Evaluation of Zolpidem, Triazolam, and Placebo As Hypnotic Drugs the Night Before Surgery

ELSEVIER

Evaluation of Zolpidem, Triazolam, and Placebo as Hypnotic Drugs the Night Before Surgery

Pamela J. Morgan, MD, CCFP, FRCPC, Roger Chapados, MD,? Frances F. Chung, MD,x Marlene Gauthier, MD,5 John W.D. Knox, MD,” Jacques Le Lorier, MD# .

Departments of Xnaesthesia, University of Toronto, Toronto, Ontario; Maisonneuve Kosemont Hospital, Montreal, Quebec; Royal Victoria Hospital, Montreal, Quebec; Queen Elizabeth II Health Sciences Center. Halifax, Nova Scotia; Hospital Sainte .Justine, Montreal. Quebec, Canada

Study Objectke: To wmpare the hypnotic effects of a bedtime dose ofzolpidem, triazolam, and placebo. Design: Double-blind, randomized, plucebo- and active-controlled, parallel-group trial. Setting: Six Canadiun hospitals. Patients: 357 patients (aged 19 to 71 years) hospitalized the night before a surgical p,octdnre. Interventions: At bedtime, each patient received either zolpidem 10 mg, triazolam 0.25 mg, or placebo, and 71~1s allowed to sleep for a maximum of 8 hourr. Measurements: Outcovtw rmmure.s wo-e subjjrctive in nntuw and included a morning qrr&ionnairp, 7Gsual analog scales, and obsPl‘c!ation ji)rms b study personnel. All con- tinuou,s variables wyre analyzed ty analysis of variance. All rategotical data were compared using the C:ochra,l-lL~an tel-Hams-e1 (CAfH) test, and the percentage of patients arle+ 71~7s compared using a CMH chi-syuarr analysis. When .signijcant overall treatment effects were obsprourl, pai,wisr compnrirons u&e undertaken. Compared with the placebo‘ group, the ,/oilort~1ng paramrter~ were c@~ficantl~ (p < 0.001) dz;ffent in the zolpidpm and tm’cc~olam groups: sleep IatancT roar shorter, total &ep time was longer, p&n ts fell asleep morp rnsity, and the n umbm of patients awake 2 hours Ffter drug trdminictration 7uas 1071~1. There wrf r/o @jkrenre,s bptwfrn anJ groups in next-morning .sornno&nrr or abililJ to conrentratr. Both drugs- ~LWQ 7~11 tolpr-nted, with adverse event lnridenc~ rates nearly iden tiral to placebo. (:onclilsions: Irl palirrrts su#hngfrom transiftlt inromnia, a single dose of zolpidem 10 mg roas a.~ rffertirje a.5 triazolam 0.25 mg, and both were more effective than placebo and i(lcrP well to&rat&. 01997 by Elsevier Science Inc.

Keywords: Insomnia, transient; sleep patterns, preoperative: triazolam; rolpidcm.

Introduction

Zolpidem (X,X,6-trimethyl-2-(4.methylphenyl) imidazo[l,2-a]-pyridine-3- acetamide hetnitartrate) is a non-benr.odiazepine hypnotic with a rapid onset

0952-8180/97,‘$17.00 and short duration of action. It has a short elimination ate-acting hypnotics such as temazepam within seven half-life of approximately 2.5 hours and no pharmacologi- nights; use of long-acting hypnotics or any type of medi- cally active metabolites.“’ Th e mechanism of action of zol- cation that would interfere with the assessment of a hyp- pidem presumably involves its interaction at specific ben- notic within 14 nights of admission to the hospital; use of zodiazepine binding sites of a certain population of cimetidine within hvo weeks prior to admission; a history central gamma aminobutyric acid-A (GABA-A) recep- of exaggerated response to benzodiazepines or other CNS tors.“-” Zolpidem has been shown to allelriate transient depressants; a histor): (within one year) of addiction, drug insomnia associated with sleeping in a strange environ- abuse, or alcoholism; history of sleep apnea or nocturnal ment” and with phase-advance of bedtime? It has been myoclonus; OI- an abnormal sleep schedule predicated by shown to be efficacious in the treatment of short-term” shift work. After approval by the Human Subjects Review and chronic insomnia.” Zolpidem studies in various in- Committees at the respective hospitals, all patients gave somniac populations have demonstrated maintenance of written informed consent prior to study entry. Seven pa- normal sleep architecture “’ and a low incidence of next- tients refused therapy after enrollment and before ran- day disturbances of psychomotor performance.” domization. Transient insomnia is a condition that typically affects people with normal sleep patterns who may have a short period of insomnia due to environmental conditions or Test instruments stress.” M’hen the environmental situation is resolved, the Scales used to evaluate efficacy included: (1) a morning insomnia will usually disappear. Patients hospitalized for questionnaire assessing sleep latency, total sleep time, diagnostic procedures or minor surgeries frequently experience this form of sleep disturbance. Short-acting hypnot- number of awakenings, and wake time during sleep as continuous variables; sleep quality (1 = excellent, 2 = good, ics are of particular value as adjunctive medications for 3 = f‘air, 4 = poor), condition on awakening (1 = better patients to induce sedation,12 especially when given the than usual, 2 = as usual, 3 = a little worse than usual, 4 = night before surgery.’ In models of transient insomnia, zolpidem 10 mg promotes sleep without impairing mot01 much worse than usual), and ability to concentrate (1 = excellent, 2 = good, 8 = fair, 4 = poor) as categorical data; performance the subsequent day.“~‘Triazolam” and other and (2) visual analog scales (VAS) evaluating feelings of short-acting hypnotics 14,” also have been used in the man- somnolence (0 = very sleepy, 100 = not sleepy at all) and agement of insomnia prior to surgical procedures. In controlled clinical trials, the short-term use of triazolam has ease of falling asleep (0 = very easy, 100 = not easy at all). Both of these kinds of instruments are widely used and been associated with disturbing side effects, including have been validated as tools for the subjective evaluation memorv and motor impairment.‘G”’ In some comparative of sleep parameters and next-day effects of hypnot- trials, the effects of triazolam were more extensive and/or ics.“,“,“‘,” In addition, a sleep observation form for study longer-lasting than those of zolpidem,““.“’ but in a recent personnel was used to record whether the patient was study of dose-effect relationships of zolpidem, triazolam. awake or asleep at half-hour intervals for the first two and temazepam assessing a multitude of daytime perfor- hours and at one-hour intervals for the rest of the night. mance tests, no difference was detected between zolpidem and triazolam at the doses employed in the present trial.‘” The objective of this study was to compare the subjec- Study Design tive efficacy and tolerability of a single nighttime dose of zolpidem 10 mg, triazolam 0.25 mg, or placebo to induce The study was a double-blind, randomized, balanced, pla- sleep in hospitalized patients when administered the night cebo- and active drug-controlled, parallel-group trial con- prior to a surgical procedure. ducted at six sites in Canada. Randomization was carried out by sealed envelope assignment at Lorex Pharmaceuti- cals, Skokie, IL. Materials and Methods Patients were admitted into standard hospital settings Patients with one or more patients per room. Each patient received a single dose of study drug (10 mg zolpidem, 0.25 mg Hospitalized patients scheduled for elective surger)l (such triazolam, or placebo) at bedtime behveen the hours of 9 as hysterectomy, hernia repair, plastic surgery, or ortho- and 1 I PM. Prior to the study night, patients had been pedic procedures) with ASA physical status I and II were informed that if they were awake two or more hours after screened for this study. Patients gave a medical and sleep study drug adminis&ation, they could request additional history, and underwent a physical examination prior to sedative medication (rescue medication). The type of res- study entry. Patients were excluded from the study for the cue medication was not standardized across study sites and following reasons: pregnant? (females of child-bearing po- was left to the discretion of the investigator. tential had to have a negative pregnancy test); lactation; Patients were awakened following a maximum of eight recent history of chronic insomnia; significant medical or hours of allotted potential sleep time. Vital signs were re- psychiatric iliness: use of short-acting central nen’ous sys- corded at awakening and prior to surgery, and patients tem (CM) medications within hvo days of admission; use completed a morning questionnaire on which the primary of alcohol on the day of admission; use of triazolam within efficacy parameters were sleep latency and total sleep time. the previous four nights; use of other short- or intermedi- Information regarding adverse events was obtained during the night and the early morning before surgery, as tion time points beyond two hours were not analyzed be- well as following surgery, from spontaneous patient re- cause rescue medication became available to patients at ports, the morning questionnaire, and physical examina- this time. Data were analyzed using the BMDP and SAS tions. After surgery, adverse event information was also (US, Inc.. Gary, NC) statistical packages. collected by the coordinator from the patient’s chart.

Results Statistical Analyses Patirnts In this single-dose study, all patients who took study drug and completed the morning questionnaire were included The study group consisted of 357 hospitalized patients in the analysis. (120 patients given zolpidem, 119 given triazolam, and Demographic variables were compared between treat- 118 given placebo) scheduled for elective surgery. The ment groups using either the Cochran-Mantel-Haenszel patients ranged in age from 19 to 71 years, with a mean (CMH) test for categorical data or by analysis of variance weight of 69.2 kg (range 43 to 114 kg); 114 patients were (ANOVA) for continuous and ordered demography and men and 243 were women. Most of the patients were Cau- sleep history measures. In the analysis of subjective sleep casian (n = 323), the remaining participants were Black (n latency, data from all patients were used, including those = 1.5), .Asian (n = 12), Hispanic (n = 3), or other (n = 4). w-ho used rescue medication. The values of the subjective The three treatment groups were comparable with respect latency included in the proportional hazards statistical to demographic characteristics and sleep history of ran- analysis were those reported by the patients. For patients domized patients. who requested a rescue medication, the subjective sleep latency was taken to be greater than the elapsed time until the rescue medication was requested. The proportional SleepInduction hazards model was used to analyze these data. The effects of treatment, center. and treatment-bv-center interaction The two primary outcome measures from the morning were assessed using the Wald chi-square statistic. AWOVA questionnaire were self-reported sleep latency (minutes was performed for other continuous variables. When sig- before the onset of sleep) and ease of falling asleep (Table nificant overall treatment differences were observed, pair- I). Subjective sleep latency was significantly shorter in the wise comparisons of the treatments were undertaken using zolpidem and triazolam groups than in the placebo group, the Student-Neuman-Keuls multiple comparison proce- with no significant differences between the two active dure. Categorical data (quality of sleep, ability to concen- treattnent groups. A 100 mm VAS was used to obtain a trate, morning sleepiness, condition on awakening) were subjective next-day measure of ease of falling asleep (Table summarized by mean scores and assessed by ANOVA. The I). Patients in both the zolpidem and triazolam groups percentage of patients asleep was compared among treat- rated themselves as falling asleep significantly more easily ment groups using a CMH chi-square analvsis. Observa- than did patients in the placebo group.

Table 1. Next-Morning Ratings of Treatment with Placebo. Zolpidenr 10 mg. or ‘Triazolam 0.2.1 mg

Placebo Zolpidem Triazolam Parameter* (n = 118) (n = 120) (n = 119) p-value

Continuotls Variables (mean + SE) Sleep laLenc)l- (min) ?:i.Ob 30.0”

J. (Xl. Anesth., LY>I.9. March 1997 99 Subjective Total Sleep The Proportion of Patients ilzuuke

Since time in bed was limited to a maximum of eight The percentage of patients awake 03, 1.0, 1.5, and 2 hours hours, total sleep time represented a measure of sleep after dosing were compared between the treatment efficiency. Mean subjective total sleep time was signifi- groups. A significantly lower percentage of patients in the cantly longer in the zolpidem and triarolam groups than zolpidem and triazolam groups than in the placebo group in the placebo group (Tnblr I), and the two active groups were awake at each of the time points (Table 2). did not differ significantly from each other.

SleepMaintenance and SleepQuality No patient who received zolpidem or triazolam experi- Patients receiving zolpidem or triazolam reported signifi- enced a serious or unexpected adverse event. One patient cantly fewer waking episodes than did patients in the pla- who received placebo experienced severe nausea two cebo group. In addition, patients receiving triazolam re- hours after dosing, which continued for 14 hours; the pa- ported significantly fewer awakenings than did patients in tient was discontinued from the study. The incidence of the zolpidem group (Table I). A significant treatment-by- other adverse events was small and similar in the three center interaction was obserwd for number of awaken- groups. ings; significantlv fewer awakenings were obsened after both zolpidem and triazolam than placebo at one center (p = 0.003). There was no statistically significant difference Discussion between groups in mean subjective wake time during the Both rolpidem 10 mg and triazolam 0.25 mg effectively night (Table 1). Lastly, patients in the rolpidem and tria- improved subjective sleep characteristics when adminis- zolam groups reported significantly better sleep qualin tered as a single dose on the evening prior to elective than did patients in the placebo group (Tab& 2). surgen. This observation is in agreement with results reported recently on numerous other outcome measures.” The improvement of sleep was of a similar magnitude in the tww groups, with no significant difference between Of the 357 patients who received drug, 42 requested a them. Compared with patients in the placebo group, pa- “rescue medication” and were listed on the case report tients in both acti\-e treatment groups reported signifi- forms as haling discontinued due to lack of efficacy. In cantly shorter sleep latency. they fell asleep more easily, agreement with the results on sleep induction, the pro- total sleep time was longer, and they reported a better portion of such patients was higher in the placebo group quality of sleep and felver awakenings. Among the 42 of a (n = 27; 22.9%) than in the rolpidem (n = 8; 6.7%) and total of’ 3.5’7 patients who requested rescue medication, 27 triazolam (II = 7; 5.9%) groups (overall CMH, r) < 0.001) were in the placebo treatment group. Overall, in people Of the 42 patients who requested a rescue medication. 14 with normal sleep patterns, the present data confirm pre- patients received triazolam, 14 received lorazepam, 12 re- viousl!. reported results with zolpidem and triazolam ob- ceived flurazepam. and 2 received oxarepam. tained in insomniac patients.‘)’ Zolpidem has been reported to be an efficacious hypnotic in other models of transient insomnia,“,7 and ben- Perforrnclncr Ratings rodiazepines have been used to induce sleep on the evening prior to surget7. ” There are several considerations As shown in TubG I, no significant differences were ob- that could actually argue against such usage. Administra- sewed between the treatment groups in the ratings of abil- tion of a benzodiazepine during a hospital admission has ity to concentrate. morning somnolence, and condition been identified as a risk factor in becoming a chronic user on awakening. of these drugs.g’i In addition, de\,elopment of tolerance

Table 2. Sutmber (%) of Patients .Iwake during First Two Hours after Dosing

Hours After Placebo Zolpidem Triazolam Overall p-value Dosing (n = 118) (n = 120) (n = 119) (cm)

0.3 92 (Xi ’ 69 (38)” 63 (33) B

CMH = (:ochI-an-!\lantel-Haen\rel statistical test. .‘~KPet-crntages with the aarne suprrwt-tprctl Icttvt- arr not significantlv tlif’lrrettt ((AlH chi-square; p 2 0.051. has been reported with repeated use of benzodiarepines. References Although tolerance might occur following a prolonged stay with benzodiazepine usage, it appears unlikely to re- 1. Rianchrtti <:, Lhthruc (:. Thiercrlin JP, et al: Clinical pharmaco- suit from a single dose of a benzodiazepine, and, for that kinems of /olpidern in mrious physiological and pathological matter. of any hypnotic. conditions. In: Sauvanet ,JP, Langer SZ, Morselli PL (eds): In& A similar argument applies to the risk of rebound in- nzc~~ridtn~.~ in .S’@J Ditordm. New York: Raven Press, 1988:155-C& 2. Th+nc,t JP, Hcr-mann P, Durand A. et al: Pharmacokinetics and somnia that, theoretically, could impact the already dis- mwhoiism of Lolpidem in various species and in humans. 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