Andrea H. Kline-Simon, MS

 Concomitant excessive alcohol consumption and benzodiazepine use is associated with adverse health outcomes. We examined associations of unhealthy alcohol use and other patient characteristics with benzodiazepine use.

 A cross-sectional analysis of 2,089,525 Kaiser Permanente of Northern California outpatients screened for unhealthy alcohol use in primary care between November 1, 2014, and December 31, 2016.

 We fit multivariable generalized linear models to estimate the associations between unhealthy alcohol use and benzodiazepine dispensation and, among patients who were dispensed a benzodiazepine, mean doses (in mean lorazepam-equivalent daily doses [LEDDs]) and prescription durations. We controlled for patient sex, age, race/ethnicity, estimated household income, Charlson Comorbidity Index (CCI) score, anxiety disorder, alcohol use disorder, insomnia, musculoskeletal pain, and epilepsy.

 In the 12 months centered around (6 months before and 6 months after) the first alcohol-screening visit, 7.5% of patients used benzodiazepines. The following characteristics were independently associated with higher rates of benzodiazepine use, higher LEDD, and longer prescription duration: older age, white race/ethnicity, lower estimated household income, higher CCI score, and the presence of an anxiety disorder, insomnia, musculoskeletal pain, or epilepsy. Women and patients with an alcohol use disorder or unhealthy alcohol use, compared with men and patients with low-risk drinking or abstinence, were more likely to use a benzodiazepine; however, their LEDDs were lower and their prescription durations were shorter.

 Benzodiazepine use in primary care was associated with older age, female sex, white race/ethnicity, lower socioeconomic status, and unhealthy alcohol use. These findings may be applied to develop policies and interventions to promote judicious benzodiazepine use.

Among patients in an integrated healthcare delivery system who were screened in primary care for unhealthy alcohol use, we examined cross-sectional benzodiazepine use patterns.

Unhealthy alcohol users, patients with an alcohol use disorder, and women were more likely to use benzodiazepines, but at lower doses and for shorter durations, compared with low-risk alcohol users and men.

Patients who were older, white, and of lower socioeconomic status were more likely to use benzodiazepines and had higher doses and prescription durations.

These findings may inform the development of systemwide interventions to address disproportionate benzodiazepine use among specific patient groups, especially among unhealthy alcohol users.

Benzodiazepines have been increasingly used in the United States, leading to increases in overdose mortality and healthcare utilization due to their potent sedative properties. Between 1996 and 2013, the percentage of US adults who filled a benzodiazepine prescription increased from 4.1% to 5.6%, and overdose mortality involving benzodiazepines increased from 0.58 to 3.07 per 100,000 adults.

 In a large primary care sample, 15% of patients were prescribed a benzodiazepine, one-third of whom received high-dose benzodiazepines (ie, a daily dose equivalent of ≥30 mg/day of diazepam); high-dose recipients were more likely than low-dose recipients to have multiple medical comorbidities and high healthcare utilization.

 Furthermore, between 2003 and 2015, the percentage of outpatient medical visits including a benzodiazepine prescription doubled, and more than half of these visits were to primary care physicians.

Between 7.5% and 20% of primary care patients acknowledge unhealthy alcohol use,

 defined as use exceeding recommended weekly or daily limits.

 Excessive alcohol use is associated with numerous individual and societal consequences, such as development or exacerbation of medical and mental health comorbidities, decreased medication adherence, increased HIV risk behaviors, motor vehicle crashes, and interpersonal violence.

 Unhealthy alcohol use may precede development of an alcohol use disorder

 and frequently goes undetected in routine clinical care.

 In this context, the US Preventive Services Task Force recommends screening all adult primary care patients for unhealthy alcohol use and offering patients with unhealthy alcohol use brief behavioral counseling.

When benzodiazepines and alcohol are used concurrently, their sedative effects significantly increase the risk of adverse events, including fatal overdose.

 In 2010, alcohol was involved in 27.2% of benzodiazepine-related visits and 21.4% of benzodiazepine-related deaths in US emergency departments.

 Long-term consequences of combined benzodiazepine and alcohol use include cardiovascular, gastrointestinal, hepatic, kidney, and neurologic injury and exacerbation of psychiatric conditions.

Nationally representative survey data from 2015-2016 suggest that past-year alcohol use or an alcohol use disorder is associated with an increased risk of concurrent benzodiazepine use, misuse, and use disorder.

 Similarly, among Medicare beneficiaries in 2002, presence of drug or alcohol use or dependence was associated with higher odds of benzodiazepine use.

 However, to our knowledge, no health system, primary care—based studies have examined patient characteristics associated with benzodiazepine dispensation, mean dose, and prescription duration. This information may inform the development of tailored interventions to reduce exposure to benzodiazepines among patients with unhealthy alcohol use.

In this study, we examined the prevalence of benzodiazepine use and its associations with patient demographic and clinical characteristics, including unhealthy alcohol use, among Kaiser Permanente of Northern California (KPNC) adult outpatients who were screened for alcohol use in primary care clinics. We hypothesized that people drinking at unhealthy levels, compared with low-risk drinkers and abstainers, would be less likely to receive benzodiazepines and would receive prescriptions of lower doses and shorter durations. Although this contrasts with previous national trends, we postulated that the combination of recent warnings about rising benzodiazepine use in the United States, concerns about concurrent use with other substances, and a primary care initiative in our healthcare system to detect and reduce unhealthy alcohol use would sensitize clinicians to reconsider benzodiazepine prescribing in this patient subgroup.

We conducted a retrospective, cross-sectional study using electronic health record (EHR)—derived data among adult outpatients screened for alcohol use in KPNC primary care clinics. KPNC is an integrated healthcare delivery system with more than 4 million members that covers approximately 30% of the population in the served geographic areas. For these analyses, we identified KPNC members 18 years or older who were screened for unhealthy alcohol use with 1 or more completed alcohol screenings as part of an ongoing primary care–based alcohol screening and brief intervention protocol (Alcohol as a Vital Sign [AVS])

 between November 1, 2014, and December 31, 2016. We defined the study period as the 12-month period centered around (6 months before and 6 months after) each patient’s clinic visit in which the first AVS screening occurred. We excluded patients with noncontinuous KPNC coverage during the study period (

]). Use of these data was approved by the institutional review boards of KPNC and the University of California, San Francisco.

We included outpatient dispensations for benzodiazepines filled at KPNC pharmacies in the 12 months centered around a patient’s first AVS screening visit in a primary care clinic. We extracted data for oral formulations of all benzodiazepine-containing medications (ie, alprazolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, temazepam, and triazolam) dispensed during the study period. For each patient, we assessed the following prescription attributes: (1) whether a benzodiazepine had been dispensed; (2) the duration of the benzodiazepine prescriptions (calculated by summing the total number of days supplied in the study period

); and (3) the mean daily benzodiazepine dose, expressed in mean lorazepam-equivalent daily dose (LEDD), which is an average over the 12-month study period (eAppendix Methods and 

Patient sex, age, and race/ethnicity (Asian, black/African American, Hispanic, white, and other/unknown) were extracted from the EHR at the time of the first AVS screening. We estimated household income from the United States Census 2010 median household income data by geocoding patients’ residential addresses to Census blocks.

International Classification of Diseases, Ninth Edition 

International Classification of Diseases, Tenth Edition, Clinical Modification 

codes, we assessed for the presence of the following encounter-associated codes in the study period: anxiety disorders, insomnia, musculoskeletal pain, alcohol use disorders (including alcohol-related psychoses, dependence, and abuse; excluding conditions in remission), and epilepsy (

). In addition, we estimated patients’ medical comorbidity burden using the Charlson Comorbidity Index score, which estimates 1-year mortality risk based on a weighted score of 17 conditions.

To determine whether a patient engaged in unhealthy alcohol use, we used EHR-documented alcohol screening data collected as part of the AVS protocol during the study period. During the primary care visit “rooming” process, medical assistants asked all patients to estimate within the past 90 days (1) the mean number of days per week they consumed alcohol and (2) how many alcoholic drinks they consumed “on a typical drinking day.” Using these variables, the EHR calculates the mean number of alcoholic drinks consumed weekly (ie, mean number of drinking days per week multiplied by the number of drinks consumed on a typical drinking day).

 Based on guidelines established by the National Institute on Alcohol Abuse and Alcoholism,

 we defined drinking severity as “low-risk alcohol use” (0-14 drinks per week for men ≤65 years or 0-7 drinks per week for all women and for men >65 years) or “unhealthy alcohol use” (>14 drinks per week for men ≤65 years or >7 drinks per week for all women and for men >65 years).

 and Wilcoxon rank-sum tests to examine differences in categorical and continuous patient demographic and clinical characteristic variables (including presence of unhealthy alcohol use) by whether the patient filled a prescription for a benzodiazepine in the 12 months centered around their first AVS screening visit. We fit multivariable logistic regression models to estimate the adjusted odds ratios (AORs) and corresponding 95% CIs of being dispensed a benzodiazepine by patient characteristics. Among patients who were dispensed a benzodiazepine during the study period, we fit log-linear and negative binomial regression models (accounting for positive skew and overdispersion of the data) to estimate the adjusted rate ratios (ARRs) of mean LEDD and duration of their prescriptions, respectively, by patient characteristics. All analyses were performed using SAS version 9.4 (SAS Institute Inc; Cary, North Carolina). Significance was assessed at 2-sided 

Approximately 87% of eligible KPNC members during the defined study period completed 1 or more AVS screenings, and 70% of the benzodiazepine prescriptions were ordered by a primary care provider (ie, internal, family, preventive, or adolescent medicine or pediatrics). Among KPNC members included in these analyses, approximately 97% had a continuous prescription benefit for KPNC pharmacies during the 12-month study period. The analytic cohort consisted of 2,089,525 patients (median [interquartile range] age = 49.0 [29.0] years; 53.7% female; 50.0% white; 4.0% unhealthy alcohol users) after excluding patients without continuous KPNC coverage in the 12 months centered around the first AVS screening (n = 803,991) and patients with missing Census-derived estimated household income data (n = 1390) (

In the study period, 157,449 patients (7.5% of the study sample) filled a prescription for a benzodiazepine (Table 1). Patients with unhealthy alcohol use had slightly higher odds of using benzodiazepines compared with patients with low-risk alcohol use (AOR, 1.15; 95% CI, 1.12-1.19) (

). From the same multivariable analysis, women had 64% higher odds of using a benzodiazepine compared with men (AOR, 1.64; 95% CI, 1.62-1.66). Conversely, nonwhite patients had significantly lower odds of using benzodiazepines compared with white patients. Among racial/ethnic groups, Asian patients were the least likely to use benzodiazepines, with an AOR of 0.38 (95% CI, 0.37-0.38), representing 62% lower odds of using benzodiazepines compared with white patients. Older patients had significantly higher odds of using benzodiazepines compared with younger patients aged 18 to 39 years, with AORs of 1.82 (95% CI, 1.79-1.84) and 1.77 (95% CI, 1.73-1.80) for patients aged 40 to 65 and older than 65 years, respectively. Anxiety disorders, insomnia, musculoskeletal pain, epilepsy, and alcohol use disorder were all significantly associated with benzodiazepine use.

Mean Daily Dose and Duration of Benzodiazepine Prescriptions

Among patients with benzodiazepine prescriptions during the study period, the mean (SD) LEDD was 0.58 (1.51) mg/day and mean (SD) duration was 87.9 (114.0) days. Patients with unhealthy alcohol use had 40% lower LEDDs (ARR, 0.60; 95% CI, 0.55-0.66) and 18% shorter durations (ARR, 0.82; 95% CI, 0.80-0.84) compared with patients with safe alcohol use (

). Women had ARRs of 0.85 (95% CI, 0.83-0.87) and 0.92 (95% CI, 0.90-0.93), representing a 15% lower LEDD and an 8% shorter duration of benzodiazepine prescriptions, respectively, compared with men. Asian patients had the lowest LEDD and shortest prescription durations of any racial/ethnic group compared with white patients. Whereas LEDD was highest among patients aged 40 to 65 years compared with patients aged 18 to 39 years (ARR, 1.49; 95% CI, 1.43-1.55), prescription durations were the longest among patients 65 years or older compared with patients aged 18 to 39 years (ARR, 2.04; 95% CI, 2.00-2.08). Higher LEDD and longer prescription durations were also significantly associated with low (compared with high) Census-derived estimated household income and the presence of an anxiety disorder, insomnia, musculoskeletal pain, and epilepsy.

This study is the first to our knowledge to examine the association of unhealthy alcohol use with benzodiazepine use, dosage, and prescription duration in a large primary care sample. Notably, 7.5% of patients in this cohort were dispensed a benzodiazepine in a 12-month period.

 In addition, women, older adults, and white patients were more likely to use benzodiazepines.

The rate of unhealthy alcohol use of 4.0% in our sample is lower than estimates from other health maintenance organization—based primary care samples (7.5%-20%)

 but is within the range estimated in population-based survey samples (0.3%-20%).

 This discrepancy may be attributable to different populations, years of data collection, and definitions of unhealthy alcohol use. Similarly, the prevalence of filled benzodiazepine prescriptions in our sample (7.5%) is consistent with a cross-sectional analysis of US retail pharmacies (5.2% of adults filled a prescription for a benzodiazepine in 2008)

 and with data from the Medical Expenditure Panel Survey (the prevalence of filled benzodiazepine prescriptions between 1996 and 2013 among noninstitutionalized adults increased from 4.1% to 5.6%).

 However, among adults in a primary care practice—based research network in 2011 and 2012, 15% of patients were prescribed a benzodiazepine.

 This larger percentage may reflect ordered prescriptions instead of filled prescriptions; the number of ordered prescriptions is likely to be greater than the corresponding number of filled prescriptions.

Comparing our results regarding the concomitant use of benzodiazepines and alcohol with other samples is challenging given the methodologic heterogeneity among previous studies. For instance, among psychiatric outpatients (n = 93), roughly 40% used a benzodiazepine and simultaneously consumed alcohol; furthermore, alcohol use severity was associated with higher odds of benzodiazepine use (OR, 2.4; 95% CI, 1.3-4.2).

 In a study examining nationally representative survey data from 1999 to 2002, Jalbert and colleagues

 found that 8% to 10% of adult respondents reported both benzodiazepine and unhealthy alcohol use. Consistent with our findings, Kroll and colleagues

 examined data from a large primary care sample and found that patients with a diagnosis of alcohol abuse (compared with those without) had higher odds of benzodiazepine use (OR, 1.5; 95% CI, 1.3-1.7). In the emergency department setting, Jones and colleagues

 found that 27.2% of benzodiazepine-related visits involved alcohol. However, in smaller studies involving older patients

 the prevalence of concomitant benzodiazepine and unhealthy alcohol use (approximately 3% in these 2 samples) was significantly lower than what we found in this sample.

Clearly, previous analyses of concomitant alcohol and benzodiazepine use vary widely in their study populations, periods, and definitions of unhealthy alcohol consumption and benzodiazepine use. However, in general, the existing literature supports our conclusion that unhealthy alcohol use is associated with a greater likelihood of concomitant benzodiazepine use.

 Our study adds to the literature by examining not only benzodiazepine use but also mean doses and prescription durations among subpopulations of primary care patients. Interestingly, we found that although patients with unhealthy alcohol consumption were more likely to use benzodiazepines, the benzodiazepines were prescribed to them at lower doses and for shorter durations. This pattern persisted even when accounting for the presence of an alcohol use disorder, for which benzodiazepines may be prescribed to manage alcohol withdrawal. These findings fail to confirm the first part of our hypothesis (ie, patients with unhealthy alcohol use are less likely to use benzodiazepines) but do confirm the second part of our hypothesis (ie, that these patients would use benzodiazepines for shorter periods and at lower doses). One possible explanation for this pattern of findings is that those drinking at unhealthy levels may be more likely to use multiple abusable substances,

 but that clinicians, aware of the contraindications of concomitant use, limit the dose and duration of benzodiazepines for these patients. It is also possible that patients with unhealthy alcohol use may voluntarily limit their use of benzodiazepines to avoid functional impairment associated with concurrent alcohol and high-dose benzodiazepine consumption.

We also found, similar to results of surveys

 that women were more likely, and nonwhite patients less likely, to use benzodiazepines. Furthermore, we found that women and nonwhite patients who used benzodiazepines used them at lower doses and for shorter durations compared with men and white patients who used benzodiazepines.

 Women may be more likely to seek treatment for an anxiety disorder.

 Therefore, women may be more likely than men to report anxiety relief and to require lower doses of benzodiazepines in part because they are simultaneously receiving nonbenzodiazepine treatments (eg, antidepressants, psychotherapy).

 Simultaneously, women may use benzodiazepines at lower doses and for shorter amounts of time compared with men in part because clinicians may believe sex moderates benzodiazepine metabolism, despite limited evidence to support this contention.

 Previous research demonstrates that nonwhite patients receive fewer benzodiazepine prescriptions than white patients; however, white patients were more likely to have a benzodiazepine dependence diagnosis.

 Nonwhite patients may be less trusting of the healthcare system, particularly as it relates to seeking help for mental health problems.

 White patients may be more assertive in requesting symptom relief

 compared with nonwhite patients, who may be less likely to seek medical help for psychiatric symptoms such as anxiety.

 Furthermore, some Asian patients may be more likely to seek nonallopathic remedies for mental health concerns in primary care.

 Symptoms of anxiety in nonwhite patients may also be underrecognized or undertreated by clinicians, resulting in fewer benzodiazepine prescriptions for nonwhite patients. These sex- and ethnicity-associated disparities in benzodiazepine prescribing may also be the result of implicit clinician biases.

These results should be interpreted in the context of several limitations. As with all observational studies, causality cannot be determined. Pharmacy data reflect dispensations and we are unable to measure patient medication consumption; nonetheless, dispensations are commonly used in pharmacoepidemiologic studies

 and, in the current sample, approximately 84% of prescribed benzodiazepines were filled in KPNC pharmacies. Additionally, our results may not be generalizable to uninsured populations. However, some of our findings are consistent with other, nationally representative samples (eg, lower benzodiazepine use among nonwhite patients

), suggesting that other findings in our study may also be applicable to the general US primary care adult population.

We are also unable to determine whether benzodiazepine use was inappropriate or unhealthy; subsequent studies may identify potentially inappropriate benzodiazepine use using algorithms, such as those used in geriatric samples.

 Likewise, by restricting our analyses to benzodiazepine use, we did not examine concurrent opioid use, especially among patients with chronic pain. Compared with patients who only use opioids, patients who use both opioids and benzodiazepines are at higher risk of overdose

; therefore, national guidelines recommend against prescribing benzodiazepines with opioids.

 Future studies may examine the association among benzodiazepine and opioid use with unhealthy alcohol consumption.

We included conditions frequently associated with benzodiazepine prescriptions; however, benzodiazepines may be prescribed for other disorders, such as anxious depression.

 Finally, statistically significant associations may be a product of the large sample size of our study; therefore, we have focused our conclusions on associations with larger AORs and ARRs, which are most likely to be clinically meaningful and successfully replicated in other primary care samples. If these associations are replicated in subsequent studies, they may be applied to develop and validate clinical decision support systems, such as a quantitative risk-stratification tool to identify patients at high risk of concomitant benzodiazepine and unhealthy alcohol use.

In this large primary care cohort, unhealthy drinking was associated with higher rates of benzodiazepine use. However, benzodiazepine mean dose was lower and duration of use was shorter among patients with unhealthy drinking. Nonetheless, these results suggest that concomitant benzodiazepine and excessive alcohol use among primary care patients should receive increased vigilance, and health system—wide efforts to reduce this potentially lethal combination should be considered.

 Department of Psychiatry and the UCSF Weill Institute for Neurosciences, University of California, San Francisco (MEH), San Francisco, CA; The Permanente Medical Group, Department of Psychiatry (MEH), Oakland, CA; Division of Research, Kaiser Permanente of Northern California (MEH, VAP, AHK-S, CIC, SAS), Oakland, CA; Indiana University School of Medicine (KK), Indianapolis, IN; Regenstrief Institute, Inc (KK), Indianapolis, IN; VA Health Services Research and Development, Center for Health Information and Communication (KK), Indianapolis, IN.

 This research was supported by a grant from the National Institute on Alcohol Abuse and Alcoholism (grant number R01-AA025902-01).

 The authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

 Concept and design (MEH, VAP, KK, SAS); acquisition of data (VAP); analysis and interpretation of data (MEH, VAP, KK, CIC, AHK-S, SAS); drafting of the manuscript (MEH, VAP, CIC); critical revision of the manuscript for important intellectual content (MEH, VAP, AHK-S, KK, CIC, SAS); statistical analysis (VAP, AHK-S); provision of patients or study materials (SAS); obtaining funding (SAS); administrative, technical, or logistic support (SAS); and supervision (SAS).

 Matthew E. Hirschtritt, MD, MPH, Department of Psychiatry and the UCSF Weill Institute for Neurosciences, University of California, San Francisco, 401 Parnassus Ave, Box 0984, San Francisco, CA 94143. Email: matthew.hirschtritt@ucsf.edu.

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Among outpatients who were screened for alcohol use, those with unhealthy alcohol use, women, and those who were older, white, and of lower socioeconomic status were more likely to use benzodiazepines.

Andrea H. Kline-Simon, MS

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