longitudinal patterns of new benzodiazepine use in the elderly

pharmacoepidemiology and drug safety 2004; 13: 669–682Published online 16 December 2003 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/pds.908

ORIGINAL REPORT

Longitudinal patterns of new Benzodiazepine use in theelderly{

Gillian Bartlett PhD1, Michal Abrahamowicz PhD2z,*, Robyn Tamblyn PhD1,2{,Roland Grad MD, CM, MSc, CCFP3, Radan Capek MD PhD4 and Roxane du Berger MSc5

1Department of Medicine, McGill University, Quebec, Canada2Department of Epidemiology and Biostatistics, McGill University, Quebec, Canada3Department of Family Medicine, McGill University, Quebec, Canada4Department of Pharmacology and Therapeutics, McGill University, Quebec, Canada5Division of Clinical Epidemiology, Montreal General Hospital Research Institute, Montreal, Quebec, Canada

SUMMARY

Purpose To characterize longitudinal patterns of Benzodiazepine use in the elderly.Methods Prospective cohort of 78 367 community-dwelling Quebec residents aged 66 years or more who were new Ben-zodiazepine users, was followed for 5 years, 1989–1994. Data acquired from four population-based, provincial administra-tive databases were used to create time-dependent measures of change in dosage, switching or adding Benzodiazepines for11 drugs listed in the provincial formulary. Subject-specific Spearman’s rank correlation coefficients between dose and timewere used to measure the tendency of increasing dose with consecutive periods of use. Multiple logistic regression and gen-eralized estimating equations (GEE) models evaluated subject characteristics associated with increasing dose.Results The mean duration of uninterrupted Benzodiazepine use was 75.5 days. The mean daily dose was about half therecommended adult daily dose but 8.6% of subjects exceeded the recommended adult dose. Some of them (28.8%) switchedmedications at least once and 8.2% filled two or more prescriptions concurrently. For women, older age at date of first pre-scription was associated with increasing dose over time (odds ratio (OR) for 10 year age increase¼ 1.23, p< 0.001).Conclusion Long periods of Benzodiazepine use are frequent among Quebec elderly. The evidence of increasing dose,particularly for older women, and long-duration of use has important implications for clinicians. Copyright # 2003 JohnWiley & Sons, Ltd.

key words— Benzodiazepines; elderly; dose; drug utilization

INTRODUCTION

The widespread consumption of Benzodiazepines incommunity-dwelling elderly has received consider-

able attention because use has been associated withan increased risk of injuries from falls.1–6 However,most studies have focused on current use.5,7 Little isknown about different aspects of the longitudinal pat-terns of new Benzodiazepine use such as rate ofswitching, tendency to increase dose over time andaccumulation of long-term use, in part because the cri-teria and methods to accurately, systematically andquantitatively describe complex patterns of medica-tion use have not been developed.8 The resultinginformation could provide a comprehensive descrip-tion of patterns of long-term use that would be perti-nent for both researchers and clinicians.9–11

One of the key issues that have not been resolved inthis context is whether elderly patients develop

Received 19 November 2003Revised 23 September 2003

Copyright # 2003 John Wiley & Sons, Ltd. Accepted 29 September 2003

* Correspondence to: Dr Michal Abrahamowicz, Division ofClinical Epidemiology, Montreal General Hospital Research Insti-tute, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada.E-mail: [email protected]{ No conflict of interest was declared.z M. Abrahamowicz is a James McGill Professor.{ R. Tamblyn is a CIHR Scientist.

Contract grant sponsors: National Health Research and DevelopmentProgram (to R.T.); Reseau FRSQ sur l’utilisation des medicaments;Natural Sciences and Engineering Research Council of Canada (toM.A. and G.B.); Canadian Institutes for Health Research (CIHR).

tolerance to the anxiolytic and sedative effects ofBenzodiazepines, which may lead to increasing doseover time.9,12,13 Tolerance is believed to occur withprolonged clinical exposure and is defined as adiminution in the efficacy of the drug with repeateduse so that higher doses are required to produce thesame effect.13,14 This is important, since dose plays arole in increasing the risk of falls that lead to fracturesin the elderly.15

If there were evidence of increasing dose over time, itwould be critical to identify susceptible patients. Manydisabilities, impairments and prescription medicationshave been associated with an increased risk of injuryfrom falls.14,16–22 Identification of the characteristicsof patients more susceptible to increasing dose overtime might help clinicians minimize the risk associatedwith Benzodiazepine use.

The objectives of this study were to characterizepatterns of Benzodiazepine use over time in an elderlycohort of new users. Specifically, we investigatedfrequency of use of specific drugs, the rate of switchingor adding medications and changes in dose over time,and attempted to identify subject characteristicsassociated with a tendency for increasing dosage overtime.

METHODS

Design and study population

A two-stage sampling process was used to assemblethe study cohort. First, a regionally stratified randomsample of 1880 Quebec physicians was selected fromthe master physician file at the Regie de l’assurancemaladie du Quebec (Quebec Health Insurance Pro-gram, RAMQ). Secondly, all the publicly insuredpatients (elderly and patients on social assistance)seen by these physicians between 1989 and 1994 wereidentified. The selected physicians saw 727 295 indi-viduals in Quebec in those 5 years (approximately89% of the elderly population). Subjects wereexcluded due to: an age of 65 years or less in 1989(205 547; 28.3%, approximately two thirds of thesesubjects were recipients of social assistance belowthe age of 65); a temporary or non-unique healthinsurance number (4186; 0.6%); death in 1989(18 258; 2.5%); a non-resident of Quebec at any time(9509; 1.3%); long-term institutionalization in 1989(23 247; 3.2%); hospitalization for the entire studyperiod (3307; 0.4%); or living in a geographically iso-lated region of Quebec (697; 0.09%).

From the remaining cohort of 462 543 elderlyQuebec residents, all subjects who did not fill a

Benzodiazepine prescription during the baseline year(1989) were followed for 5 years. The period of 1 yearwithout a Benzodiazepine prescription defined non-users based on conventions of previous research onincidence measures of medication use.23,24 New userswere identified when they filled a new prescriptionduring the study period, 1990–1994. 1 January 1990was the start of the observation period for thecalculation of the total person-time and all subjectswere followed until the end of the study or until lost tofollow up. Loss of subjects occurred with death,moving out of the province or institutionalization.

Ethics approval for the study was provided by theMcGill Faculty of Medicine Institutional ReviewBoard.

Data source and study population

Information from four population health administra-tive databases was provided by the Quebec HealthInsurance Program including patient demographics,medical services, prescription claims and hospitaliza-tion databases. All databases were linked through anencrypted, unique health care number for each sub-ject. The validity of these databases has been pre-viously established.25–27 The patient demographicdatabase provided age, sex, postal code and date ofdeath. The medical services database provided thetype, location (e.g. inpatient, emergency department,private), diagnosis, treating and referring physicianand date of all services provided on a fee-for-servicebasis (95% of all services provided in Quebec).28 Theprescription claims database from RAMQ contains allthe prescriptions billed to RAMQ by any community-based pharmacy in Quebec for persons aged 65 andolder. The prescription database provided encryptedprescribing physician identification, encrypted phar-macy identification, codes for prescription drugdosage, strength and generic name, American Hospi-tal Formulary Service (AHFS) class, quantity, dura-tion of prescription, codes for substitution, renewalstatus, date of prescription and cost. In the prescrip-tion database, there is no field to indicate if the pre-scription is pro re nata (take as needed). Thehospitalization database provided records of all hospi-tal discharges in Quebec including discharge diag-noses, admission and discharge dates.

Measurement of Benzodiazepine exposure

The start date, drug type, dosage, number of pills andduration for every prescription for each of the 11 Ben-zodiazepines available on the Quebec formulary were

670 g. bartlett ET AL.

Copyright # 2003 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety, 2004; 13: 669–682

retrieved from all the prescription claims for eachpatient and used to construct the time-dependent mea-sures of Benzodiazepine exposure. No prescriptioninformation was available during hospitalization, soperiods of hospitalization longer than 7 days weretreated as missing records and not included in the cal-culation of total person-time of observation or in theconstruction of the time-dependent measures.

Cumulative duration of Benzodiazepine exposurewas calculated as the sum of all periods of use from thestart date of the first Benzodiazepine prescription untilthe end of the follow-up period. These summarymeasures were created for overall Benzodiazepineexposure, i.e. cumulative duration across differentproducts, as well as for exposure to each of the 11individual Benzodiazepines. Given that most elderlymay occasionally forget to take a pill, may reduce theirdosage or may have difficulty seeing their physician toobtain a refill prescription,29 periods of less than 2weeks between consecutive prescriptions were unli-kely to represent ‘true’ interruptions in use. Therefore,to avoid under-estimating the cumulative duration ofuninterrupted use, periods of less than 15 days betweentwo consecutive Benzodiazepine prescriptions wereconsidered as continued use at the dosage of the earlierprescription. A distinct period of Benzodiazepine usewas defined as a period with no interruption in use andno change in dosage.

To obtain the average duration of distinct periods ofuse, the duration for each period of distinct use wascalculated for all patients. These durations were thensummed for each patient and divided by the number ofperiods of use for that patient yielding a patient-specific average duration. The distribution of thesepatient-specific average durations was then analyzed tocharacterize the entire population of Benzodiazepineusers. For example, to obtain a single overall meanduration, these patient-specific averages were dividedby the number of patients.

A standardized daily dose was calculated for eachprescription according to the following formula:

Total number of pills

Duration of prescription in days

� Dosage per pill in mg

WHO recommended adult daily dose in mg

where the first term represented the average number ofpills per day and the second term converted a givendosage into the percent of the World Health Organiza-tion (WHO) recommended adult daily dose30 for therespective drug. Clinical guidelines recommend thatelderly should be prescribed half of the recommended

adult daily dose.9,13,31 For subjects that were simulta-neously exposed to more than one Benzodiazepine,the overall daily dose was calculated as the sum ofthe corresponding standardized daily doses for indivi-dual products. Every time patients changed their doseduring use, they were considered to start a new dis-tinct period of use. In instances where there were over-lapping prescriptions of less than 5 days, theindividual was assumed to have refilled early andcompleted their first prescription before starting thesecond prescription. A count was made of the numberof times a patient added a different Benzodiazepineproduct to their current prescription.

Switching was defined as filling a prescription for aBenzodiazepine that was different from the current ormost recent Benzodiazepine product. The prescrip-tions could not be overlapping at the time of the switchand a patient was considered to have switched eachtime the type of Benzodiazepine in the currentprescription differed from the previous prescription(i.e. a patient with three prescriptions could haveswitched, at most, two times). The total number oftimes a subject switched to a different Benzodiazepinewas then calculated.

Predictors of change in dose

Potential predictors of change in Benzodiazepine dosewere retrieved from baseline data. For each subject,data were retrieved on age and sex as well as the fol-lowing variables measured in 1989: disabilities, num-ber of hospitalizations, health care use and use ofother prescription medications. Age was representedby age at time of first Benzodiazepine prescription.

The disabilities, recorded using 9th internationalclassification of disease diagnostic codes (ICD-9) fromboth the hospitalization and medical services billingdatabases, included visual impairment (ICD-9: 360–379), stroke (ICD-9: 430–438), neurological disordersincluding dementia and Parkinson’s disease (ICD-9:290, 294, 331–337, 340–342, 344), arthritis (ICD-9:274, 710–725–730, 733), seizure disorders includingepilepsy (ICD-9: 345, 780.3), depression (ICD-9: 311,298.0, 296.2, 296.3, 309.1, 300.0–300.4), alcoholabuse or dependence (ICD-9: 303, 291, 305.0, 535.3,571.0–571.3, 265.2, 425.5) and drug abuse ordependence (ICD-9: 304, 305.1–305.9, 292). Forcertain conditions, information for a patient filling aprescription for a specific medication was used inaddition to the diagnostic codes for constructing thesevariables. This included seizure disorders (AHFScategories 28:12:04, 28:12:12, 28:12:20, 28:12:92)and visual impairment (AHFS category 52:20:00).

patterns of benzodiazepine use in the elderly 671


Prescriptions for drugs other than Benzodiazepineswere retrieved from the prescription database. Patientswere considered to be users of a given medication ifthey filled at least one prescription during 1989. Thedrugs that were recorded from the database includedmedications protective of fractures (thiazides, estro-gens), other psychotropics (anti-depressants, anti-psychotics, non-Benzodiazepine sedative-hypnotics,miscellaneous psychotropics (lithium, L-tryptophan))and medications associated with a decrease in motorstability (cardiac drugs, anti-hypertensive agents,vasodilating agents, opioid agonists, opioid mixedpartial agonists/antagonists and non-thiazide diuretics).

Prior use of health care services in 1989 wassummarized by counts of: (i) the number of uniquephysicians prescribing medications; (ii) the number ofphysicians visited during the year; (iii) the total numberof medical services; (iv) the number of medicalservices made on distinct days; (v) the number ofdischarges from all hospitals and (vi) the number ofdischarges from acute care hospitals.

Statistical analyses

Frequency distributions of Benzodiazepine dose,duration and switching variables were determinedand the means, standard deviations (SD) and rangeswere reported for continuous variables. Chi-squaretests and one-way analysis of variance usingTukey–Kramer tests for multiple comparisons32,33

were used to compare the distributions of categoricaland continuous variables across different productsrespectively.

Spearman’s rank correlation coefficients were cal-culated for each subject with three or more distinctperiods of use in order to assess strength and directionof association between subsequent Benzodiazepinedoses and time. Time was represented by an ordinalvariable reflecting rank order of sequential periods ofuse with a dose being constant within each period.Subjects with high positive values of correlationcoefficient (above the 90th percentile of the sampledistribution) were then identified as showing a strongtrend for increasing dosage with consecutive timeperiods. The proposed cut-point of 0.87, correspondingto the 90th percentile of the empirical distribution ofsubject-specific time-dose rank correlations in our dataset, identifies the 10% of subjects with the strongesttrend toward a systematic dose increase. Specifically,for any sequence of up to five distinct periods ofmedication use, Spearman’s correlations equal to orhigher than 0.87 identify only those patterns of dosechanges that correspond to either strictly monotonic

increases (r¼ 1.0) or to a non-decreasing (i.e. weaklymonotonic) sequence in which the dose remains higherthan the initial dose for at least three periods, indicatinga sustained increase. Whereas other criteria may beanalyzed using methods outlined in this section, theproposed cut-point seems to strike a reasonablebalance between the need to ensure sufficient numberof ‘outcomes’ (cases identified as a systematic doseincrease) and the need to eliminate spurious or onlytransient increases.

Multiple logistic regression with independent vari-ables that included all baseline characteristics, the typeof Benzodiazepine for the first prescription and thebinary outcome defined as Spearman’s rank correlationequal or higher than 0.87, was then used to identifypatient characteristics associated with increasingdosage over time. To assess if the role of potentialpredictors was the same for men and women,interactions between sex and other potential predictorswere tested using a Wald test. To allow meaningfulinterpretation of results in the presence of interactionbetween sex and age, the age variable was transformedby subtracting the median age of the cohort from thesubject’s age in 1989. Thus, if the model includedthe interaction between transformed age and sex, theparameter estimate for sex represented the log oddsratio (OR) for men compared to women at the medianage. Statistically significant predictors were selectedusing an automated stepwise procedure with p< 0.10and p> 0.15 criteria for entry and removal respec-tively. Initially, all variables listed in the above sectionas well as all binary indicators of specific Benzodia-zepines, as listed on the first filled prescription, wereincluded as the candidates for inclusion in the model. Itshould be noted that while stepwise selection is knownto yield unstable results in small and moderatesamples, this concern is less relevant in our studygiven the large size of our database. To account for theimpact of data-dependent choices on statistical infer-ence, we have used p< 0.01 as a criterion for statisticalsignificance of the effects of potential predictors.

In the above analyses focusing on the predictors ofincreasing dose, we had only access to the values of theindependent variables measure in the baseline year,1989. To assess if the time elapsed between predictormeasurement and first Benzodiazepine prescriptionaffects the estimated associations, we carried outsensitivity analyses. Specifically, we restricted theanalyses to only those new users who received theirfirst Benzodiazepine prescription: (i) in 1990 and (ii) in1990 or 1991. In both cases we estimated the samemultiple regression model for all the new users. Notthat these restrictions imply that the putative predictors



were measured (i) about 1 year and (ii) at most 2 yearsbefore the actual use of Benzodiazepines began.

To further investigate whether older age is associatedwith a tendency for gradually increasing dose over time,we relied on a generalized estimating equations (GEE)approach, that accounts for the dependence of subse-quent observations for the same subjects.34 The totalstandardized Benzodiazepine dose at subsequent per-iods of use represented the repeated measure of aquantitative dependent variable. The independentvariables included the initial standardized dose, theage at the first Benzodiazepine prescription and thetime, represented by a rank order of subsequent periodsof use. The time variable was log-transformed toaccount for the considerable positive skewness of itsdistribution. An interaction between age and time wasthen added and tested for statistical significance in orderto assess whether the association between time and dosedepended on the subject’s age. Separate analyses werecarried out for men and women. In GEE analyses, weassumed an autoregressive order one correlationstructure of residuals.35In this type of structure, theassumption is that the residual correlation between twodoses for the same subject depends on their proximity intime and equals a single coefficient to a power that isequal to the number of periods separating the two dosesof interest. Statistical analyses were conducted usingSAS Systems 8.02 and S-Plus 4.36,37

RESULTS

From the initial cohort of 462 543 elderly patients,45% filled a Benzodiazepine prescription in 1989(209 732) and 38% never filled a Benzodiazepine pre-scription (174 444) during the study period. The base-line characteristics of the remaining 78 367 (17%)elderly subjects who filled at least one new Benzodia-zepine prescription during the study period and whowere considered ‘new users’, are presented inTable 1. The average age of elderly subjects at theirfirst Benzodiazepine prescription was 75.5 years(SD¼ 5.8) with no clinically significant differencebetween men (75.1 years) and women (75.7 years).Fifty-six percent (43 683) of the new users were hos-pitalized at least once during the follow-up for a per-iod greater than 7 days and hospitalizations were morelikely to occur among men than women (63% vs 50%,p< 0.001).

Duration of Benzodiazepine use

After filling their first prescription for a Benzodiaze-pine, the average total duration of Benzodiazepine

use was 7.5 months (Table 2), for an average observa-tion period of 52.4 months. When periods of hospita-lization were removed, after having received their firstBenzodiazepine prescription elderly patients spent anaverage of 34% of their remaining follow-up time onBenzodiazepines (Table 2). Only one subject filledconsecutive prescriptions continuously during theentire 5 years of follow-up. A total of 8887 patients(11%) filled consecutive prescriptions during all oftheir non-hospitalized observation time since fillingtheir first Benzodiazepine prescription and 11 742(15%) filled prescriptions for at least 90% of this time.The average duration of a single period of uninter-rupted Benzodiazepine use was greater than 30 daysfor 45% of the subjects (35 442). Specifically, 20.1%(15 736) of all new users had an average duration ofuse between 31–65 days, 7.6% (5 980) between 66and 95 days, 9.0% (7 035) between 96 and 185 daysand 8.5% (6 691) exceeded 185 days, with the medianslightly above clinical guidelines’ recommended limitof 30 days.13The mean of the average durations wasover two and a half months. The average duration ofuninterrupted Benzodiazepine use was not markedlyaffected by the length of follow-up or by the subject’ssex.

32 085 subjects (40.9%) had only one period ofuninterrupted use. The mean duration of the first periodof use was 70 days (SD¼ 147 days). Overall, men hadslightly longer mean duration of use for the first period,however, this difference was only statistically sig-nificant for triazolam and lorazepam (17.7 and 4.5 dayslonger for men respectively) (Table 3). By contrast,women had a significantly longer average duration offirst use for two long-elimination half-life Benzodia-zepines, flurazepam and chlordiazepoxide (differenceof 14.3 and 15.7 days respectively). For all Benzodia-zepines, the mean duration of first use exceeded 30days and for most it exceeded 60 days. While there wassome variation in average duration of the first use ofdifferent drugs, the differences were not systematicallyassociated with the length of the elimination half-life(Table 3). Subjects who started on more than oneBenzodiazepine had the longest average duration ofuse. The average duration for the first period of usedecreased on average by 12.5 days from 1990 to 1993(p< 0.01), however even in 1993 it still exceeded 2months. Subjects who filled their first Benzodiazepineprescription in 1994 were not included in this analysissince their duration of use would be artificiallyrestricted by the end of the study on 31 December1994.

The average number of distinct uninterruptedperiods of Benzodiazepine use, with no change in



Table 1. Characteristics of new male and female users of Benzodiazepines among Quebec elderly in the baseline year (1989)*

Variables Frequency or mean (SD)

Menn¼ 34 746 (44.3%)

Womenn¼ 43 621 (55.7%)

Totaln¼ 78 367

Patient demographicsMean age in years 72.6 (5.4) 73.3 (5.8) 73.6 (6.1)

Measures of health care useNo. of prescribing physicians 2.1 (1.6) 2.1 (1.6) 2.1 (1.6)No. of physician visits 4.3 (4.2) 4.2 (3.9) 4.3 (4.0)No. of days with medical services 9.7 (11.2) 9.7 (10.8) 9.7 (11.0)Total no. of medical services 11.1 (14.4) 10.8 (13.1) 11.0 (13.7)No. of acute-care hospital discharges 0.2 (0.7) 0.2 (0.5) 0.2 (0.5)

Impairments or disabilities associated with an increase risk for falls and fracturesVisual impairment 20.4% 24.5% 22.7%Arthritis 15.5% 18.6% 17.2%Stroke 3.4% 2.4% 2.8%Depression 2.7% 4.3% 3.6%Neurological disorders 2.9% 2.8% 2.9%Seizure disordersa 1.8% 1.8% 1.8%Osteoporosis 0.2% 0.8% 0.5%Alcohol abuse 0.5% 0.1% 0.3%Drug abuse 0.3% 0.2% 0.2%

Non-Benzodiazepine medications—protective of fracturesThiazide diuretics 17.7% 27.6% 23.2%Estrogen 0.02% 0.2% 0.1%

Non-Benzodiazepine medications—other psychotropicsAnti-depressants 2.8% 5.6% 4.4%Anti-psychotics 1.2% 2.1% 1.7%Sedatives 3.6% 4.6% 4.2%Lithium/L-tryptophan 0.2% 0.2% 0.2%

Non-Benzodiazepine medications—medications known to alter motor stabilityCardiac drugs 7.2% 11.3% 30.2%Anti-hypertensives 11.6% 16.7% 13.8%Vasodilators 19.2% 14.4% 16.5%Opioid agonists 0.9% 0.7% 0.8%Opioid mixed agonists/antagonista 0.1% 0.1% 0.1%Non-thiazide diuretics 10.7% 13.3% 12.1%

*Benzodiazepine use is based on any of the 12 Benzodiazepines available by prescription in community-based pharmacies. Midazolam wasnot available through community pharmacies and clobazam had no detected use before 1992.aIncludes patients who have filled a prescription for an anti-epileptic (AHF codes 281204, 281292, 281212, 281220).

Table 2. Duration* and periods of Benzodiazepine exposure in days for 78 237 new users over 5 years of follow-up**

Variable Mean (SD) Median Range

. Observation time (days) 1625.1 (407.0) 1826 10–1826

. Duration of hospitalization periods (days)a 53.6 (58.8) 34 8–1306

. Observation time excluding hospitalization (days) 1595.2 (420.8) 1809 1–1826

. Observation time after first Benzodiazepine prescription excluding periodsof hospitalization (days)

896.5 (570.2) 904 1–1826

. Total duration of Benzodiazepine use (days) 228.6 (327.3) 83 1–1826

. Number of periods of uninterrupted Benzodiazepine use 3.2 (3.3) 2 1–32

. Average duration of uninterrupted periods of Benzodiazepine use (days) 75.5 (137.2) 31 1–1826

. Average duration of interruption between periods of Benzodiazepine use (days)b 187.1 (239.9) 95.6 15–1773

*The observation period starts on 1 January 1990 (Day 0) and continues until the end of the study on 31 December 1994 (Day 1826).**Based on exposure to any of the 13 Benzodiazepines available in community-based pharmacies in Quebec.aAmong subjects hospitalized at least once for more than 7 days (43 683), only hospital stays longer than 7 days were considered resulting in aninflation of the mean and median duration.bCalculated only with those Benzodiazepine users who had two or more distinct periods of use (42 219).



dosage, was 3.2 per subject (SD¼ 3.3) with a medianof 2. Among all new users, 32 858 (41.9%) had 2–5distinct periods of Benzodiazepine use while 3 753(4.8%) had more than 10 periods of use. The averageduration for both men and women in all the first fiveperiods of use was over the recommended limit of 30days. There was no systematic trend for averageduration to increase or decrease in subsequent periodsof use (data not shown).

Predictors of increasing Benzodiazepine dosage

The average standardized dose for all subjects was0.57 (SD¼ 0.37) corresponding to just over one halfof the recommended daily adult dose, with a mediandose of 0.48 (range 0.01–11.0). The dose reflected thesum of all concurrent Benzodiazepine prescriptions.Men had a slightly higher average standardized dose(0.61) than women (0.54, p< 0.001). A value of 1.0represented the WHO recommended adult daily dose,and when the daily dose was averaged across all per-iods of use for each subject, this average exceeded 1.0for 8.6% of the elderly with similar proportions formen and women.

The Spearman’s rank correlation coefficientsbetween dose and ranks of subsequent periods werecalculated among the 35 941 subjects (45.9% of newusers) with three or more periods of distinct Benzo-diazepine use. The 90th percentile cut-off corre-

sponded to a Spearman’s correlation of 0.87 and3 666 subjects who exceeded this cut-off wereidentified as showing a strong tendency for increasingdose over time.

Older age was a statistically significant predictor ofincreased dosage with subsequent periods of use overtime (Table 4). With each year increase in age at thefirst prescription, there was a 2% increase in risk forincreasing dosage over time (OR: 1.02, 95%CI: 1.01–1.03). This represented an estimated risk increase of10% (OR: 1.10) and 22% (OR: 1.22) for an increase inage of 5 and 10 years respectively. Men were morelikely to show a trend to increasing dosage than womenof the same age (OR: 1.17, 95%CI: 1.08–1.25).Among different Benzodiazepines, subjects first pre-scribed alprazolam, oxazepam or clonazepam all had astatistically significant higher risk of increasing dosageover time than the reference group of lorazepam users(Table 4), while the opposite was true for diazepamusers (OR: 0.76, 95%CI: 0.64–0.91). Also, takingmedications that affect motor stability in 1989 reducedthe probability of increasing Benzodiazepine dosageby almost 10% (Table 4).

A very similar pattern of results was obtained in thesensitivity analyses restricted to subjects who startedBenzodiazepine use in only 1990, or both 1990 and1991 (data not shown). For all independent variables,the CI for the corresponding OR in the three analysesoverlapped substantially and the point estimates were

Table 3. Average duration of first period of uninterrupted Benzodiazepine exposure for women compared to men by type of firstprescription

Type of Benzodiazepine firstused (elimination half-life, hr)

No. of subjects(% women)

Mean duration of first period of uninterrupteduse in daysa (SD)

Difference for womenversus men (p-value)

Women Men

Triazolam (1.5–5.5) 2282 (51.2) 71.3 (152.5) 89.0 (186.4) �17.7 (0.01)Temazepam (8–24) 4049 (48.8) 98.8 (213.3) 89.5 (185.7) 9.3 (0.14)Alprazolam (6–20) 3959 (60.5) 61.0 (130.7) 65.6 (125.1) �4.6 (0.27)Oxazepam (5–20) 15 600 (55.8) 79.3 (161.6) 78.9 (153.5) 0.4 (0.85)Bromazepam (8–19) 3877 (61.4) 53.5 (119.6) 50.3 (105.3) 3.2 (0.57)Lorazepam (10–20) 32 882 (57.6) 66.0 (141.8) 70.5 (141.3) �4.5 (0.004)Nitrazepam (20–40) 1458 (52.3) 82.3 (188.7) 82.4 (174.2) �0.1 (0.99)Clonazepam (20–80) 1800 (55.6) 72.6 (149.9) 73.4 (150.5) �0.8 (0.11)Clobazamb (10–46) 28 (35.7) 81.6 (70.6) 128.2 (251.4) �46.6 (0.57)Flurazepam (40–100) 5425 (44.2) 68.1 (164.6) 53.8 (117.6) 14.3 (<0.001)Chlordiazepoxide (10–100) 887 (47.3) 54.2 (120.9) 38.5 (75.4) 15.7 (0.02)Diazepam (20-100) 4908 (57.6) 40.6 (79.6) 42.5 (86.0) �1.9 (0.41)Clorazepatec (30-100) 177 (62.1) 36.7 (30.5) 36.0 (29.1) 0.7 (0.88)>1 type 1035 (51.2) 120.9 (216.0) 130.6 (225.9) �9.7 (0.47)

aIf a subject switches or adds another Benzodiazepine after the first prescription, this will count as a period of uninterrupted use as long as theprescriptions are filled without any time in between.bClobazam was included in the provincial formulary in 1993.cClorazepate has detected use only in 1990.



quite close in magnitude. The only exception was thatthe effect for anti-psychotics and the effects forclonazepam and clorazepate as types of Benzodiaze-pines first used were stronger in the analyses restrictedto new users in only 1990, but the estimates thatincluded users in both 1990 and 1991 were very similarto those obtained for all users.

To further investigate the association between olderage and increasing dose over time, we relied on theGEE approach to test the interaction between age atfirst Benzodiazepine prescription and time, in themodel that used subsequent values of the standardizeddose as the dependent variable. Table 5 shows theresults of the GEE analyses, separately for men andwomen. To facilitate the interpretation of results in thepresence of an interaction, age was transformed bysubtracting 65 years from each subject’s age, so that theregression coefficient for time represents its effect for a65-year-old subject. The effects of all variables areadjusted for the initial dose, since it is likely that thepattern of change in the dose over time depends on thestarting dose. For men, there are no statisticallysignificant time-by-age interactions (p¼ 0.39). Themodel without interaction indicates that men have, onaverage, a statistically significant trend toward increas-ing dose over time (p< 0.0001) and the non-signifi-cance of this interaction suggests that this trend iscommon to all elderly men, regardless of their age.

A different pattern of results is observed amongwomen. For 65-year-old women, there is a statisticallysignificant, albeit weak (p¼ 0.04, Table 5) tendencyfor dose to decrease with subsequent periods of use.However, a very significant positive interaction betweentime and age (p< 0.001) indicates that this tendencyinverts with increasing age. For women aged 72 years ormore, the dose will, on average, increase over time(Table 5). Figure 1 facilitates the interpretation of thetime-by-age interaction for women. The three lines in

Table 4. Results of multiple logistic regression with stepwise selection of the correlates of increasing standardized dose levels forsubsequent time periods*

Variable Odds ratio (OR, p-value) 95% Confidence intervals (CI)

Patient characteristicsAge at first Benzodiazepine prescription 1.02 (<0.001) 1.01–1.03Men compared to women 1.17 (>0.001) 1.08–1.25

First type of Benzodiazepine used (elimination half-life)a

Lorazepam (10–20 hr) 1.00 ReferenceTriazolam (1.5–5.5 hr) 0.88 (0.32) 0.68–1.13Temazepam (8–24 hr) 0.89 (0.26) 0.73–1.09Nitrazepam (20–40 hr) 0.79 (0.17) 0.57–1.10Alprazolam (6–20 hr) 1.33 (<0.001) 1.13–1.56Oxazepam (5–20 hr) 1.43 (<0.001) 1.31–1.57Bromazepam (8–19 hr) 1.19 (0.03) 1.01–1.39Clonazepam (20–80 hr) 2.13 (<0.001) 1.76–2.57Flurazepam (40–100 hr) 0.84 (0.05) 0.71–1.00Chlordiazepoxide (10–100 hr) 0.92 (0.68) 0.62–1.37Diazepam (20–100 hr) 0.76 (0.002) 0.64–0.91Clorazepate (30–100 hr) 2.05 (0.03) 1.08–3.88

1989 Medication useOther psychotropic medications 1.14 (0.02) 1.02–1.27Medications that affect motor stability 0.91 (0.008) 0.84–0.97

*Increasing dose defined as a Spearman’s correlation coefficient� 0.87 between standardized dose and subsequent time periods.aClobazam had too few cases of incident use to estimate a parameter.Cardiac drugs, anti-hypertensive agents, vasodilating agents, opioid agonists, opioid mixed partial agonists/antagonists and non-thiazidediuretics.

Table 5. Results of generalized estimating equations (GEE)analyses of the effect of interaction between age and subsequentperiods of Benzodiazepine use on standardized dose levels in menand women.

Variable Parameterestimate

p-value

MenStandardized initial dose 0.5505 <0.0001Log time 0.0101 <0.0001Transformed age �0.0036 <0.0001

WomenStandardized initial dose 0.5394 <0.001Log time �0.0083 0.04Transformed age �0.0030 <0.001Time age interaction 0.0012 <0.001

Sixty five was subtracted from subject’s age at first Benzodiazepineprescription, so that the regression coefficient represents the effect fora 65-year-old subject.



the figure show how average standardized dose changeswith subsequent periods of use for women agedrespectively, 65, 75 and 85 at the time of their firstBenzodiazepine prescription. It shows a weak tendencyfor the dose to decrease for 65-year-old women and toincrease for 75-year-old women. In contrast, theincreasing trend is much more marked for 85-year-oldwomen. Thus, among elderly female Benzodiazepineusers the risk of increasing dose over time increaseswith older age. The interaction also indicates that theimpact of age on dose changes with subsequent periodsof use. As shown in Figure 1, in early periods, olderwomen have, on average, lower doses but withincreasing time they will end up with higher doses thanyounger women who started with the same initial dose.Overall, these results suggest that there is a subgroup ofolder women who are exposed to Benzodiazepines for along-period of time and have a tendency to increasetheir doses with increasing duration of use.

Switching or adding Benzodiazepines

Among new users, 28.8% switched at least once fromthe initial type of Benzodiazepine to another productor added a different Benzodiazepine to the current

prescription. Of these subjects, 71.5% switched Ben-zodiazepines and did not add an additional prescrip-tion. The same proportion of men and womenswitched Benzodiazepines.

Among subjects who switched at least once, theaverage number of switches was 1.9 (SD¼ 1.7) with amedian of 1 (range 1–26). There was an average of 1.0switches per person-year of observation since the firstprescription (SD¼ 1.9) and this distribution did notdepend on the Benzodiazepine used in the firstprescription. Regardless of the initial prescription,the first switches were much more frequently tolorazepam (33.4%) than to any other Benzodiazepine.The next most popular drug for the first switch wasoxazepam (17.6%). In order to ensure that these highproportions did not simply reflect higher market shareof these two products, we also estimated, separately foreach Benzodiazepine, what proportion of the first-timeusers of that given product were subjects who hadstarted on another Benzodiazepine and switched to theproduct of interest. This proportion was the highest forlorazepam (21.6%) and oxazepam (19.7%). Theproportion of switchers among first users of all otherBenzodiazepines was much lower, ranging from 6.3%for nitrazepam to 15.3% for bromazepam.

Figure 1. Predicted increase in dose for elderly women for three age categories, with an initial standardized dose of 0.5



Subjects who added an additional Benzodiazepine(n¼ 6424, 8.2%) did so an average of 1.3 times(SD¼ 0.80) during the study period with a medianvalue of 1 (range 1–14). Lorazepam was by far themost frequently added drug (41.6% of first additions)with flurazepam (20.2%) and diazepam (8.5%) beingthe only other relatively popular choices. Among thesesubjects, 82.5% added another Benzodiazepine onlyonce, 10.2% twice and 7.3% three or more times.

When relevant data on consecutive or simultaneoususe of different Benzodiazepines were combined, 4%of the subjects had both an average duration ofuninterrupted Benzodiazepine exposure greater than30 days and an average standardized dose greater than1. Among subjects exceeding 30 days average durationof use, 7.0% had a strong trend for increasing dose overtime as indicated by a strong positive correlationbetween time and dose, compared to only 1.5% ofshort-term users (average duration of use less than 30days) (p< 0.001). Almost twice as many subjects whoexceeded 30 days of use switched drugs at least oncecompared to short-term users (17.5% vs 10.0%,p< 0.001).

DISCUSSION

We analyzed the longitudinal patterns of Benzodiaze-pine use in the elderly population of Quebec residentsfollowed between 1990 and 1994. The mean dose cor-responded to about half of the recommended adultdaily dose, which was equivalent to the dose recom-mended for the elderly13with a small proportion ofthe subjects exceeding the recommended adult dailydose and thereby doubling the dose recommendedfor the elderly. On the other hand, almost half of thenew users exceeded the recommended maximum of30 days for duration of uninterrupted use.

When the average duration for the first period ofuninterrupted use was examined by the calendar year inwhich the first prescription was filled, we found a meandecrease of almost 2 weeks between 1990 and 1993.The decrease may have reflected an increasingawareness of the problems associated with long-termBenzodiazepine use in the elderly.9,38 Despite thisdecrease, the average duration for the first period of usestill exceeded 60 days in 1993.

Our findings regarding the patterns of use raiseimportant questions about the extent that physiciansfollow the clinical guidelines and whether guidelinesthat attempt to define best practice in an adultpopulation are truly applicable for geriatricpatients.13,39–41 These results indicate that the use ofBenzodiazepines is in contradiction to the Compen-

dium of Pharmaceuticals and Specialties31 productmonographs; however there is a need for research intovalid off-label uses and for differing durations accord-ing to therapeutic indications.39 The restriction of 30days for the maximum recommended duration of use isone example where the guidelines may not beuniversally valid since elderly patients being treatedfor chronic anxiety may require long-term treat-ment.13,32,39,40 Using only administrative healthrecords, we did not have enough information availableto estimate the proportion of patients with specificclinical indications among those exceeding recom-mended duration of use.

Chronic anxiety as well as chronic insomnia oftenaccompanies the aging process.41–43 Recent studiesestimate that the prevalence of anxiety disorders in theelderly population (10.2%) is similar to or higher thanthat in the younger adult population (8.7%).44,45 Non-medical treatment alternatives are available butcomparisons between the therapeutic efficacy of thesetreatments and Benzodiazepines yield inconsistentresults.9,32,38,46–49 However, not all these alternativemethods are viable for the elderly and clinicians needevidence that use over 30 days is harmful before beingdeprived of a useful tool.39

One of our more interesting findings is related to thepattern of increasing Benzodiazepine dosage overtime for certain patients. Since these analyses wererestricted to subjects with extensive Benzodiazepineexposure of at least three periods of distinct use, it wasunlikely that actual Benzodiazepine use in thosesubjects was markedly overestimated due to limita-tions of database information. A patient who was achronic user, that is filled subsequent prescriptions,was more likely to be using the Benzodiazepine daily atthe prescribed dosage. Although elderly patients seemto develop a tolerance to the unwanted effects ofBenzodiazepines, such as psychomotor impairment,there is no conclusive evidence about whether theydevelop a similar tolerance to the therapeutic action ofthe drug, which would require an escalation in dose toachieve the same effect.13,38,50,51 We were able to lookat Benzodiazepine use over a fairly long period andacross all available products and found that for women,older age is a predictor of the tendency to increase dose.This suggests that older women might be moresusceptible to tolerance or may have more progressiveillnesses, such as psychiatric disease, that wouldrequire increasing doses to maintain therapeutic effect.We were not able to assess psychosocial variablesusing a database and psychiatric diseases are oftenunder-diagnosed in administrative data, so it is possiblethat older age and female gender may act in part as



markers for these variables.52 This is supported by ourfindings that use of alprazolam and clonazepam as firstprescriptions are associated with the higher risk ofincreasing dose over time. These medications are oftenfavored by psychiatrists for first-line treatment of moreserious indications such as severe anxiety or panicdisorders.13,53,54 With these illnesses, that occur morefrequently in older women compared to men,63 there isa tendency for the symptoms to get worse over time. Inthis case, a higher dose would be administeredappropriately to treat the progressively worseningillness.55

Benzodiazepines appeared to be misused in a smallproportion of subjects. These patients not onlyexceeded both the recommended duration of use andthe recommended adult daily doses, but were morelikely to be using at least two Benzodiazepines at thesame time. Although we estimated that almost 10% ofelderly patients filled at least two Benzodiazepineprescriptions simultaneously, most of these subjectshad only one period of overlap between their prescrip-tions. Given that almost a third of the study cohortswitched from one type of Benzodiazepine to anotherat least once, it was likely that elderly patients withapparent overlap between prescriptions for twodifferent Benzodiazepines actually switched to anothermedication due to uncomfortable side-effects or a lackof therapeutic effect of the original medication. Thepopularity of prescribing lorazepam in our cohort andthe number of subjects who were switched to thismedication, support this conjecture. Our results alsoindicate that while lorazepam is the most popularchoice for first users and switchers, its popularity as thesecond line treatment cannot be simply explained by itslarge market share. Moreover, relative to its marketshare, oxazepam appears almost as popular aslorazepam as a choice for switching. The importantimplication of this finding is that the outcomes areequally affected by the fact that about one fifth of theusers of these two drugs are switchers who havetypically worse therapeutic responses and higher risksof adverse effects. If this fact is not accounted for in theanalyses, the comparisons of oxazepam and lorazepamwith other Benzodiazepines may be biased againstthese two drugs.

The phenomenon of drug discontinuation andmedication switching in the elderly is documentedwith other types of medication.29,56–58 However, usingdatabase records, we had no way of assessing whether apatient stopped taking the original prescription beforestarting a second prescription and, therefore actuallyswitched medications instead of adding an additionalprescription. Despite this limitation, our finding that

0.5% of subjects had periods of use where threeBenzodiazepine prescriptions were filled simulta-neously, provided evidence for misuse of Benzodiaze-pines in a small proportion of elderly. We are unable toassess whether this misuse is an actual abuse ofBenzodiazepines due to factors such as physiologicaldependence or whether it reflects a lack of education onthe part of the patient. Research by Tamblyn et al. oninappropriate prescribing showed that an increase inthe number of prescribing physicians was associatedwith an increase in the risk of multiple Benzodiazepineprescriptions.59 Elderly patients may be unaware thattheir ‘sleeping pill’ and their ‘anxiety pill’ are bothBenzodiazepines that have additive effects, particu-larly if the prescriptions are received from differentphysicians and/or different pharmacies.59,60

Our analyses of the predictors of increasing doseaccounted for the number of periods of Benzodiaze-pine use but not for the time elapsed from the firstprescription. While it is possible that differentcharacteristics predict a dose increase over 1 year thanover 5 years, it is unlikely that the same number ofperiods would span 1 year for some subjects and 5 yearsfor another subject. This would require the lattersubject to have either five times longer averageduration of each period of uninterrupted use or fivetimes longer average interruption between conse-cutive periods, both of which are quite unlikely giventhe rather restricted between-subject variations inthese parameters. While in principle, the issue couldbe further investigated by including in the GEE modelan additional time-dependent covariate representingactual time (e.g. in months) elapsed from the firstBenzodiazepine prescription, such a covariate wouldbe near-collinear with the variable of primary interestrepresenting rank order of consecutive use. A moreappropriate, though more complex modeling strategycould involve two other time-dependent covariates,representing mean duration of past periods of use andnon-use. Further research could investigate such anapproach and its potential to offer additional insights.

One of the main limitations of our database studywas that we were not able to verify actual Benzodia-zepine consumption and had to use the informationavailable on the Benzodiazepine prescriptions as proxymeasures for duration of exposure and actual dose. It isquite likely that we overestimated Benzodiazepine usefor subjects who were not filling consecutive Benzo-diazepine prescriptions since these prescriptions areoften given pro re nata (take as needed) andapproximately 10% of elderly report taking a Benzo-diazepine at a lower dose than prescribed.29,61 Inparticular, the average daily doses may have been



overestimated for elderly patients who filled only oneprescription (41%) or those who had long interruptionsbetween prescriptions. However, such an overestima-tion would have been less likely to occur with patientswho regularly filled consecutive prescriptions, so thebias would be minimized for estimates of the daily doseprescribed on subsequent prescriptions and thuschanges over time in current dose, the number ofperiods of use and switching patterns. Thus, despite thelimitations of our database, our prospective studydesign allowed us to accurately describe complex,longitudinal patterns of use of individual Benzodiaze-pines for a large cohort of elderly subjects.62 Theseaspects of longitudinal patterns of Benzodiazepine usemay be important in evaluating the risk of injuryassociated with these medications though furtherresearch is necessary to assess such putative relation-ships. The methods we proposed may be also useful todescribe and analyze the patterns of use of differentmedications.

We have demonstrated that a relatively smallproportion of elderly Benzodiazepine users showpatterns of use that are inconsistent with currentguidelines. However, further research is needed toinvestigate more closely which indications are asso-ciated with long-term use as well as increasing or highdoses. Since long-term use appears to be relativelycommon, studies are needed to investigate its impact,in terms of both therapeutic and adverse effects, inorder to provide clinicians with the necessary informa-tion to balance benefit with harm for their elderlypatients. The methods we used to characterize differentaspects of these patterns could be useful for evaluatingthis evidence, particularly in terms of the risk of injuryassociated with these medications. The prolongedduration of use raises the possibility that cumulative

measures of exposure may better capture the impact ofBenzodiazepines than simpler measures such ascurrent use, especially among older women.

ACKNOWLEDGEMENTS

The collection of data for this study was fundedby National Health Research and DevelopmentProgram (R.T.) and the analyses were supportedby a grant from the Reseau FRSQ sur l’utilisationdes medicaments and the Natural Sciences andEngineering Research Council of Canada awardedto M. Abrahamowicz. G. Bartlett was supported bya Doctoral Award from the Canadian Institutes forHealth Research (CIHR).

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KEY POINTS

� Average duration of new period of Benzodiaze-pine use exceeds 2.5 months.

� 10% of elderly are exceeding the recommendedadult dose for Benzodiazepines.

� Lorazepam was by far the most popular choicefor new users and switchers.

� Elderly women showed a trend for increasingdose over subsequent periods of use; riskincreased by 10% for an increase in age of 5years at date of first prescriptions (OR: 1.10).

� Elderly men, regardless of age, showed a signi-ficant increase in dose with time (p< 0.0001).



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longitudinal patterns of new benzodiazepine use in the elderly

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