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Effect of Zolpidem on sleep in women with perimenopausal and postmenopausal insomnia: a 4-week, randomized, multicenter, double-blind, placebo-controlled study
CLINICALTHERAPEUTICS®/VoL26, No. 10, 2004
Effect of Zolpidem on Sleep in Women with Perimenopausal and Postmenopausal Insomnia: A 4-Week, Randomized, Multicenter, Double-Blind, Placebo-Controlled Study C y n t h i a M. Dorsey, PhD, 1 K a t h r y n A. Lee, RN, PhD, 2 a n d Martin B. Scharf, P h D 3
lHarvard Medical School, Boston, Massachusetts, 2School of Nursing and General Clinical Research Centet, University of Cal{fornia, San Francisco, Cal{fornia, and 3Centerfor Research in Sleep Disorders, Cincinnati, Ohio
ABSTRACT
Background: Although most adults in the United States obtain less sleep than they need, women report more sleep deprivation throughout their lifetime than do men. The prevalence of self-reported sleep difficulty increases as women make the transition from the premenopausal to the postmenopausal period. Objective: The purpose of this study was to assess the clinical efficacy and safety of zolpidem as a treatrnent for insomnia in perimenopausal and postrnenopausal women. Methods: Women who were perimenopausal or postmenopausal for >6 months, who had developed insomnia in conjunction with menopausal symptoms, and who had difficulty maintaining sleep or had nonrestorative sleep for _>6 months were eligible for this 4-week, muhicenter stud> Sleep maintenance difficulty had to occur an average of _>3 nights per week and had to be accompanied by _>2 nocturnal hot flashes, hot flushes, or night sweats. Patients were randornized in a double-blind fashion to 1 of 2 treatment groups--zolpidem 10 rng or placebo. Capsules were provided in weekly blister cards, and patients were instructed to take 1 capsule each night at bedtime. Patients recorded estimates of their sleep quality and quantity and daytime functioning on daily morning and evening questionnaires, and made weekly global assessments of sleep. Results: The study included 141 women (mean age _+SD, 50.8 _+4.5 years; age range, 39-60 years). Increases in reported total sleep time were significantly greater in the zolpidem group than in the placebo group (P < 0.01) for each treatment week. Wake time after sleep onset and number of awakenings decreased significantly in the zolpidern group compared with the placebo group (P < 0.05). Each week, approximately twice as many patients in the zolpidem group as in the placebo group reported improved sleep (P < 0.001 for each week). The improvement in sleep-related difficulty with daytime functioning was significantly greater in the zolpidem group than in the placebo group (P < 0.05). The effects of zolpidem did not diminish with the duration of treatment. Conclusions: Zolpidem 10 mg/d was effective and well tolerated in the treatment of menopause-related insomnia in perimenopausal and postmenopausal women. (Clin The1: 2004;26:1578-1586) Copyright © 2004 Excerpta Medica, Inc. Key words: insomnia, menopause, women, zolpidem, medication trial. Accepted.]or p~tblicationj~2y 19, 2004. Printed in the USA. I(eproduction in whole or part is not permitted.
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doi:l 0 I016/j.clinthera.2004.10.003 0149 2918/04/$ I (2O0
Copyright © 2004 Excerpta Nedica, Inc.
C.M. Dorsey et al.
INTRODUCTION
Although most adults in the United States obtain less sleep than they need, women report more sleep deprivation throughout their lifetime compared with men, as indicated by a large survey conducted by the National Sleep Foundation. I The prevalence of selfreported sleep difficulty increases as women enter the menopausal transition period. 2-° According to data from a representative community survey, 2 23.6% of women aged 45 to 49 years report sleep difficulties, and 39.7% of women in their early fifties complain of not sleeping well. The corresponding statistics in men are 14-.4-% and 15.3%, respectively. Similarly, estimates of complaints of insomnia in perimenopausal and postmenopausal women range from ~4% to 61%, compared with 33% in premenopausal women. 7,8 In addition to insomnia, the symptoms of perimenopausal and postmenopausal estrogen withdrawal include night sweats, emotional lability, depression, and vasomotor instability (hot flushes/hot flashes). 9 A hot flctsh is defined as sudden vasodilation with a sensation of heat, usually involving the face, neck, and upper part of the chest. A hot.flash is defined as a sensation of heat involving the whole body. Either can be followed by profuse sweating. Night sweats are defined as profuse sweating at night, occurring either alone or immediately subsequent to a hot flush or hot flash. As measured by polysomnography in menopausal women with and without hot flashes, vasomotor symptoms result in lower sleep efficiency with longer periods of wakefulness and a higher number of arousals. 10,11 The majority of perimenopausal women (87%) have 1 or more menopausal symptoms, with the following prevalence: insomnia (57.80~), joint pain (55.8%), night sweats (55.6%), and hot flashes (40.2%). 12 Insomnia has important implications for cognitive performance, behavior, and mood. Although persistent insomnia in the general population is not lifethreatening, individuals with insomnia consistently report impaired health, work efficiency, and relationships, as well as a general decrease in quality of life.13,1~ Furthermore, there are significant economic costs associated with insomnia. 15 Compared with those who sleep well, insomnia patients report more anxiety and depression. 1° The respective roles of depression, anxiety, and hot flashes in menopauserelated insomnia are controversial. In fact, it has been suggested that there might be a primary menopause-
related insomnia ~ similar to the prirnary insomnia defined in the Diagnostic and Statistical Manual of
Mental Disorders, goc~rth Edition (DSM-IV). The mechanism of the positive effect of estrogen on sleep is not well understood, although many symptoms of menopausal insomnia can be successfully treated with hormone therapy. 17 However, concerns about the safety of hormone therapy have recently emerged, and it is for this reason that many premenopausal and menopausal women seek other treatments for their sleep diflicuhies. Treatment for insomnia associated with menopause with an efficacious and safe hypnotic agent is an alternative pharmacologic approach that is independent of hormonal fluctuations. Zolpidem is a hypnotic agent that has been used extensively and safely to treat many different types of insomnia, is xl To our knowledge, based on a review of the literature, this is the first study conducted specifically to assess the efficacy of a hypnotic drug in the treatment of insomnia associated with menopause. We hypothesized that a 4-week trial of nightly use of zolpidem 10 mg in perimenopausal and postmenopausal women would significantly improve subjective sleep parameters compared with placebo, as measured by weekly patient global assessments and daily morning and evening questionnaires. PATIENTS AND METHODS
This was a ~-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group outpatient study. The study was conducted at 9 sleep centers in the United States using a protocol approved by the local ethics committees. Eligible patients were informed of the potential benefits and risks of treatment with zolpidem and provided written informed consent before entry into the study. Patient Selection and Screening
Women aged 39 to 60 years were eligible to participate in the study if they had developed insomnia in temporal conjunction with menopausal symptoms. In addition, they had to have complaints of difficulty maintaining sleep or complaints of nonrestorative sleep for _>6 months. Sleep maintenance difficulty had to occur an average of _>3 nights per week and had to be accompanied by _>2 nocturnal hot flashes, hot flushes, or night sweats. Participants also had to
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CLINICAL THERAPEUTICS®
be in good mental and physical health, as determined by medical and psychiatric history, physical examination, and standard clinical laboratory tests obtained within 2 weeks of study onset. Exclusion criteria included the presence of signs or symptoms of clinical depression, as ascertained by clinical interview and a Beck Depression Inventory score of >10, 22 or any other significant psychiatric disorder, based on DSM-IV criteria; use of any overthe-counter or prescription sleep medication within 7 days or any investigational drug within 30 days before study onset; positive urine screening test for medications that could interfere with the assessment of study medication, including benzodiazepines, barbiturates, opiates, cocaine, phenothiazines, amphetamines, and cannabinoids; a history of drug abuse/ dependence or alcoholism; and a history or current symptoms of obstructive sleep apnea or periodic limb movement disorder. In addition, patients taking hormone therapy had to have been on a stable dosing regimen for at least 6 months and had to maintain this dose throughout the study. Following the initial screening interview, patients completed a sleep diary for 6 to 14 days to further assess the severity and frequency of their sleep complaints. The information from the diaries was used to establish that during this baseline period, on at least 3 of 7 consecutive nights, patients exhibited the following: (1) total sleep time (TST) of <6 hours or wake time after sleep onset (WASO) of >1 hour and (2) sleep-related difficulty with daytime functioning (SRDDF) as recorded each evening. This aspect of screening confirmed the patients' sleep complaints, assessed whether patients would comply with study requirements, and familiarized them with keeping daily sleep diaries. Once enrolled in the study, patients were required to abstain from the use of psychotropic medications or medications with known effects on sleep (eg, sedating antihistamines, beta-blockers). They also were asked not to consume large meals within 2 hours of bedtime or to drink alcohol or use central nervous system-active medications within several hours before going to bed.
drug supply in the event of a delayed visit to the sleep center. Patients were instructed to take 1 capsule with water each night at bedtime. They also were told to take only 1 capsule per night and to not use the study medication to treat early awakenings. Information was provided about a possible next-day carryover effect, and patients were cautioned to use care while doing anything that required complete alertness, such as driving a car or operating machinery, until they knew how the study medication affected them. Used and unused medication counts were monitored and recorded at each weekly clinic visit.
Study Medication Study medications were provided in weekly blister cards containing 10 capsules to ensure an adequate
Statistical Analysis For all analyses except the safety analysis, P < 0.05 was considered statistically significant (using a 2-
i580
Study Protocol Once randomized to treatment, patients recorded assessments of their sleep quality and quantity as well as daytime functioning on a daily basis via morning and evening questionnaires. The morning questionnaire was completed upon awakening and comprised 14 questions to assess different aspects of sleep, including sleep latency (SL), number of awakenings (NOA), WASO, and TST. The evening questionnaire was completed before bedtime, and patients recorded their assessments of SRDDF within the last 24 hours. Patients reported their overall morning and evening energy levels once weekly using the Lee Fatigue Scale. 23 Patients were assessed at weekly clinic visits during which the investigator conducted a clinical interview and recorded adverse events. Patients were asked to complete the General Sleep Disturbance Scale 24 and a Relationship Satisfaction Questionnaire, 2> both of which have been used in women at various reproductive stages of life. Finally, patients rated their global impression of therapy (Patient Global Impression [PGI]). The PGI included 4 items related to study medication effects, each answered on a 3-point scale (1 = positive medication eflect; 2 = no medication effect; 3 = negative medication effect). The 4 items included: (1) hypnotic efficacy (helped/worsened sleep); (2) SL (decreased/ increased time to fall asleep); (3) sleep duration (increased/decreased TST); and (4) sleep quality (provided better sleep/interfered with sleep).
C.M. Dorsey et al.
tailed test). For the safety analysis, P < 0.10 was considered statistically significant. The data are expressed as mean (SEM) because they were averaged over time. Baseline characteristics (ie, demographic characteristics, sleep history, Beck Depression Inventory scores) were compared between the 2 treatment groups. Analysis of variance, with terms for treatment, study site, and their interaction, was used for continuous measures. Categoric variables were compared using the Cochran-Mantel-Haenszel test, with control for study site. Efficacy analyses were performed separately for each study visit on an intent-to-treat basis. Mean change scores from baseline for each week were used for the 4 morning questionnaire items (St, NOA, WASO, TST), except for the baseline week analysis, which used mean values. The Cochran-MantelHaenszel test was used to analyze the PGI, SRDDF, Lee Fatigue Scale, General Sleep Disturbance Scale, and the Relationship Satisfaction Questionnaire, with control for study site. RESULTS Patients
Of 2q-2 potential participants screened for the study, 141 met eligibility criteria and were randornized to treatment. Of the 101 volunteers not eligible for the study, 86 (85.1%) failed entry criteria and 6 (5.9%) were noncompliant with the study protocol during the 6 - to 14-day screening period. The remaining patients were lost to follow-up (3 patients) or were not enrolled for administrative (3 patients) or other (3 patients) reasons. Efficacy data were available for all 141 participants. Table I depicts a flow diagram of the study population. The mean _+SD age o[ patients randomized to treatment was 50.8 _+ 4.5 years (age range, 39-60 years). No differences were found between the 2 treatment groups in dernographic characteristics, menstrual regularity, and historic sleep data (Table II). T r e a t m e n t Efficacy Patient Global Impression
All of the mean PGI ratings, indicating subjective ratings of change after medication (1 = positive effect; 2 = no eflect; 3 = negative effec0 for hypnotic efficacy (helped/worsened sleep), SL (decreased/increased time to Fall asleep), TST, and sleep quality (provided
Table I. Randomization and completion statistics for the study population (N = 141). Zolpidem
Placebo
No. of patients randomized
68
73
Discontinued during treatment Adverse events Noncompliance with procedures
II 5 2
5 2 I
I 0 }
I I 0
57
68
Use of unacceptable medication Unsatisfactory response Other Completed study
Table II. Baseline demographic and sleep measures.* Zolpidem Heasure Demographic characteristics Age
Body mass index Beck Depression Inventory score Henopausal status last 6 months, no, (%) of patients Regular period Irregular/unusual
No period Sleep variables Sleep latency, rain No. of awakenings Wake during sleep, rain Total sleep time, rain
(n
68)
Placebo
(n
73)
50,7 -- 4.5)
50,8 -- 4,5)
25,4 -- 0.35 5, I -- 0.32
24,6 -- O, I I 4,3 -- 0,33
0 24 (33.3)
2 (2_.7) 28 (38,4)
44 (64.7)
43 (58.9)
34,0 -- 3.03
37,0 -- 3,16
2,7 -- 0.16 69.0 + 5.09
2,7 -- 0,32 75.0 + 5.04
354.0 + 7.03
365.0 + 8.43
~There were no significant differences between treatment groups at baseline. IVariation in age is expressed as SD, rEher than SE[Vl. All other values are mean + SEN.
better sleep/interfered with sleep), were significantly lower--indicating better sleep--in the zolpidem group than in the placebo group at each weekly assessment (P < 0.01), with the exception of SL at weeks 2 and 3. Surnmary data for these 4 questions (ie, sum of the 4 iterns) reflect the overall beneficial subjective effects on sleep of zolpidem compared with placebo. The summary scores for weeks 1 through 4 for the zolpidem group were 5.44, 5.53, 5.63, and 5.53, respectively, compared with the i581
CLINICAL THERAPEUTICS®
scores in the placebo group of 6.83, 6.63, 6.54, and 6.87, respectively. The percentage of patients in each treatment group reporting better sleep (ie, score of 1 on item 4, "helped me get a better night's sleep") during each week is shown in Figure 1. During each week, approximately twice as many patients treated with zolpidem reported better sleep compared with those treated with placebo (P < 0.001 for each week). Daily Questionnaires Quantitative subjective estimates of sleep parameters (St, NOA, WASO, and TST) from the morning questionnaires and estimates of SRDDF from the evening questionnaires were analyred for each week of treatment. Changes from baseline in TST for both groups are displayed in Figure 2. There were significantly greater increases in reported TST for the 7olpidem group than for the placebo group for each of the 4 treatment weeks (P < 0.01). Baseline values and mean changes from baseline in values of other subjective sleep parameters from the daily questionnaires at weeks 1-4 are presented in Table III. At baseline, none of the reported values were significantly different between the 2 groups. At each week during treatment, WASO and NOA were significantly reduced from baseline (P < 0.05 for both parameters) in the zolpidem group compared with the placebo group. WASO and NOA remained stable over the treatment period in the 7olpidem group, but improved progressively in the placebo group. The change in estimates of SL did not differ between groups at any time. At each week of treatment, the mean change from baseline in SRDDF was significantly greater in the zolpidem group than in the placebo group (P < 0.05 for all weeks). Quality of Life and Ability to Function A large number of between-group comparisons were made for the 3 categoric scales: the Lee Fatigue Scale (18 questions), the General Sleep Disturbance Scale (15 questions), and the Relationship Satisfaction Questionnaire (14 questions). Only 3 statistically significant differences were found, which is within the range expected by chance for multiple comparisons. Thus, we concluded that there were no meaningful diflerences between the treatment groups for any of these items. 1582
Safety Profile Of the 141 subjects enrolled, 106 (75.2%) reported adverse events. The most frequently reported adverse events in the zolpidem and the placebo groups were headache (52.9% [36/68] vs 32.9% [24/73]; P = 0.08), upper respiratory tract infection (16.2% [11/68] vs 6.8% [5/73]; P = 0.11), and drowsiness (10.3% [7/68] vs 1.4% [1/73]; P = 0.03). The other adverse events for which there were statistically significant between-group differences were dizziness (8.8% [6/68] vs 0; P = 0.01), backache (7.4% [5/68] vs 0; P = 0.02), and irritability (7.4% [5/68] vs 2.7% [2/73]; P = 0.02). Seven (5.0%) of the 141 patients withdrew from the study because of adverse events: 5 (7.4%) in the zolpidem group and 2 (2.7%) in the placebo group. There were no correlations between adverse events or discontinuations and age, body mass index, Beck Depression Inventory score, medical history, or sleep history. Zolpidem was not associated with any clinically significant changes in clinical laboratory values or physical examination results. DISCUSSION This study assessed the efficacy and safety of zolpidem 10 mg nightly in the treatment of menopause-related insomnia in perimenopausal and postmenopausal women over a period of 4 weeks. It was found that during each week of treatment approximately twice as many zolpidem-treated patients reported better sleep compared with those in the placebo group. Zolpidem improved subjective estimates of sleep quality and quantity, including TST, NOA, and WA50, throughout the treatment period. On average, patients receiving zolpidem experienced an increase o f - 6 0 minutes in TST, a decrease o f - 4 0 minutes in WASO, and a reduction of 1 or more awakenings per night. Comparable values in the placebo group were an increase of -20 minutes in TST, a 25-minute reduction in WASO, and 0.5 fewer awakenings per night. To our knowledge, based on a review of existing literature, this is the first report of successful use of a hypnotic agent specifically in this population of insomnia patients. Not unexpectedly, a significant placebo effect is apparent for all of these subjective outcome measures. Similar observations have been reported in previous zolpidem studies, 1~-2] as well as in a recent metaanalysis 2C~of subjective sleep changes associated with placebo in clinical trials of hypnotic agents.
C.M. Dorsey et al.
Better Sleep 77.8
78.7
•
Zolpidem
[]
Placebo
75.4
~O tO aJ r~
r~
~6
I
70 ~o to
60
2
3
No Change
t
52.1
51.4
52.9
51.5
r~
,,.o
I
t~
2
,61
3
4
3
4
Worse Sleep
12
6.8
e~ i1)
I
2
Treatment Week
Figure I. Subjective reports of global impression of therapy using the Patient Global Impression assessment completed by study patients once weekly during the clinic visit. Data are expressed as mean (SEM).
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CLINICAL THERAPEUTICS®
• Zolpidem [ ] Placebo
100] 90 .~
80
•
70
E Io_ o o
.E
..c
U
I
2
3
4
Treatment Week
Figure 2. Effects of zolpidem and placebo on total sleep time. Data are expressed as mean (SEM) for the change from the baseline period. *P < 0.05 versus the placebo group.
In this study, perimenopausal and postmenopausal women were selected based on their cornplaints of difficuhy maintaining sleep rather than difficulty initiating sleep. Patients were also selected based on complaints that their weekly sleep disturbance was associated with _>2 night sweats and/or hot flashes or hot flushes. This is reflected in the baseline sleep profile, on which patients reported an average estimated TST of - 6 hours per night, with a wake time during sleep of -1 hour together with -3 awakenings per night. In contrast, SL (-35 minutes) was not particularly abnormal. As measured by assessments of both subjectively reported quality of sleep and the subjective quantitative parameters of sleep rnaintenance (ie, TST, WASO, and NOA), zolpidem significantly improved the reported menopause-related insomnia. As with all central nervous system-active medications, there is a risk of dependence and of symptoms of withdrawal with long-term zolpidem use. However, there is evidence to suggest that abuse liability is lower with zolpidem than with benzodiazepines. 2r Statistically significant differences were observed between the zolpidem and placebo groups for incidence of side effects, including headache, drowsiness,
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dizziness, backache, and irritability. These differences are consistent with adverse events reported in other zolpidem studies. >-21 Together with the improved quantity and quality of sleep, patients in the zolpidem group experienced significant and progressive improvements in their reported SRDDE On the other hand, there were no positive effects of treatment on any of the quality-of-life indicators that presumably are specific for this patient population. It is possible that only a global and general assessment of daytime activity can capture the distress in a population in which each individual has different specific complaints. This is in agreernent with observations of individuals with chronic insornnia in the general population, where the association between a complaint of chronic insomnia and perceived daytime impairment is well documented, but relationships to measures of specific daytime impairment are less clear. One potential weakness of the present study was that hot flashes and hot flushes were not measured as a function of treatment. Measuring hot flashes and hot flushes in relation to subjective sleep reports would have been interesting from the standpoint of
C.M. Dorsey et al.
Table III. Sleep-related measures obtained from the Daily Morning Questionnaire (mean + SEM). W a k e A f t e r Sleep O n s e t
Timepoint
No, o f Awakenings
Sleep Latency
Zolpidem
Placebo
Zolpidem
Placebo
Zolpidem
Baseline
69,0 -- 5,09
75,0 -- 5.04
2,7 -- O. 16
2.7 f 0,32
34,0 f
Week I
29.0 + 4.31`*
61.0 + 4.21
1.5 + 0.11`*
Week 2
31,0 -- 4,82 ~
53,0 -- 4.48
Week 3
30.0 + 4.35`*
50.0 + 4.07
Week 4
29,0 -- 5,30"*
47,0 -- 4.72
SRDDF
Placebo
Zolpidem
Placebo
3,03
37,0 -- 3.16
2,6 f 0,09
2.5 -- 0,08
2.3 + 0.11
33.0 + 4.18
37.0 + 2.45
2.2 + 0.07`*
2.2 + 0.06
1,4 -- 0. I I ~
2.0 _+ 0,09
32,0 _+ 2,66
37,0 -- 3.30
2, I + 0,09"*
2.2 -- 0,07
1.3 + 0.12`*
1.9 + 0. I I
31.0 + 2.43
32.0 + 2.51
2. I + 0.10`*
2.2 + 0.07
1,4 -- 0.12"*
1.8 + 0, 12
29,0 + 2,64
31,0 -- 2.90
2,0 + 0, I I"*
2. I -- 0,09
SRDDF sleeprelated diffculty with daytime functioning. xp < 0.05 versus placebo.
the uncertainty about the respective relationships between hot flashes and hot flushes, mood disturbance, and insomnia in this population. However, our goal for this study was not to attempt to elucidate the nature of these relationships but to determine whether zolpidem could improve subjective reports of sleep in individuals experiencing these sleep-disrupting events. The occurrence of hot flashes and hot flushes was not measured (eg, by recording skin ternperature) because there was no reason a priori to suspect that 7olpidem would have any effect on thermoregulation or occurrence of hot flashes and hot flushes. While the actual role of hot flashes and hot flushes in menopausal insomnia is controversial, ~ the results of this study suggest that use of zolpidem can help overcome their disruptive effects on sleep. As with any controlled stud> the inclusion/exclusion criteria used limit the generalizability of these findings to the population of perimenopausal and postmenopausal women with insomnia. Future research with particular focus on the specific individual complaints in this population will be needed to determine whether zolpidem has an effect on hot flashes and hot flushes and other symptoms of menopause. CONCLUSIONS
Nightly treatment with 10 mg of zolpidem was effective in treating insomnia associated with perimenopausal and postmenopausal symptoms in this population of women aged 39 to 66 years. Zolpidem appeared to be safe and was tolerated well in the population studied.
ACKNOWLEDGMENTS
This research was supported by Sanofi-Synthelabo Inc., New York, New York. In addition to the authors, the following investigators participated in the study: Martin A. Cohn, Sleep Disorders Center of SW Florida, Naples, Florida; Andrew D. Krystal, Sleep Disorders Center, Duke University Medical Center, Durham, North Carolina; Mark W. Mahowald, Minnesota Regional Sleep Disorders Center, Minneapolis, Minnesota; Paula 5chweitzer, Sleep Medicine and Research Center, Chesterfield, Missouri; Gary K. Zammit, D/B/A Sleep Disorders Institute, New York, New York; and Joan L. Shaver, University o f Illinois School of Nursing, Chicago, Illinois. REFERENCES
1. Johnson EO. 1998 Women and Sleep Poll. National Sleep Foundation; 1998. 2. Kravitz HM, Ganz PA, Brombergerj, et al. Sleep dilTiculty in women at midlife: A community sunTey of sleep and the menopausal transition. Menopause. 2003;10:19-28. 3. Shaver JL, Paulsen VM. Sleep, psychological distress, and somatic symptoms in perimenopausal women. Fan Pratt Res J. 1993;13:373-384. 4. ShaverJ, Giblin E, Lentz M, Lee K. Sleep patterns and stability in perimenopausal women. Sleep. 1988;11:556-561. 5. Rosenthal MB. Epidemiology, sleep, and menopause. Menopause. 2003;10:4-5. 6. Krystal AD, Edinger J, Wohlgemuth W, Marsh GR. Sleep in peri-menopausal and post-menopausal women. Sleep Med Re> 1998;2:243-253. ]585
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7. Brugge KL, Kripke DE Ancoli-Israel S, Gaffinkel L. The association of menopausal status and age with sleep disorders. Sleep Res. 1989;18:208. 8. Krystal AD. Insomnia in women. Cli,q Cor,qerslone. 2003~5(3):41-50. 9. Hunter M. The south-east England longitudinal study of the climacteric and postmenopause. Maturitas. 1992;14:117-126. 10. Woodward S, Freedman RR. The thermoregulatory effects of menopausal hot flashes on sleep. Sleep. 1994~ 17:497-501. I1. Woodward S, Freeman RR. Sleep tragmentafion in menopausal women with and without hot flashes. Sleep Res. 1995;24:63. 12. Goonaratna C, Fonseka P, Wijeywardene K. Perimenopausal symptoms in Sri Lankan women. Ceylo,q Med.l. 1999;44:63-69. 13. Zammit GK, Weiner j, Damato N, et al. Quality o[ life in people with insomnia. Sleep. 1999;22(Suppl 2): $379-$385. 14. Roth T, Ancoli-Israel S. Daytime consequences and correlates of insomnia in the United States: Results of the 1991 National Sleep Foundation Surve): II. Sleep. 1999;22(Suppl 2):$354-$358. 15. Walsh JK, Engelhardt CL. The direct economic costs of insomnia in the United States for 1995. Sleep. 1999; 22(Suppl 2):$386-$393. 16. Moline ML, Broch L, Zak R, Gross V Sleep in women across the life cycle from adulthood through menopause. Sleep Meal Re> 2003;7:155-177. 17. Striper A, Trachsel L, Guldner J, et al. Neurosteroid pregnenolone induces sleep-EEG changes in man corn-
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Address c o r r e s p o n d e n c e to: Cynthia M. Dorsey, PhD, Sleep Research Lab, McLean Hospital, 115 Mill Street, Belmont, MA 02478. E-mail: c y n t h i a - d ° r s e y @ h m s h a r v a r d e d u
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Effect of Zolpidem on Sleep in Women with Perimenopausal and Postmenopausal Insomnia: A 4-Week, Randomized, Multicenter, Double-Blind, Placebo-Controlled Study C y n t h i a M. Dorsey, PhD, 1 K a t h r y n A. Lee, RN, PhD, 2 a n d Martin B. Scharf, P h D 3
lHarvard Medical School, Boston, Massachusetts, 2School of Nursing and General Clinical Research Centet, University of Cal{fornia, San Francisco, Cal{fornia, and 3Centerfor Research in Sleep Disorders, Cincinnati, Ohio
ABSTRACT
Background: Although most adults in the United States obtain less sleep than they need, women report more sleep deprivation throughout their lifetime than do men. The prevalence of self-reported sleep difficulty increases as women make the transition from the premenopausal to the postmenopausal period. Objective: The purpose of this study was to assess the clinical efficacy and safety of zolpidem as a treatrnent for insomnia in perimenopausal and postrnenopausal women. Methods: Women who were perimenopausal or postmenopausal for >6 months, who had developed insomnia in conjunction with menopausal symptoms, and who had difficulty maintaining sleep or had nonrestorative sleep for _>6 months were eligible for this 4-week, muhicenter stud> Sleep maintenance difficulty had to occur an average of _>3 nights per week and had to be accompanied by _>2 nocturnal hot flashes, hot flushes, or night sweats. Patients were randornized in a double-blind fashion to 1 of 2 treatment groups--zolpidem 10 rng or placebo. Capsules were provided in weekly blister cards, and patients were instructed to take 1 capsule each night at bedtime. Patients recorded estimates of their sleep quality and quantity and daytime functioning on daily morning and evening questionnaires, and made weekly global assessments of sleep. Results: The study included 141 women (mean age _+SD, 50.8 _+4.5 years; age range, 39-60 years). Increases in reported total sleep time were significantly greater in the zolpidem group than in the placebo group (P < 0.01) for each treatment week. Wake time after sleep onset and number of awakenings decreased significantly in the zolpidern group compared with the placebo group (P < 0.05). Each week, approximately twice as many patients in the zolpidem group as in the placebo group reported improved sleep (P < 0.001 for each week). The improvement in sleep-related difficulty with daytime functioning was significantly greater in the zolpidem group than in the placebo group (P < 0.05). The effects of zolpidem did not diminish with the duration of treatment. Conclusions: Zolpidem 10 mg/d was effective and well tolerated in the treatment of menopause-related insomnia in perimenopausal and postmenopausal women. (Clin The1: 2004;26:1578-1586) Copyright © 2004 Excerpta Medica, Inc. Key words: insomnia, menopause, women, zolpidem, medication trial. Accepted.]or p~tblicationj~2y 19, 2004. Printed in the USA. I(eproduction in whole or part is not permitted.
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doi:l 0 I016/j.clinthera.2004.10.003 0149 2918/04/$ I (2O0
Copyright © 2004 Excerpta Nedica, Inc.
C.M. Dorsey et al.
INTRODUCTION
Although most adults in the United States obtain less sleep than they need, women report more sleep deprivation throughout their lifetime compared with men, as indicated by a large survey conducted by the National Sleep Foundation. I The prevalence of selfreported sleep difficulty increases as women enter the menopausal transition period. 2-° According to data from a representative community survey, 2 23.6% of women aged 45 to 49 years report sleep difficulties, and 39.7% of women in their early fifties complain of not sleeping well. The corresponding statistics in men are 14-.4-% and 15.3%, respectively. Similarly, estimates of complaints of insomnia in perimenopausal and postmenopausal women range from ~4% to 61%, compared with 33% in premenopausal women. 7,8 In addition to insomnia, the symptoms of perimenopausal and postmenopausal estrogen withdrawal include night sweats, emotional lability, depression, and vasomotor instability (hot flushes/hot flashes). 9 A hot flctsh is defined as sudden vasodilation with a sensation of heat, usually involving the face, neck, and upper part of the chest. A hot.flash is defined as a sensation of heat involving the whole body. Either can be followed by profuse sweating. Night sweats are defined as profuse sweating at night, occurring either alone or immediately subsequent to a hot flush or hot flash. As measured by polysomnography in menopausal women with and without hot flashes, vasomotor symptoms result in lower sleep efficiency with longer periods of wakefulness and a higher number of arousals. 10,11 The majority of perimenopausal women (87%) have 1 or more menopausal symptoms, with the following prevalence: insomnia (57.80~), joint pain (55.8%), night sweats (55.6%), and hot flashes (40.2%). 12 Insomnia has important implications for cognitive performance, behavior, and mood. Although persistent insomnia in the general population is not lifethreatening, individuals with insomnia consistently report impaired health, work efficiency, and relationships, as well as a general decrease in quality of life.13,1~ Furthermore, there are significant economic costs associated with insomnia. 15 Compared with those who sleep well, insomnia patients report more anxiety and depression. 1° The respective roles of depression, anxiety, and hot flashes in menopauserelated insomnia are controversial. In fact, it has been suggested that there might be a primary menopause-
related insomnia ~ similar to the prirnary insomnia defined in the Diagnostic and Statistical Manual of
Mental Disorders, goc~rth Edition (DSM-IV). The mechanism of the positive effect of estrogen on sleep is not well understood, although many symptoms of menopausal insomnia can be successfully treated with hormone therapy. 17 However, concerns about the safety of hormone therapy have recently emerged, and it is for this reason that many premenopausal and menopausal women seek other treatments for their sleep diflicuhies. Treatment for insomnia associated with menopause with an efficacious and safe hypnotic agent is an alternative pharmacologic approach that is independent of hormonal fluctuations. Zolpidem is a hypnotic agent that has been used extensively and safely to treat many different types of insomnia, is xl To our knowledge, based on a review of the literature, this is the first study conducted specifically to assess the efficacy of a hypnotic drug in the treatment of insomnia associated with menopause. We hypothesized that a 4-week trial of nightly use of zolpidem 10 mg in perimenopausal and postmenopausal women would significantly improve subjective sleep parameters compared with placebo, as measured by weekly patient global assessments and daily morning and evening questionnaires. PATIENTS AND METHODS
This was a ~-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group outpatient study. The study was conducted at 9 sleep centers in the United States using a protocol approved by the local ethics committees. Eligible patients were informed of the potential benefits and risks of treatment with zolpidem and provided written informed consent before entry into the study. Patient Selection and Screening
Women aged 39 to 60 years were eligible to participate in the study if they had developed insomnia in temporal conjunction with menopausal symptoms. In addition, they had to have complaints of difficulty maintaining sleep or complaints of nonrestorative sleep for _>6 months. Sleep maintenance difficulty had to occur an average of _>3 nights per week and had to be accompanied by _>2 nocturnal hot flashes, hot flushes, or night sweats. Participants also had to
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CLINICAL THERAPEUTICS®
be in good mental and physical health, as determined by medical and psychiatric history, physical examination, and standard clinical laboratory tests obtained within 2 weeks of study onset. Exclusion criteria included the presence of signs or symptoms of clinical depression, as ascertained by clinical interview and a Beck Depression Inventory score of >10, 22 or any other significant psychiatric disorder, based on DSM-IV criteria; use of any overthe-counter or prescription sleep medication within 7 days or any investigational drug within 30 days before study onset; positive urine screening test for medications that could interfere with the assessment of study medication, including benzodiazepines, barbiturates, opiates, cocaine, phenothiazines, amphetamines, and cannabinoids; a history of drug abuse/ dependence or alcoholism; and a history or current symptoms of obstructive sleep apnea or periodic limb movement disorder. In addition, patients taking hormone therapy had to have been on a stable dosing regimen for at least 6 months and had to maintain this dose throughout the study. Following the initial screening interview, patients completed a sleep diary for 6 to 14 days to further assess the severity and frequency of their sleep complaints. The information from the diaries was used to establish that during this baseline period, on at least 3 of 7 consecutive nights, patients exhibited the following: (1) total sleep time (TST) of <6 hours or wake time after sleep onset (WASO) of >1 hour and (2) sleep-related difficulty with daytime functioning (SRDDF) as recorded each evening. This aspect of screening confirmed the patients' sleep complaints, assessed whether patients would comply with study requirements, and familiarized them with keeping daily sleep diaries. Once enrolled in the study, patients were required to abstain from the use of psychotropic medications or medications with known effects on sleep (eg, sedating antihistamines, beta-blockers). They also were asked not to consume large meals within 2 hours of bedtime or to drink alcohol or use central nervous system-active medications within several hours before going to bed.
drug supply in the event of a delayed visit to the sleep center. Patients were instructed to take 1 capsule with water each night at bedtime. They also were told to take only 1 capsule per night and to not use the study medication to treat early awakenings. Information was provided about a possible next-day carryover effect, and patients were cautioned to use care while doing anything that required complete alertness, such as driving a car or operating machinery, until they knew how the study medication affected them. Used and unused medication counts were monitored and recorded at each weekly clinic visit.
Study Medication Study medications were provided in weekly blister cards containing 10 capsules to ensure an adequate
Statistical Analysis For all analyses except the safety analysis, P < 0.05 was considered statistically significant (using a 2-
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Study Protocol Once randomized to treatment, patients recorded assessments of their sleep quality and quantity as well as daytime functioning on a daily basis via morning and evening questionnaires. The morning questionnaire was completed upon awakening and comprised 14 questions to assess different aspects of sleep, including sleep latency (SL), number of awakenings (NOA), WASO, and TST. The evening questionnaire was completed before bedtime, and patients recorded their assessments of SRDDF within the last 24 hours. Patients reported their overall morning and evening energy levels once weekly using the Lee Fatigue Scale. 23 Patients were assessed at weekly clinic visits during which the investigator conducted a clinical interview and recorded adverse events. Patients were asked to complete the General Sleep Disturbance Scale 24 and a Relationship Satisfaction Questionnaire, 2> both of which have been used in women at various reproductive stages of life. Finally, patients rated their global impression of therapy (Patient Global Impression [PGI]). The PGI included 4 items related to study medication effects, each answered on a 3-point scale (1 = positive medication eflect; 2 = no medication effect; 3 = negative medication effect). The 4 items included: (1) hypnotic efficacy (helped/worsened sleep); (2) SL (decreased/ increased time to fall asleep); (3) sleep duration (increased/decreased TST); and (4) sleep quality (provided better sleep/interfered with sleep).
C.M. Dorsey et al.
tailed test). For the safety analysis, P < 0.10 was considered statistically significant. The data are expressed as mean (SEM) because they were averaged over time. Baseline characteristics (ie, demographic characteristics, sleep history, Beck Depression Inventory scores) were compared between the 2 treatment groups. Analysis of variance, with terms for treatment, study site, and their interaction, was used for continuous measures. Categoric variables were compared using the Cochran-Mantel-Haenszel test, with control for study site. Efficacy analyses were performed separately for each study visit on an intent-to-treat basis. Mean change scores from baseline for each week were used for the 4 morning questionnaire items (St, NOA, WASO, TST), except for the baseline week analysis, which used mean values. The Cochran-MantelHaenszel test was used to analyze the PGI, SRDDF, Lee Fatigue Scale, General Sleep Disturbance Scale, and the Relationship Satisfaction Questionnaire, with control for study site. RESULTS Patients
Of 2q-2 potential participants screened for the study, 141 met eligibility criteria and were randornized to treatment. Of the 101 volunteers not eligible for the study, 86 (85.1%) failed entry criteria and 6 (5.9%) were noncompliant with the study protocol during the 6 - to 14-day screening period. The remaining patients were lost to follow-up (3 patients) or were not enrolled for administrative (3 patients) or other (3 patients) reasons. Efficacy data were available for all 141 participants. Table I depicts a flow diagram of the study population. The mean _+SD age o[ patients randomized to treatment was 50.8 _+ 4.5 years (age range, 39-60 years). No differences were found between the 2 treatment groups in dernographic characteristics, menstrual regularity, and historic sleep data (Table II). T r e a t m e n t Efficacy Patient Global Impression
All of the mean PGI ratings, indicating subjective ratings of change after medication (1 = positive effect; 2 = no eflect; 3 = negative effec0 for hypnotic efficacy (helped/worsened sleep), SL (decreased/increased time to Fall asleep), TST, and sleep quality (provided
Table I. Randomization and completion statistics for the study population (N = 141). Zolpidem
Placebo
No. of patients randomized
68
73
Discontinued during treatment Adverse events Noncompliance with procedures
II 5 2
5 2 I
I 0 }
I I 0
57
68
Use of unacceptable medication Unsatisfactory response Other Completed study
Table II. Baseline demographic and sleep measures.* Zolpidem Heasure Demographic characteristics Age
Body mass index Beck Depression Inventory score Henopausal status last 6 months, no, (%) of patients Regular period Irregular/unusual
No period Sleep variables Sleep latency, rain No. of awakenings Wake during sleep, rain Total sleep time, rain
(n
68)
Placebo
(n
73)
50,7 -- 4.5)
50,8 -- 4,5)
25,4 -- 0.35 5, I -- 0.32
24,6 -- O, I I 4,3 -- 0,33
0 24 (33.3)
2 (2_.7) 28 (38,4)
44 (64.7)
43 (58.9)
34,0 -- 3.03
37,0 -- 3,16
2,7 -- 0.16 69.0 + 5.09
2,7 -- 0,32 75.0 + 5.04
354.0 + 7.03
365.0 + 8.43
~There were no significant differences between treatment groups at baseline. IVariation in age is expressed as SD, rEher than SE[Vl. All other values are mean + SEN.
better sleep/interfered with sleep), were significantly lower--indicating better sleep--in the zolpidem group than in the placebo group at each weekly assessment (P < 0.01), with the exception of SL at weeks 2 and 3. Surnmary data for these 4 questions (ie, sum of the 4 iterns) reflect the overall beneficial subjective effects on sleep of zolpidem compared with placebo. The summary scores for weeks 1 through 4 for the zolpidem group were 5.44, 5.53, 5.63, and 5.53, respectively, compared with the i581
CLINICAL THERAPEUTICS®
scores in the placebo group of 6.83, 6.63, 6.54, and 6.87, respectively. The percentage of patients in each treatment group reporting better sleep (ie, score of 1 on item 4, "helped me get a better night's sleep") during each week is shown in Figure 1. During each week, approximately twice as many patients treated with zolpidem reported better sleep compared with those treated with placebo (P < 0.001 for each week). Daily Questionnaires Quantitative subjective estimates of sleep parameters (St, NOA, WASO, and TST) from the morning questionnaires and estimates of SRDDF from the evening questionnaires were analyred for each week of treatment. Changes from baseline in TST for both groups are displayed in Figure 2. There were significantly greater increases in reported TST for the 7olpidem group than for the placebo group for each of the 4 treatment weeks (P < 0.01). Baseline values and mean changes from baseline in values of other subjective sleep parameters from the daily questionnaires at weeks 1-4 are presented in Table III. At baseline, none of the reported values were significantly different between the 2 groups. At each week during treatment, WASO and NOA were significantly reduced from baseline (P < 0.05 for both parameters) in the zolpidem group compared with the placebo group. WASO and NOA remained stable over the treatment period in the 7olpidem group, but improved progressively in the placebo group. The change in estimates of SL did not differ between groups at any time. At each week of treatment, the mean change from baseline in SRDDF was significantly greater in the zolpidem group than in the placebo group (P < 0.05 for all weeks). Quality of Life and Ability to Function A large number of between-group comparisons were made for the 3 categoric scales: the Lee Fatigue Scale (18 questions), the General Sleep Disturbance Scale (15 questions), and the Relationship Satisfaction Questionnaire (14 questions). Only 3 statistically significant differences were found, which is within the range expected by chance for multiple comparisons. Thus, we concluded that there were no meaningful diflerences between the treatment groups for any of these items. 1582
Safety Profile Of the 141 subjects enrolled, 106 (75.2%) reported adverse events. The most frequently reported adverse events in the zolpidem and the placebo groups were headache (52.9% [36/68] vs 32.9% [24/73]; P = 0.08), upper respiratory tract infection (16.2% [11/68] vs 6.8% [5/73]; P = 0.11), and drowsiness (10.3% [7/68] vs 1.4% [1/73]; P = 0.03). The other adverse events for which there were statistically significant between-group differences were dizziness (8.8% [6/68] vs 0; P = 0.01), backache (7.4% [5/68] vs 0; P = 0.02), and irritability (7.4% [5/68] vs 2.7% [2/73]; P = 0.02). Seven (5.0%) of the 141 patients withdrew from the study because of adverse events: 5 (7.4%) in the zolpidem group and 2 (2.7%) in the placebo group. There were no correlations between adverse events or discontinuations and age, body mass index, Beck Depression Inventory score, medical history, or sleep history. Zolpidem was not associated with any clinically significant changes in clinical laboratory values or physical examination results. DISCUSSION This study assessed the efficacy and safety of zolpidem 10 mg nightly in the treatment of menopause-related insomnia in perimenopausal and postmenopausal women over a period of 4 weeks. It was found that during each week of treatment approximately twice as many zolpidem-treated patients reported better sleep compared with those in the placebo group. Zolpidem improved subjective estimates of sleep quality and quantity, including TST, NOA, and WA50, throughout the treatment period. On average, patients receiving zolpidem experienced an increase o f - 6 0 minutes in TST, a decrease o f - 4 0 minutes in WASO, and a reduction of 1 or more awakenings per night. Comparable values in the placebo group were an increase of -20 minutes in TST, a 25-minute reduction in WASO, and 0.5 fewer awakenings per night. To our knowledge, based on a review of existing literature, this is the first report of successful use of a hypnotic agent specifically in this population of insomnia patients. Not unexpectedly, a significant placebo effect is apparent for all of these subjective outcome measures. Similar observations have been reported in previous zolpidem studies, 1~-2] as well as in a recent metaanalysis 2C~of subjective sleep changes associated with placebo in clinical trials of hypnotic agents.
C.M. Dorsey et al.
Better Sleep 77.8
78.7
•
Zolpidem
[]
Placebo
75.4
~O tO aJ r~
r~
~6
I
70 ~o to
60
2
3
No Change
t
52.1
51.4
52.9
51.5
r~
,,.o
I
t~
2
,61
3
4
3
4
Worse Sleep
12
6.8
e~ i1)
I
2
Treatment Week
Figure I. Subjective reports of global impression of therapy using the Patient Global Impression assessment completed by study patients once weekly during the clinic visit. Data are expressed as mean (SEM).
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• Zolpidem [ ] Placebo
100] 90 .~
80
•
70
E Io_ o o
.E
..c
U
I
2
3
4
Treatment Week
Figure 2. Effects of zolpidem and placebo on total sleep time. Data are expressed as mean (SEM) for the change from the baseline period. *P < 0.05 versus the placebo group.
In this study, perimenopausal and postmenopausal women were selected based on their cornplaints of difficuhy maintaining sleep rather than difficulty initiating sleep. Patients were also selected based on complaints that their weekly sleep disturbance was associated with _>2 night sweats and/or hot flashes or hot flushes. This is reflected in the baseline sleep profile, on which patients reported an average estimated TST of - 6 hours per night, with a wake time during sleep of -1 hour together with -3 awakenings per night. In contrast, SL (-35 minutes) was not particularly abnormal. As measured by assessments of both subjectively reported quality of sleep and the subjective quantitative parameters of sleep rnaintenance (ie, TST, WASO, and NOA), zolpidem significantly improved the reported menopause-related insomnia. As with all central nervous system-active medications, there is a risk of dependence and of symptoms of withdrawal with long-term zolpidem use. However, there is evidence to suggest that abuse liability is lower with zolpidem than with benzodiazepines. 2r Statistically significant differences were observed between the zolpidem and placebo groups for incidence of side effects, including headache, drowsiness,
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dizziness, backache, and irritability. These differences are consistent with adverse events reported in other zolpidem studies. >-21 Together with the improved quantity and quality of sleep, patients in the zolpidem group experienced significant and progressive improvements in their reported SRDDE On the other hand, there were no positive effects of treatment on any of the quality-of-life indicators that presumably are specific for this patient population. It is possible that only a global and general assessment of daytime activity can capture the distress in a population in which each individual has different specific complaints. This is in agreernent with observations of individuals with chronic insornnia in the general population, where the association between a complaint of chronic insomnia and perceived daytime impairment is well documented, but relationships to measures of specific daytime impairment are less clear. One potential weakness of the present study was that hot flashes and hot flushes were not measured as a function of treatment. Measuring hot flashes and hot flushes in relation to subjective sleep reports would have been interesting from the standpoint of
C.M. Dorsey et al.
Table III. Sleep-related measures obtained from the Daily Morning Questionnaire (mean + SEM). W a k e A f t e r Sleep O n s e t
Timepoint
No, o f Awakenings
Sleep Latency
Zolpidem
Placebo
Zolpidem
Placebo
Zolpidem
Baseline
69,0 -- 5,09
75,0 -- 5.04
2,7 -- O. 16
2.7 f 0,32
34,0 f
Week I
29.0 + 4.31`*
61.0 + 4.21
1.5 + 0.11`*
Week 2
31,0 -- 4,82 ~
53,0 -- 4.48
Week 3
30.0 + 4.35`*
50.0 + 4.07
Week 4
29,0 -- 5,30"*
47,0 -- 4.72
SRDDF
Placebo
Zolpidem
Placebo
3,03
37,0 -- 3.16
2,6 f 0,09
2.5 -- 0,08
2.3 + 0.11
33.0 + 4.18
37.0 + 2.45
2.2 + 0.07`*
2.2 + 0.06
1,4 -- 0. I I ~
2.0 _+ 0,09
32,0 _+ 2,66
37,0 -- 3.30
2, I + 0,09"*
2.2 -- 0,07
1.3 + 0.12`*
1.9 + 0. I I
31.0 + 2.43
32.0 + 2.51
2. I + 0.10`*
2.2 + 0.07
1,4 -- 0.12"*
1.8 + 0, 12
29,0 + 2,64
31,0 -- 2.90
2,0 + 0, I I"*
2. I -- 0,09
SRDDF sleeprelated diffculty with daytime functioning. xp < 0.05 versus placebo.
the uncertainty about the respective relationships between hot flashes and hot flushes, mood disturbance, and insomnia in this population. However, our goal for this study was not to attempt to elucidate the nature of these relationships but to determine whether zolpidem could improve subjective reports of sleep in individuals experiencing these sleep-disrupting events. The occurrence of hot flashes and hot flushes was not measured (eg, by recording skin ternperature) because there was no reason a priori to suspect that 7olpidem would have any effect on thermoregulation or occurrence of hot flashes and hot flushes. While the actual role of hot flashes and hot flushes in menopausal insomnia is controversial, ~ the results of this study suggest that use of zolpidem can help overcome their disruptive effects on sleep. As with any controlled stud> the inclusion/exclusion criteria used limit the generalizability of these findings to the population of perimenopausal and postmenopausal women with insomnia. Future research with particular focus on the specific individual complaints in this population will be needed to determine whether zolpidem has an effect on hot flashes and hot flushes and other symptoms of menopause. CONCLUSIONS
Nightly treatment with 10 mg of zolpidem was effective in treating insomnia associated with perimenopausal and postmenopausal symptoms in this population of women aged 39 to 66 years. Zolpidem appeared to be safe and was tolerated well in the population studied.
ACKNOWLEDGMENTS
This research was supported by Sanofi-Synthelabo Inc., New York, New York. In addition to the authors, the following investigators participated in the study: Martin A. Cohn, Sleep Disorders Center of SW Florida, Naples, Florida; Andrew D. Krystal, Sleep Disorders Center, Duke University Medical Center, Durham, North Carolina; Mark W. Mahowald, Minnesota Regional Sleep Disorders Center, Minneapolis, Minnesota; Paula 5chweitzer, Sleep Medicine and Research Center, Chesterfield, Missouri; Gary K. Zammit, D/B/A Sleep Disorders Institute, New York, New York; and Joan L. Shaver, University o f Illinois School of Nursing, Chicago, Illinois. REFERENCES
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7. Brugge KL, Kripke DE Ancoli-Israel S, Gaffinkel L. The association of menopausal status and age with sleep disorders. Sleep Res. 1989;18:208. 8. Krystal AD. Insomnia in women. Cli,q Cor,qerslone. 2003~5(3):41-50. 9. Hunter M. The south-east England longitudinal study of the climacteric and postmenopause. Maturitas. 1992;14:117-126. 10. Woodward S, Freedman RR. The thermoregulatory effects of menopausal hot flashes on sleep. Sleep. 1994~ 17:497-501. I1. Woodward S, Freeman RR. Sleep tragmentafion in menopausal women with and without hot flashes. Sleep Res. 1995;24:63. 12. Goonaratna C, Fonseka P, Wijeywardene K. Perimenopausal symptoms in Sri Lankan women. Ceylo,q Med.l. 1999;44:63-69. 13. Zammit GK, Weiner j, Damato N, et al. Quality o[ life in people with insomnia. Sleep. 1999;22(Suppl 2): $379-$385. 14. Roth T, Ancoli-Israel S. Daytime consequences and correlates of insomnia in the United States: Results of the 1991 National Sleep Foundation Surve): II. Sleep. 1999;22(Suppl 2):$354-$358. 15. Walsh JK, Engelhardt CL. The direct economic costs of insomnia in the United States for 1995. Sleep. 1999; 22(Suppl 2):$386-$393. 16. Moline ML, Broch L, Zak R, Gross V Sleep in women across the life cycle from adulthood through menopause. Sleep Meal Re> 2003;7:155-177. 17. Striper A, Trachsel L, Guldner J, et al. Neurosteroid pregnenolone induces sleep-EEG changes in man corn-
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Address c o r r e s p o n d e n c e to: Cynthia M. Dorsey, PhD, Sleep Research Lab, McLean Hospital, 115 Mill Street, Belmont, MA 02478. E-mail: c y n t h i a - d ° r s e y @ h m s h a r v a r d e d u
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