The year 2009 has been one of economic uncertainty,

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1 Recent Trends in Utilization of Antianxiety Medication Drug Trends Anna A. Theodorou, RPh, MBA; Kelly M. Johnson, MBA; Julie Slezak, MS; and John A. Szychowski, BS The year 2009 has been one of economic uncertainty, rising unemployment, declining consumer confidence, and a looming fear of a flu pandemic. Each factor contributes to abnormal stress and subsequently to increased levels of short-term anxiety potentially increasing the use of antianxiety medication. Although some populations may have an advantage in preparedness or conditioning, having previously experienced a recession or the ability to sustain financial stability, the depth and breadth of the current downturn appear to be collectively taking its toll on the American population. However, certain demographic groups appear to be more heavily affected. Approximately 40 million American adults age 18 years and older, or about 18.1% of people in this age group in a given year, have an anxiety disorder, which is more likely to be present in women. 1 Two therapeutic classes are commonly used to treat anxiety: benzodiazepines and selective serotonin reuptake inhibitors (SSRIs). The SSRIs are utilized for longer-term treatment of anxiety combined with various levels of depression. Compared with benzodiazepines, SSRIs have a lower generic dispensing rate, and a higher average gross cost per day. This article will focus on the utilization of the older class of antianxiety agents: the benzodiazepines. Benzodiazepines (4-digit Generic Product Identifier 5710) are primarily prescribed for the short-term treatment of anxiety, insomnia, and panic disorders. 2-4 Demonstrating efficacy for more than 40 years, many drugs in this class are used intermittently and as a first-line treatment. The article is intended to provide an overview of benzodiazepine utilization and gross trend, including demographic details on users of benzodiazepines. METHODS The analysis is a retrospective study and was conducted using million prescription claims from CVS Caremark s computerized database. The population identified for the study consisted of 29.4 million members across funded benefit prescription plans administered by CVS Caremark. The plan sponsors included Medicaid, national and local employers, health plans, managed care organizations, insurance companies, unions, and government agencies located throughout the United States with prescription claims for all months between July 1, 2007, and June 30, The members were categorized by generation with the following age bands: GI generation (age 83 years), Silent generation (age years), Baby Boomers (age years), Generation X (age years), Generation Y (age years), and Generation Z (age 17 years). 5 In addition to categorizing utilizers by age band, we also separated metrics by sex. The utilization trend was based on average days supply and gross cost (which included both plan sponsor and member contributions), reported on a per member per month (PMPM) basis. Medicare Part D plans were excluded. The plan sponsors had average eligibility changes limited to within a ±15% period over period. Note that Klonopin (clonazepam), although classified as a benzodiazepine, was not included in this study as it is primarily indicated as an anticonvulsant (4-digit Generic Product Identifier 7210). THERAPEUTIC CLASS BACKGROUND Indications Benzodiazepines often are used to treat short-term anxiety for a variety of conditions and are commonly used in conjunction with talk therapy. 2-4 Antianxiety medications work to alter GABA (γ-aminobutyric acid, an amino acid that induces relaxation and sleep) neurotransmitters in the brain. However, the exact method of action is unknown. Benzodiazepines are not recommended as monotherapy for social anxiety patients with major depression or a history of substance abuse. 2 Table 1 shows the approved US Food and Drug Administration indications for benzodiazepines. Note that all of these drugs are available as generics. Despite the introduction of newer drugs such as SSRIs, benzodiazepines are widely used for short-term and intermittent use and have a rapid onset of action. They are contraindicated for long-term use because of an apparent VOL. 1, NO. 4 The American Journal of Pharmacy Benefits 225

2 n Theodorou Johnson Slezak Szychowski Table 1. US Food and Drug Administration Indications for Benzodiazepines 4 Indication Xanax (alprazolam) Treatment of patients with panic disorder, with or without agoraphobia Management of anxiety disorders or short-term relief of the symptoms of anxiety Valium (diazepam) Ativan (lorazepam) Tranxene (chlorazepate dipotassium) Symptomatic relief for patients suffering from acute alcohol withdrawal Useful adjunct for the relief of skeletal muscle spasm due to reflex spasm Used adjunctively for convulsive disorders Treatment of anxiety associated with depressive symptoms Adjunctive therapy in the management of partial seizures loss of efficacy over time, the possibility of addiction, and the risk of potentially severe withdrawal symptoms. Benzodiazepines are also regulated as Schedule IV controlled substances. In contrast, SSRIs are indicated for longer-term utilization, and have a much slower onset of action (commonly 6 to 8 weeks to reach full potential), limiting effectiveness for short-term anxiety. Additionally, SSRIs have greater variability in response than benzodiazepines and are not associated with the same risk of drug dependence. Utilization and Gross Cost Trend Benzodiazepines continue to experience growth in utilization and are currently ranked in the top 20 therapeutic classes by volume. However, these drugs are far less costly than drugs in other classes, because all drugs in this class are available as generics. Utilization trend Table 2. Year-Over-Year (YOY) Ranking for Benzodiazepines % Change YOY by Drug PMPM a Rank (Gross) Drug Name Claims Days 1 Alprazolam Lorazepam Xanax Valium Diazepam Class total PMPM indicates per member per month. a Twelve-month comparison (July 2007-June 2008 vs July 2008-June 2009). increased 5.1% (July 2007-June 2008 compared with July 2008-June 2009), while the year-over-year gross trend declined 3.1%, driven by a 7.9% decrease in the trend for gross cost per day. The generics, alprazolam, lorazepam, and diazepam, experienced both prescription claim and days supply increases per member per month, while the 2 major brandname drugs, Xanax and Valium, experienced declines (Table 2). Further, while all 3 major generic drugs experienced increased utilization, associated gross cost per day figures declined. Alprazolam continued to dominate the class at 53.1% and continued to outpace all other drugs in year-over-year growth. Xanax (alprazolam) is a short-acting benzodiazepine launched in the early 1980s that is approved for the treatment of generalized anxiety and panic disorders. The extended-release formulation of the drug (Xanax XR) was launched in 1996 and is indicated only for panic disorder. Generics of both products have been on the market for several years. 6 The increased utilization of alprazolam also is noted nationally. According to an August 2008 study by the Drug Testing Advisory Board (DTAB) of the federal Substance Abuse and Mental Health Services Administration (part of the Department of Health and Human Services), the total number of extended units dispensed for alprazolam through outpatient retail pharmacies increased by 83% from 1998 to 2007, representing 1.18 billion more units dispensed in 2007 than in The total number of prescriptions 226 The American Journal of Pharmacy Benefits Winter

3 Utilization of Antianxiety Medication increased by 71% during that time, from 24.8 million to 42.4 million. 7 In addition to the greatly increased volume of prescriptions, there may be a utilization shift by demographics. Table 3. Percentage of Benzodiazepine Utilizers by Sex Sex July 2007-June 2008 July 2008-June 2009 Female Male Source: CVS Caremark Industry Analytics Trend Cohort, July 1, 2007 through June 30, Demographics The DTAB study also found that alprazolam was the most commonly dispensed benzodiazepine for both men and women at outpatient retail pharmacies. For both sexes, the majority of prescriptions were dispensed to individuals age 41 to 50 years (Table 3). 8 Women were more likely to be diagnosed and treated for anxiety than men. However, results from our study indicate the number of men receiving benzodiazepines increased from 34.8% to 37.0% year-over-year. There was a decrease in the percentage of female utilizers from 65.2% in July 2007-June 2008 to 63.1% in July 2008-June IMPACT BY GENERATION The cohort membership population grew 1.7% yearover-year while the number of unique benzodiazepine utilizers increased 6.5%, almost 4 times the rate of growth for the cohort population. The Baby Boomers experienced the largest increase in unique utilizers year-over-year, followed by the X and Y Generations. However, Generation Y experienced the largest percentage increase, followed by the GI and Z Generations. Interestingly, all 6 age bands experienced significant year-over-year growth in unique utilizers (Table 4). During the first period of the study, a ratio of approximately 108 benzodiazepine utilizers per 10,000 members was present. In the second year of the study, the ratio increased to 114 utilizers per 10,000 members, demonstrating noteworthy growth in benzodiazepine utilization. In the Summer and Fall issues of The American Journal of Pharmacy Benefits, the overall generational impact on prescription drug trend was reviewed in detail. 5,9 The Baby Boomers (born between 1946 and 1964) and Generation X (born between 1965 and 1978) were the highest utilizers of the benzodiazepines in both time periods (Figure). But as Table 4 shows, there was a substantial increase in utilization for Generation Y (born between 1979 and 1990) in the July 2008-June 2009 time frame. DISCUSSION The benzodiazepine class experienced a 4.5% PMPM growth in claims and a 5.1% PMPM growth in days supply year-over-year. The CVS Caremark study found a 1.14% prevalence of benzodiazepine utilizers for the July June 2009 period, an increase of 0.06% year-over-year. The number of benzodiazepine utilizers was significantly lower than the number of persons diagnosed with anxiety in a given year, as suggested by several industry experts. This may be due to the popularity of SSRIs for treatment of anxiety. However, we are seeing an increase in benzodiazepine utilization, which may indicate that these agents are used for short-term situational anxiety. In addition, the theory that anxiety is underdiagnosed as well as undertreated may be changing as younger generations are more comfortable seeking assistance. The increase in unique utilizers across all 6 age bands combined with overall growth in benzodiazepine utilization is likely attributable to the additional stresses surrounding the economic recession. The substantial change in the percentage of Generation Y utilizers (higher than other age bands) may be due to several factors including increased prevalence, abuse, dependence, and/or a substantial shift in utilization from other generations. In 2006 and 2007, persons aged Table 4. Unique Benzodiazepine Utilizers by Generation a Total No. of Unique Benzodiazepine Utilizers Generation Period 1 Period 2 % Change YOY GI Silent 42,997 45, Baby Boomer 143, , Generation X 76,253 80, Generation Y 34,856 38, Generation Z 10,167 10, Utilizers, N 313, , Members in study, N 28,908,426 29,385, Utilizers, % YOY indicates year-over-year. a Twelve-month comparison (July 2007-June 2008 [period 1] vs July 2008-June 2009 [period 2]). Source: CVS Caremark Book of Business 2009 Trend Cohort. VOL. 1, NO. 4 The American Journal of Pharmacy Benefits 227

4 n Theodorou Johnson Slezak Szychowski Figure. Percentage of Benzodiazepine Utilization by Generation, July 2008 June 2009 Baby Boomer Generation 43.4% Generation X 22.8% Generation Y 15.8% Silent Generation 12.3% Generation Z 3.6% GI Generation 2.2% Source: CVS Caremark Book of Business Metrics 2009 Trend Cohort excluding Medicare Part D (July June 2008 vs July 2008-June 2009). specific anxiety disorders may also play a significant role in utilization growth as not-for-profit organizations and several media outlets use print, the Internet, and broadcast television to assist the public in obtaining information on anxiety and anxiety-related conditions. 4 The potential for benzodiazepine abuse has been identified. However, metrics obtained in our study did not provide an indication that abuse played a significant role in utilization growth. 18 to 25 years were more likely (17.9%) than any other group to experience serious psychological distress, of which 38.8% of all sufferers received prescription medication. 8 Additionally, those aged 18 to 25 years have the highest prevalence of serious mental illness (7.4%) of all age groups. 8 Although these figures do not show a direct relationship to benzodiazepine utilization, they do demonstrate that this age group is susceptible to stressrelated disorders. A potential contributor to a recent increase in anxiety levels may be attributed to the economic downturn. Anecdotal evidence in the secondary literature suggests that Generation Y members have been most affected by a slumping economy that has shed millions of jobs since the recession was declared to have officially begun in December Consequently, greater job competition leaves job seekers with less experience at a significant disadvantage. According to Labor Department figures, the unemployment rate jumped to more than 11% in December 2008 (compared with less than 9% the previous year) for workers under age 29 years. 11 For those aged 20 to 24 years, the unemployment rate increased to 13%. 10 A disadvantage in professional experience, a sense of entitlement, and the potential for stress-related disorders, combined with financial instability, may be influencing a higher rate of growth in benzodiazepine utilization for Generation Y. Benzodiazepines provide a low-cost, rapid-onset option for the treatment of anxiety and other disorders. Increased awareness of their utility for general and more CONCLUSION The 5.1% increase in benzodiazepine utilization by days supply, an overall increase in the number of utilizers, and the year-over-year prescription claim increases for SSRIs and other antidepressants demonstrate the growing demand for psychotherapeutic medications. Whether the economic recession acts as a primary driver or simply a catalyst, there appears to be a correlation between higher levels of psychotherapeutic drug utilization and the overall economic condition of the country. As the effects of the recession linger and the population ages, benzodiazepine utilization is projected to increase as more people will likely seek relief from symptoms of short-term anxiety. Since benzodiazepines are primarily utilized for shortterm treatment, combined with the class having lowercost generic availability, overall cost trends will be less impacted by benzodiazepine utilization than by utilization of other therapeutic classes and medications that are only available as brand-name products. Consequently, although utilization of the benzodiazepine class is expected to continue to increase, overall class costs should continue to remain low. Author Affiliations: From the Division of Analytics & Outcomes (AAT), CVS Caremark, Scottsdale, AZ; and the Division of Analytics & Outcomes (KMJ, JS, JAS), CVS Caremark, Northbrook, IL. Funding Source: None reported. Author Disclosure: The authors (AAT, KMJ, JS, JAS) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article. Address correspondence to: Anna A. Theodorou, RPh, MBA, Director, Industry Analytics, CVS Caremark, 9501 East Shea Blvd, Mail Code #034, Scottsdale, AZ anna.theodorou@caremark.com. 228 The American Journal of Pharmacy Benefits Winter

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