MENSTRUALLY RELATED AND NONMENSTRUAL MIGRAINES IN A FREQUENT MIGRAINE POPULATION: FEATURES, CORRELATES, AND ACUTE TREATMENT DIFFERENCES A dissertation presented to the faculty of the College of Arts and Sciences of Ohio University In partial fulfillment of the requirements for the degree Doctor of Philosophy Brenda F. Pinkerman March 2006 This dissertation entitled MENSTRUALLY RELATED AND NONMENSTRUAL MIGRAINES IN A FREQUENT MIGRAINE POPULATION: FEATURES, CORRELATES, AND ACUTE TREATMENT DIFFERENCES by BRENDA F. PINKERMAN has been approved for the Department of Psychology and the College of Arts and Sciences by Kenneth A. Holroyd Distinguished Professor of Psychology Benjamin M. Ogles Interim Dean, College of Arts and Sciences PINKERMAN, BRENDA F. Ph.D. March 2006. Clinical Psychology Menstrually Related and Nonmenstrual Migraines in a Frequent Migraine Population: Features, Correlates, and Acute Treatment Differences (307 pp.) Director of Dissertation: Kenneth A. Holroyd This research describes and compares menstrually related migraines as defined by recent proposed guidelines of the International Headache Society (IHS, 2004) to nonmenstrual migraines in a population of female migraineurs with frequent, disabling migraines. Migraines are compared by frequency per day of the menstrual cycle, headache features, use of abortive and rescue medications, and acute migraine treatment outcomes. In addition, this study explores predictors of acute treatment response and headache recurrence within 24 hours following acute migraine treatment for menstrually related migraines. Participants are 107 menstruating female migaineurs who met IHS (2004) proposed criteria for menstrually related migraines and completed headache diaries using hand-held computers. Diary data are analyzed using repeated measures logistic regression. The frequency of migraines is significantly increased during the perimenstrual period, and menstrually related migraines are of longer duration and greater frequency with longer lasting disability than nonmenstrual migraines. Participants report using more doses of triptans and rescue medication for menstrually related migraines than for migraines occurring at other times during the month. A pain- free response at two hours after acute treatment is half as likely with menstrually related than with nonmenstrual migraines (6.7% vs. 13.4%, OR .45, 95% CI .26-.80). Following a four hour pain-free response, menstrually related migraines are twice as likely to recur within 24 hours as nonmenstrual migraines (36.0% vs. 19.6%, OR 2.12, 95% CI 1.27- 3.53). In addition, birth control medication use is associated with a higher proportion of migraine recurrences (38.6%) after pain-free within 24 hours after initial dosing of acute medication than non-use [22.7%; �2 (1, 107) = 4.97, p=.026]. Pain-free response and headache recurrence is not associated with psychological or gynecological variables. However, use of rescue medication is associated with greater pain catrastrophizing and lack of reproductive event influences on migraines. This research indicates that menstrually related migraines are different from and have less favorable acute treatment outcomes than nonmenstrual attacks. Thus, these findings support the separate diagnostic classification of menstrually related migraine as proposed by the IHS (2004). Approved: Kenneth A. Holroyd Distinguished Professor of Psychology Acknowledgments First, I would like to express my gratitude to Kenneth Holroyd, Ph.D., for providing guidance and support throughout the dissertation process. He possesses a tremendous talent for being able to focus and shape ideas into a final product that is both relevant and comprehensible. He has been responsive with timely and helpful comments and suggestions to improve the overall quality of this research even during periods of personal adversity. Even more importantly, I appreciate his willingness to mentor me by providing me with encouragement and the opportunity to interact with and learn from him over the past several years. Second, I wish to thank Bernadette Heckman, Ph.D., for her role in providing me with emotional support and the wisdom of her experiences. She is a wonderful role model, both professionally and personally. She embodies the spirit of a true scientist- practitioner, and it was a privilege to work with her in the Headache Treatment and Research Project. I have appreciated her assistance in traversing the internship and postdoctoral experience. I also wish to thank the remainder of my committee, Christopher France, Ph.D., Timothy Heckman, Ph.D., and Anne Loucks, Ph.D., for giving of their time and expertise. Each of these committee members was helpful in directing this project and providing insights that guided and challenged my ideas. The overall quality of this project is significantly greater because of their input. I am indebted to the patients who shared their time and information and the numerous administrators and staff members of the Ohio University Headache Treatment and Research Project for assistance in collecting data for this project. Without the cooperation and assistance from the following people, this research could not have taken place: Connie Cottrell, Donna Shiels, Jana Drew, Gregg Tkachuk, Linda Kaufman, Sharon Waller, Raquelle Echelberger, Bernadette Heckman, Carol Nogrady, Kathleen Romenek, Kimberly Hill, Suzanne Smith, and Jessica Gibson. As my graduate education draws to a close, I also wish to thank my family for their love and sacrifices during my years of graduate education in Clinical Psychology. I thank them for sharing my trials and triumphs during this time. I especially thank my husband, Morgan Pinkerman, for his unfailing belief in my ability to succeed. 7 TABLE OF CONTENTS Page ABSTRACT 3 ACKNOWLEDGMENTS 5 LIST OF TABLES 11 LIST OF FIGURES 14 INTRODUCTION 15 Migraine Diagnosis and Epidemiology 17 Migraine Impact on Women 26 Reproductive Events and Migraine in Women 28 Menstruation and Headaches 29 Pregnancy and Migraine 35 Postpartum and Migraine 38 Menopause and Migraine 39 Exogenous Hormines and Migraine 40 Oral contraceptives 40 Hormone therapy 43 Comparison of Menstrually Related and Nonmenstrual Migraines 44 Migraine Pathophysiology and Menstrually Related Migraines 44 Neurochemicals and Migraine Pathophysiology: An Overview 46 Estrogen and Menstrual Migraine Pathogenesis 49 Headache Features and Menstrually Related Migraine 57 Acute Treatment and Menstrually Related Migraines 64 Overview of Acute Migraine Treatment 64 Nonsteroidal Antiinflammatory Drugs (NSAIDS), Combination 66 Analgesics, and Menstrual Migraines Triptans and Menstrually Related Migraines 71 NSAIDS and Triptans: Comparison and Combination 78 8 TABLE OF CONTENTS: continued Acute Migraine Treatment Response and Recurrence 83 Acute Treatment Response 85 Response and Psychological Factors 85 Response and Gynecologic Factors 87 Recurrence Following Acute Treatment 89 Summary and Overview of Present Study 90 METHOD 93 Participants 93 Procedure 106 Measures 109 Eligibility Assessment Measures 109 Structured Headache Interview 109 Migraine Disability Assessment 109 Beck Depression Inventory II 112 Primary Care Evaluation for Mental Disorders 114 Outcome Measure 115 Hand-held Computer Headache Diary 115 Treatment Response and Recurrence Predictor Measures 117 Gynecological History: Long and Short Forms 118 Migraine-Specific Quality of Life Questionnaire 122 Pain Catastrophizing Scale 124 Statistical Analysis 126 Power Analysis 132 RESULTS 133 Prevalence of Headache per Day of the Menstrual Cycle 133 Comparison of Menstrually Related and Nonmenstrual Migraines 135 Headache Features 135 Medication Use per Migraine 142 Acute Treatment Outcomes 146 9 TABLE OF CONTENTS: continued Birth Control Medication and Menstrually Related Migraines 151 Prevalence of Migraines Across the Menstrual Cycle 154 Headache Features 156 Medication Use per Migraine 159 Acute Treatment Outcomes 162 Exploratory Analyses: Predictors of Response and Headache Recurrence Following Acute Treatment of Migraines 166 DISCUSSION 176 Summary of Findings 177 Comparison to Previous Findings 178 Frequency of Menstrually Related Migraines 178 Headache Features of Menstrually Related Migraines 180 Use of Abortive and Rescue Medications per Migraine 184 Acute Migraine Treatment Outcomes 186 Exploratory Analyses: Predictors of Response and Headache Recurrence 192 Implications of Findings 195 Limitations of the Study 198 Future Directions 199 Conclusions 203 REFERENCES 205 APPENDICES 251 Appendix A Handheld Electronic Headache Diary Instructions 251 Appendix B Beck Depression Inventory-II 254 Appendix C Gynecological History, Long Form 259 Appendix D Gynecological History, Short Form 267 10 TABLE OF CONTENTS: continued Appendix E Migriane-Specific Quality of Life Questionnaire 271 Appendix F Pain Catastrophizing Scale 276 Appendix G TSM-Human Subjects Informed Consent Form: Assessment 277 & Treatment Phase Appendix H TSM-Human Subjects Informed Consent Form: Evaluation 283 Phase Appendix I Structured Headache Interview 286 Appendix J TSM Treatment Decision Protocol 290 Appendix K Primary Care Evaluation for Mental Disorders 294 Appendix L Patient Handout on Frequently Asked Medication Questions 301 Appendix M Summary of Repeated Measures Logistic Regression for 306 Anxiety and Depressive Symptoms with Treatment Outcomes 11 LIST OF TABLES Table Page 1. International Headache Society Diagnostic Criteria for Migraine without Aura 19 2. International Headache Society Diagnostic