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Lower doses of sublingual Zolpidem are more effective than oral Zolpidem to anticipate sleep onset in healthy volunteers
Sleep Medicine 14 (2013) 20–23
Contents lists available at SciVerse ScienceDirect
Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Original Article
Lower doses of sublingual Zolpidem are more effective than oral Zolpidem to anticipate sleep onset in healthy volunteers Kette D. Valente a,⇑, Rosa Hasan a, Stella M. Tavares a, Wagner F. Gattaz b a b
Laboratory of Clinical Neurophysiology, Institute of Psychiatry, University of São Paulo School of Medicine, São Paulo, Brazil Laboratory of Neuroscience (LIM 27), Institute of Psychiatry, University of São Paulo School of Medicine, São Paulo, Brazil
a r t i c l e
i n f o
Article history: Received 21 June 2012 Received in revised form 4 September 2012 Accepted 6 September 2012 Available online 4 December 2012 Keywords: Insomnia Zolpidem Polysomnography Sublingual
a b s t r a c t Objective: To compare the efficacy of sublingual Zolpidem (5 and 10 mg) to conventional oral Zolpidem (10 mg). Methods: This was an open, randomized, double-blind, double-dummy, controlled, and single center study. The study took place at the Laboratory of Clinical Neurophysiology and total number of participants was 58 volunteers completed the study whose demographics of age, gender, body mass index (BMI) were similar among everyone. Scores in Epworth, Pittsburgh, Beck and Hamilton Scales did not differ among groups. A model of transient insomnia was determined by the sleep anticipation in 120 minute. Subjects were randomly divided in three groups for drug administration (5 m SL; 10 mg SL and 10 mg oral), given in a single dose prior to polysomnography (PSG). Sleep parameters were assessed by PSG and post-sleep questionnaires. Results: A significant main treatment effect was evident considering the sleep onset latency (SOL) and persistent sleep latency (PSL). An earlier sleep onset was induced by SL Zolpidem 10 mg (SOL = p < 0.004; PSL = p < 0.006) and SL Zolpidem 5 mg (SOL = p < 0.025; PSL = p < 0.046) compared to oral Zolpidem 10 mg. Subjects that received SL Zolpidem 10 mg reported an earlier sleep onset (latency to sleep and latency until persistent sleep) when compared to subjects from other groups (p < 0.005). Conclusions: Sublingual Zolpidem, both 5 and 10 mg, induced faster sleep initiation than 10 mg oral Zolpidem. A subjective perception of earlier sleep onset was reported by subjects using SL 10 mg. Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction The report of the 2005 State of Science conference convened by the US National Institute of Healthy [13] concluded that about 30% of the population present sleep complaints from transient insomnia (lasting for a few days to a couple of weeks) and about 10% of adults have symptoms of daytime impairment from chronic insomnia (dissatisfaction with the quantity, quality or timing of sleep for a period of at least 1 month). Clinical studies showed that 30–50% of adults present sleep complaints in the USA and Europe [3,12,16]. It is recognized that, left untreated, transient insomnia can evolve to a chronic condition [3,16]. One of the most common interventions for short-term insomnia is pharmacotherapy with a hypnotic agent. Available therapies include benzodiazepines, non-benzodiazepine GABAergic medications, melatonin receptor agonist, and sedating antidepressants [14]. ⇑ Corresponding author. Address: R. Dr. Ovídio Pires de Campos 785, 05403-010 São Paulo, SP, Brazil. E-mail address: [email protected] (K.D. Valente). 1389-9457/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2012.09.003
Zolpidem, a non-benzodiazepine agent, is one of the most frequently prescribed hypnotic drugs [21]. Zolpidem was proven as effective as benzodiazepines in the management of short-term insomnia, but with fewer adverse effects [21,7]. The aim of the development of the sublingual Zolpidem, approved by FDA, is to provide an earlier sleep onset and minimize residual daytime effects with lower doses [17,18]. In this context, sublingual Zolpidem may represent a suitable treatment of shortterm insomnia. The present trial was designed to compare the efficacy of sublingual Zolpidem to conventional oral Zolpidem in healthy volunteers inducing sleep two hours prior to their nighttime sleep. The primary endpoint was to evaluate the efficacy of single doses of sublingual Zolpidem (5 and 10 mg) versus oral Zolpidem (10 mg) in healthy volunteers, with regard to objective sleep parameters, especially sleep onset latency, evaluated by polysomnographic recordings. Secondary endpoints were to compare the treatment effects on subjective sleep parameters. In addition, we also evaluated adverse effects reported by subjects in the morning after polysomnographic recording.
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K.D. Valente et al. / Sleep Medicine 14 (2013) 20–23
2. Methods
Table 1 Patients demographics.
2.1. Subjects The study was conducted at the Psychiatric Institute of the Clinics Hospital of University of Sao Paulo. The study protocol was approved by the local Ethics Committee. Subjects had to provide a written informed consent after the study procedures were explained in detail. Non-smoking subjects were considered eligible for this study having a non-excessive consumption of alcohol (640 g/day) or caffeine containing beverages (<6 cups/day) and regular bedtime hours. Subjects with concomitant treatment with CNS acting drugs were excluded. The subjects were evaluated by a board-certified sleep specialist to determine whether they had a normal and regular sleep pattern. Subjects assessed and not excluded by clinical analysis, were screened with the Pittsburgh Sleep Quality Index Questionnaire [2] and Epworth Sleepiness Scale [9] Depressive and anxiety symptoms were assessed by Beck Depression Inventory [1,5] and Hamilton Anxiety Scale [6], respectively. After this evaluation, subjects with daytime sleepiness based on Epworth Sleepiness Scale (score > 10), clinical diagnosed sleep disorder, poor quality of sleep determined by Pittsburgh and moderate/severe depressive and anxiety symptoms were excluded. Eligible subjects completed every morning, during 14 days, a Sleep Diary following awakening to verify sleep pattern regularity and determine usual bedtime. Sixty-eight volunteers were recruited. Ten subjects were excluded from the study before any treatment: one due to excessive sleepiness (Epworth 13), two for consent withdrawal, and seven for inadequate sleep habits (sleep deprivation). Fifty-eight volunteers completed the study. Clinical variables such as, age, gender, body mass index (BMI) were similar among the three groups. (Table 1). Scores in Epworth, Pittsburgh, Beck and Hamilton Scales did not differ among groups (Table 2). 2.2. Study design This was an open, randomized, double-blind, double-dummy, controlled, single center study. A model of transient insomnia was determined by the sleep anticipation in 120 minute. Subjects were randomly divided in three groups for drug administration: Group I: 1 tablet of 5 mg SL Zolpidem + 1 tablet of SL placebo + 1 tablet of oral placebo. Group II: 2 tablets of SL Zolpidem 5 mg + 1 tablet of oral placebo. Group III: 2 tablets of SL placebo + 10 mg of oral Zolpidem. 2.3. Drug administration Sublingual (5 or 10 mg of Zolpidem SL, EMS, Brazil) or oral (10 mg of Zolpidem oral administration, EMS, Brazil) tablets were administered 2 hours prior the subject’s regular bedtime under the supervision of the clinical staff.
Mean age (years) Gender Body mass index
Group I (n = 19)
Group II (n = 20)
Group III (n = 19)
p
36.1 ± 9.7 9F:11 M 26.73 ± 4.37
33.0 ± 7.9 13F:7 M 25.22 ± 4.00
33.5 ± 6.2 12F:7 M 26.28 ± 4.08
0.427 0.370 0.495
F, female; M, male.
Table 2 Scores in Epworth, Pittsburgh and Beck e Hamilton Scales.
Epworth Pittsburgh Beck Hamilton
Group I (n = 19)
Group II (n = 20)
Group III (n = 19)
p
3.25 ± 2.31 4.30 ± 3.31 1.9 ± 2.27 2.15 ± 2.35
3.70 ± 2.20 3.85 ± 2.56 2.35 ± 1.81 3.00 ± 3.11
2.68 ± 1.94 5.52 ± 5.56 2.49 ± 3.,21 3.73 ± 5.13
0.348 0.405 0.229 0.411
diographic lead, snoring, nasal/oral airflow, nasal air pressure, thoracic effort, abdominal effort, SaO2 and body position were also assessed. Wake and sleep stages (N1, N2, N3 NREM and REM - Rapid Eye Movements) were visually scored in 30 seconds epochs according to standard criteria determined by American Academy of Sleep 2007 [8]. The night summary variables were derived from the visual scoring of recordings and were divided into sleep continuity and sleep architecture parameters according to American Academy of Sleep Medicine. The evaluated variables consisted of sleep onset latency (SOL), which was defined as the time from lights off to the first epoch of sleep (minutes); persistent sleep latency (PSL), defined as the measure from lights out until the first four consecutive 30 seconds epochs of sleep (minutes); total sleep time (minutes); REM sleep latency (minutes); total time of N1, N2, N3 and REM (minutes); wake after sleep onset (minutes); number and index of arousals; apneas-hypopneas index; lowest SaO2; periodic limb movements index.
2.5. Subjective sleep evaluations and next-day residual effects In the morning following drug administration, subjects completed the Sleep Evaluation Questionnaire developed in our Service in order to assess subjective sleep parameters such as: 1. latency to sleep (‘‘getting to sleep’’); 2. total sleep time; 3. awakenings from sleep: number and duration; 3. satisfaction with sleep compared with regular sleep and 6. spontaneous complaints following sleep (adverse-effects) in the morning, after such as somnolence, were headache and fatigue. Latency to sleep, total sleep time and sleep quality perception were categorized in a numerical scale from 1 (worse than usual) to 5 (better than usual).
2.4. Sleep recordings
2.6. Statistical analysis
Sleep recordings consisted of one recording night, scheduled to start 120 minute before regular bedtime determined by the Sleep Diary. The polysomnographic montage consisted of six channels (bipolar recordings) of EEG recording (F3-A2; F4-A1; C3-A2; C4A1; O1-A2; O2-A1), bilateral electrooculograms (EOG; left and right outer canthi with each eye derivation also referenced to A2), and one submental electromyogram (EMG). One electrocar-
The three group comparisons were carried out with one way ANOVA and Kruskal–Wallis for the continuous variables and Chisquared test for the categorical variables. Post-hoc tests with multiple comparisons for significant differences in the three group analysis were assessed with Bonferroni correction. Adherence to normality was tested with Q–Q plots for all continuous variables. Significance was set at 5 percent and all tests were two tailed and further analyses were conducted on SPSS v14.
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K.D. Valente et al. / Sleep Medicine 14 (2013) 20–23
3. Results 3.1. Objective sleep parameters A significant main treatment effect was evident considering the SOL (p 0.003) and PSL (p 0.006). Post-hoc pairwise comparisons showed that the SL Zolpidem 10 mg induced sleep earlier (SOL = 9.96 ± 5.62 minute; PSL = 12.97 ± 6.19 minute) than oral Zolpidem 10 mg (SOL = 21.02 ± 15.07 minute, p < 0.004; PSL = 24.02 ± 15.38, p 0.006) (Table 3). Furthermore, for SL Zolpidem 5 mg, SOL was 12.09 ± 7.67 minute (p < 0.025) and PSL was 15.62 ± 8.19 minute (p 0.046) as compared to oral Zolpidem 10 mg. Other sleep architecture parameters were similar among groups (Table 3), as well apneas-hypopneas index, lowest SaO2 and periodic limb movements index (Table 4).
3.2. Subjective sleep parameters Subjects that received SL Zolpidem 10 mg reported an earlier sleep onset (latency to sleep) when compared to subjects from other groups (p < 0.005). Total sleep time, satisfaction with sleep and awakenings from sleep did not differ among groups. No adverse-effects were reported.
4. Discussion This study has shown that the sublingual Zolpidem has a faster sleep induction effect than the oral formulation, whereas, both did not differ with regard to sleep architecture, sleep maintenance or common adverse effects. The mean decrease in sleep onset latency provided by SL Zolpidem was clinically relevant, (reduction of 8.93 minute with SL 5 mg and 11.07 minute in SL 10 mg) compared to an oral Zolpidem (21.02 ± 15.07 minute). Furthermore, latency until persistent sleep was also significantly decreased with SL 5 mg and 10 mg. These findings represent a reduction of approximately 50% of the time to initiate sleep in this artificial model of insomnia. The clinical impact can be observed by analyzing some parameters based on subject’s perception about their sleep. In this sample, subjects that received SL Zolpidem 10 mg had a perception of an earlier sleep onset.
The reduction of SOL and PSL after 5 mg SL Zolpidem was greater than after 10 mg of the oral formulation. In line with earlier studies [17] that tackle residual daytime sedation and concerns with higher doses, our findings suggest that this sublingual formulation may allow the use of lower doses of Zolpidem to obtain the same clinical effects. The primary aim of the study was specifically to compare the doses and route of administration against the well established comparator. This work demonstrated that SL Zolpidem – 5 and 10 mg – was more effective than oral doses in reducing the sleep latency onset. Placebo effects are more relevant in insomnia patients than in healthy volunteers, since the latter do not expect clinical improvement and consequently do not have the ‘‘drug expectancy effect’’. [15] Although a placebo group is not part of this work, our study design – double blinded and double dummy – associated with the superior subjective effect of 10 mg versus 5 mg Zolpidem SL, favors the medication effect against a placebo effect in our sample. In line with the literature [10], we found no effects of Zolpidem on sleep architecture, indicating that the effects of Zolpidem on sleep initiation were not at the expense of sleep maintenance. Hypnotic zolpidem is a positive allosteric modulator of c-aminobutyric acid (GABA) action, with preferential although not exclusive binding for a1 subunit-containing GABA(A) receptors. The pharmacological profile of this drug is different from that of classical benzodiazepines, although it acts through benzodiazepine binding sites at GABA(A) receptors [20]. The effect obtained with lower doses of Zolpidem might reflect that rate of change of occupancy of receptors may be as important (or more important) as total number of receptors occupied [4]. One may pose the question whether these findings are reproducible for a population of patients with insomnia. There are some disadvantages of studying patients with insomnia such as the intensification of the placebo effect, as previously mentioned. There are several models of artificial insomnia and all present advantages and disadvantages [18]. In this study we used two concomitant models one is the phase-advanced model consisting of advancing usual bedtime 2 hours and the other one is the first night effect without adaptation to Sleep Laboratory. The main disadvantage of the phase-advanced model is that the sleep-inducing effect of a drug and its next-day residual effects could be confounded by circadian factors [22]. This was not observed in our sample. The first night effect insomnia model has been reported
Table 3 Effects of sublingual zolpidem (Group I [5 mg] and Group II [10 mg]) and oral zolpidem [10 mg] (Group III) on objective sleep variables.
Sleep onset latency (minute) Latency until persisten sleep (minute) Total sleep time (minute) REM sleep latency (minute) Total time of N1 (minute) Total time of N2 (minute) Total time of N3 (minute) Total time of REM (minute) Wake after sleep onset (minute) Number of arousals Arousals index *
Group I (n = 19)
Group II (n = 20)
Group III (n = 19)
p
12.09 ± 7.67 15.62 ± 8.19 463.84 ± 66.89 125.68 ± 44.65 4.48 ± 3.33 54.75 ± 12.98 20.81 ± 6.24 17.29 ± 3.75 36.74 ± 23.09 152.25 ± 94.76 20.59 ± 13.34
9.95 ± 5.62 12.97 ± 6.19 489.57 ± 103.84 150.15 ± 79.23 4.21 ± 1.85 54.21 ± 13.59 23.05 ± 11.00 16.51 ± 10.00 33.95 ± 12.62 126.30 ± 93.23 15.83 ± 10.68
21.02 ± 15.07 24.02 ± 15.38 478.99 ± 54.70 148.63 ± 56.12 3.93 ± 2.70 52.85 ± 14.74 21.45 ± 9.04 17.84 ± 5.49 32.74 ± 12.67 126.52 ± 41.72 16.11 ± 5.66
0.003* 0.006* 0.593 0.398 0.792 0.908 0.727 0.837 0.754 0.514 0.283
p < 0.005.
Table 4 Respiratory and motor data.
Apneas-hypopneas index Lowest SaO2 Periodic limb movements index
Group I (n = 19)
Group II (n = 20)
Group III (n = 19)
p
12.56 ± 18.52 85.95 ± 5.33 5.40 ± 12.14
6.24 ± 15.20 85.505.60 6.32 ± 13.03
4.22 ± 5.20 85.803.86 5.28 ± 9.55
0.171 0.958 0.955
K.D. Valente et al. / Sleep Medicine 14 (2013) 20–23
to delay sleep initiation, but to interfere with REM sleep regulation [19,11]. However, in our study, all groups were exposed to the same environmental factors and are therefore, suitable for comparison. 5. Conclusion In conclusion, the present study showed that sublingual Zolpidem, both 5 and 10 mg, induced faster sleep initiation than 10 mg oral Zolpidem. The differences between the effects of the 5 mg and the 10 mg doses sublingual were not significant regarding the objective sleep initiation parameters. However, a subjective perception of earlier sleep onset was reported by subjects using SL 10 mg. Both oral and SL formulations were well-tolerated and none of them, irrespective of the administered dose, cause relevant adverse-effects. Our findings suggest a higher efficacy of the sublingual formulation of Zolpidem, which may allow the use of lower doses to obtain similar effects in patients suffering from acute initial insomnia. Conflict of Interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2012.09.003. References [1] Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh G. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:53–63. [2] Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989;28:193–213. [3] Doghramji K. The epidemiology and diagnosis of insomnia. Am J Manage Care 2006;12:S214–20. [4] Fahley JM, Grassi JM, Reddi JM, Greenblatt DJ. Acute zolpidem administration produces pharmacodynamics and receptor occupancy changes at similar doses. Pharmacol Biochem Behav 2006;83:21–7. [5] Gorenstein C, Andrade L, Vieira Filho AHG, Tung TC, Artes R. Psychometric properties of the Portuguese version of the Beck Depression Inventory on Brazilian college students. J Clin Psychol 1999;55:553–62.
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[6] Hamilton M. The assessment of anxiety states by rating. Brit J Med Psychol 1959;32:50–5. [7] Holm KJ, Goa KL. Zolpidem: an update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia. Drugs 2000;59:865–89. [8] Iber C, Ancoli-Israel S, Chesson A, Quan SF. The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications. 1st ed. Westchester: American Academy of Sleep Medicine; 2007. [9] Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14:540–5. [10] Kanno O, Sasaki T, Watanabe H, Takazawa S, Nakagome K, Nakajima T, et al. Comparison of the effects of zolpidem and triazolam on nocturnal sleep and sleep latency in the morning: a cross-over study in healthy young volunteers. Prog Neuropsychopharmacol Biol Psychiatry 2000;24:897–910. [11] Le Bon O, Staner L, Hoffmann G, Dramaix M, San Sebastian I, Murphy JR, et al. The first night effect may last more than one night. J. Psychiatry Res 2001;35:165–72. [12] Leger D, Poursain B. An international survey of insomnia: under-recognition and under-treatment of a polysymptomatic condition. Curr Med Res Opin 2005;21:1785–92. [13] Statement NIH. National institutes of healthy state of the science conference statement. Sleep 2005;28:1049–57. [14] Ownby RL. New approaches in the treatment of short term and middle of the night insomnia: emerging evidences for a role for sublingual zolpidem tablets. Nat Sci Sleep 2010;2:63–9. [15] Rosenzweig P, Brohier S, Zipfel A. The placebo effect in healthy volunteers: influence of experimental conditions on physiological parameters during phase I studies. Br J Clin Pharmacol 1995;39:657–64. [16] Roth T, Drake C. Evolution of insomnia: current status and future direction. Sleep Med 2004;5:S23–30. [17] Roth T, Hull SG, Lankford DA, Rosenberg R. Intermezzo Study Group. Low-dose sublingual zolpidem tartrate is associated with dose-related improvement in sleep onset and duration in insomnia characterized by middle-of-the-night (MOTN) awakenings. Sleep 2008;31:1277–84. [18] Staner L, Eriksson M, Cornette F, Santoro F, Muscat N, Luthinger R, et al. Sublingual zolpidem is more effective than oral zolpidem in initiating early onset of sleep in the post-nap model of transient insomnia: a polysomnographic study. Sleep Med 2009;10(6):616–20. [19] Toussaint M, Luthringer R, Schaltenbrand N, Carelli G, Lainey E, Jacqmin A, et al. First-night effect in normal subjects and psychiatric inpatients. Sleep 1995;18:463–9. [20] Vlainic´ J, Švob Štrac D, Jazvinšc´ak Jembrek M, Vlainic´ T, Pericˇic´ D. The effects of zolpidem treatment on GABA(A) receptors in cultured cerebellar granule cells: changes in functional coupling. Life Sci 2012;90(23–24):889–94. [21] Vermeeren A. Residual effects of hypnotics. Epidemiology and clinical implications. CNS Drugs 2004;18:297–328. [22] Walsh JK, Schweitzer PK, Sugerman JL, Muehlbach MJ. Transient insomnia associated with a 3-hour phase advance of sleep time and treatment with zolpidem. J Clin Psychopharmacol 1990;10:184–9.
Contents lists available at SciVerse ScienceDirect
Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Original Article
Lower doses of sublingual Zolpidem are more effective than oral Zolpidem to anticipate sleep onset in healthy volunteers Kette D. Valente a,⇑, Rosa Hasan a, Stella M. Tavares a, Wagner F. Gattaz b a b
Laboratory of Clinical Neurophysiology, Institute of Psychiatry, University of São Paulo School of Medicine, São Paulo, Brazil Laboratory of Neuroscience (LIM 27), Institute of Psychiatry, University of São Paulo School of Medicine, São Paulo, Brazil
a r t i c l e
i n f o
Article history: Received 21 June 2012 Received in revised form 4 September 2012 Accepted 6 September 2012 Available online 4 December 2012 Keywords: Insomnia Zolpidem Polysomnography Sublingual
a b s t r a c t Objective: To compare the efficacy of sublingual Zolpidem (5 and 10 mg) to conventional oral Zolpidem (10 mg). Methods: This was an open, randomized, double-blind, double-dummy, controlled, and single center study. The study took place at the Laboratory of Clinical Neurophysiology and total number of participants was 58 volunteers completed the study whose demographics of age, gender, body mass index (BMI) were similar among everyone. Scores in Epworth, Pittsburgh, Beck and Hamilton Scales did not differ among groups. A model of transient insomnia was determined by the sleep anticipation in 120 minute. Subjects were randomly divided in three groups for drug administration (5 m SL; 10 mg SL and 10 mg oral), given in a single dose prior to polysomnography (PSG). Sleep parameters were assessed by PSG and post-sleep questionnaires. Results: A significant main treatment effect was evident considering the sleep onset latency (SOL) and persistent sleep latency (PSL). An earlier sleep onset was induced by SL Zolpidem 10 mg (SOL = p < 0.004; PSL = p < 0.006) and SL Zolpidem 5 mg (SOL = p < 0.025; PSL = p < 0.046) compared to oral Zolpidem 10 mg. Subjects that received SL Zolpidem 10 mg reported an earlier sleep onset (latency to sleep and latency until persistent sleep) when compared to subjects from other groups (p < 0.005). Conclusions: Sublingual Zolpidem, both 5 and 10 mg, induced faster sleep initiation than 10 mg oral Zolpidem. A subjective perception of earlier sleep onset was reported by subjects using SL 10 mg. Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction The report of the 2005 State of Science conference convened by the US National Institute of Healthy [13] concluded that about 30% of the population present sleep complaints from transient insomnia (lasting for a few days to a couple of weeks) and about 10% of adults have symptoms of daytime impairment from chronic insomnia (dissatisfaction with the quantity, quality or timing of sleep for a period of at least 1 month). Clinical studies showed that 30–50% of adults present sleep complaints in the USA and Europe [3,12,16]. It is recognized that, left untreated, transient insomnia can evolve to a chronic condition [3,16]. One of the most common interventions for short-term insomnia is pharmacotherapy with a hypnotic agent. Available therapies include benzodiazepines, non-benzodiazepine GABAergic medications, melatonin receptor agonist, and sedating antidepressants [14]. ⇑ Corresponding author. Address: R. Dr. Ovídio Pires de Campos 785, 05403-010 São Paulo, SP, Brazil. E-mail address: [email protected] (K.D. Valente). 1389-9457/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2012.09.003
Zolpidem, a non-benzodiazepine agent, is one of the most frequently prescribed hypnotic drugs [21]. Zolpidem was proven as effective as benzodiazepines in the management of short-term insomnia, but with fewer adverse effects [21,7]. The aim of the development of the sublingual Zolpidem, approved by FDA, is to provide an earlier sleep onset and minimize residual daytime effects with lower doses [17,18]. In this context, sublingual Zolpidem may represent a suitable treatment of shortterm insomnia. The present trial was designed to compare the efficacy of sublingual Zolpidem to conventional oral Zolpidem in healthy volunteers inducing sleep two hours prior to their nighttime sleep. The primary endpoint was to evaluate the efficacy of single doses of sublingual Zolpidem (5 and 10 mg) versus oral Zolpidem (10 mg) in healthy volunteers, with regard to objective sleep parameters, especially sleep onset latency, evaluated by polysomnographic recordings. Secondary endpoints were to compare the treatment effects on subjective sleep parameters. In addition, we also evaluated adverse effects reported by subjects in the morning after polysomnographic recording.
21
K.D. Valente et al. / Sleep Medicine 14 (2013) 20–23
2. Methods
Table 1 Patients demographics.
2.1. Subjects The study was conducted at the Psychiatric Institute of the Clinics Hospital of University of Sao Paulo. The study protocol was approved by the local Ethics Committee. Subjects had to provide a written informed consent after the study procedures were explained in detail. Non-smoking subjects were considered eligible for this study having a non-excessive consumption of alcohol (640 g/day) or caffeine containing beverages (<6 cups/day) and regular bedtime hours. Subjects with concomitant treatment with CNS acting drugs were excluded. The subjects were evaluated by a board-certified sleep specialist to determine whether they had a normal and regular sleep pattern. Subjects assessed and not excluded by clinical analysis, were screened with the Pittsburgh Sleep Quality Index Questionnaire [2] and Epworth Sleepiness Scale [9] Depressive and anxiety symptoms were assessed by Beck Depression Inventory [1,5] and Hamilton Anxiety Scale [6], respectively. After this evaluation, subjects with daytime sleepiness based on Epworth Sleepiness Scale (score > 10), clinical diagnosed sleep disorder, poor quality of sleep determined by Pittsburgh and moderate/severe depressive and anxiety symptoms were excluded. Eligible subjects completed every morning, during 14 days, a Sleep Diary following awakening to verify sleep pattern regularity and determine usual bedtime. Sixty-eight volunteers were recruited. Ten subjects were excluded from the study before any treatment: one due to excessive sleepiness (Epworth 13), two for consent withdrawal, and seven for inadequate sleep habits (sleep deprivation). Fifty-eight volunteers completed the study. Clinical variables such as, age, gender, body mass index (BMI) were similar among the three groups. (Table 1). Scores in Epworth, Pittsburgh, Beck and Hamilton Scales did not differ among groups (Table 2). 2.2. Study design This was an open, randomized, double-blind, double-dummy, controlled, single center study. A model of transient insomnia was determined by the sleep anticipation in 120 minute. Subjects were randomly divided in three groups for drug administration: Group I: 1 tablet of 5 mg SL Zolpidem + 1 tablet of SL placebo + 1 tablet of oral placebo. Group II: 2 tablets of SL Zolpidem 5 mg + 1 tablet of oral placebo. Group III: 2 tablets of SL placebo + 10 mg of oral Zolpidem. 2.3. Drug administration Sublingual (5 or 10 mg of Zolpidem SL, EMS, Brazil) or oral (10 mg of Zolpidem oral administration, EMS, Brazil) tablets were administered 2 hours prior the subject’s regular bedtime under the supervision of the clinical staff.
Mean age (years) Gender Body mass index
Group I (n = 19)
Group II (n = 20)
Group III (n = 19)
p
36.1 ± 9.7 9F:11 M 26.73 ± 4.37
33.0 ± 7.9 13F:7 M 25.22 ± 4.00
33.5 ± 6.2 12F:7 M 26.28 ± 4.08
0.427 0.370 0.495
F, female; M, male.
Table 2 Scores in Epworth, Pittsburgh and Beck e Hamilton Scales.
Epworth Pittsburgh Beck Hamilton
Group I (n = 19)
Group II (n = 20)
Group III (n = 19)
p
3.25 ± 2.31 4.30 ± 3.31 1.9 ± 2.27 2.15 ± 2.35
3.70 ± 2.20 3.85 ± 2.56 2.35 ± 1.81 3.00 ± 3.11
2.68 ± 1.94 5.52 ± 5.56 2.49 ± 3.,21 3.73 ± 5.13
0.348 0.405 0.229 0.411
diographic lead, snoring, nasal/oral airflow, nasal air pressure, thoracic effort, abdominal effort, SaO2 and body position were also assessed. Wake and sleep stages (N1, N2, N3 NREM and REM - Rapid Eye Movements) were visually scored in 30 seconds epochs according to standard criteria determined by American Academy of Sleep 2007 [8]. The night summary variables were derived from the visual scoring of recordings and were divided into sleep continuity and sleep architecture parameters according to American Academy of Sleep Medicine. The evaluated variables consisted of sleep onset latency (SOL), which was defined as the time from lights off to the first epoch of sleep (minutes); persistent sleep latency (PSL), defined as the measure from lights out until the first four consecutive 30 seconds epochs of sleep (minutes); total sleep time (minutes); REM sleep latency (minutes); total time of N1, N2, N3 and REM (minutes); wake after sleep onset (minutes); number and index of arousals; apneas-hypopneas index; lowest SaO2; periodic limb movements index.
2.5. Subjective sleep evaluations and next-day residual effects In the morning following drug administration, subjects completed the Sleep Evaluation Questionnaire developed in our Service in order to assess subjective sleep parameters such as: 1. latency to sleep (‘‘getting to sleep’’); 2. total sleep time; 3. awakenings from sleep: number and duration; 3. satisfaction with sleep compared with regular sleep and 6. spontaneous complaints following sleep (adverse-effects) in the morning, after such as somnolence, were headache and fatigue. Latency to sleep, total sleep time and sleep quality perception were categorized in a numerical scale from 1 (worse than usual) to 5 (better than usual).
2.4. Sleep recordings
2.6. Statistical analysis
Sleep recordings consisted of one recording night, scheduled to start 120 minute before regular bedtime determined by the Sleep Diary. The polysomnographic montage consisted of six channels (bipolar recordings) of EEG recording (F3-A2; F4-A1; C3-A2; C4A1; O1-A2; O2-A1), bilateral electrooculograms (EOG; left and right outer canthi with each eye derivation also referenced to A2), and one submental electromyogram (EMG). One electrocar-
The three group comparisons were carried out with one way ANOVA and Kruskal–Wallis for the continuous variables and Chisquared test for the categorical variables. Post-hoc tests with multiple comparisons for significant differences in the three group analysis were assessed with Bonferroni correction. Adherence to normality was tested with Q–Q plots for all continuous variables. Significance was set at 5 percent and all tests were two tailed and further analyses were conducted on SPSS v14.
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3. Results 3.1. Objective sleep parameters A significant main treatment effect was evident considering the SOL (p 0.003) and PSL (p 0.006). Post-hoc pairwise comparisons showed that the SL Zolpidem 10 mg induced sleep earlier (SOL = 9.96 ± 5.62 minute; PSL = 12.97 ± 6.19 minute) than oral Zolpidem 10 mg (SOL = 21.02 ± 15.07 minute, p < 0.004; PSL = 24.02 ± 15.38, p 0.006) (Table 3). Furthermore, for SL Zolpidem 5 mg, SOL was 12.09 ± 7.67 minute (p < 0.025) and PSL was 15.62 ± 8.19 minute (p 0.046) as compared to oral Zolpidem 10 mg. Other sleep architecture parameters were similar among groups (Table 3), as well apneas-hypopneas index, lowest SaO2 and periodic limb movements index (Table 4).
3.2. Subjective sleep parameters Subjects that received SL Zolpidem 10 mg reported an earlier sleep onset (latency to sleep) when compared to subjects from other groups (p < 0.005). Total sleep time, satisfaction with sleep and awakenings from sleep did not differ among groups. No adverse-effects were reported.
4. Discussion This study has shown that the sublingual Zolpidem has a faster sleep induction effect than the oral formulation, whereas, both did not differ with regard to sleep architecture, sleep maintenance or common adverse effects. The mean decrease in sleep onset latency provided by SL Zolpidem was clinically relevant, (reduction of 8.93 minute with SL 5 mg and 11.07 minute in SL 10 mg) compared to an oral Zolpidem (21.02 ± 15.07 minute). Furthermore, latency until persistent sleep was also significantly decreased with SL 5 mg and 10 mg. These findings represent a reduction of approximately 50% of the time to initiate sleep in this artificial model of insomnia. The clinical impact can be observed by analyzing some parameters based on subject’s perception about their sleep. In this sample, subjects that received SL Zolpidem 10 mg had a perception of an earlier sleep onset.
The reduction of SOL and PSL after 5 mg SL Zolpidem was greater than after 10 mg of the oral formulation. In line with earlier studies [17] that tackle residual daytime sedation and concerns with higher doses, our findings suggest that this sublingual formulation may allow the use of lower doses of Zolpidem to obtain the same clinical effects. The primary aim of the study was specifically to compare the doses and route of administration against the well established comparator. This work demonstrated that SL Zolpidem – 5 and 10 mg – was more effective than oral doses in reducing the sleep latency onset. Placebo effects are more relevant in insomnia patients than in healthy volunteers, since the latter do not expect clinical improvement and consequently do not have the ‘‘drug expectancy effect’’. [15] Although a placebo group is not part of this work, our study design – double blinded and double dummy – associated with the superior subjective effect of 10 mg versus 5 mg Zolpidem SL, favors the medication effect against a placebo effect in our sample. In line with the literature [10], we found no effects of Zolpidem on sleep architecture, indicating that the effects of Zolpidem on sleep initiation were not at the expense of sleep maintenance. Hypnotic zolpidem is a positive allosteric modulator of c-aminobutyric acid (GABA) action, with preferential although not exclusive binding for a1 subunit-containing GABA(A) receptors. The pharmacological profile of this drug is different from that of classical benzodiazepines, although it acts through benzodiazepine binding sites at GABA(A) receptors [20]. The effect obtained with lower doses of Zolpidem might reflect that rate of change of occupancy of receptors may be as important (or more important) as total number of receptors occupied [4]. One may pose the question whether these findings are reproducible for a population of patients with insomnia. There are some disadvantages of studying patients with insomnia such as the intensification of the placebo effect, as previously mentioned. There are several models of artificial insomnia and all present advantages and disadvantages [18]. In this study we used two concomitant models one is the phase-advanced model consisting of advancing usual bedtime 2 hours and the other one is the first night effect without adaptation to Sleep Laboratory. The main disadvantage of the phase-advanced model is that the sleep-inducing effect of a drug and its next-day residual effects could be confounded by circadian factors [22]. This was not observed in our sample. The first night effect insomnia model has been reported
Table 3 Effects of sublingual zolpidem (Group I [5 mg] and Group II [10 mg]) and oral zolpidem [10 mg] (Group III) on objective sleep variables.
Sleep onset latency (minute) Latency until persisten sleep (minute) Total sleep time (minute) REM sleep latency (minute) Total time of N1 (minute) Total time of N2 (minute) Total time of N3 (minute) Total time of REM (minute) Wake after sleep onset (minute) Number of arousals Arousals index *
Group I (n = 19)
Group II (n = 20)
Group III (n = 19)
p
12.09 ± 7.67 15.62 ± 8.19 463.84 ± 66.89 125.68 ± 44.65 4.48 ± 3.33 54.75 ± 12.98 20.81 ± 6.24 17.29 ± 3.75 36.74 ± 23.09 152.25 ± 94.76 20.59 ± 13.34
9.95 ± 5.62 12.97 ± 6.19 489.57 ± 103.84 150.15 ± 79.23 4.21 ± 1.85 54.21 ± 13.59 23.05 ± 11.00 16.51 ± 10.00 33.95 ± 12.62 126.30 ± 93.23 15.83 ± 10.68
21.02 ± 15.07 24.02 ± 15.38 478.99 ± 54.70 148.63 ± 56.12 3.93 ± 2.70 52.85 ± 14.74 21.45 ± 9.04 17.84 ± 5.49 32.74 ± 12.67 126.52 ± 41.72 16.11 ± 5.66
0.003* 0.006* 0.593 0.398 0.792 0.908 0.727 0.837 0.754 0.514 0.283
p < 0.005.
Table 4 Respiratory and motor data.
Apneas-hypopneas index Lowest SaO2 Periodic limb movements index
Group I (n = 19)
Group II (n = 20)
Group III (n = 19)
p
12.56 ± 18.52 85.95 ± 5.33 5.40 ± 12.14
6.24 ± 15.20 85.505.60 6.32 ± 13.03
4.22 ± 5.20 85.803.86 5.28 ± 9.55
0.171 0.958 0.955
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