SEDATIVE-HYPNOTIC PRESCRIBING IN THE UNITED STATES FROM 1993 TO 2010: RECENT TRENDS AND OUTCOMES by Christopher Norfleet Kaufmann A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland July, 2015 © 2015 Christopher Norfleet Kaufmann All Rights Reserved Abstract BACKGROUND: Studies show sedative-hypnotic medications (benzodiazepines [BZDs] and non-benzodiazepine receptor agonists [nBZRAs]) to be associated with adverse outcomes. This dissertation examined prescribing trends of these medications from 1993-2010, and comprised of three studies: study 1 examined trends in prescribing of sedative-hypnotics, study 2 examined physician practice style as a contributing factor for trends seen in study 1, and study 3 examined visits involving sedative-hypnotics in emergency departments (EDs). METHODS: Data for studies 1 and 2 came from the National Ambulatory Medical Care Survey (NAMCS). Study 1 analyzed trends in the proportion of visits from 1993-2010 where a BZD and/or nBZRA was prescribed. Study 2 examined trends in the proportion of physicians prescribing BZDs and nBZRAs, as well as the predicted number of visits (based on regression models) that a BZD or nBZRA was prescribed among BZD and nBZRA prescribers respectively. Data for study 3 came from the Drug Abuse Warning Network. Analyses used logistic regression to determine the association between ED visits involving BZDs and/or nBZRAs and the seriousness of visit outcomes. RESULTS: From 1993-2010, we found increases in the proportion of visits resulting in a prescription for a BZD (from 2.6% to 4.4%, p<0.001) and a nBZRA (from 0% to 1.4%, p<0.001), as well as the co-prescribing of these agents at the same visit (from 0% to 0.4%, p<0.001). Over this same period, we observed increases in the proportion of NAMCS physicians each year who prescribed BZDs (from 23.8% to 44.4%, p<0.001) and ii nBZRAs (from 1.0% to 25.8%, p<0.001), and in the predicted number of NAMCS visits that an nBZRA was prescribed among nBZRA prescribers (from 1.33 to 1.72, p<0.001). ED visits involving BZDs without nBZRAs and BZDs + nBZRAs were associated with increased odds for more serious outcomes compared to visits involving neither medication (odds ratio [OR]=1.34, 95% confidence interval [CI]=1.20-1.50 for BZDs without nBZRAs; OR=3.15, 95% CI=2.01-4.94 for BZDs + nBZRAs). CONCLUSIONS: Efforts to encourage safe prescribing of sedative-hypnotics, and greater dissemination of behavioral treatments for insomnia and anxiety disorders, could have the potential to decrease the public health burden attributed to prescribing of these medications. Advisors: Adam P. Spira, PhD; Associate Professor, Mental Health Ramin Mojtabai, MD, PhD, MPH; Professor, Mental Health Thesis Committee: G. Caleb Alexander, MD, MS; Associate Professor, Epidemiology Lainie Rutkow, JD, PhD, MPH; Associate Professor, Health Policy and Management Karen Bandeen-Roche, PhD; Professor, Biostatistics Alternates: Vanya Jones, PhD, MPH; Assistant Professor, Health, Behavior and Society Jeanine M. Parisi, PhD; Associate Scientist, Mental Health iii Acknowledgements I have received fabulous training and excellent mentorship at Hopkins. Each of you who contributed to my education have done so in a unique way and I want to recognize each of you individually: Adam: A couple days after I graduated from the MHS program, I remember sitting with you in Hampton House Cafe. We were talking about my future as a doctoral student, and you exclaimed, “Who knows! Maybe you’ll do your dissertation research on sleep!” Little did I know that I would become fascinated with sleep and its treatments and focus my research and dissertation work on the topic. You have been a pivotal part of my doctoral education—you’ve been available and enthusiastic about my development as a researcher, challenged me (always with a smile on your face), and advocated relentlessly for me. You have been a wonderful advisor and mentor, and I want to “pay it forward” and be a good mentor to others like you have been for me. Ramin: During my first year at Hopkins, all students were required to take a course called “Perspectives in Public Health Research.” You were one of the guests speakers, and lectured on the rise in prescribing of SSRIs. Needless to say, you did not get through the first three slides of your PowerPoint presentation before the class erupted in debate on the reasons for the increase in SSRI prescriptions. You fed the fire by asking questions—I was lucky to get out of the class session alive! This lecture was representative of your mentorship to me as we continued working together in the following years. You encouraged me to think about ideas in different ways, you taught me to ask creative research questions, and you challenged me while always recognizing iv my strengths. Like Adam, you have been a fabulous mentor and advisor, and I am grateful for your support. Karen: You were the instructor of my first class at Hopkins: Biostatistics 621. While this may seem insignificant, what encouraged me to grow my statistical skills (and consequently further my education) was the fact that you made a point to remember my name. At first, I struggled learning biostatistics because it had been quite some time since I took a math class. By remembering my name and rooting for me after each midterm and final, you helped me gain confidence in my skills in statistics. I’ve enjoyed having you on my committee. Caleb: I have greatly enjoyed being a part of your Center for Drug Safety and Effectiveness. I also feel fortunate to have had the opportunity to travel with you to attend the ISPE conferences in Montreal and Taipei. Interacting with you formally at Center events, and informally during our travels, have taught me about good work ethic and being passionate about my research. Lainie: You were the first person that hired me at Hopkins! After I graduated from the MHS program and before I began doctoral studies, you hired me to help in writing a paper on prescribing authority during disasters. You also connected me with the Cochrane Collaboration to work on their systematic reviews on gabapentin. You planted the seed that got me interested in prescribing trends of psychiatric medications— a topic that would form the basis for my dissertation research. Classmates and friends at Hopkins: Studying at Hopkins can be stressful at times, but having a supportive cohort of colleagues like you made it both tolerable and v fun! I enjoyed our activities together and mutual support we gave each other. I hope that we can continue to collaborate in the future. Mom, Dad, Ginny, Steve, and Cally: Your love and support while I completed my doctoral education helped me get through the good and bad times. You told me that I could do it even when I didn’t believe in myself. I am so grateful that I will be able to build my research career in San Diego and live closer to you. Finally, I have been fortunate to receive funding for my doctoral degree that I would like to acknowledge. This includes a doctoral student scholarship from the Department of Mental Health, a fellowship position on the Drug Dependence Epidemiology Training Program (PI: Debra Furr-Holden, PhD), and an individual pre- doctoral National Service Research Award from the National Institute on Aging. vi Table of Contents Abstract ........................................................................................................................................... ii Acknowledgements ....................................................................................................................... iv Table of Contents ......................................................................................................................... vii List of Tables ............................................................................................................................... viii List of Figures ................................................................................................................................ ix List of Supplemental Tables .......................................................................................................... x Chapter 1: Introduction ................................................................................................................ 1 Overview of dissertation .............................................................................................................. 1 Pharmacology of sedative-hypnotic medications ........................................................................ 3 Prescribing trends up until the early 2000s ................................................................................ 6 Concerns about BZD and nBZRA safety ..................................................................................... 7 Efforts to discourage BZD and nBZRA prescribing .................................................................... 8 Unanswered questions ................................................................................................................. 9 Chapter 2: Trends in prescribing of benzodiazepines and non-benzodiazepine receptor agonists in the United States: 1993-2010 .................................................................................... 11 Chapter 3: Changes in physician prescribing of benzodiazepines and non-benzodiazepine receptor agonists between 1993 and 2010 .................................................................................