE, % 76.9 ± 9.3a 80.3 ± 10.5a 90.0 ± 4.7b
Sleep stage, min (%)
1 58.6 ± 32.7 (15.7)a 50.2 ± 36.3 (13.7)a 48.0 ± 23.6 (12.1)a
2 194.3 ± 54.5 (52.2)a 188.5 ± 50.2 (51.4)a 155.8 ± 49.7 (39.4)b
3/4 55.0 ± 31.2 (14.8)a 65.5 ± 27.8 (17.9)a 120.0 ± 53.3 (30.4)b
REM 64.7 ± 26.5 (17.4)a 64.2 ± 30.3 (17.5)a 71.9 ± 26.2a (18.2)a
AHI > 10, % 41.2a 42.2a 11.5b
PLMD, % 35.3a 39.1a 38.5a
Subjective data
TST, min 348.9 ± 72.4a 313.6 ± 60.9b 424.1 ± 43.9c
WASO, min 113.3 ± 62.8a 121.7 ± 64.5a 10.5 ± 9.5b
SOL 38.11 ± 27.1a 35.4 ± 28.3a 11.5 ± 9.7b
SE, % 68.6 ± 13.0a 66.1 ± 12.0a 86.8 ± 6.4b
Daytime sleepiness 3.0 ± 0.8a 2.8 ± 0.7a 4.2 ± 0.8b
Psychological functioning
Depression (BDI) 10.5 ± 5.8a 7.1 ± 5.1b 2.5 ± 3.1c
Anxiety (STAI-T) 44.5 ± 9.1a 38.7 ± 8.8b 26.6 ± 5.1c
Anxiety (STAI-S) 40.1 ± 6.0a 35.3 ± 8.7b 26.2 ± 5.8c
Data are provided as mean ± SD (%), mean ± SD, or percentage. TST refers to total sleep time; WASO, wake time after sleep onset; SOL,
sleep-onset latency; SE, sleep efficiency; REM, rapid eye movement sleep; AHI, apnea-hypopnea index; PLMD, periodic limb movement
disorder (15 or more periodic limb movements per hour of sleep without arousal); BDI, Beck Depression Inventory; STAI, State-Trait Anxiety
Inventory; a, b, c = different letters within the same line signify significant (p < 0.05) differences between the groups
Statistics Sleep Disorders
SPSS for Windows version 17 (SPSS, Inc., Chicago, Ill) was Approximately 41% to 42% of the patients qualified for a
used in the statistical analysis. One-way analysis of variance diagnosis of sleep apnea (AHI > 10) in both the zopiclone users
with posthoc tests and Pearson χ² test were used to test for dif- and drug-free insomniacs. In the latter group, the average AHI
ferences between the 3 groups. The level of significance was set was 11.5, compared with an AHI of 9.8 among the drug-free pa-
at less than 0.05. tients with insomnia and an AHI of 4.3 among the good sleepers
(p < 0.05). There were no significant group differences in the
RESULTS prevalence of PLMD.
Sleep Parameters Daytime Functioning
Based on polysomnography, the group comprising the chron- All 3 groups differed significantly on both anxiety and de-
ic zopiclone users had significantly more wake time during the pression, with the zopiclone users reporting the highest levels
night (114.5 minutes), had a longer sleep latency (37.9 min- of depression and anxiety on both the Beck Depression Inven-
utes), and consequently had a lower sleep efficiency (76.9%), tory and State-Trait Anxiety Inventory (see Table 1 for details).
compared with the good sleepers (44.3 minutes, 7.7 minutes, In the zopiclone group, 35.3% had a Beck Depression Invento-
and 90.0%, respectively; all p < 0.05). The chronic zopiclone ry score of 10 or more (mild depression), compared with 17.8%
users had also significantly less SWS (55.0 minutes) compared in the drug-free insomnia group. None of the controls fulfilled
with the good sleepers (120.0 minutes, p < 0.001). The drug- these criteria. In terms of daytime sleepiness, both the zopi-
free patients with insomnia did not differ from the chronic zo- clone users and the drug-free insomnia group reported worse
piclone users on any of the polysomnographic parameters but functioning, compared with the good sleepers (Table 1).
scored significantly worse on most sleep measures compared
with the group of good sleepers (see Table 1 for details). DISCUSSION
Similar to polysomnography, the sleep diaries revealed few dif-
ferences on the sleep parameters between the zopiclone users and In the present study, we found that older patients treated with
drug-free insomniacs, whereas both groups scored worse on all daily use of zopiclone for more than 1 year had significantly
sleep parameters compared with the good sleepers. There were no impaired sleep, compared with a sample of age-matched good
significant differences in reported bedtimes among the 3 groups. sleepers, as indicated by both polysomnographic and subjective
Journal of Clinical Sleep Medicine, Vol.5, No. 4, 2009 351B Sivertsen, S Omvik, S Pallesen et al data. Sleep parameters did not differ significantly from those infarction,54 stroke, and mortality.55 Untreated sleep apnea also of drug-free patients with insomnia. We also found high a fre- increases the risk of automobile crashes,56 leads to poor qual- quency of sleep apnea in the 2 clinical groups, compared with ity of life,57 and has been linked with several neurocognitive the sample of good sleepers. consequences.58,59 Also, symptoms of sleep apnea have recently In addition to increased wake time and sleep-onset latency, been found to predict both long-term sick leave and permanent as well as decreased sleep efficiency, found among the chron- work disability.60 Given these consequences of untreated sleep ic zopiclone users, perhaps the most noteworthy finding was apnea, we consider it disturbing that as many as 41% of the the reduced amount of SWS in this group. A few studies have chronic zopiclone users fulfilled the diagnostic criteria for sleep investigated the polysomnographic effects of zopiclone in pa- apnea. The findings emphasize the need to inform healthcare tients with chronic insomnia, with the majority of studies show- professionals in primary care settings about the relatively high ing that the amount of SWS remains unchanged or increases prevalence rates of sleep disorders in this age cohort, as well as following 2 to 3 weeks of drug administration.40-42 However, the appropriate treatment options for the specific disorders. Failure findings are mixed, and SWS has also been found to decrease to do so may result in patients receiving inappropriate treatment following short-term use of zopiclone.13,43,44 Although a recent for their condition. This is particularly a concern regarding hyp- trial showed sustained effects of eszopiclone on self-reported notics, which actually may exacerbate the sleep apnea.61 measures after 6 months,7 no studies have, to our knowledge, There are several limitations in the present study. First, the examined the effects of long-term use of zopiclone on objec- sample sizes were small, limiting the generalizability of the re- tive sleep measures. As such, the present study thus provides sults and, thus, preventing us from determining exact frequency the first evidence that using zopiclone on a daily basis for more rates in the population. Second, the sample sizes in the 3 groups than 1 year is associated with reduced duration of SWS. were not identical, resulting in different statistical power when Also, the subjective sleep data and increased daytime sleepi- comparing the groups. Third, the age and sex distribution ness underscore the patients’ sleep problems in the zopiclone across the 3 groups were not identical, which may have influ- group. There were few differences between the zopiclone users enced some of the findings. For example, the low frequency of and drug-free insomniacs on either the objective or subjective sleep apnea in the sample of good sleepers may be related to an measures, indicating that the zopiclone users were still dissatis- overrepresentation of women in this group. Fourth, no attempts fied with their sleep after prolonged use of zopiclone. were undertaken to standardize the patients’ nightly dose of However, an alternative explanation for the poor sleep found zopiclone. Moreover, the different recruiting procedures may among the chronic zopiclone users may be that these patients have resulted in biased samples, excluding patients not willing had worse sleep quality to begin with. Also, our finding that the or unable to submit to the burden of completing 2 nights of zopiclone users reported higher levels of anxiety and depres- polysomnographic assessments. On one hand, this may result sion than did the other 2 groups may suggest potential group in inclusion of healthier subjects, which again may lead to an differences in psychopathology or health in general and, conse- underestimation of possible pathology. Alternatively, this may quently, may indicate a possible group-selection bias. However, also have led to the inclusion of participants who were seeking the cross-sectional nature of the current study and, hence, the help for their sleep problems. Unfortunately, the current design lack of baseline data do not permit us to examine possible dif- did not allow us to assess the severity of the sleep problems ferences concerning initial insomnia severity nor to determine of the chronic users before they started taking hypnotics. Also, the direction of causality—whether the symptoms of anxiety or we did not measure the body mass index of all participants and depression serve as consequences of poor sleep or as prodromal were, thus, unable to examine potential group differences in symptoms preceding the sleep problems. obesity. And, because the sleep structure of patients with sleep Still, our findings support the general scientific opinion that apnea is characterized by several electroencephalographic al- nonpharmacologic treatments should be considered as an alter- terations, including reductions in SWS,62,63 we cannot disregard native to chronic use of hypnotics. Today, cognitive behavior the possibility that potential group differences in obesity may therapy is the most widely used nonpharmacologic interven- have influenced the study results. Finally, the polysomnograph- tion for insomnia, and several meta-analyses have concluded ic data in the 3 groups were collected and scored on different that most people with insomnia will benefit from such inter- time points, and scorers were consequently not blinded for pur- ventions.45-47 Although most randomized controlled trials have poses of the present study. focused on younger and middle-aged adults, there is now also In conclusion, the current study shows that the sleep of chronic evidence that older adults will significantly benefit from cogni- users of zopiclone is no better than that of drug-free patients with tive behavior therapy, in both the short- and long-term manage- insomnia. We also find it disturbing that more than 40% of the ment of insomnia.13,48,49 patients treated pharmacologically for insomnia also suffer from In the present study, we also found high frequency rates of sleep apnea. Consequently, we suggest careful sleep assessment sleep apnea in both clinical samples, compared with the sample as a prerequisite for long-term prescription of sleep medications. of good sleepers. However, although high, the rates are in fact comparable with what other studies in this age cohort previously ACKNOWLEDGMENTS have found.50 As for insomnia, untreated sleep apnea represents a significant burden for both the affected individual, as well as This research was funded by grants from the University of for society as a whole. For example, sleep apnea has been shown Bergen, the Meltzer fund, the EXTRA funds from the Norwe- to be a risk factor for a range of medical conditions, including gian Foundation for Health and Rehabilitation, and the Re- glucose intolerance,51 impotence,52 hypertension,53 myocardial search Council of Norway. The funding organizations had no Journal of Clinical Sleep Medicine, Vol.5, No. 4, 2009 352
Sleep Disorders in Users of Zopiclone and Drug-free Insomniacs
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