PharmocoEconomlcs 1996: 10 Suppl.l : 39-44 117G-7690/96/OC1Jl-<Xl39/S03.00/0

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Health-Related Quality of Life in Patients with Insomnia Treated with Zopiclone Damien Leger,l Maria Antonia Quera-Salva2 and Pierre Philip3

1 Unite de Sommeil, Hotel Dieu de Paris, Paris, France 2 Unite de Sommeil, Hopital Raymond Poincare, Garches, France 3 Unite de Sommeil, Hopital Pellegrin, Bordeaux, France

Summary Insomnia can cause impaired productivity and absenteeism from work, in­creased risk of accidents, and impaired quality of family and social life. Thus, it can compromise quality oflife in affected individuals and result in costs to society as a whole. The nonbenzodiazepine hypnotic zopiclone is effective and well tolerated in the treatment of insomnia. Importantly, it also has minimal effects on next-day performance and psychological function.

458 patients treated with zopiclone for 14 days showed significantly greater improvement compared with placebo recipients in sleep evaluation questions and scores for activity, social and professional quality-of-life aspects. After 8 weeks, the improvement in scores for sleep, activity and social questions remained sig­nificantly higher in patients who had received zopiclone compared with placebo recipients.

No significant differences were observed between 167 patients who had been taking zopiclone for at least 12 months and a control group of 381 persons with no sleep problems in virtually all of the 5 aspects of the quality-of-life question­naire. Some important aspects such as relationships and professional life were not modified by zopiclone.

When insomnia is treated appropriately, compared with no treatment, patients' feelings about their quality of life are improved and, furthermore, do not appear to differ significantly from perceptions of quality of life in those without sleep­related problems.

Insomnia is a common symptom reported by an estimated one-third of the adult population in any given year in developed countries.l1,21 It is further

estimated that an overwhelming 95% of all people experience some kind of sleep disturbance in their

lifetimes. Insomnia usually takes one or more of the following forms: delayed sleep onset, difficulty in staying asleep or awakening too early. Several nationally representative probability sample sur-

veys have recently reported the prevalence of in­somnia in general populations. In such a survey conducted in the US in 1991 by the Gallup Orga­nizationpl 36% of adults reported some problem

with sleep, with 9% saying that it was a regular chronic problem, and 27% that it was an occasional problem. Weyerer and Dilling[31 reported the re­

sults of a survey conducted by research psychia­trists in a Bavarian representative probability sam-

40

pIe of 1536 persons aged> 15 years; they found that the prevalence of insomnia was 28.5% (mild, 15.0%; moderate/severe, 13.5%).

1. Quality of Life

Quality of life is a complex and multidimen­sional term that has been defined as 'A concept encompassing a broad range of physical and psy­chological characteristics and limitations which describe an individual's ability to function and to derive satisfaction from doing so' .[4] A patient's subjective well-being is influenced both by factors unrelated to disease, such as socio-cultural back­ground and education, and by those relating more directly to the severity of the disease and treatment intervention. The term health-related quality of life has been used to describe the latter factors, and has become an important criterion for patients and phy­sicians in evaluating the benefits of pharmacolog­ical interventions in relation to risk and COSt.[5] While the importance of evaluating quality of life in clinical trials is becoming increasingly recognised, the subjective nature of patients' as­sessments of their physical dysfunction or psycho­logical discomfort often makes interpretation of re­sults from these trials difficult.[6] The use of appropriate measurement techniques is vital to en­sure valid analysis and interpretation of quality-of­life outcomes.

The consequences of insomnia with regard to daytime alertness and patient quality of life are generally not taken into account in epidemiological studies. From a clinical viewpoint, insomnia is not only a problem relating to sleep - it also has day­time consequences such as fatigue, sleepiness, im­paired functioning and impaired ability to concen­trate, as well as depression, anxiety or other mood changes. In fact, without these daytime effects, the only severe consequence of insomnia would be an unsatisfactory perception of sleep,!7] For that rea­son, an individual's perception of his or her day­time life is important when evaluating the impact of insomnia. [8]

A good hypnotic agent needs to be effective both in improving sleep difficulties and in maintaining

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Leger et al.

good waking vigilance and daytime functioning.[9] However, until recently, quality-of-life aspects of insomnia had not been considered to a great degree when studying new treatments or examining the effects of treatment in patients with insomnia com­pared with individuals with no sleep prob­lems.!lO,ll]

Zopiclone, a nonbenzodiazepine hypnotic, has been shown to be effective and well tolerated in the treatment of insomnia, and appears to have a more favourable effect on sleep architecture than benzodiazepines. It has a short elimination half-life (3.5 to 6.5 hours), and minimal effects on perfor­mance and psychological functioning during the day after treatment. In contrast to benzodiazepines, zopiclone has little effect on short term memory and causes little rebound insomnia.!12,13] The pur­pose of the present article is to review the available data on the quality of life of zopiclone in patients with insomnia.

2. Results of Clinical Trials

To date, 2 clinical trials have directly assessed quality-of-life aspects of zopiclone treatment in pa­tients with insomnia.! 14, 15] Sleep disturbances were defined as difficulty in falling asleep (sleep latency > 30 minutes), waking during the night (> 2 awak­enings) and waking too early in the morning (i.e. 1 hour before the usual time with no return to sleep),[14,15] or sleep duration less than 6 hours.[15] Goldenberg and colleagues[15] also considered the presence of daily symptoms attributable to dis­turbed sleep. These trials provided data on the ef­fects of short and long term treatment with zopiclone on quality of life.

In the double-blind randomised trial of Gold­enberg et al.,[15] 458 patients with insomnia and aged between 25 and 60 years received either zopiclone 7.5mg or placebo nightly for 14 days and for a further 6 weeks on demand. In our investiga­tion,[14] we assessed quality of life in 167 patients who had been using zopiclone (dosage not stated) for the previous 12 months and compared the re­sults with those obtained from a control group of 381 patients with no sleep problems (or occasion-

PharmacoEconomlcs 1996; 10 Suppl. 1

ZopicIone and Quality of Life 41

Table I. Aspects used in questionnaires evaluating the effects of zopiclone on sleep and quality of life in clinical trials in patients with insomnia

Goldenberg et al.1151 Leger et al.1141

Psychological General Well-Being Index (22 items) Treatments taken by the patient at the time of the study (5 items)

Sleep Evaluation Questionnaire (5 items)

Leeds Sleep Evaluation Questionnaire (9 items)

Daily activities (8 items)

Social life (7 items)

Professional life (7 items)

Global evaluation question (1)

Sleep evaluation (10 items)

Leisure aspect"

Domestic aspect"

Relational and sentimental aspects'

Professional aspect"

Safety aspect"

a The 5 aspects of quality of life constituted 8 items on the questionnaire.

ally only one) who had received no hypnotic treat­ment within that time period. It was felt that people who asserted that they had experienced no sleep disturbances at all during the previous 12 months would not reflect individuals from the general pop­ulation, and especially those from the aging popu­lation, who considered themselves good sleepers.

Questionnaires were used to assess the effects of zopiclone on sleep and various quality-of-life dimensions, although it was not clear how results were scored. The reliability and validity of the questionnaires were established in one study.(15) In a broad sense, questionnaires from both trials mea­sured physical, emotional and social dimensions (see table I for details).

2.1 Effects of Zopiclone on Sleep

Sleep quality, ease of awakening and daily well­being improved significantly in patients treated with zopiclone for 14 days, and for up to 8 weeks, compared with placebo recipients (p ~ O.05)JI5) Occasional sleep disturbances were found in the patients who had received long term treatment (12 months) with zopiclone and in those in the control group without sleep disturbancesJI4) In this study, patients treated with zopiclone had more difficul­ties in falling asleep than control patients (13% vs 3%), but fewer occasional awakenings during the night (52% vs 61 %). However, there was no differ­ence between the 2 groups in either the percentage of awakenings lasting> 45 minutes per night or in occasional early awakenings.

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In our investigation,[14) we noted some differ­ences in alertness and performance upon waking between patients treated with zopiclone and those in the control group; however, the influence of fac­tors such as age may have contributed.

2.2 Effects of Zopiclone on Quality of Life

Compared with placebo recipients, patients treated with zopiclone for 14 days showed a signif­icantly greater improvement in scores for activity, social and professional quality-of-life aspects (fig. I)JI5) After completion of this study, scores for ac­tivity and social questions remained significantly higher in patients who had received zopiclone. There were no significant differences between treatment groups in scores for the Psychological General Well-Being Index or the single global evaluation question. No interactions between treat­ment and countries were detected in this multina­tional study (5 countries), although there was con­siderable variation in observations made in the participating countries (no further information available).

No significant differences were observed be­tween patients who had been taking zopiclone for the previous 12 months and a control group of per­sons with no sleep problems (or occasionally only one) in almost all the 5 aspects of the quality-of-life questionnaire (table II). However, the demo­graphic profile of persons enrolled in this trial was not discussed, nor was the zopiclone dosage stated; it was also unclear whether patients with insomnia had been taking zopiclone on a continuous or in-

PharmacoEconomics 1996: 10 Suppl. 1

42 Leger et al .

• Study end·point Z = Zopiclone o Day 14 P = Placebo o Baseline

80

70

'" 60 l" 0 u 50 '" ~ 40 '0

k 30 p Z P Z P CIS

Z P Z P Z P Z :::J 0 20

10

0~ __ L--L-L __ L--L~~ __ ~L--L __ ~L--L __ ~L--L __ L-

PGWBI Sleep evaluation

Activity Social Professional Global evaluation

Quality-ol-life parameter

Fig. 1. Quality-ol-lile scores in patients with insomnia who received treatment with zopiclone 7.5mg (n = 231) or placebo (n = 227) once daily at night lor 14 nights, then as needed (not to exceed 1 dose per night) until the study end-point ot :5 8 weeks,C15J A quality-ot-lite questionnaire was used to assess patients at baseline, day 14 and at study end-point. Abbreviation and symbols: PGWBI = Psychological General Well-Being Index; • p < 0.01, •• P < 0.0001 vs placebo at day 14.

termittent basis over the l2-month period. This in­formation would help to confirm that treatment re­sponse was not influenced by factors such as age and drug dosage.

3_ Discussion

Most studies evaluating the effects of treatments for insomnia use methods that reflect only the med­ical aspects of therapy, such as doctor interviews. This may introduce considerable bias: first, be­cause insomnia is viewed only from a medical per­spective and, second, because of the complex rela­tionship between the patient and the practitioner. In our trial,[J4] we excluded medical bias by enroll­ing patients using a national survey institute (Sofres, France). This organisation is similar to the Gallup Institute in the US[2] in that it surveys more than 20 000 households regularly and is not a spe­cialist in medical surveys alone. This method was also used to choose a control group of individuals who had no sleep disturbances, or occasionally only one.

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A questionnaire survey - methodology that could be considered as merely a subjective evalu­ation - was used to perform sleep and quality­of-life evaluations,fJ6] The sensitivity of quality­of-life instruments has sometimes been questioned in trials where treatment effects were not de­tected,[J7.J8] and reinforces the need for the devel­opment and use of appropriate measurement strategies.

It was observed that, in most instances, patients receiving long term therapy with zopiclone were equivalent in terms of quality of life to those with­out sleep-related problems. In addition, significant improvements in quality-of-life scores were ob­served for the majority of aspects assessed after 14 days of treatment with zopiclone compared with placebo. Some very important aspects, such as close personal relationships and professional life, were not negatively modified in zopiclone-treated patients, and had in fact improved when these pa­tients were compared with placebo recipients. One fear patients have regarding drugs affecting the central nervous system is that they will alter their

PharmacoEconomlcs J 996; 10 Suppl. 1

Zopic1one and Quality of Life 43

Table II. Results from a clinical trial evaluating quality of I~e in patients with insomnia who had been taking zopiclone (Z) [dosage not stated) for the previous 12 months (n = 167) compared with a control group (C) of individuals with no sleep problems (or occasionally only one) [n = 381)(141

Qua(ity-of·l~e aspect

Professional (number of employed: Z = 75; C = 230)

Had difficulty carrying out work

Felt good in their job

Relational/sentimental

Content with sentimental life

Went out in the evening

Received visitors at home

Went out during the day

Domeatlc

Did housework normally

Went shopping

Did odd jobs or gardening

leisure Walked or played sport

Watched television

Safety Experienced drowsiness while driving

Had near car accidents while driving because of sleepiness

Symbol: ' p < 0.05 vs zopiclone.

perceptions of their usual environment. Available results suggest that there is no difference in this regard between patients with insomnia treated with zopiclone and persons with normal sleep habits.

One could argue that the group of patients treated with zopiclone for more than 12 months was heterogeneous, since it included individuals whose insomnia was cured and for whom zopiclone was no longer useful and taken only because of psychological dependence, as well as individuals who still had insomnia and for whom zopiclone was still helpful. Thus, there would be less differ­ence between the 2 groups. However, since 1989, France has had a regulation limiting prescriptions for hypnotics to 28 days. At the end of this period, the prescription has to be renewed by a doctor. De­spite the lack of knowledge GPs generally have regarding sleep disorders, we can assume that the length of zopiclone prescribing in our group (i.e. for more than 12 months) was because of chronic insomnia.

As well as having consequences for the individ­ual, insomnia also has economic implications for

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Percentage of patients

zopiclone control

t4 18

93 97

91 94

59 64

n 83

87 93'

69 67

88 81

6t 62

n 72

90 95

6 t4

5 10

society.(19) Thus, it is not surprising that patients who are severely affected are responsible for much of the burden that insomnia constitutes for society (the costs of medical treatment and drugs and indi­rect costs such as those resulting from reduced pro­ductivity, absenteeism, accidents, increased mor­bidity and mortality).I2°-22) One major goal of future research would be to determine the effect of treatment with hypnotic agents on these economic consequences.

The risk of motor vehicle accidents associated with drowsiness has been well documented,(23) and some studies have found that a high percentage of injured drivers had measurable blood concentra­tions of benzodiazepines. [24.25) The lack of residual drowsiness seen in patients using zopiclone may contribute to the low incidence of near-accidents in these patients, although this has not been corre­lated with blood concentrations of the drug. Care­ful interpretation of this fact is needed and it may, indeed, be explained by a greater awareness and concern regarding drug-induced sleepiness in pa­tients with insomnia compared with individuals in

PharmacoEconamlcs 1996; 10 Suppl. 1

44

the general population. However, it is generally thought that people taking hypnotic drugs are at greater risk of accidents)26]

It can be speculated that the relative lack of next-day residual effects of zopiclone compared with the longer-acting benzodiazepines may im­prove the quality of life of patients and reduce costs related to the loss of productivity, and to absentee­ism and accidents. Zopiclone also appears to be associated with a lower risk of withdrawal syn­dromes, dependency and abuse than benzo­diazepines. If proven, this might reduce costs re­sulting from repeated clinic visits and the treatment of dependency)l3]

Health-related quality of life should be an im­portant consideration when evaluating new hyp­notic agents for the treatment of insomnia. When insomnia is treated appropriately, compared with no treatment, patients' feelings about their quality of life are improved and, furthermore, do not ap­pear to differ significantly from perceptions of quality of life in those without insomnia.

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Correspondence and reprints: Dr Damien Leger, Unite de Sommeil, Service de Physiologie, Hotel Dieu de Paris, 1 pI. du Parvis Notre Dame, 75181 Paris Cedex 04, France.

PharmacoEconomlcs 1996: 10 Suppl. 1