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Predictors of chronic benzodiazepine use in a health maintenance organization sample
J Clin Epidemiol Vol. 49, No. 9, pp. 1067-1073, Copyright 0 1996 Elsevier Science Inc.
1996
0895-4356/96/$15.00 PII SO895-4356(96)00139-4 ELSEVIER
PHARMACOEPIDEMIOLOGY
REPORT
Predictors of Chronic Benzodiazepine Use in a Health Maintenance Organization Sample William
Gregory E. Simon, Michael VonKorff, Barlow, Chester Pabiniak, Edward Wagner CENTER
GROUP
HEALTH
COOPERATIVE
FOR
OF PUGET
HEALTH SOUND,
STUDIES, SEATTLE,
WASHINGTON,
UNITED
STATES
ABSTRACT. While expert recommendations caution against long-term benzodiazepine use in the elderly, survey data suggest increasing benzodiazepine use with age. Computerized pharmacy records of staff-model HMO were used to examine benzodiazepine prescribing. Six-month prevalence of benzodiazepine use (2.8%) and prevalence of continued use (0.7?’ o ) were lower than earlier reports. Prevalence was higher in women and increased steadily with age. Among 7012 patients beginning benzodiazepine treatment, duration of use increased with patient age, prescription by a psychiatrist (vs. primary care or medical/surgical specialist), use of higher-potency drugs (lorazepam, and alprazolem, clonazepam) and larger number of pills in the initial prescription. Individual physicians varied significantly in drug choice, initial prescription size, and likelihood of chronic use. Among 200 patients treated in primary care, the physician-recorded indication for prescription was anxiety or depression in 27%, insomnia in 20%, and pain symptoms in 38%. These findings indicate a gap between benzodiazepine efficacy research and current clinical practice. J CLIN EPIDEMIOL 49;9:1067-1073, 1996. KEY
WORDS.
Benzodiazepines,
epidemiology,
anxiety,
Indications for benzodiazepine use have been a source of controversy for more than 20 years. When first introduced, benzodiazepines were clearly a safer alternative to earlier anxiolytics and hypnotics. Benzodiazepines steadily replaced barbiturates in the drug treatment of sleep disturbance [I]. During the 1970s and 1980s however, both the general public (2,3] and the medical community [4] expressed increasing concern about the risks of chronic use and dependence. More recent prescribing data suggest significant decreases in the prevalence of benzodiazepine use during the 1980s [5]. Current prescribing guidelines typically endorse benzodiazepine treatment of specific anxiety disorders (such as panic disorder or agoraphobia) but caution against long-term use by the elderly or those with primary insomnia (6-101. Such cautions are based on epidemiological data demonstrating increased rates of accidents, falls, and fractures among benzodiazepine users [l l-151 as well as evidence that therapeutic doses of benzodiazepines can impair cognitive function in the elderly [16,17]. Community surveys, however, suggest that current practice differs considerably from expert recommendations. A 1979 survey reported by Mellinger and colleagues [18,19] found that approximately 2% of U.S. adults reported chronic, regular use of anxiolytic or sedative/ hypnotic medication. Swartz et al. [20] found that approximately 10% of responents in a 1983 North Carolina community survey (the Piedmont site of the Epidemiologic Catchment Area survey) reported some use of benzodiazepines during the prior year. Using data from the 1987 National Medical Expenditure Survey, Olfson [5] found that 6.2% of community residents reported some benzodiazepine use over a 12-month period. In that sample, approximately 10% of benzodiazepine users reported 12 months of continuous use. In all three of these U.S. community surveys, benzodiazepine use inAddress reprint requests to: Gregory Simon, Center Minor Avenue, Seattle, Washington 98101-1448. Accepted for publication on 7 February 1996.
for Health
Studies, 1730
insomnia,
anxiolytics,
hypnotics
creased dramatically with age. Other community and primary care surveys in Ireland [21], New Zealand [22], Sweden [23,24], Brazil [25], and the United Kingdom [26] found similar overall rates of benzodiazepine use and a similar increase in prevalence with age. In these community samples, many benzodiazepine users report chronic difficulties with insomnia or generalized anxiety, but few appear to suffer from well-defined anxiety disorders [20,21]. While community and patient surveys are well suited to study of individual factors associated with benzodiazepine use, they have important limitations in evaluation of benzodiazepine prescribing. First, cross-sectional surveys are limited in assessment of longitudinal drug use. Second, survey data rely on patient recall of drug consumption. Finally, community surveys usually lack physician-level data on prescribing practices or indication for prescription. Analyses of population-based prescription data can address some of these limitations and contribute to the understanding of current practice. This article uses computerized pharmacy and outpatient visit diagnosis data from a large staff-model health maintenance organization (HMO) to examine patterns of benzodiazepine prescribing. These data were used to address the following questions: What is the period prevalence of short-term and longer-term benzodiazepine use? Among patients receiving a new benzodiazepine prescription, what are the patient characteristics and prescribing patterns associated with continued use?
METHODS
Study Setting Group Health Cooperative of Puget Sound (GHC) is a large staffmodel HMO serving approximately 380,000 residents (including approximately 280,000 adults) of western Washington state. GHC provides comprehensive care on a capitated basis with members typically receiving GHC health care coverage through employer-subsidized plans. The GHC enrollment includes approximately 45,000
1068
G. E. Simon
TABLE 1. Demographic characteristics operative of Puget Sound members area and U.S. residents” GHC members
Characteristic Age
(%)
of Group compared
Health Cowith Seattle
Seattle area (%)
United States (%)
(years)
18-44 45-64 65+ Percent male Race Caucasian Black Asian/Pacific Other Years of education <12
12 13-15 16+ Annual income <$15,000
$15,000-25,000 $25,000-35,000 $35,000-50,000 >$50,000
61 26 13 45
61 26 13 49
49
91
90 4 4 2
83 12 2 3
ii
18 35 23 24
34 35 16 16
20 24 23 20 13
23 18 19 21 19
24 20 19 19 18
3 4 2 9 24
“GHC data based on a random sample of 1 ,133 adult members 1984. Seattle and US. data based on 1990 census.
57 27 16
surveyed
in
Medicare members and 22,000 members covered by Medicaid or by Washington’s Basic Health Plan (a state program for low-income residents). Table 1 compares the demographic characteristics of GHC members surveyed in 1984 with those of Seattle area residents and the U.S. population. The proportion of GHC members covered by programs for low-income residents (Medicaid and Basic Health Plan) has approximately doubled since the 1984 survey. GHC members are similar to Seattle area residents except for higher educational level and less representation of the high and low extremes of income. Approximately 360 GHC physicians (full-time and parttime) provide adult primary care with each full-time physician responsible for a defined panel of approximately 1600 patients. Over 95% of physicians providing primary care to adults are trained in family medicine, with most of the remainder trained in internal medicine. Specialty care is available on referral from approximately 400 medical and surgical specialists. Approximately 20 psychiatrists provide care for both self-referred and physician-referred patients. Over 90% of primary care physicians and specialists are certified by appropriate specialty boards. The GHC computerized information systems include data on all outpatient visits to GHC clinics and all outpatient prescriptions filled at GHC pharmacies. Prescription medicines (including benzodiazepines) are covered by all GHC health plans subject to copayments of up to $7 per prescription. Previous surveys of GHC memhers have found that over 95% of prescriptions are filled at GHC pharmacies [27].
et al.
These analyses used timing of prescription refills to estimate duration of daily drug use. For a sample of patients filling first benzodiazepine prescriptions, all prescription records (new prescription and refills) were organized chronologically. Data on quantity of medication dispensed and timing of refills were then used to computer an average rate of consumption for each prescription fill or refill (average use per day equals number of pills dispensed divided by number of days until next benzodiazepine refill). On the basis of these computed consumption rates, each patient was assigned an estimated duration of daily use equal to the time between his/her first benzodiazepine prescription and the date on which his/her rate of consumption fell below one pill per day. For patients who completely discontinued benzodiazepines during the follow-up period, no consumption rate could be computed for the final refill (i.e., no date of subsequent retill available). In these cases, estimated duration of daily use for the final refill was assumed to lie halfway between the minimum and maximum possible values. Varying this assumption had minimal effect on subsequent analyses. Data on duration of daily use were then used to establish an appropriate cut point for dehning continued daily use. Figure 1 displays the survival curve for daily use (defined above) following a first benzodiazepine prescription. On the basis of distribution, a cut point of 60 days was chosen to discriminate short-term or intermittent users from continued users. Varying this cut point between 45 and 90 days did influence the estimated likelihood of continuing daily use, but had no impact on the correlates or predictors of continued use. In summary, this algorithm used prescription refill records to identify patients using henzodiazepines for at least 60 days and refilling prescriptions frequently enough to indicate average consumption of at least one pill per day.
Cross-Sectional
Sample
Computerized pharmacy records were used to identify all GHC members 18 years of age and over receiving any benzodiazepine prescription (new prescription or refill) between January 1, 1992 and June 30, 1992. Data on prescription dates, number of doses dispensed, and patient age and sex were organized to examine prevalence of benzodiazepine use for specific age/sex groups. Criteria for continued daily
1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
Definition
of Continued
Daily
Use
Preliminary analyses of the GHC computerized pharmacy records were conducted to develop and test an algorithm identifiying continued daily benzodiazepine users from pharmacy refill records (algorithm available from the first author on request).
0
20
40
60 DAYS
FIGURE at rate patients
SINCE
80 INITIAL
100
120
140
160
180
PRESCRIPTION
1. Survival curve for continued benzodiazepine greater than one pill per day in cohort of 7012 receiving a new benzodiazepine prescription.
use HMO
Predictors
of Chronic
Benzodiazepine
Use in a Health
Maintenance
use (described above) were applied to determine which of these patients used benzodiazepines at a rate of at least one pill per day for 60 days or more with at least some portion of the 60-day interval falling within the prevalence period (January 1, 1992 to June 30, 1992). To assure complete availability of prescription records for the relevant period, only those continuously enrolled in GHC from November 1, 1991 to August 30, 1992 were included in these analyses. Denominators for prevalence rates include all GHC members satisfying the above-cited eligibility criteria regardless of benzodiazepine use. Cohort
Sample
Pharmacy records were used to identify all GHC members, age 18 years and over receiving new episodes of benzodiazepine use between January 1,1992 and June 30,1992. A new episode of use was defined by a prior interval of at least 90 days free of any benzodiazepine use (based on computerized pharmacy records). Patients joining GHC during the 90 days prior to the index prescription were excluded because prior use could not be assessed using GHC pharmacy records. Those leaving GHC during the 180 days following the index prescription were also excluded because duration of use could not be accurately asssessed. Records for subsequent benzodiazepine refills were analyzed (using the criteria described above) to identify those patients in the cohort developing a pattern of continued use (use for at least 60 days at a rate of at least one pill per day).
Statistical
Analysis
Univariate analyses (frequencies, means, chi-square, and analysis of variance) were performed with the SAS software package (SAS Institute, Research Triangle Park, NC). Multivariate modeling of the likelihood of continued use (using logistic regression) was performed with the EGRET software package (Statistics and Epidemiology Research Corporation, Seattle, WA). Th e extension of Fisher’s exact test to R X C tables (a valid test for sparse contingency tables) was performed using the StatXact software package (Cytel Corp., Cambridge, MA). RESULTS
Cross-Sectional
Prevalence
Of the approximately 280,000 adults enrolled during the study period, 240,946 were continuously enrolled from November 1, 1991 to June 30, 1992. Of that sample, 3.8% received at least one benzodiazepine prescription (fill or refill) during the 6-month prevalence period from January 1, 1992 to June 30, 1992. Approximately 25% of those patients (or 1% of adult GHC members) satisfied criteria for continued use (use of one pill per day for 60 days or more). Table 2 displays the prevalence of benzodiazepine use according to age and sex. Rates of use were higher among women than among men and increased steadily with age. Among members 65 years of age or more, approximately 2% of men and 3% of women were classified as continued users.
Longitudinal of Continued
Predictors Use (Cohort
Sample)
The procedures described above identified a cohort of 7012 GHC members receiving new benzodiazepine prescriptions between January 1, 1992 and June 30, 1992. Characteristics of patients initiating treatment are shown in the first column of Table 3.The sample was
Organization
1069
Sample
TABLE 2. Six-month anxiolytic and hypnotic erative of Puget Sound
prevalence rates for various levels of drug use among Group Health Coopmembers according to age and sex” Percent using benzodiazepines in a 6.month period Number population
Total Females (age, years) 18-44 45-64 65+ Males (age, years) 18-44 45-64 65+ “Percentages sex group.
represent
in
240,946 132,239 69,863 37,140 25,236 108,707 56,222 34,727 17,758 prevalence
among
Any
use 3.81 4.69 2.72 5.48 9.01 2.74 1.72 2.93 5.57
all GHC
members
Daily use for 60 days 1.04 1.24 0.58 1.39 2.85 0.81 0.21 0.85 1.99 for each age-
TABLE 3. Odds ratios for continuing daily benzodiazepine use lasting more than 60 days among cohort of 7012 patients receiving an initial benzodiazepine prescription” Percentage (number) of cases
Patient characteristic Sex Male Female Age (years) 18-44 45-64 65+ Specialty Primary care Medical specialty Psychiatry Drug prescribed Diazepam Lorazepam Alprazolam Temazepam Triazolam Flurazepam Chlordiazepoxide Clonazepam Oxazepam Clorazepate Size of initial prescription l-10 Pills 1 l-20 Pills 21-30 Pills >30 Pills “Displayed
Odds ratio for daily use >60 days
95% confidence interval
31.9 68.1
(2236) (4776)
1 0.84
0.71-0.99
37.2 33.7 29.1
(2607) (2364) (2041)
1 1.15 1.89
0.94-1.41 1.55-2.31
79.3 (5563) 17.1 (1197) 3.6 (252)
1 1.24 2.11
1.00-1.57 1.52-2.53
29.9 21.3 14.6 13.5 8.6 6.0 2.9 1.5 1.2 0.6
(2096) (1492) (1024) (945) (601) (423) (205) (1.03) (81) (42)
1 2.92 2.39 1.59 1.64 1.04 1.46 6.96 2.50 2.13
2.29-3.72 1.82-3.12 1.18-2.16 1.17-2.30 0.68-1.61 0.88-2.42 4.33-11.17 1.31-4.76 0.86-5.31
28.9 37.5 26.3 7.3
(2026) (2633) (1844) (509)
1 1.40 2.44 7.00
1.09-1.79 1.91-3.12 5.27-9.29
odds ratios reflect adjustment
fc>r all covariates
listed here.
G. E. Simon predominantly female, with older patients somewhat overrepresented in proportion to the GHC population. Nearly 80% of initial benzodiazepine prescriptions were written by primary care physicans with fewer than 4% written by psychiatrists. Three-fourths of initial prescriptions were for fewer than 20 pills, with only 7.3% of patients receiving more than 30 pills. The algorithm to assess chronic use described above identified 10.9% (n = 767) of those initiating benzodiazepine treatment as continuing at a rate of one pill per day for at least 60 days. A logistic regression model was used to examine various predictors of continued use. Results of the full model are displayed in the second and third columns of Table 3. This model produced a good fit to the data (residual deviance 4299, with 6994 degrees of freedeom), and regression diagnostics [28] did not reveal any observations with undue influence on estimated odds ratios. Likelihood of chronic use was weakly associated with male sex, but strongly associated with increasing age. Patients 65 years of age or over were nearly twice as likely to continue regular use as were those aged 18 to 44 years. Compared with patients treated by primary care physicians, chronic use was slightly more common among those treated by medical specialists and twice as common among those treated by psychiatrists. Likelihood of chronic use varied significantly among different benzodiazepines. The pattern of variability suggested greater likelihood of continued use among patients prescribed high-potency drugs (lorazepam, alprazolam, triazolam, and clonazepam). In a separate logistic model, use of these four high-potency drugs was associated with a two-fold increase of chronic use when compared to all other drugs (odds ratio, 2.09; 95% confidence interval, 1.78-2.47). Restricting the analysis to prescriptions written by primary care physicians had no appreciable impact on differences among drugs in likelihood of proceeding to continued use. Chronicity increased progressively with the number of pills dispensed at the initial prescription. Restriction of the sample to primary care prescriptions did not affect the relationship between prescription size and probability of continued use. To assure that the relationship between initial prescription size and continued use was not an artifact of the algorithm used, a secondardy analysis examined the likelihood of refilling an initial benzodiazepine prescription according to initial prescription size. Likelihood of refill increased from 11.9% among initial prescriptions of fewer than 10 pills to 44.20/ 0 among initial prescriptions of greater than 30 pills (Mantel-Haenszel chi-square for linear association = 295, df = 1, p < 0.0001). Examination of interrelationships among various independent variables revealed significant variation in prescribing patterns by patient age. The portion of patients receiving an initial prescription for more than 20 pills increased from 26.5% among those aged 1844 years to 34.7% among those aged 45-64 years to 41.2% among those aged 65 years and over (Mantel-Haenszel chi-square for linear association = 112.6, df = 1, p < 0.0001). Drug selection also varied significantly by patient age (chi-square = 256.92, df = 18, p < 0.0001) with older patients somewhat less likely to receive drugs typically prescribed for anxiety symptoms (diazepam, alprazolam) and somewhat more likely to receive drugs traditionally prescribed for insomnia (temazepam, flurazempam).
Variation
Among
Physicians
Because the relationship of chronicity to prescribing patterns (drug selection and prescription size) might reflect either baseline clinical differences among patients or a true influence of prescribing practice on chronicity of use, further analyses examined how prescribing pat-
et al.
terns and patients’ duration of use varied among individual physicians. These analyses were restricted to the group of primary care physicians writing at least 10 new benzodiazepine prescriptions for patients in the longitudinal sample (n = 200 physicians, n = 4998 patients). We first examined how duration of use varied among individual primary care physicians. The likelihood of continued benzodiazepine use (daily use for 60 days or more) showed significantly greater variability across physicians than expected by chance (extended Fisher’s exact test statistic = 252, df = 199, p = 0.0068. We next examined physician variability in the prescribing patterns associated with continued use. The analyses demonstrated greater than chance variability in both the mean number of pills dispensed at the initial prescription (F = 3.82, df = 199, 4798, p < 0.0001) and in the distribution of drugs prescribed (extended Fisher’s exact test statistic = 3757, df = 1791, p < 0.0001). Even when the sample was restricted to those physicians with at least 20 new prescriptions (n = 119) and to those patients (n = 3083) treated with the four most commonly prescribed drugs (diazempam, lorazepam, alprazolam, and temazepam) medication choice varied significantly among physicians (extended Fisher’s exact test statistic = 1645, df = 354, p < 0.0001). We next used a series of logistic regression models to examine how variation among physicians in these two prescribing practices (drug selection and initial prescription size) predicted patients’ duration of use. These analyses used logistic regression to predict likelihood of continued use at the patient level while incorporating physician-level indices of prescribing as either fixed or random effects. The first analysis confirmed the above-described finding of greater than expected variability among physicians in patients’ likelihood of proceeding to chronic use. In a logistic model containing patient age and gender (model l), addition of physician as a random effect made a significant contribution to the prediction of continued use (likelihood ratio statistic = 14.9, p < O.OOl), indicating significant variability in outcome among physicians after adjustment for patient age and sex. The second set of models examined how specific physician-level prescribing indices contributed to prediction of patientlevel likelihood of continued benzodiazepine use. For this analysis, physician-level indices were computed to reflect each physician’s average prescription size and each physician’s likelihood of prescribing drugs associated with chronic use. In a model containing patient age and sex, each of these indices made a significant positive contribution to prediction of chronicity (p < 0.001 by Wald test for both variables). Addition of physician as a random effect to this model made only a marginally significant additional contribution (likelihood ratio statistic = 2.37, p = 0.06). Comparison with model 1 described above indicates that most of the physician-level variability in outcomes can be explained by differences in physicians’ prescribing patterns (tendency to prescribe drugs associated with longerterm use or to prescribe a larger number of pills at the initial precription). Pharmacy data were linked to physician demographic data to examine the relationship of prescribing patterns to physician age. When physicians were categorized by age (age ~40 years, age 4049 years, age 50+ years), older physicians were somewhat less likely to prescribe small initial quantities, with the proportion of new prescriptions written for 10 or few pills declining from 27.5% among younger physicians to 16.8% among those 50 years of age or more (Mantel-Haenszel chi-square for linear association = 14.1, df = 1, p = 0.0002). Drug selection also differed significantly by age, with older physicians somewhat less likely to prescribe higher potency drugs (lorazepam, alprazolam, triazolam, and clonazepam). The por-
Predictors
TABLE patients
of Chronic
Benzodiazepine
Use
in a Health
4. Indication (from chart review) initiating benzodiazepine treatment
Number Total Anxiety/depression/ situational stress Insomnia Back/neck pain Headache or other pain No indication give
200 54
Maintenance
for primary
care
Percentage of aU new users
Percent likelihood of continued use
100 27
10.5 16.7
30 27 49
20 13.5 24.5
16.7 7.4 6.1
30
15
6.7
tion of newer prescriptions written for higher-potency drugs decreased from 53.3% among younger physicians to 46.5% among those 50 years of age or more (Mantel-Haenszel chi-square for linear association = 11.8, df = 1, p = 0.0006). Consequently, older physicians more often prescribed initial quantities of benzodiazepines associated with chronic use but were less likely to prescribe drugs associated with chronic use. Likelihood of chronic use was modestly related to prescriber age; the portion continuing to chronic use decreased from 13.2% among patients of younger physicians to approximately 10% among patients of physicians 40 years of age or more (Mantel-Haenszel chi-square for linear association = 6.6, df = 1, p = 0.01). While older physicians cared for older panels of patients, stratification for patient age did not signficantly affect the abovedescribed relationships between physician age and prescribing patterns.
indications
for Treatment
From the sample of primary care patients tilling new benzodiazepine prescriptions a random sample of 200 was selected and outpatient charts were reviewed to identify indication for prescription. The new benzodiazepine prescription followed a primary care visit for 123 patients and followed a telephone call for 70. No mention of the benzodiazepine prescription in the outpatient record could be located for seven patients. Results regarding indication are shown in Table 4. Psychological symptoms (including anxiety, depression, and situational stress) accounted for the largest group of patients (slightly over one-quarter of the total). Insomnia accounted for 20% of prescriptions and an additional 38% were intended for treatment of back pain, neck pain, headache, or other pain complaints. Psychological complaints and insomnia were associated with a higher likelihood of continued use (16.7%) while duration of use was lower than average for musculoskeletal and pain complaints (6.6%). This difference in likelihood of continued use was marginally significant (chi-square = 3.88, p = 0.05). Likelihood of a psychological symptom indication decreased from 36% among those less than 45 years of age to 19% among those 65 years of age or more (Mantel-Haenszel chisquare for linear association = 5.88, df = 1, p = 0.015).
DISCUSSION Cross-sectional pharmacy data from this staff-model HMO show a pattern of benzodiazepine use generally similar to that seen in community-based surveys. While the overall rate of use over a 6-month
Organization
Sample
1071
period (3.8%) and the prevalence of continued use (1%) are somewhat lower than those reported in earlier community surveys [5,18, 201, these data show the same pattern of increasing prevalence of use with age. The rate of longer-term use among the elderly is quite similar to the 2 to 4% prevalence seen in previous studies. These pharmacy-based data do give a more detailed view of benzodiazepine prescribing practices. Psychiatrists are responsible for fewer than 4% of initial benzodiazepine prescriptions for all patients and fewer than 2% among the elderly. Most initial prescriptions were for fewer than 20 pills, but initial prescription size was significantly larger in the elderly. Among primary care patients receiving new prescriptions for benzodiazepines, insomnia and pain complaints account for the majority of prescriptions, with fewer than 25% of prescriptions intended for the treatment of anxiety symptoms or disorders. Age was associated with both a higher risk of initiating benzodiazepine treatment and a higher risk of chronic use. This finding agrees with a number of earlier reports describing an increasing risk of chronic benzodiazepine use with age [18,21-23,291. The likelihood of chronic use among the elderly may reflect both age-related differences in both drug metabolism and more lenient physician attitudes about benzodiazepine use in the elderly. Reduced drug clearance among the elderly may increase the likelihood of physiological dependence developing during intermittent use. Alternatively, more lenient prescribing to older patients (larger initial prescriptions, more refills) may reflect primary care physicians’ view that older patients are less likely to “abuse” benzodiazepines or are less amenable to nonpharmacological interventions. These data also contribute to the picture of chronic benzodiazepine users. While psychiatric patients had a higher likelihood of long-term benzodiazepine use, primary care patients accounted for 75% of all patients in the cohort sample using benzodiazepines at least daily for 60 days. The typical chronic benzodiazepine user was an older female presenting for care of chronic medical conditions or nonspecific physical complaints. Among primary care patients, psychiatric symptoms were associated with longer duration of use, but the majority of chronic benzodiazepine users were taking benzodiazepine for less specific indications such as insomnia or pain complaints. These findings agree with previous community data suggesting a low prevalence of well-defined psychiatric disorders among older benzodiazepine users [20]. These results do suggest some unexpected hypotheses about physician prescribing practices associated with continued benzodiazepine use. Some of the prescribing factors associated with longer-term use may reflect the clinical characteristics of patients requiring longerterm treatment. For example, a longer duration of benzodiazepine use among patients treated by psychiatrists may not reflect more literal prescribing by pychiatrists as much as it indicates more severe anxiety disorders among psychiatric patients. Some of the abovedescribed findings, however, may identify prescribing patterns that contribute to longer-term use. Increasing size of the initial prescription and use of higher-potency benzodiazepines (lorazepam, alprazolam, clonazepam, and triazolam) were strongly associated with increasing duration of use. While these associations may also reflect clinical characteristics of patients likely to need chronic treatment (i.e., more severely or chronically ill patients receive larger initial prescriptions), individual physicians varied considerably in both drug choice and prescription size. At least some of this variability among physicians (especially variability in drug selection) is more likely to reflect variation in clinician practice than clinical differences among patients treated. The logistic regression analyses incor-
1072 porating physician-level variation and physician-level prescribing indices support this explanation. Variability among individual primary care physicians in likelihood of chronic use was significantly greater than predicted by chance. Much of this variability among physicians in duration of use appeared to be related to differences in drug selection and prescription size. The variability among drugs in likelihood of chronicity suggests the possibility that higher-potency drugs may produce greater dependence. This relationship appeared quite strong and physicianlevel analysis suggests that the higher chronicity rates for specific drugs do not simply reflect baseline clinical differences. Given the absence of corroborating evidence from clinical or preclinical studies, this finding must be interpreted cautiously. In a study of benzodiazepine withdrawal, Rickels and colleagues did report more prominent withdrawal symptoms among patients treated with short halflife benzodiazepines [30,3 11. While the pattern observed in this sample (chronicity related to potency) differs from that reported earlier (chronicity related to half-life), the disagreement between these two patterns depends on the high observed chronicity among the small number of patients prescribed clonazepam (a drug with long halflife and high potency). The strong relationship between prescription size and duration of use allows several possible explanations. This association may represent a direct causal effect: a larger initial supply of medication may increase the likelihood that dependence will develop. Alternatively, larger initial prescriptions may reflect the severity or chronicity of the symptoms for which the benzodiazepine was prescribed. Because individual physicians varied considerably in prescription size, prescription of a larger number of pills may also reflect physician attitudes related to granting future refills. While these observational data cannot establish a causal relationship between prescription size and chronic use, a causal relationship is certainly plausible. Medication use data alone are not sufficient to judge the appropriateness of benzodiazpine prescribing. Epidemiological data do demonstrate significant risks of chronic benzodiazepine use in the elderly, but large data sets lack the clinical detail necessary to evaluate benefit. Our demonstration of a significant rate of chronic benzodiazepine use in the elderly does not in itself demonstrate that the observed rate is too high. While crosssectional surveys [18,20] can evaluate the level of psychological distress or functional impairment in benzodiazepine users, they cannot evaluate whether benzodiazepine treatment has actually reduced distress or improvement function. Addressing that question will require longitudinal assessment following the initiation of benzodiazepine use. These findings do indicate that much of the available research on the efficacy of benzodiazepines is not relevant to community practice. Clinical anxiety research has focused on management of well-defined anxiety disorders among young and middle-aged psychiatric patients. These data and others suggest that most benzodiazepines are prescribed to older primary care patients who present with insomnia or nonspecific physical complaints. Few benzodiazepine users in community samples appear to meet criteria for well-defined anxiety disorders. Clinical insomnia research has typically focused on short-term efficacy as judged by polysomnographic measurement. While most research demonstrates fairly rapid accommodation to the therapeutic effects of hypnotic benzodiazepines, long-term hypnotic users typically report significant continued benefit [21,32]. Research focused on a broader range of patients and clinical conditions will be needed to evaluate the appropriateness of “real world” practice.
G. E. Simon Supported by NIMH Grant 5 1338, a grant from the Center for Disease to the University of Wathington’s Center on Health Promotion for Older and a grant from the Group Health Cooperative medical staff.
et al. Connol Adults,
References 1. Wysowski D, Baum C. Outpatient use of prescription sedative-hypnotic drugs in the United States, 1970 through 1990. Arch Intern Med 1991; 151: 1779-1883. 2. Mannheimer D, Davidson ST, Baiter MB. Popular attitudes and beliefs about tranquilizers. Am J Psychiatry 1973; 130: 1246-1258. 3. Clinthorne J, Cisin IH, Baiter MH, Mellinger GD, Uhlenhuth EH. Changes in popular attitudes and beliefs about tranquilizers. Arch Gen Psychiatry 1986; 43: 527-532. 4. Lader M. Dependence on benzodiazepines. J Clin Psychiatry 1983; 44: 121-127. 5. Olfson M, Pincus HA. Use of benzodiazepines in the community. Arch Int Med 1994; 154: 1235-1240. 6. Amencan Psychiatric Association Task Force on Benzodiazepine Toxicity. Benzodiazepine dependence, toxicity, and abuse. American Psychiatric Press, Washington, D.C., 1990. 7. Gillin J, Byerly W. The diagnosis and management of insomnia. N Engl J Med 1990; 322: 239-248. 8. Prim P, Vitiello M, Raskind M, Thorpy M. Geriatrics: Sleep disorders and aging. N Engl J Med 1990; 323: 520-526. 9. Maletta G, Mattox KM, Dyksen M. Guidelines for prescribing psychoactive drugs in the elderly. Geriatrics 1991; 46: 40-47. 10. NIH Consensus Development Conference. Drugs and insomnia: The use of medicatmns to promote sleep. JAMA 1984; 251: 2410-2414. 11. Oster G, Russell MW, Huse DM, Adams SF, Imbimbo J. Accidentand injury-related health-care utilization among benzodiazepine users and nonusers. J Clin Psychiatry 1987; 48(Suppl.): 17-21. 12. Ray W, Griffin M, Schaffner W, Baugh D, Melton L. Psychotropic drug use and the risk of hip fracture. N Engl J Med 1987; 316: 262-369. 13. Sorock G, Shimkin E. Benzodiazepine sedatives and the risk of falling in a community-dwelling elderly cohort. Arch Intern Med 1988; 148: 2441-2444. 14. Tinetti M, Speechley M, Ginter S. Risk factors for falls among elderly persons living in the community. N Engl J Med 1988; 319: 1701-1707. MD. Psychoactive drugs and the risk of injun15. Ray W, Fought R, Decker ous motor vehicle crashes in elderly drivers. Am J Epidemiol 1992; 136: 873-883. 16. Golombok S, Moodley P, Lader M. Cognitive impairment in long-term benzodiazepine users. Psycho1 Med 1988; 18: 365-374. 17. Nikaido A, Ellinwood E, Heatherly D, Gupta S. Age-related increase in CNS sensitivity to benzodiazepines as assessed by task difficulty. Psychopharmacology 1900; 100: 90-97. 18. Mellinger G, Baiter M, Uhlenhuth E. Prevalence and correlates of the long-term regular use of anxiolytic. JAMA 1984; 251: 375-379. 19. Mellinger G, Baiter M, Uhlenhuth E. Insomnia and its treatment. Arch Gen Psychiatry 1985; 42: 225-232. 20. Swartz M, Landerman R, George L, Melville M, Blazer D, Smith K. Benzodiazepine anti-anxiety agents: Prevalence and correlates of use in a southern community. Am J Public Health 1991; 81: 592-596. 21. Nolan L, O’Malley K. Patients, prescribing, and benzodiazepines. Eur J Clin Pharmacol 1988; 35: 225-229. 22. North D, McAvoy B, Powell A. Benzodiazepine use in general practice-is it a problem? NZ Med J 1992; 105: 287-289. 23. lsacson D, Carsjo K, Bergman U, Blackhurn JL. Long-term use of henzodiazepines in a Swedish community: An eight-year follow-up. J Clin Epidemiol 1992; 45: 429-436. G, Romelsjo A, Leifman H, Leifman A, Karlsson G. Sedatives 24. Blenrow and hypnotics in Stockholm: Social factors and kmds of use. Am J Public Health 1994; 84: 242-246. 25. Mari J, Almeida-Filho N, Coutinho E, Andreoli SB, Miranda CT, Streiner D. The epidemiology of psychotropic drug use in the city of Sao Pa&. Psycho1 Med 1993; 23: 467-474. 26. Morgan D, Dallossso H, Ebrahim S, Arie T, Fentem PH. Prevalence, frequency, and duration of hypnotic drug use among the elderly living at home. Br Med J Clin Res Ed 1988; 296: 601-602. K, Stergachis A, VonKorff M. Group Health Cooperative of 27. Saunders Puget Sound. In: Pharmacoepldemiology (Strom B, ed.). John Wiley & Sons, New York; 1994. 28. Pregihon D. Resistant fits for some commonly used logistic models with medical applications. Biometrics 1982; 38: 485-498.
Predictors 29. 30.
of Chronic
Benzodiazepine
Use in a Health
Maintenance
Lyndon R, Russell J. Benzodiazepme use in a rural general practice population. Aust NZ J Psychiatry 1988; 22: 293-298. Rick& K, Schweizer E, Case WC, Greenblatt DJ. Long-term therapeutic use of benzodiazepines. 1. Effects of abrupt discontinuation. Arch Gen Psychiatry 1990; 47: 899-907.
Organization 31.
32.
Sample
1073
Schweizer E, Rickels K, Case WC, Grenblatt DJ. Long-term therapeutic use of benzodiazepines. 11. Effects of gradual taper. Arch Gen Psychiatry 1990; 47: 908-915. Pinsker H, Suljaga-Petchel K. Use of benzodiazepines in primary-care geriatric patients. J Am Geriatr Sot 1984; 32: 595-597.
1996
0895-4356/96/$15.00 PII SO895-4356(96)00139-4 ELSEVIER
PHARMACOEPIDEMIOLOGY
REPORT
Predictors of Chronic Benzodiazepine Use in a Health Maintenance Organization Sample William
Gregory E. Simon, Michael VonKorff, Barlow, Chester Pabiniak, Edward Wagner CENTER
GROUP
HEALTH
COOPERATIVE
FOR
OF PUGET
HEALTH SOUND,
STUDIES, SEATTLE,
WASHINGTON,
UNITED
STATES
ABSTRACT. While expert recommendations caution against long-term benzodiazepine use in the elderly, survey data suggest increasing benzodiazepine use with age. Computerized pharmacy records of staff-model HMO were used to examine benzodiazepine prescribing. Six-month prevalence of benzodiazepine use (2.8%) and prevalence of continued use (0.7?’ o ) were lower than earlier reports. Prevalence was higher in women and increased steadily with age. Among 7012 patients beginning benzodiazepine treatment, duration of use increased with patient age, prescription by a psychiatrist (vs. primary care or medical/surgical specialist), use of higher-potency drugs (lorazepam, and alprazolem, clonazepam) and larger number of pills in the initial prescription. Individual physicians varied significantly in drug choice, initial prescription size, and likelihood of chronic use. Among 200 patients treated in primary care, the physician-recorded indication for prescription was anxiety or depression in 27%, insomnia in 20%, and pain symptoms in 38%. These findings indicate a gap between benzodiazepine efficacy research and current clinical practice. J CLIN EPIDEMIOL 49;9:1067-1073, 1996. KEY
WORDS.
Benzodiazepines,
epidemiology,
anxiety,
Indications for benzodiazepine use have been a source of controversy for more than 20 years. When first introduced, benzodiazepines were clearly a safer alternative to earlier anxiolytics and hypnotics. Benzodiazepines steadily replaced barbiturates in the drug treatment of sleep disturbance [I]. During the 1970s and 1980s however, both the general public (2,3] and the medical community [4] expressed increasing concern about the risks of chronic use and dependence. More recent prescribing data suggest significant decreases in the prevalence of benzodiazepine use during the 1980s [5]. Current prescribing guidelines typically endorse benzodiazepine treatment of specific anxiety disorders (such as panic disorder or agoraphobia) but caution against long-term use by the elderly or those with primary insomnia (6-101. Such cautions are based on epidemiological data demonstrating increased rates of accidents, falls, and fractures among benzodiazepine users [l l-151 as well as evidence that therapeutic doses of benzodiazepines can impair cognitive function in the elderly [16,17]. Community surveys, however, suggest that current practice differs considerably from expert recommendations. A 1979 survey reported by Mellinger and colleagues [18,19] found that approximately 2% of U.S. adults reported chronic, regular use of anxiolytic or sedative/ hypnotic medication. Swartz et al. [20] found that approximately 10% of responents in a 1983 North Carolina community survey (the Piedmont site of the Epidemiologic Catchment Area survey) reported some use of benzodiazepines during the prior year. Using data from the 1987 National Medical Expenditure Survey, Olfson [5] found that 6.2% of community residents reported some benzodiazepine use over a 12-month period. In that sample, approximately 10% of benzodiazepine users reported 12 months of continuous use. In all three of these U.S. community surveys, benzodiazepine use inAddress reprint requests to: Gregory Simon, Center Minor Avenue, Seattle, Washington 98101-1448. Accepted for publication on 7 February 1996.
for Health
Studies, 1730
insomnia,
anxiolytics,
hypnotics
creased dramatically with age. Other community and primary care surveys in Ireland [21], New Zealand [22], Sweden [23,24], Brazil [25], and the United Kingdom [26] found similar overall rates of benzodiazepine use and a similar increase in prevalence with age. In these community samples, many benzodiazepine users report chronic difficulties with insomnia or generalized anxiety, but few appear to suffer from well-defined anxiety disorders [20,21]. While community and patient surveys are well suited to study of individual factors associated with benzodiazepine use, they have important limitations in evaluation of benzodiazepine prescribing. First, cross-sectional surveys are limited in assessment of longitudinal drug use. Second, survey data rely on patient recall of drug consumption. Finally, community surveys usually lack physician-level data on prescribing practices or indication for prescription. Analyses of population-based prescription data can address some of these limitations and contribute to the understanding of current practice. This article uses computerized pharmacy and outpatient visit diagnosis data from a large staff-model health maintenance organization (HMO) to examine patterns of benzodiazepine prescribing. These data were used to address the following questions: What is the period prevalence of short-term and longer-term benzodiazepine use? Among patients receiving a new benzodiazepine prescription, what are the patient characteristics and prescribing patterns associated with continued use?
METHODS
Study Setting Group Health Cooperative of Puget Sound (GHC) is a large staffmodel HMO serving approximately 380,000 residents (including approximately 280,000 adults) of western Washington state. GHC provides comprehensive care on a capitated basis with members typically receiving GHC health care coverage through employer-subsidized plans. The GHC enrollment includes approximately 45,000
1068
G. E. Simon
TABLE 1. Demographic characteristics operative of Puget Sound members area and U.S. residents” GHC members
Characteristic Age
(%)
of Group compared
Health Cowith Seattle
Seattle area (%)
United States (%)
(years)
18-44 45-64 65+ Percent male Race Caucasian Black Asian/Pacific Other Years of education <12
12 13-15 16+ Annual income <$15,000
$15,000-25,000 $25,000-35,000 $35,000-50,000 >$50,000
61 26 13 45
61 26 13 49
49
91
90 4 4 2
83 12 2 3
ii
18 35 23 24
34 35 16 16
20 24 23 20 13
23 18 19 21 19
24 20 19 19 18
3 4 2 9 24
“GHC data based on a random sample of 1 ,133 adult members 1984. Seattle and US. data based on 1990 census.
57 27 16
surveyed
in
Medicare members and 22,000 members covered by Medicaid or by Washington’s Basic Health Plan (a state program for low-income residents). Table 1 compares the demographic characteristics of GHC members surveyed in 1984 with those of Seattle area residents and the U.S. population. The proportion of GHC members covered by programs for low-income residents (Medicaid and Basic Health Plan) has approximately doubled since the 1984 survey. GHC members are similar to Seattle area residents except for higher educational level and less representation of the high and low extremes of income. Approximately 360 GHC physicians (full-time and parttime) provide adult primary care with each full-time physician responsible for a defined panel of approximately 1600 patients. Over 95% of physicians providing primary care to adults are trained in family medicine, with most of the remainder trained in internal medicine. Specialty care is available on referral from approximately 400 medical and surgical specialists. Approximately 20 psychiatrists provide care for both self-referred and physician-referred patients. Over 90% of primary care physicians and specialists are certified by appropriate specialty boards. The GHC computerized information systems include data on all outpatient visits to GHC clinics and all outpatient prescriptions filled at GHC pharmacies. Prescription medicines (including benzodiazepines) are covered by all GHC health plans subject to copayments of up to $7 per prescription. Previous surveys of GHC memhers have found that over 95% of prescriptions are filled at GHC pharmacies [27].
et al.
These analyses used timing of prescription refills to estimate duration of daily drug use. For a sample of patients filling first benzodiazepine prescriptions, all prescription records (new prescription and refills) were organized chronologically. Data on quantity of medication dispensed and timing of refills were then used to computer an average rate of consumption for each prescription fill or refill (average use per day equals number of pills dispensed divided by number of days until next benzodiazepine refill). On the basis of these computed consumption rates, each patient was assigned an estimated duration of daily use equal to the time between his/her first benzodiazepine prescription and the date on which his/her rate of consumption fell below one pill per day. For patients who completely discontinued benzodiazepines during the follow-up period, no consumption rate could be computed for the final refill (i.e., no date of subsequent retill available). In these cases, estimated duration of daily use for the final refill was assumed to lie halfway between the minimum and maximum possible values. Varying this assumption had minimal effect on subsequent analyses. Data on duration of daily use were then used to establish an appropriate cut point for dehning continued daily use. Figure 1 displays the survival curve for daily use (defined above) following a first benzodiazepine prescription. On the basis of distribution, a cut point of 60 days was chosen to discriminate short-term or intermittent users from continued users. Varying this cut point between 45 and 90 days did influence the estimated likelihood of continuing daily use, but had no impact on the correlates or predictors of continued use. In summary, this algorithm used prescription refill records to identify patients using henzodiazepines for at least 60 days and refilling prescriptions frequently enough to indicate average consumption of at least one pill per day.
Cross-Sectional
Sample
Computerized pharmacy records were used to identify all GHC members 18 years of age and over receiving any benzodiazepine prescription (new prescription or refill) between January 1, 1992 and June 30, 1992. Data on prescription dates, number of doses dispensed, and patient age and sex were organized to examine prevalence of benzodiazepine use for specific age/sex groups. Criteria for continued daily
1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
Definition
of Continued
Daily
Use
Preliminary analyses of the GHC computerized pharmacy records were conducted to develop and test an algorithm identifiying continued daily benzodiazepine users from pharmacy refill records (algorithm available from the first author on request).
0
20
40
60 DAYS
FIGURE at rate patients
SINCE
80 INITIAL
100
120
140
160
180
PRESCRIPTION
1. Survival curve for continued benzodiazepine greater than one pill per day in cohort of 7012 receiving a new benzodiazepine prescription.
use HMO
Predictors
of Chronic
Benzodiazepine
Use in a Health
Maintenance
use (described above) were applied to determine which of these patients used benzodiazepines at a rate of at least one pill per day for 60 days or more with at least some portion of the 60-day interval falling within the prevalence period (January 1, 1992 to June 30, 1992). To assure complete availability of prescription records for the relevant period, only those continuously enrolled in GHC from November 1, 1991 to August 30, 1992 were included in these analyses. Denominators for prevalence rates include all GHC members satisfying the above-cited eligibility criteria regardless of benzodiazepine use. Cohort
Sample
Pharmacy records were used to identify all GHC members, age 18 years and over receiving new episodes of benzodiazepine use between January 1,1992 and June 30,1992. A new episode of use was defined by a prior interval of at least 90 days free of any benzodiazepine use (based on computerized pharmacy records). Patients joining GHC during the 90 days prior to the index prescription were excluded because prior use could not be assessed using GHC pharmacy records. Those leaving GHC during the 180 days following the index prescription were also excluded because duration of use could not be accurately asssessed. Records for subsequent benzodiazepine refills were analyzed (using the criteria described above) to identify those patients in the cohort developing a pattern of continued use (use for at least 60 days at a rate of at least one pill per day).
Statistical
Analysis
Univariate analyses (frequencies, means, chi-square, and analysis of variance) were performed with the SAS software package (SAS Institute, Research Triangle Park, NC). Multivariate modeling of the likelihood of continued use (using logistic regression) was performed with the EGRET software package (Statistics and Epidemiology Research Corporation, Seattle, WA). Th e extension of Fisher’s exact test to R X C tables (a valid test for sparse contingency tables) was performed using the StatXact software package (Cytel Corp., Cambridge, MA). RESULTS
Cross-Sectional
Prevalence
Of the approximately 280,000 adults enrolled during the study period, 240,946 were continuously enrolled from November 1, 1991 to June 30, 1992. Of that sample, 3.8% received at least one benzodiazepine prescription (fill or refill) during the 6-month prevalence period from January 1, 1992 to June 30, 1992. Approximately 25% of those patients (or 1% of adult GHC members) satisfied criteria for continued use (use of one pill per day for 60 days or more). Table 2 displays the prevalence of benzodiazepine use according to age and sex. Rates of use were higher among women than among men and increased steadily with age. Among members 65 years of age or more, approximately 2% of men and 3% of women were classified as continued users.
Longitudinal of Continued
Predictors Use (Cohort
Sample)
The procedures described above identified a cohort of 7012 GHC members receiving new benzodiazepine prescriptions between January 1, 1992 and June 30, 1992. Characteristics of patients initiating treatment are shown in the first column of Table 3.The sample was
Organization
1069
Sample
TABLE 2. Six-month anxiolytic and hypnotic erative of Puget Sound
prevalence rates for various levels of drug use among Group Health Coopmembers according to age and sex” Percent using benzodiazepines in a 6.month period Number population
Total Females (age, years) 18-44 45-64 65+ Males (age, years) 18-44 45-64 65+ “Percentages sex group.
represent
in
240,946 132,239 69,863 37,140 25,236 108,707 56,222 34,727 17,758 prevalence
among
Any
use 3.81 4.69 2.72 5.48 9.01 2.74 1.72 2.93 5.57
all GHC
members
Daily use for 60 days 1.04 1.24 0.58 1.39 2.85 0.81 0.21 0.85 1.99 for each age-
TABLE 3. Odds ratios for continuing daily benzodiazepine use lasting more than 60 days among cohort of 7012 patients receiving an initial benzodiazepine prescription” Percentage (number) of cases
Patient characteristic Sex Male Female Age (years) 18-44 45-64 65+ Specialty Primary care Medical specialty Psychiatry Drug prescribed Diazepam Lorazepam Alprazolam Temazepam Triazolam Flurazepam Chlordiazepoxide Clonazepam Oxazepam Clorazepate Size of initial prescription l-10 Pills 1 l-20 Pills 21-30 Pills >30 Pills “Displayed
Odds ratio for daily use >60 days
95% confidence interval
31.9 68.1
(2236) (4776)
1 0.84
0.71-0.99
37.2 33.7 29.1
(2607) (2364) (2041)
1 1.15 1.89
0.94-1.41 1.55-2.31
79.3 (5563) 17.1 (1197) 3.6 (252)
1 1.24 2.11
1.00-1.57 1.52-2.53
29.9 21.3 14.6 13.5 8.6 6.0 2.9 1.5 1.2 0.6
(2096) (1492) (1024) (945) (601) (423) (205) (1.03) (81) (42)
1 2.92 2.39 1.59 1.64 1.04 1.46 6.96 2.50 2.13
2.29-3.72 1.82-3.12 1.18-2.16 1.17-2.30 0.68-1.61 0.88-2.42 4.33-11.17 1.31-4.76 0.86-5.31
28.9 37.5 26.3 7.3
(2026) (2633) (1844) (509)
1 1.40 2.44 7.00
1.09-1.79 1.91-3.12 5.27-9.29
odds ratios reflect adjustment
fc>r all covariates
listed here.
G. E. Simon predominantly female, with older patients somewhat overrepresented in proportion to the GHC population. Nearly 80% of initial benzodiazepine prescriptions were written by primary care physicans with fewer than 4% written by psychiatrists. Three-fourths of initial prescriptions were for fewer than 20 pills, with only 7.3% of patients receiving more than 30 pills. The algorithm to assess chronic use described above identified 10.9% (n = 767) of those initiating benzodiazepine treatment as continuing at a rate of one pill per day for at least 60 days. A logistic regression model was used to examine various predictors of continued use. Results of the full model are displayed in the second and third columns of Table 3. This model produced a good fit to the data (residual deviance 4299, with 6994 degrees of freedeom), and regression diagnostics [28] did not reveal any observations with undue influence on estimated odds ratios. Likelihood of chronic use was weakly associated with male sex, but strongly associated with increasing age. Patients 65 years of age or over were nearly twice as likely to continue regular use as were those aged 18 to 44 years. Compared with patients treated by primary care physicians, chronic use was slightly more common among those treated by medical specialists and twice as common among those treated by psychiatrists. Likelihood of chronic use varied significantly among different benzodiazepines. The pattern of variability suggested greater likelihood of continued use among patients prescribed high-potency drugs (lorazepam, alprazolam, triazolam, and clonazepam). In a separate logistic model, use of these four high-potency drugs was associated with a two-fold increase of chronic use when compared to all other drugs (odds ratio, 2.09; 95% confidence interval, 1.78-2.47). Restricting the analysis to prescriptions written by primary care physicians had no appreciable impact on differences among drugs in likelihood of proceeding to continued use. Chronicity increased progressively with the number of pills dispensed at the initial prescription. Restriction of the sample to primary care prescriptions did not affect the relationship between prescription size and probability of continued use. To assure that the relationship between initial prescription size and continued use was not an artifact of the algorithm used, a secondardy analysis examined the likelihood of refilling an initial benzodiazepine prescription according to initial prescription size. Likelihood of refill increased from 11.9% among initial prescriptions of fewer than 10 pills to 44.20/ 0 among initial prescriptions of greater than 30 pills (Mantel-Haenszel chi-square for linear association = 295, df = 1, p < 0.0001). Examination of interrelationships among various independent variables revealed significant variation in prescribing patterns by patient age. The portion of patients receiving an initial prescription for more than 20 pills increased from 26.5% among those aged 1844 years to 34.7% among those aged 45-64 years to 41.2% among those aged 65 years and over (Mantel-Haenszel chi-square for linear association = 112.6, df = 1, p < 0.0001). Drug selection also varied significantly by patient age (chi-square = 256.92, df = 18, p < 0.0001) with older patients somewhat less likely to receive drugs typically prescribed for anxiety symptoms (diazepam, alprazolam) and somewhat more likely to receive drugs traditionally prescribed for insomnia (temazepam, flurazempam).
Variation
Among
Physicians
Because the relationship of chronicity to prescribing patterns (drug selection and prescription size) might reflect either baseline clinical differences among patients or a true influence of prescribing practice on chronicity of use, further analyses examined how prescribing pat-
et al.
terns and patients’ duration of use varied among individual physicians. These analyses were restricted to the group of primary care physicians writing at least 10 new benzodiazepine prescriptions for patients in the longitudinal sample (n = 200 physicians, n = 4998 patients). We first examined how duration of use varied among individual primary care physicians. The likelihood of continued benzodiazepine use (daily use for 60 days or more) showed significantly greater variability across physicians than expected by chance (extended Fisher’s exact test statistic = 252, df = 199, p = 0.0068. We next examined physician variability in the prescribing patterns associated with continued use. The analyses demonstrated greater than chance variability in both the mean number of pills dispensed at the initial prescription (F = 3.82, df = 199, 4798, p < 0.0001) and in the distribution of drugs prescribed (extended Fisher’s exact test statistic = 3757, df = 1791, p < 0.0001). Even when the sample was restricted to those physicians with at least 20 new prescriptions (n = 119) and to those patients (n = 3083) treated with the four most commonly prescribed drugs (diazempam, lorazepam, alprazolam, and temazepam) medication choice varied significantly among physicians (extended Fisher’s exact test statistic = 1645, df = 354, p < 0.0001). We next used a series of logistic regression models to examine how variation among physicians in these two prescribing practices (drug selection and initial prescription size) predicted patients’ duration of use. These analyses used logistic regression to predict likelihood of continued use at the patient level while incorporating physician-level indices of prescribing as either fixed or random effects. The first analysis confirmed the above-described finding of greater than expected variability among physicians in patients’ likelihood of proceeding to chronic use. In a logistic model containing patient age and gender (model l), addition of physician as a random effect made a significant contribution to the prediction of continued use (likelihood ratio statistic = 14.9, p < O.OOl), indicating significant variability in outcome among physicians after adjustment for patient age and sex. The second set of models examined how specific physician-level prescribing indices contributed to prediction of patientlevel likelihood of continued benzodiazepine use. For this analysis, physician-level indices were computed to reflect each physician’s average prescription size and each physician’s likelihood of prescribing drugs associated with chronic use. In a model containing patient age and sex, each of these indices made a significant positive contribution to prediction of chronicity (p < 0.001 by Wald test for both variables). Addition of physician as a random effect to this model made only a marginally significant additional contribution (likelihood ratio statistic = 2.37, p = 0.06). Comparison with model 1 described above indicates that most of the physician-level variability in outcomes can be explained by differences in physicians’ prescribing patterns (tendency to prescribe drugs associated with longerterm use or to prescribe a larger number of pills at the initial precription). Pharmacy data were linked to physician demographic data to examine the relationship of prescribing patterns to physician age. When physicians were categorized by age (age ~40 years, age 4049 years, age 50+ years), older physicians were somewhat less likely to prescribe small initial quantities, with the proportion of new prescriptions written for 10 or few pills declining from 27.5% among younger physicians to 16.8% among those 50 years of age or more (Mantel-Haenszel chi-square for linear association = 14.1, df = 1, p = 0.0002). Drug selection also differed significantly by age, with older physicians somewhat less likely to prescribe higher potency drugs (lorazepam, alprazolam, triazolam, and clonazepam). The por-
Predictors
TABLE patients
of Chronic
Benzodiazepine
Use
in a Health
4. Indication (from chart review) initiating benzodiazepine treatment
Number Total Anxiety/depression/ situational stress Insomnia Back/neck pain Headache or other pain No indication give
200 54
Maintenance
for primary
care
Percentage of aU new users
Percent likelihood of continued use
100 27
10.5 16.7
30 27 49
20 13.5 24.5
16.7 7.4 6.1
30
15
6.7
tion of newer prescriptions written for higher-potency drugs decreased from 53.3% among younger physicians to 46.5% among those 50 years of age or more (Mantel-Haenszel chi-square for linear association = 11.8, df = 1, p = 0.0006). Consequently, older physicians more often prescribed initial quantities of benzodiazepines associated with chronic use but were less likely to prescribe drugs associated with chronic use. Likelihood of chronic use was modestly related to prescriber age; the portion continuing to chronic use decreased from 13.2% among patients of younger physicians to approximately 10% among patients of physicians 40 years of age or more (Mantel-Haenszel chi-square for linear association = 6.6, df = 1, p = 0.01). While older physicians cared for older panels of patients, stratification for patient age did not signficantly affect the abovedescribed relationships between physician age and prescribing patterns.
indications
for Treatment
From the sample of primary care patients tilling new benzodiazepine prescriptions a random sample of 200 was selected and outpatient charts were reviewed to identify indication for prescription. The new benzodiazepine prescription followed a primary care visit for 123 patients and followed a telephone call for 70. No mention of the benzodiazepine prescription in the outpatient record could be located for seven patients. Results regarding indication are shown in Table 4. Psychological symptoms (including anxiety, depression, and situational stress) accounted for the largest group of patients (slightly over one-quarter of the total). Insomnia accounted for 20% of prescriptions and an additional 38% were intended for treatment of back pain, neck pain, headache, or other pain complaints. Psychological complaints and insomnia were associated with a higher likelihood of continued use (16.7%) while duration of use was lower than average for musculoskeletal and pain complaints (6.6%). This difference in likelihood of continued use was marginally significant (chi-square = 3.88, p = 0.05). Likelihood of a psychological symptom indication decreased from 36% among those less than 45 years of age to 19% among those 65 years of age or more (Mantel-Haenszel chisquare for linear association = 5.88, df = 1, p = 0.015).
DISCUSSION Cross-sectional pharmacy data from this staff-model HMO show a pattern of benzodiazepine use generally similar to that seen in community-based surveys. While the overall rate of use over a 6-month
Organization
Sample
1071
period (3.8%) and the prevalence of continued use (1%) are somewhat lower than those reported in earlier community surveys [5,18, 201, these data show the same pattern of increasing prevalence of use with age. The rate of longer-term use among the elderly is quite similar to the 2 to 4% prevalence seen in previous studies. These pharmacy-based data do give a more detailed view of benzodiazepine prescribing practices. Psychiatrists are responsible for fewer than 4% of initial benzodiazepine prescriptions for all patients and fewer than 2% among the elderly. Most initial prescriptions were for fewer than 20 pills, but initial prescription size was significantly larger in the elderly. Among primary care patients receiving new prescriptions for benzodiazepines, insomnia and pain complaints account for the majority of prescriptions, with fewer than 25% of prescriptions intended for the treatment of anxiety symptoms or disorders. Age was associated with both a higher risk of initiating benzodiazepine treatment and a higher risk of chronic use. This finding agrees with a number of earlier reports describing an increasing risk of chronic benzodiazepine use with age [18,21-23,291. The likelihood of chronic use among the elderly may reflect both age-related differences in both drug metabolism and more lenient physician attitudes about benzodiazepine use in the elderly. Reduced drug clearance among the elderly may increase the likelihood of physiological dependence developing during intermittent use. Alternatively, more lenient prescribing to older patients (larger initial prescriptions, more refills) may reflect primary care physicians’ view that older patients are less likely to “abuse” benzodiazepines or are less amenable to nonpharmacological interventions. These data also contribute to the picture of chronic benzodiazepine users. While psychiatric patients had a higher likelihood of long-term benzodiazepine use, primary care patients accounted for 75% of all patients in the cohort sample using benzodiazepines at least daily for 60 days. The typical chronic benzodiazepine user was an older female presenting for care of chronic medical conditions or nonspecific physical complaints. Among primary care patients, psychiatric symptoms were associated with longer duration of use, but the majority of chronic benzodiazepine users were taking benzodiazepine for less specific indications such as insomnia or pain complaints. These findings agree with previous community data suggesting a low prevalence of well-defined psychiatric disorders among older benzodiazepine users [20]. These results do suggest some unexpected hypotheses about physician prescribing practices associated with continued benzodiazepine use. Some of the prescribing factors associated with longer-term use may reflect the clinical characteristics of patients requiring longerterm treatment. For example, a longer duration of benzodiazepine use among patients treated by psychiatrists may not reflect more literal prescribing by pychiatrists as much as it indicates more severe anxiety disorders among psychiatric patients. Some of the abovedescribed findings, however, may identify prescribing patterns that contribute to longer-term use. Increasing size of the initial prescription and use of higher-potency benzodiazepines (lorazepam, alprazolam, clonazepam, and triazolam) were strongly associated with increasing duration of use. While these associations may also reflect clinical characteristics of patients likely to need chronic treatment (i.e., more severely or chronically ill patients receive larger initial prescriptions), individual physicians varied considerably in both drug choice and prescription size. At least some of this variability among physicians (especially variability in drug selection) is more likely to reflect variation in clinician practice than clinical differences among patients treated. The logistic regression analyses incor-
1072 porating physician-level variation and physician-level prescribing indices support this explanation. Variability among individual primary care physicians in likelihood of chronic use was significantly greater than predicted by chance. Much of this variability among physicians in duration of use appeared to be related to differences in drug selection and prescription size. The variability among drugs in likelihood of chronicity suggests the possibility that higher-potency drugs may produce greater dependence. This relationship appeared quite strong and physicianlevel analysis suggests that the higher chronicity rates for specific drugs do not simply reflect baseline clinical differences. Given the absence of corroborating evidence from clinical or preclinical studies, this finding must be interpreted cautiously. In a study of benzodiazepine withdrawal, Rickels and colleagues did report more prominent withdrawal symptoms among patients treated with short halflife benzodiazepines [30,3 11. While the pattern observed in this sample (chronicity related to potency) differs from that reported earlier (chronicity related to half-life), the disagreement between these two patterns depends on the high observed chronicity among the small number of patients prescribed clonazepam (a drug with long halflife and high potency). The strong relationship between prescription size and duration of use allows several possible explanations. This association may represent a direct causal effect: a larger initial supply of medication may increase the likelihood that dependence will develop. Alternatively, larger initial prescriptions may reflect the severity or chronicity of the symptoms for which the benzodiazepine was prescribed. Because individual physicians varied considerably in prescription size, prescription of a larger number of pills may also reflect physician attitudes related to granting future refills. While these observational data cannot establish a causal relationship between prescription size and chronic use, a causal relationship is certainly plausible. Medication use data alone are not sufficient to judge the appropriateness of benzodiazpine prescribing. Epidemiological data do demonstrate significant risks of chronic benzodiazepine use in the elderly, but large data sets lack the clinical detail necessary to evaluate benefit. Our demonstration of a significant rate of chronic benzodiazepine use in the elderly does not in itself demonstrate that the observed rate is too high. While crosssectional surveys [18,20] can evaluate the level of psychological distress or functional impairment in benzodiazepine users, they cannot evaluate whether benzodiazepine treatment has actually reduced distress or improvement function. Addressing that question will require longitudinal assessment following the initiation of benzodiazepine use. These findings do indicate that much of the available research on the efficacy of benzodiazepines is not relevant to community practice. Clinical anxiety research has focused on management of well-defined anxiety disorders among young and middle-aged psychiatric patients. These data and others suggest that most benzodiazepines are prescribed to older primary care patients who present with insomnia or nonspecific physical complaints. Few benzodiazepine users in community samples appear to meet criteria for well-defined anxiety disorders. Clinical insomnia research has typically focused on short-term efficacy as judged by polysomnographic measurement. While most research demonstrates fairly rapid accommodation to the therapeutic effects of hypnotic benzodiazepines, long-term hypnotic users typically report significant continued benefit [21,32]. Research focused on a broader range of patients and clinical conditions will be needed to evaluate the appropriateness of “real world” practice.
G. E. Simon Supported by NIMH Grant 5 1338, a grant from the Center for Disease to the University of Wathington’s Center on Health Promotion for Older and a grant from the Group Health Cooperative medical staff.
et al. Connol Adults,
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Predictors 29. 30.
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Organization 31.
32.
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