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 Criteria for Migraine with Aura 20
3. Estrogen and Menstrual Migraine Affect/Effect on Biochemicals Implicated in 51 Migraines
4. Inclusion and Exclusion Criteria for Treatment of Severe Migraine Study 97
5. Demographic Characteristics of the Eligible Participants vs. Treatment of 98 Severe Migraine Study Drop-outs
6. Demographic Characteristics of Participants with Menstrually Related 99 Migraines
7. Headache Diary Characteristics for Participants with Menstrually Related 101 Migraines
8. Self-reported Descriptive Characteristics for Gynecological Variables 102
9. Descriptive Statistics for Psychological Variables 106
10. Summary of Study Measures 110
11. Descriptive Statistics for Migraine Features 137
12. Summary of Repeated Measures Logistic Regression Analysis for Headache 140 Features: Menstrually Related Migraines vs. Nonmenstrual Migraines
13. Descriptive Statistics for Medication Use per Migraine and Treatment 143 Outcome
14. Summary of Repeated Measures Logistic Regression Analysis for Use of 144 Migraine Medications: Menstrually Related Migraines vs. Nonmenstrual Migraines
15. Descriptive Statistics for Treatment Outcomes 147 12
LIST OF TABLES: continued
Table Page
16. Summary of Repeated Measures Logistic Regression Analysis for Treatment Outcomes: Menstrually Related Migraines vs. Nonmenstrual Migraines 149
17. Demographic Characteristics of Participants with Menstrually Related 152 Migraines by Birth Control Medication Use
18. Headache Characteristics for Users and Nonusers of Birth Control 153 Medication
19. Descriptive Statistics for Migraine Features by Migraine Type and Birth 157 Control Medication Use
20. Summary of Repeated Measures Logistic Regression Analysis for Migraine 158 Features by Birth Control Medication Use and Menstrual Status
21. Descriptive Statistics for Medication Use by Migraine Type and Birth 160 Control Medication Use
22. Summary of Repeated Measures Logistic Regression Analysis for 161 Medication Use with Birth Control Medication and Menstrually Related Migraine
23. Descriptive Statistics for Treatment Outcomes by Migraine Type 163 and Birth Control Medication Use
24. Summary of Repeated Measures Logistic Regression Analysis for Treatment 165 Outcomes with Birth Control Medication and Menstrually Related Migraine
25. Descriptive Statistics for Treatment Outcomes by Birth Control for 167 Mentrually Related Migraines Treated with Acute Medication
26. Descriptive Statistics for Treatment Outcomes by Treatment Regimen for 167 Mentrually Related Migraines Treated with Acute Medication
13
LIST OF TABLES: continued
Table Page
27. Summary of Repeated Measures Logistic Regression Analysis for Treatment 168 Treatment Outcomes with Birth Control Medication Use for Menstrually Related Migraines Treated with Acute Medication
28. Summary of Repeated Measures Logistic Regression Analysis for Treatment 169 Outcomes with Treatment Regimen for Menstrually Related Migraines
29. Descriptive Statistics for Gynecological Predictors of Response and 170 Recurrence Following Acute Treatment for Menstrually Related Migraines
30. Descriptive Statistics for Psychological Predictors of Response Following 171 Acute Treatment for Menstrually Related Migraines
31. Summary of Repeated Measures Logistic Regression Analysis for Predictors 172 of Four Hour Pain-free Response after Acute Drug Treatment for Menstrually Related Migraines
32. Summary of Repeated Measures Logistic Regression Analysis for Predictors 173 of Use of Rescue Medication after Acute Drug Treatment for Menstrually Related Migraines
33. Summary of Repeated Measures Logistic Regression Analysis for 174 Gynecological Predictors of Recurrence within 24 Hours Following a Pain-free Response after Acute Drug Treatment for Menstrually Related Migraines
34. Summary of Repeated Measures Logistic Regression Analysis for 175 Psychological Predictors of Recurrence within 24 Hours Following a Pain-free Response after Acute Drug Treatment for Menstrually Related Migraines
35. Comparison of Acute Migraine Treatment Outcomes for Menstrually 187 Related Migraines: Current Study vs. Granella et al.
14
LIST OF FIGURES
Figure Page
1. Gender differences in migraine prevalence by age, adjusted by race, income, 22 urban versus rural residence, and region
2. Menstrual cycle: Hormones, ovulations, temperature 30
3. The pathogenesis of pain in migraine 46
4. Participant flow in the study 95
5. Percent of partcipants with migraine and tension-type headaches per day of 134 the menstrual cycle
6. Proportion of migraines with headache feature by type of migraine 138
7. Headache feature scores by type of migraine 139
8. Odds ratio with 95% confidence interval of headache feature for menstrually 141 related migraines
9. Proportion of migraines treated by type of medication and type of migraine 143
10. Participant medication use by type of medication and type of migraine 144
11. Odds ratio with 95% confidence interval of amount of medication use for 145 menstrually related migraines
12. Headache acute treatment outcomes by type of migraine 148
13. Odds ratio with 95% confidence interval of treatment outcomes for 150 menstrually related migraine
14. Percent of participants with migraine headaches per day of the menstrual 155 cycle by birth control medication use
15. Headache acute treatment outcomes by type of migraine and birth control 164 medication use
15
INTRODUCTION
Migraine is a common, often disabling, disorder that affects twenty-eight million
Americans (Lipton, Stewart, Diamond, Diamond, & Reed, 2001). The estimated prevalence of migraine in women is 18%, compared to just 6% in men (Lipton, Stewart,
Diamond et al., 2001; Stewart, Lipton, Celentano, and Reed, 1992). By age 40, women are three times more likely than men to experience migraine headaches (Lipton, Stewart,
Diamond et al., 2001). The impact of migraines in women is, therefore, considerable, with migraine headaches in women responsible for 80% of the estimated one billion dollars in direct medical expenses spent for migraines and total labor cost losses related to migraines each year (Hu, Markson, Lipton, Stewart, and Berger, 1999).
There is abundant evidence to indicate that migraine in women is related to fluctuations in female hormones (e.g., Bille, 1962; Granella et al., 1993; Marcus, Scharff,
& Turk, 1999; Martin, Burnier, Segre, & Huix, 1971; Neri et al., 1993; Somerville,
1972b). Reproductive events, such as menarche (Bille, 1962), pregnancy (Marcus et al.,
1999; Somerville, 1972b), and menopause (Martin et al., 1971; Neri et al., 1993) are associated with significant changes in migraine frequency. Furthermore, as many as
60% of women experience an increase in migraine frequency associated with their menstrual cycle, while up to 10% of women have migraines only around the time of menstruation (Granella et al., 1993).
However, the character of migraines associated with menstruation is more debatable. Although there is an apparent increase in the frequency of migraine associated with the perimenstrual period (Dalton 1973; Johannes et al., 1995; MacGregor, Chia, 16
Vohrah, & Wilkinson, 1990; MacGregor & Hackshaw, 2004; Stewart, Lipton, Chee,
Sawyer, & Silberstein, 2000; Waters & OConnor, 1971), research findings are mixed in regards to whether migraines during the perimenstrual period are different in quality
(Granella et al., 2004; MacGregor & Hackshaw, 2004; Martin et al., 2000; Martin et al.,
2002; Stewart, Lipton, Chee, et al., 2000; Szekely et al., 1986). Prospective clinical studies indicate significant differences in the severity of headache symptoms across the menstrual cycle (Granella et al., 2004; MacGregor & Hackshaw, 2004; Martin et al.,
2000; Martin et al., 2002; Szekely et al., 1986), whereas a large-sample population-based sample failed to find clinically significant differences in headache features for various phases of the menstrual cycle (Stewart, Lipton, Chee, et al., 2000).
It is also commonly believed that perimenstrual migraines are more difficult to treat than migraines that occur at other times during the menstrual cycle (Massiou &
Bousser, 2000). However, research is emerging that questions this long held belief [e.g.,
Dalessio et al., 1996; Silberstein et al., 1999, 2000; Salonen & Saiers, 1999 (review)].
Several research studies found that triptans and other abortive treatments are effective for menstrually related migraines [Salonen & Saiers, 1999 (review)]. Studies with direct comparisons of menstrually associated and nonmenstrual migraines also suggest that treatment effectiveness is similar for both (Dalessio et al., 1996; Silberstein et al., 1999,
2000).
Although epidemiologic and research findings strongly indicate that an increase in migraine frequency is associated with menstruation, existing research findings are ambiguous in regards to whether menstrually related migraines represent a separate 17 diagnostic entity with unique features and treatment outcomes or simply a variation of migraine resulting from a robust endogenous trigger. Therefore, this study is designed to
1) address this issue prospectively by (a) determining the menstrual cycle migraine distribution, (b) migraine features, and (c) acute medication usage and treatment outcomes for menstrually related and nonmenstrual migraines in a frequent migraine clinical sample. In addition, this research will 2) explore risk factors for nonresponse and headache recurrence within 24 hours following acute migraine treatment for menstrually related migraines.
The introduction will review relevant literature using the following approach.
First, the diagnosis, epidemiology, and impact for menstrually related migraines will be considered in the broader perspective of migraines to establish the importance of researching menstrually related migraines. Second, reproductive events and their affect on migraines will be examined to ascertain the association between female hormones and migraines. Third, nonmenstrual and menstrually related migraines will be compared with respect to pathophysiology, headache features, and treatment outcomes. Last, clinical, gynecological, and psychological correlates of migraine treatment response and headache recurrence within 24 hours following acute migraine treatment will be explored.
Migraine Diagnosis and Epidemiology
Migraine is a neurological disorder currently believed to result from a trigeminovascular system dysfunction, which may be triggered by a variety of different factors, including foods, medications, psychological stress, physical trauma, and menstruation (Buzzi and Moskowitz, 1992). It is characterized by episodic headaches 18 that last four to seventy-two hours in adults. These headaches are accompanied by certain associated symptoms, which include nausea with or without vomiting, and/or photophobia (light hypersensitivity) and phonophobia (sound hypersensitivity)
[Headache Classification Subcommittee of the International Headache Society (IHS),
2004].
A migraine is characterized by at least two of the following pain features: unilateral (one-sided) location, moderate to severe intensity, throbbing or pulsating quality, or exacerbation by routine physical activity (IHS, 2004; see Table 1).
Approximately 10 to 25% of migraine sufferers also report experiencing migraines with aura, which are migraines with fully reversible, focal neurological symptoms. These symptoms involve visual, sensory, and/or dysphasic speech disturbances that develop gradually over 5 to 60 minutes prior to headache onset, with each symptom lasting 5 to
60 minutes (IHS, 2004; see Table 2).
No diagnostic test for migraine exists. Therefore, a migraine diagnosis is determined by the occurrence of migraine signs and symptoms that occur in close temporal relation to the first episode of a headache with migraine features and the exclusion of secondary causes of headache. Tables 1 and 2 detail the diagnostic criteria for migraine without aura (formerly called common migraine) and migraine with aura
(formerly called classic migraines; IHS, 2004).
At present, the Headache Classification Subcommittee of the International
Headache Society (2004) asserts that migraines associated with the menstrual cycle have not been sufficiently validated by research studies to warrant classification as a separate 19
Table 1. International Headache Society Diagnostic Criteria for Migraine without Aura
(2004).
______
Diagnostic Criteria
1. A minimum of 5 headache attacks that meet the criteria described in items
2-5;
2. headaches last from 4-72 hours;
3. at least two of the following pain characteristics must be present: a
pulsating pain quality, moderate to severe intensity, unilateral location,
and headache aggravation with routine physical activity;
4. one of the three following symptoms must occur: nausea, vomiting, or
phonophobia with photophobia,
5. at least one of the following must be confirmed:
a. history and physical do not suggest headaches secondary to
organic or systemic metabolic disease,
b. history and/or physical and/or neurologic examinations do suggest such disorder, but is ruled out by appropriate investigations, or
c. such disorder is present, but migraine attacks do not occur for the first time in close temporal relation to the disorder.
20
Table 2. International Headache Society Diagnostic Criteria for Migraine with Aura
(2004).
Diagnostic Criteria
1. At least two attacks fulfilling criteria 1 4 of Diagnostic Criteria for Migraine Without Aura (see previous)
2. Aura consisting of at least one of the following, but no motor weakness:
a. fully reversible visual symptoms including positive features (e.g., flickering lights, spots or lines) and/or negative features (i.e., loss of vision)
b. fully reversible sensory symptoms including positive features (i.e., pins and needles) and/or negative features (i.e., numbness)
c. fully reversible dysphasic speech disturbance
3. At least two of the following:
a. homonymous visual symptoms and/or unilateral sensory symptoms1
b. at least one aura symptom develops gradually over > five and < 60 minutes
c. each symptom lasts > 5 and < 60 minutes
4. Headache fulfilling criteria 1-4 for Migraine Without Aura (see previous) begins during the aura or follows aura within 60 minutes
5. Not attributed to another disorder (see 5 for Migraine Without Aura)
1Additional loss or blurring of central vision may occur.
21 entity. However, they did propose research criteria for classification of pure menstrual migraines and menstrually related migraines (IHS, 2004). Because studies indicate that migraine without aura is significantly more frequent in patients with menstrually related migraines than migraine with aura (Cupini, et al., 1995; Granella et al., 1993; Johannes et al., 1995; Rasmussen & Olesen, 1992; Russell, Rasmussen, Fenger, & Olesen, 1996), the
Committee (IHS, 2004) recommended that criteria for menstrually related migraines include classification as migraine without aura.
In both of these proposed entities, the migraine attacks must fulfill criteria for migraines without aura and occur on day 1 + 2 (i.e., days 2 to +3, with the first day of menstruation as day 1 and the preceding day as day 1) of menstruation in at least two out of three menstrual cycles. In pure menstrual migraines, the migraine attacks occur at no other times of the cycle, whereas in menstrually related migraines, migraine attacks also occur at other times. Because of a tendency to over report the association of migraines with the menstrual cycle in retrospective data (Diamond and Dalessio, 1982;
Digre & Damasio, 1987; MacGregor et al., 1997), the Headache Classification
Committee (IHS, 2004) recommended that prospectively recorded evidence of migraine occurrence be obtained.
Epidemiologic studies reveal that migraine headache is a chronic, disabling disorder that affects 18% of women and 6% of men in the United States population
(Lipton, Stewart, Diamond et al., 2001; Stewart et al., 1992) and up to 29% of patients presenting in a primary care setting (Couch, Taylor, & Hilliard, 2003; Katzelnick et al.,
2003; Kobak et al., 2005). Although these studies have demonstrated that the prevalence 22 of migraine differs across gender, age, racial, and socioeconomic groups, one of the more consistent findings is that the prevalence of migraine in adults is higher for females than males by a ratio of approximately 3:1 (Lipton, Stewart, Diamond et al., 2001; Stewart et al., 1992). More than fifty population-based studies conducted throughout the world attest to the greater prevalence of migraine among women than among men (Stewart,
Shechter, & Rasmussen, 1994). As shown is Figure 1, these gender differences in prevalence begin at puberty (Abu-Arefeh and Russell, 1994), peak between the ages 35 and 45 during the years in which ovarian follicles decline and reproductive hormones levels, including estrogen, increase in variability (OConner, Holman, and Wood, 2001).
Migraine activity declines, but does not disappear, after menopause (see Figure 1; Lipton and Stewart, 1993; Lipton, Stewart, Diamond et al., 2001).
______
Figure 1. Gender differences in migraine prevalence by age, adjusted by race, income, urban versus rural residence, and region.
30 Female 25 Male 20 15 10 5 % Prevalence 0 0 10 20 30 40 50 60 70 80
Note: From Abu-Arefeh and Russell, 1994; Lipton, Stewart, Diamond et al., 2001. 23
Population-based studies have reported an increased incidence of migraines during the perimenstrual period in women diagnosed with migraine (Johannes et al.,
1995; Stewart et al., 2000; Rasmussen, 1993; Waters & OConnor, 1971). Reports describing prevalence of menstrual or menstrually related migraines are limited, in part, because universally accepted definitions of these entities were lacking in previous research (MacGregor et al., 1990). Using definitions approximating IHS (2004) proposed criteria, Couturier and colleagues (Couturier, Bomhof, Neven, & van Duijn,
2003) found that 3% and 0.85% of women suffered from menstrually associated and pure menstrual migraines, respectively, in a population-based study of 13- to 55-year-old women. In a more select sample of female university students, Dzoljic and fellow researchers (Dzoljic et al., 2002) found 6.1% and 1.5% prevalence rates of menstrually related and pure menstrual migraines, respectively, using definitions similar to IHS
(2004) proposed criteria. Given these figures and recently reported overall migraine prevalence (Lipton, Stewart, Diamond et al., 2001), an estimated 17% to 33% of female migraineurs suffer from menstrually related migraines and approximately 5% to 8% of women with migraines meet the diagnostic criteria for pure menstrual migraines. This translates into approximately four to eight million women in the United States that potentially experience menstrually related migraines, based on current population statistics (Census Bureau, 2004; Central Intelligence Agency, 2004).
The influence of race, ethnicity, or socioeconomic background on migraines in general is important when considering epidemiologic factors affecting migraines associated with menstruation. Notably, migraine prevalence rates have been found to 24 vary by race and ethnicity. When comparing migraine rates by country of residence, studies suggest higher lifetime prevalence rates in North America and Europe (i.e., 8-
28%; e.g., Breslau, Davis, and Andreski, 1991; Cull, Wells, and Miocevich, 1992; Göbel,
Pettersen-Braun, and Soyka, 1994; Pryse-Phillips et al., 1992; Rasmussen, Jensen,
Schroll, and Olesen, 1991; Stewart, Lipton, Celantano & Reed, 1992; Stewart, Lipton, and Liberman, 1996) than in Asia and Africa (i.e., 1.0-9.0%; Alders, Hentzen, and Tan,
1996; Abduljabbar, Ogunniyi, al Balla, Alballaa, and al-Dalaan, 1996; Sakai & Igarashi,
1997; Tekle-Haimanot, Seraw, Forsgren, Ekbom, & Ekstedt, 1995; Wong, Wong, Yu, &
Kay, 1995). Within the United States, the prevalence rates significantly differ across racial groups, with 20% of Caucasians, 16% of African Americans, and 9% of Asian
Americans reported experiencing migraines (Stewart et al., 1996). These differences found across races within the same country suggest that migraine development involves an interaction of genetic vulnerability to migraine and cultural and environmental factors
(Breslau & Rasmussen, 2001).
The relationship between migraine and socioeconomic status is more ambiguous because of conflicting research findings. Several epidemiologic studies have found no relationship between income or education and migraine in North America (Kryst &
Scherl, 1994; OBrien, Goeree, & Streiner, 1994; Pryse-Phillips et al., 1992) and Europe
(Merikangas, Angst, & Isler, 1990; Rasmussen, 1992). However, two large population- based cross-sectional studies in the United States (n=20,468, Stewart et al., 1992; n=12,750, Carson et al., 2004), and an epidemiologic study of European female 25 migraineurs (Markush, Karp, Heyman, and OFallon, 1975) found that household income and level of education were strongly correlated with the prevalence of migraine.
Specifically, Stewart and colleagues found that migraines were 60% more prevalent in the lowest income group (less than $10,000 annual household income) than in the highest income group (more than $30,000 annual household income) in their cross- sectional study. In a population-based study of older adults, Carson and associates
(Carson et al., 2004) reported that individuals with family income less than $16,000, compared to individuals with family income of $75,000 or greater, were significantly more likely to experience migraine headaches. In addition, Markush and colleagues
(Markush et al., 1975) found that the number of migraine symptoms was inversely related to family income in a representative, nonclinical urban sample (n=451) of women, aged
15 to 44.
Markush and colleagues (Markush et al., 1975) also reported that the relationship between educational level and the frequency of migraine symptoms was significant and may be characterized by a U-shaped correlation curve. Women with only an elementary school education, followed by those with some college education, reported the most symptoms of migraine, whereas women who completed high school, but did not go to college, reported the fewest migraine symptoms. Similarly, Carson and associates
(Carson et al., 2004) found individuals with less than 12 years of education had a significantly increased prevalence of migraine with aura.
Breslau and Rasmussen (2001) proposed three explanations for an effect of socioeconomic status on migraines. Differences might reflect a greater tendency for 26 individuals with higher socioeconomic status to consult a physician for migraine (Waters
& OConnor, 1971). In addition, conditions associated with low socioeconomic level
(e.g., poor living standards, stress, limited access to health-care) could lead to an increased prevalence of migraine. Furthermore, increased prevalence of migraines potentially leads to difficulties in maintaining employment, and thus low socioeconomic status, which in turn increases the prevalence of migraine.
Migraine Impact on Women
Migraine contributes to considerable personal and societal burden. Based on estimates of a representative population-based sample (n=3401), 91% of the 27.9 million migraine sufferers in the United States would be classified as functionally impaired by migraines, with 53% requiring bed rest and 51% reducing productivity at work or school during migraine attacks. Perhaps particularly relevant to women, family or social activities were more likely to be disrupted than school or work (Lipton, Stewart,
Diamond et al., 2001; MacGregor, Brandes, Eidermann, & Giammarco, 2004), with an average of 4.2 days missed from family/social/leisure activities as compared to 2.4 days from paid employment (MacGregor et al., 2004). When compared to men, womens headaches were longer in duration, had more symptoms, required more bed rest, and were more disruptive of work and social activities (Lipton, Stewart, Diamond et al.,
2001; MacGregor et al., 2004). For instance, 10% more women missed one or more days of work in the preceding three months than men, with 35% women and 25% men reporting this amount of work loss. Women also describe higher levels of migraine- related disability, with almost twice as many women reporting moderate to severe 27 disability associated with their migraines than men (MacGregor et al., 2004). Hus and fellow researchers (1999) analysis of the American Migraine Study II and U.S. Census projections further illustrated differences in reported disability between men and women.
Women migraineurs were restricted to total bed rest 5.6 days annually in contrast to 3.8 days annually for men. Similarly, women reported more bed rest than men for migraines, averaging six hours bed rest per attack compared to four hours for men.
Because of migraines disportionate prevalence and impact on women, migraines impact on the family is substantial (Lipton et al., 2003; MacGregor et al., 2004). The disruption that migraine attacks imposes on individuals is translated to increased disharmony in family relationships. For example, partners of migraineurs report that migraine negatively impacted communication, time spent with partner, and domestic harmony (Lipton et al., 2003). MacGregor and colleagues (2004) found that 49% of partners of migraineurs affirmed that living with a migraineur had a moderate or great impact on home and family life. In another study (Smith, 1998), frequency and quality of sexual relationships were diminished, resulting in divorce in some situations. In addition, living with a migraineur is associated with decreased work performance and increased job dissatisfaction by partners of people with migraines (Lipton et al., 2003). Thus, the personal and economic burden of migraine extends to household partners of migraineurs.
The burden of migraine involves both direct medical expenditures and indirect economic costs. Hu and others (1999) estimated that annual expenses of migraine treatment in the United States alone include roughly $1 billion dollars in direct and $13 billion in indirect costs; approximately 80% of this financial burden involves female 28 patients. Adults with migraine have been found to have significantly higher annual total direct medical costs when compared to matched healthy cohorts ($7,089 vs. $2,923, p<.0001; Pesa & Lage, 2004).
Indirect cost estimates reported by an employer in one clinic-based study were approximately $3,309 (U.S.) annually per migraine patient for migraine-related lost work productivity (Gerth, Carides, Dasbach, Visser, & Santanello, 2001). When considering lost productivity at home and with other roles, such as work, one estimate of annual indirect costs reported that losses were almost twice as high for female as male migraineurs (Hu et al., 1999). In another large two-year prospective study (n=662), women were two to three times more likely than men to experience reductions in work productivity because of headaches (Stang, Von Korff, & Galer, 1998); thus, the economic burden of migraine disproportionately affects women.
Although these studies provide estimates, the actual economic and personal burden of migraine might not be accurately portrayed in these figures because they do not consider lost economic potential (Rains, Penzien, and Martin, 2002). Chronic, disabling disorders, such as migraine, might lower expectations and restrict occupational choices, and, as a consequence, limit professional growth, achievement, and advancement. These limitations could be especially detrimental to women when combined with gender discrimination to upward mobility in the workplace.
Reproductive Events and Migraine in Women
Considerable evidence indicates that migraine (reviews: Digre & Damasio, 1987;
MacGregor, 2000; Silberstein & Merriam, 1999) and other primary headaches (Nappi et 29 al., 1983; Rasmussen, 1993) are related to fluctuations in female hormones associated with the menstrual cycle and with various reproductive events. Both endogenous and exogenous female hormones can influence migraine occurrence throughout a womens life. The normal female hormonal milestones, including menstruation, pregnancy, and menopause, will be reviewed with reference to associated changes in migraine patterns.
In addition, the effects of oral contraceptive and hormone therapy on migraines will be discussed.
Menstruation and Headaches
The menstrual cycle is governed by smooth changes in hormone levels requiring coordinated activity of the hypothalamus, pituitary, ovaries, and uterus. The hypothalamus secretes gonadotropin-releasing hormone (GnRH), the pituitary secretes luteinizing hormone (LH) and follicle-stimulating hormone (FSH), the ovary secretes estrogens, progesterone, inhibins, and other ovarian modulators, and the endometrial lining of the uterus responds to estrogen and progesterone. Ovarian estrogen, primarily estradiol, and progesterone secretion provide feedback to the pituitary to modulate the relative amounts of LH and FSH and to the hypothalamus to control GnRH (see Figure 2;
Espey and Lipner, 1994; Silberstein & Merriam, 1999).
The target of FSH and LH is the ovary where the hormones stimulates follicular growth. The growing follicle produces estrogen; as estrogen levels rise, FSH initially falls. At mid-cycle, however, there is a reversal of this trend, and a large surge of FSH and LH secretion is produced. This surge is triggered by a small rise in progesterone and temporary inhibition of estrogen production resulting from high levels of estrogens 30 causing feedback inhibition. This surge in LH is followed 16 to 32 hours by ovulation and the transformation of the follicle into the corpus luteum, which secretes progesterone and estrogen (Silberstein & Merriam, 1999).
Estrogen stimulates development and growth of the endometrium; progesterone causes the endometrium to secrete various substances, including the vasoactive peptides and prostaglandins. If fertilization of the mature oocyte (ovum) does not occur, the corpus luteum recedes 10 to 12 days after ovulation, followed by rapidly falling estrogen and progesterone. Progesterone withdrawal leads to arterial spasms and menses
(Silberstein & Merriam, 1999). Menstruation normally occurs 14 days following ovulation (Espey and Lipner, 1994).
Figure 2. Menstrual Cycle: Hormones, ovulation, temperature1.
Note: From http://embryology.med.unsw.edu.au/wwwhuman/MCycle/MCycle.htm. 31
Menstruation is described as a precipitating factor, or trigger, for several headache disorders, including migraines [Karli, Zarifoglu, Calisir, & Akgoz, 2005;
Rasmussen, 1993; Silberstein & Merriam, 1999 (review)], tension-type headaches
[Rasmussen, 1993; Marcus, 2001 (review)], and chronic daily headaches [Marcus, 2004
(review)]. The proportion of women reporting menses as a trigger for headaches is similar for migraine and tension-type headaches, with reports ranging from 24% to 68% for women listing menstruation as a trigger (Karli, Zarifoglu, Calisir, & Akgoz, 2005;
Rasmussen, 1993; Rothrock, Patel, Lyden, & Jackson, 1996; Scharff, Turk, & Marcus,
1995). Few studies have studied the role of reproductive events and chronic daily headache, but estimates indicate less influence (Marcus, 2004). Menses was reported as a precipitating factor in chronic daily headache in less than 10% (Deleu, 1999) and in 30
% (Lantéri-Minet et al., 2003) of women in two independent studies. This general tendency for primary headache disorders to be associated with menstruation may be associated with an impaired ability of the individual to adapt to cyclic internal biological changes, resulting in an increased risk of clinical symptomatology, including headaches
(Nappi et al., 1983).
In particular, the association between menstruation and migraine has been studied extensively. In 1972, Somerville (1972a) noted that menstrual migraines occurred during or after the rapidly falling levels of estrogen and progesterone prior to menstruation.
Further research indicated that estrogen, but not progesterone, administration given premenstrually delayed the onset of migraine but not menstruation (Somerville, 1971;
Somerville, 1975a, b). Somerville (1975) concluded that estrogen withdrawal could 32 trigger pure menstrual or menstrually related migraines in susceptible women. Other researchers supported this conclusion by finding that percutaneous estradiol gel preparations (de Lignieres, Vincens, Mauvais, et al., 1986; Dennerstein et al., 1988;
Mago, Zilka, & Studd, 1983) and subcutaneous estradiol implants (Magos, Zilka, &
Studd, 1983; Whitty, Hockaday, & Whitty, 1986) were similarly effective in preventing menstrual migraines.
Although changes in progesterone levels might not trigger a migraine, progesterone, as well as estrogen, could play a role in reducing pain severity and disability in female migraineurs. A more recent study found that women at the midluteal phase of their menstrual cycle during the associated period of high levels of estrogen and progesterone recorded the lowest migraine severity and disability when compared to the other phases of the menstrual cycle (Martin et al., 2000). Thus, research suggests that both estrogen and progesterone affect migraines across the menstrual cycle.
Research suggests a number of potential biochemical mechanisms by which menstrual cycle changes in estrogen and progesterone levels exert their effects on migraines. Estrogen could affect migraine pain mechanisms through its influence on regulatory pathways in the brainstem, such as serotonergic (Bethea, Pecins-Thompson,
Schutzer, Gundlah, and Lu, 1998), adrenergic (Klangkalya and Chan, 1988), and opiatergic (Genazzani, Petraglia, Volpe, & Facchinetti, 1985; Facchinetti, Martignoni,
Fioroni, Sances, and Genazzani, 1990) systems or through direct (Magness & Rosenfeld,
1989) or indirect (Sarchielli et al., 1996; Shimomura, Murakami, Kotani, Ikawa, and
Kono, 1999) vascular effects. While fluctuating estrogen levels potentially activate pain 33 pathways, progesterone and its metabolites possibly exert the opposite effect by being an agonist of �-aminobutryric acid receptors (Rupprecht, Hauser, Trapp, & Holsboer, 1996),
postsynaptic receptors that appear to exert an inhibitory effect on the trigeminal pain
pathways.
In the United States, the median age of menarche is at 12.43 years, with 90% of
all girls menstruating by 13.75 years (Chumlea et al., 2003). Age of menarche is
genetically determined as well as a function of numerous health aspects of a population,
including growth and nutritional status and environmental conditions (Chumlea et al.,
2003). Under the control of the Central Nervous System (CNS), menarche involves
carefully orchestrated changes in the ovaries and ovarian hormone production (see Figure
2; Silberstein & Merriam, 1999).
Before these hormones changes at puberty, migraine is about equally distributed
between males and females (Abu-Arefeh and Russell, 1994, Bille, 1962; Stewart, Linet,
Celentano, Van Natta, and Ziegler, 1991). However, in one-quarter to one-third of
female migraine sufferers, menarche is associated with the first migraine attack (Epstein,
Hockaday, and Hockaday, 1975; Nattero, 1982), especially for women with migraine
without aura (Russell et al., 1996). Beginning at puberty and its associated increase in
ovarian hormone production, migraine prevalence is greater for females than males (see
Figure 1; Abu-Arefeh and Russell, 1994; Bille, 1962; Stewart et al., 1991; Stewart et al.,
1994; Lipton, Stewart, Diamond et al., 2001), reaching nearly a 4:1 ratio of female to
male prevalence by age 40 (se Figure 1; Stewart et al., 1992; Stewart et al., 1994; Lipton,
Stewart, Diamond et al., 2001). By adulthood, 24% to 68% of female migraineurs report 34 that migraine attacks occurs during the time of menses (Epstein et al., 1975; MacGregor et al., 1990; MacGregor et al., 2004; Scharff et al., 1995).
Peak incidence of migraine for women is reported to be within two days of the first day of menses (Dalton, 1973; Granella et al., 2004; Johannes et al., 1995;
MacGregor et al., 1990; MacGregor & Hackshaw, 2004); Pinkerman and Holroyd, 2003;
Stewart et al., 2000; Waters & OConnor, 1971). Migraines during the perimenstrual period have been reported to last longer (Granella et al., 2004; Martin et al., 2000, 2002), to be more painful (Granella et al., 2004; MacGregor & Hackshaw, 2004; Martin et al.,
2000, 2002), and to be associated with more disability (Granella et al., 2004; Martin et al., 2000, 2002). However, these results were not replicated in a community-based population (Stewart et al., 2004).
Although a continuum, the menstrual cycle is generally considered to begin on the first day of the menses and to end on the last day before the next menses (Espey and
Lipner, 1994). The average woman has a cycle length of 28 days (range=25 to 34; Espey and Lipner, 1994), a menstrual flow that lasts for five days (range=three to seven; Espey and Lipner, 1994), and an average blood loss of 40 mL (range=20 to 80 mL; Hallberg,
Högdahl, Nilsson, & Rybo, 1966). Research suggests that migraines (Breslau and Davis,
1993; Grant, 1965; Johannes et al., 1995; Tietjen, Conway, Utley, and Herial, 2003) and chronic daily headaches (Hotovy, Rains, Davig, & Penzien, 1997) are associated with menstrual abnormalities (see Acute Migraine Treatment Response and Recurrence section below). 35
Pregnancy and Migraine
With pregnancy, the secretion of a new hormone, human chorionic gonadotropin
(hCG), prolongs the lifespan of the corpus luteum. It functions to maintain progesterone and estrogen levels until approximately the ninth to tenth week of gestation, by which time the placenta's production of estrogen and progesterone is well established. During early pregnancy, estrogen and progesterone levels fluctuate with the waxing and waning of the corpus luteum (Yoshimi, Strott, Marshall & Lipton, 1969). Both estrogen and progesterone increase rapidly during the first trimester of pregnancy and stabilize at a level 100 times those of cycling women. Estrogen level increases are primarily associated with the production of estriol by the placenta from androstenedione, which is produced by the fetal adrenal gland. The placenta produces progesterone from maternal cholesterol.
Both estrogen and progesterone levels drop sharply approximately 24 hours before the onset of labor (Espey and Lipner, 1994).
Migraines in pregnancy are most common in the first trimester, which correlates with fluctuations of estrogen and progesterone levels associated with the waxing and waning of the corpus luteum (Yoshimi et al., 1969). In the second and third trimesters of pregnancy when estrogen levels are high and relatively stable, migraine headaches generally improve (Callaghan, 1968; Critchley & Ferguson, 1933; Silberstein, 1997).
Retrospective studies indicate that 48-80% of women with migraines, especially migraine without aura, reported an improvement or a disappearance of migraine during pregnancy
(Bousser, Ratinahirana, & Darbois, 1993; Callaghan, 1968; Granella et al., 1993; Lance and Anthony, 1966; Maggioni Alessi, Maggioni, & Zanchin, 1997; Rasmussen, 1993; 36
Somerville, 1972b), with the majority of studies reporting that greater than two-thirds improved (Bousser et al., 1993; Granella et al., 1993; Maggioni et al., 1995; Somerville,
1970). This improvement is more frequent in women whose migraines began at menarche
(Granella et al., 1993; Somerville, 1972b) or whose migraines occur regularly with their menstrual cycle (Bousser et al., 1993; Epstein et al., 1975; Lance & Anthony, 1966).
Prospective studies of migraine during pregnancy, however, have produced mixed findings. In one small-scale study of pregnant women with chronic headaches (n=49),
Marcus and colleagues (1999) surveyed women about their experiences with migraine during their first trimester and, starting with the second trimeter, had women use a daily headache diary to monitor their migraine activity. They found significant improvement of migraines reported through self-report in the first trimester of pregnancy, but this improvement did not significantly differ from the improvement demonstrated by pregnant women with tension-type headaches. The daily recordings in the second and third trimester yielded no significant changes over time. However, this might be due to relatively stable estrogen levels during this period of the pregnancy and, therefore, significant changes in headache activity would not be expected.
Two other prospective studies demonstrated significant improvement in migraines during pregnancy. In a large-scale prospective study of 40,273 patients, Chen and
Leviton (1994) found that most women (79%) with a history of migraine before pregnancy experienced a reduction (62%) or disappearance of migraines (17%) during pregnancy. This study had several shortcomings. The 484 migraineurs were drawn from a large sample of pregnant women (n=40,273), with some of the data collected as long 37 ago as 1959-1966, which was before diagnostic criteria for migraine were well established (IHS, 1988). The low prevalence of migraine (1.3%) suggests that many of the migraine sufferers were not diagnosed; thus, the resulting sample is not representative.
However, another prospective study confirmed these results. Of 49 migraine patients (two with migraine with aura and 47 with migraine without aura), migraine improved in 46.8% of 47 women with migraine without aura during the first trimester, in
83.0% during the second, and in 87.2% during the third. Complete remission was achieved by 10.6%, 53.2%, and 78.7% of the women in each trimester, respectively
(Sances et al., 2003).
For a minority of women, migraine headaches during pregnancy lack improvement or become worse. This occurs in 5% to 30% of female migraineurs, and is more common in women whose migraines meet the IHS criteria for migraine with aura
(IHS, 1988; Bousser et al., 1993), in women with menstrually related migraine before pregnancy (Sances et al., 2003), in women who are multigravidas (i.e., pregnant women who have been pregnant one or more times previously; Chen and Leviton, 1994), and in women with hyperemesis (i.e., severe and intractable nausea and vomiting) or a pathological pregnancy course (Sances et al., 2003). Of note, approximately 10-15% of women experience their first migraine during pregnancy (Bousser et al., 1993;
Chancellor, Wroe, & Cull, 1990; Somerville, 1972b; Uknis & Silberstein, 1991).
However, this phenomenon might be associated with a treatment referral bias related to neurologic symptoms in migraine with aura (Wright & Patel, 1986). 38
Although rising or sustained high levels of estrogen might be responsible for the improvement in headache during pregnancy, this mechanism cannot explain the worsening or new onset of migraine that sometimes occurs in pregnancy. Silberstein &
Merriam (1991) proposed that the sensitivity of the intrinsic estrogen receptor of the hypothalamic neuron could differ in some women. In most women, rising or high stable estrogen levels decrease migraine attacks, whereas in the minority of women these changes actually trigger migraine.
Postpartum and Migraine
The large hormonal and metabolic changes following delivery, including the rapid fall in the level of sex steroids, weight loss, and alterations in serotonin metabolism, are associated with increases in headaches during the first post-partum week (Sances et al.,
2003; Stein, 1981; Stein et al., 1984). Postnatal headaches are common; over one-third of all women, and nearly two-thirds of women with migraine reported headaches during the first postpartum week. Increased risk for postnatal headaches is related to a prior personal or family history of migraine, especially for migraines associated with the menstrual cycle (Marcus, et al., 1999; Stein 1981; Stein et al., 1984). For women with a prior history of migraines, the postnatal migraines are often described as less painful than their typical migraine headaches (Stein 1981; Stein et al., 1984). Findings of one study suggest that breast-feeding might protect women from migraine recurrence during postpartum (Sances et al., 2003) but demonstrated no effect on headache activity in another (Marcus et al., 1999).
39
Menopause and Migraine
As women age and produce fewer developing follicles, a decline in the protein, inhibin, occurs. Luteal and follicle production of inhibin is stimulated by FSH secretion and increasing levels suppress FSH secretion. Because of declining production of inhibin,
FSH increases, which initially results in greater estradiol production among women aged
45 to 50 while they are still menstruating. During the perimenopausal years, the menstrual cycle becomes irregular and tremendous fluctuations in estrogen occur.
However, overall estrogen levels are usually well maintained until late perimenopause.
In the transition to menopause, LH levels increase and estradiol levels decline markedly as ovarian follicular cells are depleted in postmenopausal women. After meopause, the ovary is virtually devoid of follicles and is no longer a primary site of estrogen and progesterone synthesis (Burger, Dudley, Roberton, & Dennerstein, 2002; Espey and
Lipner, 1994).
In the perimenopausal years, hormonal fluctuations are related to worsening of migraine headaches (Silberstein & Merriman, 1991; Wang et al., 2003). But with advancing age, migraine prevalence decreases (Lipton and Stewart, 1998; Stewart et al.,
1992). Changes in migraines during perimenopause and menopause are more likely to occur when there was a history of premenstrual syndrome (Mattsson, 2003; Wang et al.,
2003) or migraines associated with menses (Wang et al., 2003).
In spontaneous menopause, two-thirds of women with migraine experience improvement (Neri et al., 1993; Granella et al., 1993; Wang, Fuh, Lu, Juang, & Wang,
2003). However, surgical menopause is associated with exacerbation of migraine 40 symptoms in as many as two-thirds of female migraineurs (Neri et al., 1993; Granella et al., 1993; Wang, Fuh, Lu, Juang, & Wang, 2003). This relationship exists whether the surgical menopause involved a hysterectomy only or a hysterectomy with unilateral or bilateral ovariectomy (Wang et al., 2003). Although the relationship between migraine prevalence and severity is supported by multiple studies, the underlying mechanism is not understood. Hysterectomy has been reported to be associated with early ovarian failure when compared to women undergoing spontaneous menopause (Siddle, Sarrel, &
Whitehead, 1987). The increased frequency and severity of migraines associated with surgical menopause may be related to preexisting conditions that lead to surgery or to a disturbed hormonal environment following the hysterectomy (Wang et al., 2003).
Exogenous Hormones and Migraine
Oral Contraceptives
The most common oral contraceptives used in the United States contain combinations of synthetic estrogen and progestogen taken 21 days each month, followed by 7 days of no tablets or placebo tablets (Crosignani, Parazzini, La Vecchia, Meroni, &
Ricci, 1997). The synthetic estrogens are either ethinylestradiol or mestranol; the progestins are a synthetic derivative of 9-norprogesterone. The doses of estrogen can remain the same (i.e., monophasic) or vary (i.e., biphasic or triphasic; Loder, Buse, &
Golub, 2005). Doses of estrogen have decreased in recent years to reduce the risk of thrombotic complications, with no reduction in contraceptive efficacy (Petitti, 2003).
Today, most low-dose estrogen oral contraceptives contain < 30 µg ethinylestradiol 41
(Massiou & MacGregor, 2000); some formulations have been reduced as low as 15 µg
(Allais, De Lorenzo, Mana, & Benedetto, 2004).
Combined oral contraceptives interfere with the midcycle surge of hypothalmic and pituitary gonadotripins, thus preventing ovulation (Wentz, 1985). Another hormonal contraceptive method involves progestogen-only pills and injections, which inhibits the
LH surge (Wentz, 1985). Progestogen-only pills generally do not entirely abolish the ovarian cycle; therefore, fluctuations in estrogen levels can still occur. However, the injectable progestogen usually inhibits the ovarian cycle and induces amenorrhoea
(Wentz, 1985).
Migraines can be induced, changed, or alleviated by oral contraceptives (Becker,
1999). Early studies found that the onset of new migraines was significantly more common in women taking oral contraceptives than in those who were not (Larsson-Cohn
& Lundberg, 1970; Ryan, 1978) and usually occurred with initiation of use (Ryan, 1978).
More recent studies, including double-blind, placebo controlled studies, have found that the prevalence of migraine was not significantly different for oral contraceptive users than for nonusers (Couturier et al., 2003; Silberstein, 1991). In one study of female university students (n=1943), no participant reported that the initiation of birth control medication use was associated with the beginning of migraine attacks (Dzoljic et al.,
2002). Overall, headache incidence with use of oral contraceptives has reduced from approximately 10% with earlier formulations (Guillebaud, 1983) to roughly 5% with oral contraceptives containing 30 µg of ethinylestradiol (Fotherby, 1998) and to <2% with oral contraceptive containing 20 µg ethinylestradiol (Fotherby, 1992). 42
Research findings for the influence of oral contraceptives on the severity and pattern of migraines are highly variable (Massiou & MacGregor, 2000). In 30% to 50% of women with migraine, oral contraceptive use results in no difference or an improvement in migraine patterns (Cullberg, 1972; Nilsson and Solvell, 1967; Ryan,
1978). However, studies from neurologic or migraine clinics indicate that existing migraines may exacerbate during use of combination pill oral contraceptives, with headaches more likely to occur in the drug-free interval of the cycle when estrogen levels are rapidly declining (Carroll, 1971; Dalton, 1976; Kudrow, 1975; Phillips, 1968; Whitty et al., 1986). Although discontinuation results in headache relief in approximately seventy percent of woman, improvement might not occur after stopping of the oral contraceptives, and delays in headache relief of one year or longer have been reported
(Kudrow, 1975; Dalton, 1976).
These research findings, however, were not replicated in the primary care setting.
Studies from contraceptive clinics and general practitioners are more likely to report either improvement or no worsening of migraines by oral contraceptive users (Culberg,
1972; Goldzieher, Moses, Averkin, Scheel, & Taber, 1971; Kappius & Goolkasian, 1987;
Ramcharan, Pellegrin, Ray, and Hsu, 1980; Ramos, Apelo, Osteria, and Vilar, 1989).
Moreover, Holroyd and Lipchik (2000) noted that studies reporting an increase in frequency or severity of headaches in women taking oral contraceptive were performed principally in the 1960s and 1970s when oral contraceptives contained higher estrogen content than is common today. Additional research using current oral contraceptives is needed to clarify the influence of oral contraceptives on migraine. 43
Hormone Therapy
Hormone therapy (HT) with estrogens, alone and in combination with progestins or androgens, is used to relieve symptoms in perimenopausal and menopausal women.
Estrogens, alone and in combination, are usually administered sequentially for 25 days per month, although they can be administered daily. Initiation of cyclic HT, however, might exacerbate migraine for women who are susceptible to fluctuations in estrogen and progesterone (Kudrow, 1975).
Overall, the findings for the effect of HT on migraine are variable. In one large- scale (n=17,107) population-based study, Misakian and fellow researchers (2003) reported that the odds of having a migraine headache was 1.42 greater for women who were current users of HT than for never users (OR=1.42, 95% CI=1.24-1.62). However, these results were not confirmed in a smaller (n=728) population-based study (Mattsson,
2003).
Clinical studies also reported variable findings; estrogen therapy for menopausal symptoms exacerbated migraine (Aylward, Holly, & Parker, 1974; Kudrow, 1975) alone
(Martin, Burnier, Segre, & Huix, 1971) or in combination with testosterone (Greenblatt
& Bruneteau, 1974). In an attempt to optimize HT treatment, Facchinetti and fellow researchers (Facchinetti, Nappi, Tirelli, Polatti, & Nappi, 2002) evaluated three regimens of oral HT [i.e., 1) continuous combined, 2) combined with progesterone added in the last
14 days, and 3) a sequential cyclical scheme] following a seven-day run-in period.
However, each HT regimen significantly increased the frequency and severity of migraines, although the duration of the migraine decreased. 44
Double-blind studies concurred with these variable findings. Exacerbation of migraine by HT was confirmed in two studies (Coope, 1975; Facchinetti et al., 2002), while migraine relief by HT was noted in another (Campbell, 1975). Additional controlled studies on the influence of HT on migraine are needed to clarify these mixed findings.
Comparison of Menstrually Related and Nonmenstrual Migraines
In order to validate the proposed IHS (2004) diagnostic criteria for menstrually related migraines, physiological, clinical, and treatment distinctions between menstrually related and nonmenstrual migraines need corroboration by empirical studies. At the present, there is a paucity of research involving direct comparisons of these entities.
Therefore, studies that characterize, as well as compare, menstrual and menstrually related will be reviewed.
Migraine Pathophysiology and Menstrually Related Migraines
In theory, the physiological etiology of menstrually related and nonmenstrual migraines could differ, resulting in different clinical features or a different treatment response (Nappi, Costa, Tassorelli, & Santorelli, 2000). Although the pathophysiology of menstrually related migraines is not altogether understood, a cyclical drop in estrogen levels is believed to trigger physiologic changes in the pain regulatory pathways in the brainstem or in the vascular system (Rains, Penzien and Martin, 2002). Notably, ovarian steroids play a limited role in the overall regulation of the menstrual cycle. Therefore, it is likely that the effect of falling estrogen levels on the development of menstrually related migraine is related more to its effect on other biochemical and metabolic 45 pathways, rather than a direct effect of estrogen or other sex hormones (MacGregor,
2000).
In order to understand the pathophysiology of menstrual migraines, it is important to briefly review the systems involved in migraine in general. Four key factors play a role in the pathogenesis (see Figure 3): 1) the central nervous system; 2) the cranial blood vessels; 3) the trigeminal innervation of the vessels; and 4) the reflex connections of the trigeminal system with the cranial parasympathetic outflow (Goadsby, Lipton, and
Ferrari, 2002; see Figure 3). While the brain itself is mostly insensitive, the large cranial vessels, the proximal intracranial vessels, or the dura mater can produce pain. Branches of the trigeminal nerve stimulate these vessels.
According to Moskowitzs (1993) trigeminal model, a hypersensitivity of the trigeminal system to certain stimuli causes changes in the neurotransmission of serotonin from the dorsal raphe nucleus and norepinephrine from the locus ceruleus. The dysfunction of these brain-stem pathways results in a cascade of vasodilatation of cranial blood vessels and plasma extravasation, or leakage of plasma proteins, into the dura mater. Although the mechanism of pain generation is not completely understood, a potent cranial vasodilator is released during extravasation, leading to neurogenic inflammation, which, in turn, leads to a migraine headache. 46
Figure 3. The pathogenesis of pain in migraine1.
Note: From Goadsby, P., Lipton R., Ferrari, M., (2002). Migraine. Current understanding and treatment. The New England Journal of Medicine, 346, 257-270. ©
2002. Massachusetts Medical Society. All rights reserved.
Neurochemicals and Migraine Pathophysiology: An Overview
Several biochemicals have been implicated in migraine pathophysiology. For example, neuroamines appear to occupy a pivotal role in the pathogenesis of migraine
(Kornstein & Parker, 1997). Several studies have demonstrated a relationship between 47 increased serotonin transmission and headache (DAndrea, Hasselmark, Cananzi, &
Alecci, 1995; Curren, Hinterberger, & Lance, 1965). Serotonin is involved in the transmission of noxious stimuli and generation of nausea by stimulating the area postrema, a brain stem area bordering the fourth ventricle.
Norepinephrine and norepinephrine metabolite plasma levels have been found to decrease (Fog-Miller, Genefke, & Bryndum, 1978) and increase (Curren, Hinterberger, and Lance et al., 1965), respectively, during a migraine attack. In addition, a growing body of evidence suggests dopamine is involved in the pathophysiology of migraine
(Rebaudengo et al., 2004; Fanciullacci, Alessandri, and Rosso, 2000), although some believe its role is secondary to serotonin (Mascia, Afra, and Schoenen, 1998).
Studies also indicate that changes in the �-endorphin system are involved in migraine development (Kornstein & Parker, 1997). Interictal plasma levels of �- endorphin in migraine patients were found to be lower than in age-matched controls
(Helm-Hylkema, Orlebeke, Enting, Thijssen, and van Ree, 1990). During an acute migraine attack, plasma and cerebrospinal fluid levels of �-endorphin decline significantly (Anselmi, Baldi, Casacci, & Salmin, 1980; Della-Bella et al., 1982; Fettes,
Gawel, Kuzniak, & Edmeads, 1985; Leone, Sacerdote, DAmico, Panerai, & Bussone,
1992; Vecsei et al., 1992).
Prostaglandins also appear to be involved in migraine pain by decreasing noradrenergic transmission, sensitizing nociceptors, and promoting neurogenic inflammation (Silberstein, 1992). Production of a throbbing headache has been demonstrated to occur after infusion of prostaglandins in man (Bergström, Carlson, 48
Ekelund, and Orö, 1965; Carlson, Ekelund, & Orö, 1968). Prostaglandin plasma levels have also been shown to significantly increase during spontaneous migraine attacks
(Sarchielli, Alberti, Codini, Floridi, and Gallai, 2000).
Olesen and colleagues (Olesen, Thomsen, Lassen, & Olesen, 1995) proposed a nitric oxide hypothesis of migraine. Nitric oxide is a potent vasodilator produced by the endothelium (Sarchielli et al., 2000). Significant increases in platelet nitric oxide
(Shimomura , Murakami, Kotani, Ikawat and Kono, 1999) and blood nitric acid
(Sarchielli et al., 2000) metabolites have been reported during spontaneous migraine when compared to controls.
Pineal gland dysfunction, with associated abnormal secretion of melatonin, has been proposed as an important mediator in the pathogenesis of migraine (Sandyk, 1992;
Toglia, 1986). Compared to controls, patients with both migraine and tension-type headache demonstrated a significantly lower nocturnal plasma melatonin level during the time that the plasma level of melatonin typically peaks (Claustrat et al., 1989). In contrast to these findings, a questionnaire study of an Arctic population suggested that prolonged light exposure during the bright Arctic summer season, not prolonged darkness, was more likely to trigger headaches in migraine patients than in nonmigranous headache patients (Salvesen & Bekkelund, 2000). Claustrat and fellow researchers
(Claustrat, Brun, Chiquet, Chazot, & Borson-Chazot, 2004) found that melatonin suppression following light exposure was more pronounced in migraineurs than healthy controls. In addition, research suggests that melatonin administration might relieve migraine symptoms (Claustrat et al., 1997). 49
Estrogen and Menstrual Migraine Pathogenesis
Numerous studies have demonstrated the effect of estrogen on the aforementioned biochemicals that are involved in migraine pathophysiology (see Table 3; Kornstein &
Parker, 1997). Although estrogen withdrawal prior to menses might trigger menstrual migraines (Somerville, 1972a), estrogen appears to exert an indirect effect primarily on the pain modulatory brainstem pathways, such as the serotonergic, noradrenergic, dopaminergic, and opiatergic systems, or through indirect vascular effects (Kornstein &
Parker, 1997; Rains et al., 2002). Research on the pathophysiology of menstrual migraines, thus far, has been limited from lack of an accepted definition of menstrual migraine (MacGregor, 1996) and from lack of comparison to nonmenstrual migraines.
Research indicates a direct relationship between serum estradial and blood serotonin levels (Marcus, Scharff, & Turk, 1996). Because central measures of serotonin are impractical, alternate measures have been investigated, including platelet serotonin levels. Platelets serve as reservoir for serotonin and possibly mirror central neuronal activity because of similarities in uptake, storage, metabolism and receptor binding
(Marcus, 1995).
Nattero and colleagues (1988) found significantly increased platelet serotonin levels perimenstrually in women with menstrual migraine (i.e., onset of the migraine attack only prior to, during, or at the end of menstruation) when compared to healthy controls. However, during a spontaneous migraine attack, women with menstrual migraine exhibited a marked decline in platelet serotonin levels to below the level of controls. These results were duplicated in a subsequent study of patients with migraines 50 associated with menstruation (i.e., migraines occurring exclusively from day 3 to day +4 of the menstrual cycle; Fioroni, DAndrea, Alecci, Cananzi, & Facchinetti, 1996). These findings suggest that increased catabolism of platelet serotonin occurs in women prior to menstruation, and that this effect is exaggerated in women with menstrually related migraines (de Belleroche, 1996).
Norepinephrine has also been associated with estrogen and its effects on brainstem pain pathways and on blood vessels (Marcus, Scharff, Turk, 1996). Estradial receptor sites have been found in the nuclei of numerous norepinephrine-rich brainstem areas (Heritage, Stumpf, Sar, and Grant, 1980). Norepinephrine regulation by estrogen has been demonstrated in several studies on animals (Barclay & Harding, 1990; Condon,
Ronnekleiv, & Kelly, 1989; Wagner, Crutcher, & Davis, 1979). Animal studies have also demonstrated that vasoconstriction produced by norepinephrine is dependent on estrogen (Ikeda & Ikenoue, 1994; Miller & Vanhoutte, 1990).
Two studies have addressed the role of norepinephrine in women with menstrually associated migraines (Fioroni, Martignoni, and Facchinetti, 1995; Magos,
Brinca and Studd, 1985). In a study of women with menstrual migraine, Fioroni and fellow researchers (1995) evaluated the action of clonidine administration, an agonist at central �2-adrenergic receptors, during the follicular and late luteal phase of the menstrual cycle. Normally, opiods are inhibited by �2-adrenergic receptors. Clonidine administration reverses this action and stimulates the release of �-endorphin release, while simultaneously reducing norepinephrine levels. In women diagnosed with 51
Table 3. Estrogen and Menstrual Migraine Affect/Effect on Biochemicals Implicated in
Migraines.
Biochemical Estrogen Affect Menstrual Migraine Effect
Increased plasma levels but marked Increases plasma serotonin Serotonin decline perimenstrually (Fioroni et al. (Marcus et al., 1996) 1996; de Belleroche, 1996)
Function dependent on Perimenstrual � -adrenergic receptor Norepinephrine estrogen (e.g., Barclay and 2 hyposensitivity (Fioroni et al., 1995) Harding, 1990)
Increases hypothalamic Decreased functional hypothalamic �-endorphin levels (e.g., Rebar & Spitze, opioid activity (Facchinetti et al., 1987) 1990)
Increases synthesis (Olson, Vascular hypersensitivity (Nattero et Prostaglandin Skinner, and Challis, 1983) al., 1989)
Increases nitric oxide Increased nitric oxide formation in all Nitric oxide production (Sarchielli et al., menstrual phases, especially in the 1996) luteal phase (Sarchielli et al., 1996)
Suppressed melatonin secretion in Melatonin Inconsistent findings luteal phase (Murialdo, et al., 1994)
menstrual migraine, this pattern was exhibited during the follicular phase of the menstrual cycle. However, the action of clonidine-released �-endorphin was significantly reduced during the late luteal phase when compared to a control group. 52
This data suggests that women with menstrually related migraine exhibit �2-adrenergic receptor hyposensivitity during the perimenstrual period (Fioroni et al., 1995).
In another study, researchers found that serum dopamine �-hydroxylase, the enzyme that catalyses the conversion of dopamine to noradrenaline and is considered to be a more reliable index of sympathetic activity than the concentration of norepinephrine, varied across the menstrual cycle in women with menstrually associated migraines.
Little difference was demonstrated in the control group. This finding suggests that extreme fluctuations of the sympathetic nervous system might be relevant in menstrual migraine (Magos et al., 1985).
Dopamine and prolactin have also been associated with the occurrence of menstrual migraine (Kornstein & Parker, 1997). Prolactin levels are influenced by dopamine and serotonin; serotonin appears to increase anterior pituitary production of prolactin by inhibiting dopamine (Silberstein & Merriam, 1999). Although prolactin baseline levels are normal for female migraineurs in all phases of the menstrual cycle
(Silberstein & Merriam, 1999), enhanced prolactin release following injection of dopaminergic antagonists was found to occur in female migraineurs with and without menstrually associated migraine (i.e., migraine attacks occurring only five days preceding menstrual bleeding and during menstrual bleeding) during the follicular phase of the menstrual cycle when compared to normal controls (Murialdo et al., 1986). These results suggest altered dopaminergic control of prolactin secretion in all migrainous women, not just women with menstrually related migraine. 53
�-endorphin hypothalamus concentration, which acts locally as a neuromodulator
(Polinsky et al., 1987), also varies in relation to estrogen levels (Silberstein & Merriam,
1991). The endogenous opioid system plays a role in the modulation of the hypothalamic-pituitary-adrenal (HPA) axis (Johnson, Kamilaris, Chrousos, & Gold,
1992). In turn, the HPA axis modulates the levels of various reproductive hormones.
Naloxone administration, an opioid antagonist, blocks the tonic opioid inhibition of the
HPA axis activity, thereby resulting in an increased release of �-endorphin and cortisol.
Facchinetti and colleagues (1990) compared the response to naloxone for women with menstrually associated migraine and nonheadache controls. They found that menstrual migraine patients demonstrated a significantly increased hormone response to the administration of naloxone only in the follicular phase when compared the premenstrual period (p<.02). In the control group, naloxone evoked a significant release of �-endorphin and cortisol in both the follicular and premenstrual phases, with no significant differences between phases (p>.05). These results suggest an impairment of the adaptive hypothalamic control of stress and pain exerted by opioids on the HPA axis in women with menstrual migraines during the premenstrual period and could establish a causal relationship between menstrually related migraine headaches and premenstrual opioid hyposensitivity (Facchinetti et al., 1990).
Estrogens are also powerful stimulators of prostaglandin synthesis (Olson,
Skinner, & Challis, 1983). In women with menstrually associated migraine (i.e., migraine attacks occurring only prior to, during or at the end of menstruation), platelet sensitivity to prostaglandins is significantly different from that of normal woman 54
(Benedetto, Massobrio, Zonica, & Melzi et al., 1987; Nattero, 1987). In another study, women with menstrually associated migraine demonstrated lower plasma levels of
Prostaglandin I2 than normal controls throughout the menstrual cycle (Nattero et al.,
1989). This study suggests that deficiencies in Prostaglandin I2, an important protecting agent against ischemia (Majerus, 1983), might cause vascular hypersensitivity to stimuli in menstrual migraine.
A recent study also suggests that nitric oxide formation is influenced by estrogen fluctuations (Sarchielli et al., 1996). In a previous study, researchers demonstrated that the baseline platelet arginine/nitric pathway was activated in adult migraineurs (Gallai et al., 1996). To evaluate variations in the platelet arginine/nitric oxide pathway across the menstrual cycle, Sarchielli and his fellow researchers (1996) evaluated collagen- stimulated production of platelet nitric oxide interictally in women during the follicular phase, at mid-cycle, and in the luteal phase. They compared women with menstrually associated migraine (i.e., migraine attacks occurring on or between days 2 to +3 of the menstrual cycle and at no other time) and nonmenstrual migraine (i.e., migraine attacks that did not show any relationship to particular phases of the menstrual cycle) to age- matched controls.
Pair-wise comparisons revealed that collagen stimulated nitric oxide formation in both migraine groups were significantly different than controls, as well as each other, across all phases of the menstrual cycle; the degree and type of change was different between the two migraine groups. Women with menstrually associated migraines exhibited significantly higher nitric oxide formation in all menstrual phases than controls; 55 the increase was greater in the luteal phase of the cycle than during the follicular phase
(p<0.005). A significant increase in nitric oxide production in platelets also occurred in women with non-menstrual migraines when compared to controls; this increase was less pronounced than in women with menstrually associated migraine, and it was most apparent at ovulation (p<0.001).
Collagen stimulated nitric oxide formation in platelets was also significantly increased during migraine attacks with respect to the interictal period in both patient groups, with increases most evident at ovulation in women with non-menstrual migraines and in the luteal phase in women with menstrual migraines. Although this data suggests that activation of the platelet arginine/nitric oxide pathway occurs in all female migraineurs, the activation of the pathway is more pronounced in the luteal phase in menstrual migraine patients. This increased activation during the luteal phase in women with menstrually associated migraine might be the cause of the increased susceptibility to migraine attacks in the perimenstrual period (Sarchielli et al., 1996).
Gonadal steroid hormones have been found to influence the secretion of melatonin (Cardinali et al., 1987). Measurements of blood or urine melatonin during the menstrual cycle have yielded inconsistent findings, however, with some studies finding no significant changes (Berga & Yen, 1990; Brzezinski et al., 1988) and with other studies reporting significant fluctuations in melatonin (Brun, Claustrat, & David, 1987;
Murialdo et al., 1994; Wetterberg et al., 1976). When significant differences were noted, melatonin was higher in the luteal (Brun, Claustrat, & David, 1987; Murialdo et al.,
1994) or perimenstrual phase (Wetterberg et al., 1976). 56
When compared to controls, however, studies have demonstrated that female migraine patients exhibit less pronounced increases in melatonin secretion during the luteal phase than healthy controls (Murialdo et al., 1994). In addition, patients with migraine without aura with associated increased frequency and intensity of perimenstrual migraine attacks demonstrated significantly lower mean nocturnal melatonin excretion throughout the menstrual cycle when compared to age-matched controls (Brun, Claustrat,
Saddier, & Chazot, 1995). These studies suggest that normal menstrual cycle fluctuations in melatonin are disrupted in migraine patients, with more pronounced changes occurring in women with menstrually related migraine.
In summary, the physiological etiology of menstrually related and nonmenstrual migraines appears similar. However, few studies evaluated direct comparisons (Murialdo et al., 1986; Sarchielli et al., 1996). In these studies, biochemical changes during the menstrual cycle occurred either equally in menstrual migraine and non-menstrual migraine (Murialdo et al, 1986) or were simply more pronounced in menstrual migraine
(Sarchielli et al., 1996). As such, these studies suggest that menstrually related migraine does not have a distinct etiology, but that women suffering from menstrually related migraine exhibit increased hypersensitivity to cyclical hormonal changes when compared to other migraineurs. Based on these pathophysiological findings, headache features and treatment response of menstrual and nonmenstrual migraines could be expected to be qualitatively similar, although possibly quantitatively different.
However, caution should be evoked when interpreting these studies because of the lack of a standard definition of menstrual or menstrually related migraine. As indicated 57 by MacGregor (1996), identification of the pathophysiology of menstrual migraine cannot begin without an accepted definition of the condition. Thus, further research on mechanisms using proposed IHS (2004) definition of menstrual migraine is needed. In order to identify possibly etiological distinctions, future research should compare menstrual migraine to nonmenstrual migraine findings, as well as nonheadache control groups.
Headache Features and Menstrually Related Migraines
Several recent headache textbooks (Raskin, 1988; Silberstein, Lipton, and
Goadsby, 1999; MacGregor, 2003; Massiou and Bousser, 2000; Silberstein, Saper, and
Freitag, 2001) support the common belief that menstrually related migraines headache features are more severe than nonmenstrual headaches (Massiou, 1999). Although numerous studies reported an increase in the frequency of migraine associated with the premenstrual period (Dalton, 1973; Johannes et al., 1995; MacGregor & Hackshaw,
2004); MacGregor et al., 1990; Stewart et al., 2000; Waters & OConnor, 1971), scientific evidence is mixed as to whether menstrually related migraines are qualitatively different than nonmenstrual migraines (Beckham et al., 1992; Couturier et al., 2003;
Dowson, Kilminster, Salt, Clark, & Bundy, 2005; Dzoljic et al., 2002; MacGregor &
Hackshaw, 2004; Martin et al., 2000, 2002; Pinkerman & Holroyd, 2003; Stewart et al.,
2000; Tatrow and Blanchard, 2002). Because of possible differences in findings between type of population (Stewart et al., 2000) and type of assessment (MacGregor, Igaahi, and
Wilkison, 1997), relevant research will be reviewed with respect to whether the research 58 involves a population-based or clinical sample and retrospective or prospective data collection.
In recent retrospective studies of population-based samples, more severe migraine features have been reported with migraines associated with menses (Couturier et al.,
2003; Dzoljic et al., 2002). An epidemiologic survey of 1181 Dutch women (Couturier et al., 2003) found that overall women (n=32) reported that their menstrually associated migraine attacks were more severe and of longer duration, and that they experienced more disability with these migraines than with migraines that occurred at other times of the month. In a more select sample of female university students (n=1943; Dzoljic et al.,
2002), migraine during menses, when compared to migraine unrelated to menstruation, was reported to exhibit increased pain severity in 53.5%, increased aggravation with physical activity in 61.3%, worsening of nausea in 16%, increased photophobia in 26%, and increased phonophobia in 26.9% of these female students.
The accuracy of characterizing and associating migraine with menstruation in retrospective questionnaires, however, has been questioned by MacGregor and associates
(1997) based on their findings comparing subjective and objective assessment of headaches. In their study, over 50% of women subjectively thought that their migraine attacks were related to menstruation. Yet, only 15% of these women fulfilled the criteria of menstrually related migraine when confirmed by review of headache diaries kept over three menstrual cycles.
Prospective studies, nevertheless, have generally concurred with the findings of retrospective studies. Using self-reported menstrual bleeding and hormone levels to 59 differentiate the different phases of the menstrual cycle, four small-scale clinical, prospective studies reported that increased headache index or activity, both of which depend of severity as well as frequency of migraines, was associated with menstruation in female migraineurs (Beckham et al., 1992; Martin et al., 2000, 2002; Tatrow and
Blanchard, 2002). In one study of 14 female volunteers who met diagnostic criteria for migraine headache, pair-wise comparison of daily headache activity, defined as the rating of headache pain on an 11-point scale (0=no headache pain to 10=extremely painful headache), was significantly higher (p<.05) during the premenstrual phase of their cycle than during other phases (Beckman et al., 1992). Similarly, Tatrow and Blanchard (n =
74; 2002) found daily headache activity, defined as the rating of headache pain on a 6- point scale (0=no headache to 5=intense, incapacitating headache), was higher during the premenstrual period (F3,45=3.16, p<05).
In two prospective, clinical studies on female migraineurs, Martin and colleagues
(2000, 2002) assessed not only the headache index and disability, which were derived
from both frequency and magnitude of severity or disability, but also headache severity,
which only assesses the magnitude of the pain severity. In their first study (n=13),
Martin and others (2000) examined headache severity and disability in the different
phases of the menstrual cycle. The headache severity and disability scores were
significantly greater in the early follicular phase (i.e., days one through six of the
menstrual cycle) than during the midluteal phase (i.e., days including three days before
the mid-luteal peak of progesterone and two following days; p=.0033 and p=.002,
respectively). In another study (n=21), Martin and his fellow researchers (2002) reported 60 similar findings. Using pair-wise comparisons, they found that the headache index
(p<.0001), headache disability (p<.0001), and headache severity (p=.0006) were
significantly greater on days one to six of the menstrual cycle when compared to days in
the midluteal phase.
In another prospective study of patients attending a tertiary headache clinic,
MacGregor and Hackshaw (2004) obtained diary data from 155 women migraineurs for
two to six menstrual cycles, of which all participants recorded menstrual and migraine
episodes; 81 participants additionally noted migraine pain severity and associated
symptoms. No participant was using birth control medication; diagnosis of menstrual
migraine was not reported. Migraines were characterized as premenstrual or menstrual
using two time windows (onset of menses + 2 days or onset of menses + 5 days, with days before onset of menses as premenstrual and day of onset and days after onset as menstrual). Days outside the first day of the cycle + 5 days were considered nonmenstrual days.
Results indicated that the risk of having a migraine was significantly more likely
during the 5-day window from 2 days before to 2 days after the first day of menstruation
(RR 2.50, p<.0001). Premenstrual (RR 2.06, p<.003) and menstrual migraines (RR 3.41,
p<.0001) in this time window were at increased risk of being severe. In addition,
menstrual migraines in this time window were at increased risk of being associated with
vomiting (RR 2.60, p<.0001). Significant results were also obtained for the 10-day
menstrual window; however, the relative risks for similar characteristics were of less
magnitude. 61
Whereas the other studies evaluated migraineurs in a tertiary clinic population,
Dowson and colleagues (2005) investigated the disability associated with headaches occurring inside and outside the menstrual period in a primary care sample (n=30).
Using ranked sums, they found that perimenstrual migraines were associated with significantly more hours of disability at less than 50% productivity per attack (p=.01) than nonmenstrual migraines. Numerically, more lost time from normal activities was found for migraines perimenstrually; however, this difference was not statistically significant. In addition, they evaluated nonmigraine headaches and found a tendency for these headaches to be associated with more disability in the nonmenstrual than the menstrual period; however, the difference was not statistically significant.
In contrast to these results, Stewart and associates (2000), in a well-designed prospective survey of 81 women migraineurs involving a population-based sample, failed to find clinically significant differences in pain intensity, associated symptoms, disability, or duration of migraines without aura during the perimenstrual period compared to other times in the cycle. Using repeated measures logistic and linear regression to account for intrasubject correlation, they reported that migraine headaches were only slightly more painful (i.e., an overall difference of 0.39 on a 1 to 10 point scale) on the first two days of menses. Because subjects in this sample generally averaged fewer headaches per month than subjects in previously cited clinical studies, the differences in findings could be attributed to possible differences in the character of migraines in subjects with occasional versus frequent migraines. 62
However, results from a study of a frequent migraine population (Pinkerman &
Holroyd, 2003) conflicts with this later conclusion. In this study, 92 female migraineurs treated a total of 836 migraine headaches [menstrually associated (n=181) and nonmenstrual (n=655)] with abortive medications, including combinations of analgesics, antiemetics, and triptans. No significant differences were found in headache features between menstrually associated and nonmenstrual migraines, which concur with results reported for an epidemiologic sample (Stewart et al., 2000).
Both retrospective and prospective studies reviewed thus far have not distinguished between women with menstrually related migraines (e.g., migraines that occur in two out of three menstrual cycles) and women with nonmenstrual migraines
(e.g., migraines that do not occur regularly with menses). Granella and colleagues
(2004), however, compared menstrual and nonmenstrual migraines in women diagnosed exclusively with menstrually related migraines referred to headache clinics who were being treated with acute migraine medications. In their prospective study of sixty-four women with menstrually related migraines, they found significant differences between migraine features for perimenstrual attacks when compared to nonmenstrual attacks.
Using repeated measures logistic regression, Granella and his fellow researchers determined the odds-ratio of various migraine features for three perimenstrual phases: 1) premenstrual, defined as two days before menses, 2) menstrual, defined as days one and two of the cycle, and 3) late menstrual, defined as days three to seven of the cycle.
When compared to nonmenstrual migraines, the odds of having status migrainosus, an attack of migraine lasting more than 72 hours despite treatment (IHS, 63
1988), were 9.50 (95% CI=1.61-55.96) during the premenstrual phase and 5.99 (95%
CI=1.03-34.80) during the menstrual phase. These findings were associated with significantly shorter attack duration in nonmenstrual attacks (16.2+15.1 hours) than in premenstrual attacks (29.6+24.1 hours, p<0.0001), menstrual attacks (33.7+24.8 hours, p<0.0001), and late menstrual attacks (24.0+21.8 hours, p<0.002). The characteristics of
pain in the perimenstrual migraines did not differ from the nonmenstrual migraines,
except for the presence of a greater severity of pain in the late menstrual attacks
(OR=2.98, 95% CI=1.33-6.68).
Thus, attack length was the most distinguishing migraine feature between
perimenstrual and nonmenstrual migraines in Granella and colleagues study (2004).
However, it should be noted that most of the subjects in this study took nonsteroidal anti-
inflammatory drugs for their migraine attacks. Untreated migraines or migraines treated
with triptans might exhibit different features.
In summary, the majority of retrospective and prospective research indicates that
migraines occurring during the perimenstrual period demonstrate more severe symptoms
when compared to migraines that occur nonmenstrually. These findings have been
reproduced in a sample with diagnosed menstrually related migraines. However,
divergent findings from an epidemiological and a clinical study suggest that the
differences between migraine features occurring perimenstrually and at other times
during the menstrual cycle might not be clinically significant. 64
Acute Treatment and Menstrually Related Migraines
Overview of Acute Migraine Treatment
In the treatment of menstrually related migraine, the same drug categories, including nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans (Massiou, 1999), and acute treatment regimens are used as in nonmenstrual migraine (MacGregor, 2000;
Mannix, 2003). The US Headache Consortium (Matchar, Young, & Rosenberg, 2000) identified two general principles of acute migraine management based on a practical approach to treating the patient. These include: (1) engage patients in their own management (e.g., discuss treatment/medication preferences), and (2) tailor treatment to the individuals needs (e.g., based on severity of illness, comorbidity/coexisting conditions, prior response to medications). In a review of the empirical evidence, the
US Headache Consortium concluded that oral NSAIDs and combination analgesics were a reasonable initial treatment for mild-to-moderate migraine attacks or severe attacks that have been responsive in the past to similar NSAIDs or nonopiate analgesics. They also found that triptans are an acceptable treatment choice and could be selected for treatment of patients with moderate-to-severe migraine who have no contraindications for its use.
In rating the quality of evidence for use of NSAIDs, combination analgesics, or triptans, the US Headache Consortium rated the scientific evidence as Grade A, which indicates that multiple, well-designed randomized, clinical trials, with a consistent pattern of findings, supported the conclusions. In addition, the US Headache Consortium recommended the addition of oral antiemetics and the employ of intranasal or subcutaneous triptans for treating migraine patients with nausea and vomiting, although 65 there was an absence of relevant randomized, controlled trials to support these conclusions.
The degree of treatment response for triptans to migraine attacks varies by formulation and type of triptan studied (Goadsby et al., 2002). For example, subcutaneous sumatriptan, at a dose of 6 mg, yielded the best clinical efficacy and intrapatient consistency in multiple attacks when compared to oral sumatriptan and other types of triptans administered orally. However, the incidence of adverse events with subcutaneous sumatriptan is higher, and their intensity is greater than oral administration.
Oral triptans also vary in their treatment response profiles (Goadsby et al., 2002).
For example, when compared to 100 mg of oral sumatriptan, rizatriptan provides superior relief at two hours, sustained freedom from pain, and consistency of effect, as well as being equally tolerated by patients. Compared to oral formulation, intranasal sumatriptan has a quicker onset of action but, like oral sumatriptan, does not develop maximum therapeutic effect until two hours (Tfelt-Hansen, 1998).
For acute migraine treatment, at least three different strategies have been proposed: step-care across attacks, step-care within attacks, and stratified care (Lipton,
Stewart, Stone, Láinez, and Sawyer, 2000). Step-care across attacks uses nonspecific, low cost therapies, such as nonprescription NSAIDs and combination analgesics, regardless of attack characteristics, associated symptoms, or associated disability. If the treatment outcome is inadequate, patients visit their health care provider for treatment changes. This process is repeated until a satisfactory treatment outcome is realized. 66
Step-care within attacks also uses nonspecific agents first, but with failure, the patient proceeds to specific treatment, such as triptans, for the same headache attack. In stratified care, treatment decisions are based on an assessment of the characteristics of acute attacks, associated symptoms, and disability. Prescription of medications is based on the likely migraine severity, presence of nausea or vomiting, degree of disability, and prior response to previous medications (Lipton, Stewart et al., 2000).
Lipton, Stewart, and colleagues (2000) demonstrated significantly better clinical outcomes with stratified care than step-care approaches. In agreement with these findings, The US Headache Consortium (Matchar et al., 2000) recommended the use of migraine-specific agents in patients with severe migraine and in those whose headaches fail to respond satisfactorily to NSAIDs or combination analgesics. Other groups have proposed similar recommendations (Diener, Kaube, and Limmroth, 1998; Pryse-Phillips et al., 1997).
Nonsteriodal Antiinflammatory Drugs (NSAIDs), Combination Analgesics, and
Menstrual Migraines
Three studies have examined the efficacy of either NSAIDs or combination analgesics for menstrually associated migraine (Al-Waili, 2000; Granella et al., 2004;
Silberstein et al., 1999). In the first such study, Silberstein and fellow researchers (1999) contrasted treatment outcomes for the nonprescription combination of acetaminophen, aspirin, and caffeine in menstrually associated and nonmenstrual migraines and compared these outcomes to a placebo. Female migraineurs were classified as either having menstrually associated or nonmenstrual migraine based on their menstrual status at the 67 time they began treating a migraine attack with the study medication. The group categorized as menstrually associated (n=185, treatment subgroup=85, placebo subgroup=100) included only women who were currently menstruating. The nonmenstrual group (n=781, treatment subgroup=383, placebo subgroup=396) included women who were not currently menstruating, but had regular menstrual cycles, as well as women who were surgically or naturally postmenopausal (n=119). Each participant treated only one migraine and was excluded from the study if migraine attacks were associated with incapacitating disability (i.e., attacks requiring bed rest greater than 50% of the time) or vomiting in > 20% of attacks.
When compared to placebo, each group exhibited significantly better outcomes at two hours for headache pain response and associated symptoms, including photophobia and phonophobia. Descriptive statistics for these two groups were comparable; no inferential statistics were performed contrasting the two groups directly. One difference in treatment outcomes was noted. Two-hour no nausea was significantly better for treated nonmenstrual migraines versus placebo; however, no treatment difference was exhibited between treated menstrual migraines and placebo. Rescue medications were used infrequently in both groups and did not significantly differ from placebo.
Two salient limitations exist in Silberstein and associates research (1999) that restricts its generalizability to women with diagnosed menstrually related migraines.
First, this study excluded women with severe disability or those who experienced vomiting greater than or equal to 20% of their attacks. As such, this population is potentially not representative of patients with menstrually related migraines. Secondly, 68 this research study considered menstrual attacks, not patients with menstrually related migraines. Therefore, they almost certainly included patients with attacks that occurred by chance during the menstrual period, as well as patients with menstrually related and pure menstrual migraines.
Attempting to address this latter limitation, Al-Waili (2000) used retrospective self-report to diagnose menstrually associated migraine in a small-scale, double-blind, placebo controlled study that compared the treatment of menstrual migraine with the prostaglandin synthesis inhibitor mefenamic acid. He used strict criteria to define menstrual migraine as severe to moderate migraine attacks that occurred within the first two days of the onset of menstruation and that had occurred on more than one day per month for more than one year by self-report. All patients were previously diagnosed with migraine without aura using IHS (1988) criteria. Women who experienced vomiting with their migraines were excluded because vomiting would affect absorption of the study drug.
In this study, 24 women aged 18 to 35 years were diagnosed with menstrually associated migraine without aura by self-report. The subjects were treated for two consecutive menstrual cycles; during one cycle, mefenamic acid, 500 mg, was administered at the beginning of a migraine attack, and during the other cycle, migraine attacks were treated with placebo. In addition, this dose was repeated every eight hours following the initial treatment as a prophylaxis. At two hours, mefenamic acid was superior to placebo for reduction in pain intensity (0.62 vs. 2.26, respectively, on a four- point scale from 0 to 3, with 3 being severe pain; p<0.05), increase in pain relief (i.e., 69 reduction in severe to moderate pain to mild or none; 79.16% vs. 16.6%, p<0.05), and creation of a pain-free state (66.6% vs. 8.3%, p<0.05). Mefenamic acid treatment of menstrual migraines also greatly reduced use of rescue medication taken after two hours when compared to placebo (83.3% vs. 20.8%, respectively, p<0.05). This research suggests that mefenamic acid is effective for treatment of migraines during the menstrual cycle. However, these results need duplication for women prospectively diagnosed with menstrually related migraines and need comparison to nonmenstrual migraines.
Granella and fellow researchers (2004) also used retrospective self-report to diagnose menstrually associated migraines in subjects recruited from a tertiary headache clinic (n=64). They included women who retrospectively reported the occurrence of at least one perimenstrual migraine attack per month during five to six of the previous six months and met the IHS (1988) diagnosis of migraine without aura. To meet inclusion criteria, women also needed to report the occurrence of two to six migraines without aura per month during the previous six months. Although they excluded subjects who had taken prophylactic medication within the last three months, their inclusion criteria did not specify the type of symptomatic medication used. They noted that most migraine attacks were treated with NSAIDS; however, triptans were taken in 26.4% of the attacks, with no reported differences in the proportion of attacks treated with triptans between the various phases of the menstrual cycle. The phases of the menstrual cycle were defined as premenstrual (PMP; i.e., two days before menses), menstrual (MP; days one and two of the cycle), and late menstrual (i.e., LMP; days three to seven of the cycle). All other days were defined as nonmenstrual (NMP). 70
Initial headache response was similar across phases, except that the odds of being pain-free at two hours were significantly lower for menstrually related than nonmenstrual migraine attacks (OR 0.41, 95% CI 0.22-0.76). However, the odds of recurrence, 24- hour sustained headache response, and 24-hour sustained pain-free yielded significantly poorer outcomes for PMP and MP attacks, with the odds of recurrence approximately two times, of sustained headache response less than one-half, and of sustained pain-free reponse less than one-third when compared to nonmenstrual attacks. For late menstrual attacks, the only significant difference was that the odds of sustained pain-free was one- half nonmenstrual attacks (OR 0.50, 95% CI 0.27-0.95). The mean number of acute drug doses taken per headache was also higher in the perimenstrual phases (PMP=2.0+1.4, p=0.06 vs. NMP; MP=2.3+1.4, p<0.0001 vs. NMP; LMP=1.9+1.2, p=0.1 vs. NMP) than in the nonmenstrual phase (1.6+1.1).
Granella and colleagues (2004) research also contains several significant limitations. First, the diagnosis of menstrually associated migraines in this study relies on retrospective analysis, which counters IHS (2004) recommendations for the proposed criteria. As previously noted, the accuracy of subjective recall of menstrually associated migraines is questionable (MacGregor et al., 1997). Second, it is difficult to draw definitive conclusions about treatment outcomes because of the heterogeneous nature of the symptomatic medications; the type of NSAIDs used was not specified and 26.4% of attacks were treated with triptans. Third, the subjects of this study were a select population of women (i.e., tertiary headache center patients; women with two to six 71 migraine headaches per month), and therefore, these results might not generalize to all women with menstrually related migraines.
Triptans and Menstrually Related Migraines
Studies indicate that triptans are an effective acute treatment for migraines that occur with menstruation. Efficacy for menstrual migraines has been reported with sumatriptan (Salonen & Saiers, 1999, review), rizatriptan (Massiou, Silberstein,
McCarroll, Allen, and Lines, 2000; Silberstein et al., 2000; Silberstein, Massiou,
McCarroll, and Lines, 2002), eletriptan (MacGregor, 1998; Pitei and Hettiarachchi,
2000), and zolmitriptan (Dalessio et al., 1996; Loder & Silberstein, 1999; Schoenen &
Sawyer, 1997). Currently, no studies or meta-analyses have compared the relative efficacy of the different triptans for treatment of migraines associated with menstruation.
Trials involving the treatment of menstrually associated migraines with triptans have typically been similar in design; studies are randomized, double-blinded, and placebo-controlled, and involve administering triptans or placebo for attacks during a womans menstrual period, with no attempt to select women who have been diagnosed with menstrually related migraines (Facchinetti, Bonellie, Kangasniemi, Pascual, and
Schuaib, 1995; Loder & Silberstein, 1999; Massiou, Silberstein et al., 2000; Pitei and
Hettiarachchi, 2000). For example, Facchinetti and fellow researchers (1995) compared the efficacy and safety of subcutaneous sumatriptan with placebo in the treatment of migraines associated with the menstrual cycle. They used a double-blind, placebo- controlled, parallel group design (n=179), and evaluated two attacks that occurred during menstruation. Of the sumatriptan-treated subjects, 73% and 81% reported pain relief at 72 two hours (i.e., reduction of a severe or moderately severe headache to a mild or no headache) compared with 31% and 29% of the placebo-treated subjects (p<.001). In another study, Massiou and colleagues (Massiou, Silberstein et al., 2000) performed a retrospective meta-analysis of single attack data from two double-blind, placebo- controlled trials involving 139 patients on rizatriptan 10 mg and 81 patients on placebo, who treated a migraine during their menstrual period. Compared to placebo, more women on rizatriptan were pain and associated symptom free (i.e., nausea, photophobia, phonophobia, vomiting, disability) at two hours (35% vs. 9%, p<0.001) and 24-hour sustained pain-free status (32% vs. 7%, p<0.001).
Some studies also compared treatment response for menstrually associated and nonmenstrual migraines (Silberstein et al., 2000; Silberstein et al., 2002; Solbach &
Waymer, 1993). In the first published study of triptans and menstrually associated migraines, Solbach and Waymer (1993) retrospectively analyzed the data of 157 women determined to have migraines during the perimenstrual phase (defined as beginning one day before to four days after the onset of menstruation) and 512 women who treated a nonmenstrual migraine. These women were participating in two randomized, double- blind, placebo-controlled, parallel-group trials originally conducted to compare the efficacy and tolerability of subcutaneous sumatriptan with placebo. The results from this study suggested that subcutaneous sumatriptan 6 mg treatment response was comparable for menstrually associated and nonmenstrual migraine attacks.
Specifically, in the group with menstrually associated migraines, 80% of migraineurs treated with subcutaneous sumatriptan reported a two-hour headache 73 response (moderate or severe pain reduced to mild or no pain) compared with 19% of placebo-treated subjects (p<0.001). Descriptively, these results are comparable to the nonmenstrual migraine group, where 70% of women treated with subcutaneous sumatriptan reported two-hour headache response compared with 20% of placebo-treated subjects (p<0.001). In addition, 24-hour sustained headache response was similar in both groups, with 68% of women who treated menstrually associated migraines and 60% of women who treated nonmenstrual migraine attacks maintained headache response for at least 24 hours after injecting sumatriptan. This response was compared to 15% and 23% of placebo-treated women with menstrually associated and nonmenstrual migraine attacks, respectively. Subcutaneous sumatriptan response rates for no photophobia and
no nausea at one hour were similar between women treating a menstrually associated migraine (35% and 20%, respectively) and a nonmenstrual migraine (43% and 29%, respectively), and both responses were superior to placebo (p<.001).
In another study that compared treatment response of oral rizatriptan for menstrually associated and nonmentrual migraines, Silberstein, Massiou, and others
(Siberstein, Massiou, McCarrol, and Lines, 2000) retrospectively analyzed data from two large clinical trials with randomized, double-blinded, placebo-controlled, two-period, crossover designs. A menstrually associated attack was defined as a migraine that occurred within three days before or after the onset of menstruation. In this retrospective analysis, rizatriptan, 10 and 5 mg, produced similar two-hour pain relief in menstrual
(68%, n=139; 70%, n=115, respectively) and nonmenstrual (69%, n=393; 66%, n=391, respectively) migraines, and all responses were significantly different than placebo 74
(p<.05). No statistically significant differences were found in menstrually associated and nonmenstrual migraines with other response variables, including two hour pain-free, photophobia, phonophobia, and taking escape medications (power=80% to detect difference of 6%, �=.05, two-tailed test). Neither group demonstrated significant differences in no nausea when compared to placebo. Twenty-four hour headache recurrence was more or less equal to one-third of patients who reported two-hour pain relief after treatment with rizatriptan or placebo apart from menstrual status.
In the six-month study of the efficacy of oral rizatriptan 10 mg wafers, Silberstein and colleagues (2002) compared menstrually associated and nonmenstrual migraines in women using three different definitions of menstrual migraines for various time periods.
Menstrually associated and nonmenstrual migraine treatment response was evaluated within the same group using a logistic regression model that was fit using generalized estimating equations to account for the correlation of attacks within patients. The odds of having two-hour pain relief or pain free and 24-hour sustained pain free headache response were similar regardless of the definition used, with no significant differences between menstrual and nonmenstrual migraines. Using the time period suggested by the
IHS (2004; -2 to +2 days), they found that rizatriptan treatment produced a pain-free response in 48% of menstrually related and 52% of nonmenstrual migraines at two hours and a 24-hour sustained pain free response in 32% and 37% of menstrually related and nonmenstrual migraines. In approximately one-third of subjects, headache recurred after initial relief was reported at two hours; however, no differences between menstrually related and nonmenstrual migraines were found. 75
In addition to comparing menstrually related and nonmenstrual migraines within this group, Silberstein and associates (2002) classified 86 patients who treated at least three attacks with rizatriptan as having lower or higher percentage of menstrual attacks by dividing the subjects into two groups based on whether they were below or above the median percentage. This analysis found no differences in pain relief or pain free at two- hour and 24-hour sustained pain-free headache response between groups. But as
Silberstein (1992) noted in previous comments, frequency of migraines does not indicate whether the migraine occurred on a regular basis during the menstrual period. Thus, this arbitrary grouping is not comparable to grouping women based on occurrence of migraine during menstruation in two of three months, as defined in recommendations by the IHS (2004).
One significant weakness of all triptan studies discussed so far is that they made no attempt to differentiate women with migraines that occur regularly with menstruation
(i.e., pure menstrual and menstrually related migraine) from migraines that occur by chance during the menstrual period. Two studies evaluating the efficacy of sumatriptan were identified that defined menstrually related migraines as those that occurred regularly with menstruation (Gross, Barrie, Bates, Dowson, & Elrington, 1995; Nett,
Landy, Shackelford, Richardson, & Ames, 2003).
In a prospective trial of menstrual migraine, Gross and fellow researchers (1995) selected women who were diagnosed retrospectively with menstrually associated migraine. Menstrually associated migraines were defined as having more than 80% of all migraine attacks occurring between three days before and five days after the onset of 76 menstruation. Using a double-blinded, placebo-controlled, crossover design, sumatriptan tablets 100 mg were similarly effective for attacks occurring within the defined menstrual window (n=39 attacks) as attacks occurring outside the defined period (n=41 attacks) in women with menstrually associated migraine. Four-hour headache relief (e.g., reduction in pain from severe or moderate to mild or none) was 67% with oral sumatriptan vs. 33% with placebo for attacks occurring within the defined menstrual window and 79% with oral sumatritan vs. 31% with placebo for attacks occurring outside the defined menstrual window.
In another prospective study, Nett and associates (2003) assessed the efficacy of oral sumatriptan when treatment was administered during mild pain in 349 women who were diagnosed with menstrually associated migraine. A randomized, double-blind, placebo-controlled design was used to treat a single attack. To be eligible for this study, women had to report the occurrence of migraine attacks within the perimenstrual period in at least two of their last three menstrual periods before they were screened. The perimenstrual period was defined as two days before through the fourth day of the menstrual period. Patients were excluded if they had more than 15 tension-type headaches or more than six migraine attacks per month; subjects averaged approximately one and one-half migraines per month.
At two hours, significantly more women who treated their menstrually associated migraine with oral sumatriptan, 50 mg (n=116) or 100 mg (n=115), were pain free when
compared to placebo (n=118; p<0.001; 61% and 51% of subjects who used oral
sumatriptan, 100 mg and 50 mg, respectively, compared with only 29% of subjects who 77 used placebo). In addition, the associated migraine symptoms of phonophobia and photophobia were absent at two hours in significantly more subjects who took sumatriptan 100 mg (73%) and sumatriptan 50 mg (69%) when compared with the placebo group (53%). No statistically significant differences were observed for nausea; however, baseline reports of nausea were low. The authors noted that the magnitude of these findings was comparable to results obtained in two prospective studies that treated nonmenstrually associated migraines, suggesting sumatriptan is equally effective in treating menstrually and nonmenstrually associated migraines.
Even in studies that defined menstrually associated migraines based on regular occurrence with the menstrual cycle limitations exist. Gross and fellow researchers
(1995) prospectively confirmed only 52% of the diagnoses of menstrually associated migraine obtained retrospectively, indicating the problem of using patient self-report for defining menstrually related migraines as previously reported in another study
(MacGregor et al., 1997). In Nett and associates study (2003), they relied on patient self-report of the occurrence of migraine attacks within the perimenstrual period, which potentially caused bias in defining women with menstrually related migraines. In addition, neither study defined the time period for menstrually associated migraine as recommended in recent guidelines by IHS (2004). Thus, a need exists for a study to evaluate triptan headache response in a population of women with prospectively diagnosed menstrually related migraines based on recommendations by IHS (2004). 78
NSAIDS and Triptans: Comparison and Combination
No studies have directly compared the efficacy of NSAIDs and triptans for menstrually related migraines. Several studies comparing the efficacy of NSAIDs alone, or in combination with other drugs or with an antiemetic, versus triptans and placebo in migraines, in general, have been reported. These studies will be briefly examined to review potential expectations of treatment response for menstrually related and nonmenstrual migraines.
All studies reviewed compared NSAIDs to sumatriptan; no studies were found that compared the newer triptans, which have better bioavailability, to NSAIDs. These studies can be grouped into studies that examined NSAIDs alone and those that compared
NSAIDs in combination with other drugs. In addition, the route of administration will be considered.
Few studies compared sumatriptan and an NSAID alone. The majority of these studies suggest that NSAIDs are equivalent or superior in migraine treatment outcomes and produce less adverse effects when compared to sumatriptan, and that both treatments are superior to placebo (The Diclofenac-K/Sumatriptan Migraine Study Group, 1999;
Diener, 1999; Meredith, Wait, and Brewer, 2003, Myllyal et al., 1998). In contrast, only one study reported superior treatment response for sumatriptan when compared to
NSAIDs (Diener, 1999; The Oral Sumatriptan and Aspirin plus Metoclopramide
Comparative Study Group, 1992).
In a double-blind, placebo-controlled, multicenter study (n=278), subcutaneous sumatriptan demonstrated a significantly better two hour reduction in pain (91.2% vs. 79
73.9%, p<0.001) and greater two hour pain-free response (76.3% vs. 43.7%, p<.0001) than intravenous acetylsalicylce acid lysinate (L-ASA). Yet, both treatment outcomes were significantly better than placebo. Treatment with L-ASA, however, resulted in fewer adverse effects than sumatriptan (7.6% vs. 37.8%, p<0.0001; Diener, 1999).
In two studies NSAIDs exhibited significantly faster responses (The Diclofenac-
K/ Sumatriptan Migraine Study Group, 1999; Meredith et al., 2003). Oral diclofenac-K, a new diclofenac with a faster onset of action than diclofenac-sodium, provided significant pain relief at 60 minutes when compared to placebo, whereas oral sumatriptan did not differ significantly from placebo until 90 minutes after dosing (n=156; The
Diclofenac-K/Sumatriptan Migraine Study Group). Intravenous ketorolac also demonstrated faster response than nasal sumatriptan, yielding a significant difference in pain severity when compared to sumatriptan at 60 minutes (n=29; Meredith et al., 2003).
Associated symptoms, such as nausea and photophobia were found to respond better (The
Diclofenac-K/ Sumatriptan Migraine Study Group, 1999) or the same (Diener, 1999;
Myllyla et al., 1998) to NSAIDs as sumatriptan.
In studies that compared NSAIDs in combination with other drugs and triptans, only comparisons with sumatriptan were reported in the literature as in the case with
NSAIDs alone (Di Monda et al., 2003; Dowson, Ball, and Haworth, 2000; Freitag et al.,
2001; Tfelt-Hansen, 2000; Tfelt-Hansen, Henry, Mulder, Scheldewaert, Schoenen, and
Chazot, 1995). Typical combination drugs for treatment of migraine contain an antiemetic (Di Monda et al., 2003; Dowson, Ball, and Haworth, 2000; The Oral
Sumatriptan and Aspirin plus Metoclopramide Comparative Study Group, 1992; Tfelt- 80
Hansen, 2000; Tfelt-Hansen et al., 1995) and caffeine (Di Monda et al., 2003; Goldstein et al., 2005). One preparation contains a vasoconstrictor and muscle relaxer in addition to an NSAID (Freitag et al., 2001).
Overall, research suggests that NSAID combination medications are as effective as or more effective than sumatriptan (Di Monda et al., 2003; Dowson et al., 2000;
Freitag et al., 2001; Goldstein et al., 2005; Tfelt-Hansen, 2000; Tfelt-Hansen et al.,
1995). Superior reductions in nausea (Freitag et al., 2001; Tfelt et al., 1995) and two hour pain-free response have been reported (Freitag et al., 2001; Goldstein et al., 2005).
However, one of these studies (Freitag et al., 2001) has been criticized for patient selection bias (i.e., patients with less severe migraines than average) and others for suboptimal dose of sumatriptan (Landy, Richardson, and OQuinn, 2002; Goldstein et al.,
2005).
In contrast, mixed findings were reported in another study comparing oral sumatriptan with oral aspirin plus oral metoclopramide, an antiemetic, for three migraine attacks (The Oral Sumatriptan and Aspirin plus Metaclopramide Comparative Study
Group, 1992). In this double-blind, placebo-controlled study (n=358), 100 mg oral sumatriptan produced equivalent two-hour headache relief (i.e., reduction in severity of headache pain from severe or moderate to mild or no pain) when compared to 900 mg oral aspirin plus 10 mg metoclopramide. However, for attacks two and three, headache relief with sumatriptan was significantly better than with aspirin plus metaclopramide
(attack 2, 58% vs. 36%; attack 3, 65% vs. 34%; p<.001). No significant differences were 81 found for relief from nausea, vomiting, photophobia and phonophobia between treatment groups.
There is a paucity of research related to the use of triptans and NSAIDs in concurrent treatment. Three studies evaluated their simultaneous use (Smith et al., 2005;
Krymchantowski, 2000; Krymchantowski, Adriano, and Fernandes, 1999), while one assessed sequential use within an attack (Lipton, Stewart et al., 2000). Concurrent use of triptans and NSAIDs was proposed to address potential decrease in migraine recurrence by using both medications (Smith et al., 2005; Krymchantowski, 2000; Krymchantowski et al., 1999), while sequential use was used to assess the efficacy of different treatment approaches (Lipton, Stewart et al., 2000).
Krymchantowski and colleagues (1999, 2000) research suggests that NSAIDs, when used concurrently with triptans, decreases migraine recurrence. With retrospective analysis (n=50), Krymchantwoski and fellow researchers (1999) found that when oral tolfenamic acid 200 mg was taken with oral sumatriptan 100 mg migraine recurrence within 24 hours was reduced from 62.5% to 23.8%. In a prospective, crossover study
(n=67), oral naproxen sodium 550 mg taken with sumatriptan 100 mg reduced recurrence from 59% to 25.5% when compared to sumatriptan taken with a placebo (p <0.0003;
Krymchantowski, 2000).
In their four-arm multicenter, randomized, double-blind, double-dummy, placebo- controlled, prospective study, Smith and colleagues (2005) found that not only was concurrent therapy more effective in reducing recurrence than sumatriptan or analgesic alone or than placebo (p<.001), the concurrent use of 50 mg sumatriptan and 500 mg 82 naproxen sodium yielded significantly more effective two hour pain-free response
(p<.001) and reduction in two-hour associated symptoms (p<.001). In addition, no significant increase in adverse effects was noted with concurrent therapy when compared to monotherapy (p>.05). Smith and colleagues (2005) noted that to insure that the treatments were blinded, the medications were encapsulated. This has been shown to reduce the speed of absorption of sumatriptan during a migraine attack (Fuseau et al.,
2001), and, therefore, may have reduced the efficacy of sumatriptan in this study.
In a well-designed, multisite study (n=835) comparing various migraine treatment approaches, Lipton, Stewart, and fellow researchers (2000) compared the sequential administration of, first, an NSAID plus an antiemetic and, second, a triptan when there was no response at two hours post-dose (i.e., step-care within attacks), to an approach that used disability scores to select treatment (i.e., stratified care). In stratified care, subjects with lower disability scores were given the NSAID plus an antiemetic, while subjects with higher disability scores were treated with a triptan.
When using NSAIDs and triptans, the stratified approached demonstrated a superior response when compared to the step-care within attack approach (two hour headache response, 52.7% vs. 40.6%, respectively, p<.001). Subject selection bias, however, could prevent these findings from being generalized to typical migraine sufferers. Subjects were recruited from tertiary headache clinics, with over 85% of subjects reporting moderate to severe disability.
Another study used an individualized acute treatment plan, which included use of
NSAIDS, combination analgesics, antiemetics, and/or triptans based on the patients prior 83 treatment response, headache severity, and associated symptoms, such as nausea and vomiting, for treating migraines across the menstrual cycle (n=92; Pinkerman and
Holroyd, 2003). Initial treatment response did not differ between migraines associated with the perimenstrual period and migraines occurring at other times. However, migraines associated with the menstrual cycle were 1.6 times more likely to demonstrate headache recurrence than migraines occurring at other times during the menstrual cycle
(OR=1.71+.31, p<.0001).
In summary, the combination of NSAIDS and triptans has been effectively used to treat migraines, including migraines associated with the menstrual cycle. When NSAIDS and triptans are taken together, evidence suggests that headache recurrence can be reduced. Acute treatment of migraines can also be optimized when choice of treatment depends on individual response, associated disability, or headache features.
Acute Migraine Treatment Response and Recurrence
The efficacy of acute treatment for migraine has been well established in controlled clinical trials (Lipton, Bigal, and Goadsby, 2004; Matchar et al., 2000;
McCrory and Gray, 2003; Pascual, 2004; Wenzel, Sarvis, & Krause, 2003). However, 20 to 25 percent of migraine sufferers rarely experience headache relief with acute medications (Diener & Limmroth, 2001; Visser, de Vriend, Jaspers, and Ferrari, 1996) and up to one-half of acute treatment responders experience headache recurrence within twenty-four hours (Dahlöf, 1992; Ferrari et al., 1994; Visser, de Vriend, et al., 1996).
There is insufficient research on acute treatment of menstrual migraine to provide reliable 84 estimates of response and recurrence, but it is likely to be comparable or worse than estimates of migraine acute treatment efficacy in general.
The probability of headache response for an individual patient is relatively consistent over time for a specific medication, suggesting patient-related effects (i.e., consistent in each attack of the patient) rather than attack-related effects (i.e., variable per attack within a patient; Visser, Burggraafet al., 1996; Visser, de Vriend, et al., 1996;
Visser, Jaspers, de Friend, and Ferrari, 1996). Several studies have found that neither clinical headache characteristics (Meckling, Becker, Rose, & Dalby, 2001; Visser, de
Vriend, et al., 1996) nor individual pharmacokinetic differences (Visser et al., 1996) were found to predict headache response. Therefore, researchers have more recently examined patient variables as correlates of acute treatment response (Breslau, Lipton, Stewart,
Schultz, and Welch, 2003; Guidetti et al., 1998; Litaker, Solomon, and Genzen, 1997;
Marcus, 2000; Martin et al., 2002; Meckling et al., 2001; Sarchielli et al., 2005; Tatrow and Blanchard, 2002; Tietjen et al., 2003; Zwart et al., 2003).
Migraine recurrence does not appear to be related to initial clinical efficacy
(Géraud, Keywood, & Senard, 2003) but has been reported to occur more frequently in patients with more severe attacks and longer untreated attack duration (Sheftell,
OQuinn, S., Watson, C., Pait, D., & Winter, P., 2000; Visser et al., 1996). In addition, the incidence of migraine recurrence differs between classes of triptans (Géraud,
Keywood, & Senard, 2003). These findings suggest that different risk factors could be involved for headache response and recurrence. Therefore, patient risk factors associated with migraine headache response and recurrence will be considered separately. 85
Acute Treatment Response
Patients who do not respond to acute migraine treatment could potentially be different biologically from those who do (Meckling et al., 2001). These biological differences might manifest as differences in psychological and, especially in women with menstrually related migraines, in gynecological features. Evidence supporting this proposal will be reviewed.
Response and Psychological Factors
Pain catastrophizing, has been associated with more severe pain (Hassinger,
Semenchuck & OBrien, 1999; Ukestad & Wittrock, 1996) and less favorable outcomes
(Hursey & Jacks, 1992) in headache sufferers. Although correlated with depression and anxiety (Keefe, Brown, Wallston, & Caldwell, 1989; Lackner & Quigley, 2005; Lackner,
Quigley, & Blanchard, 2004; Sullivan, Rodgers, & Kirsch, 2001; Sullivan, Thorn,
Rodgers, & Ward, 2004; Willoughby, Hailey, Mulkana, & Rowe, 2002), research indicates that pain catastrophizing predicts unique variation in pain intensity (Granot &
Ferber, 2005; Sullivan et al., 1995; Sullivan et al., 2004). Like anxiety, pain catastrophizing involves the process of focusing on and exaggerating pain (Turner &
Aaron, 2001). But is also involves expressing fear and worry about harmful physical, emotional, and social effects of pain, as well as expressing feelings of incompetence about ones ability to cope with pain (Ellis & DEon, 2002). Pain catastrophizing reliably predicts negative outcomes for individuals with a variety of pain disorders (Ellis
& DEon, 2002). 86
Pain catastrophizing is frequently associated with pain avoidance behavior
(Lethem, Slade, Troup, & Bentley, 1983). For example, in one study of 59 women who had recently received surgery for breast cancer, the amount of analgesic use over the first three post-operative days was significantly associated with pain catastrophizing
(Jacobsen & Butler, 1996). Likewise, Mellegård and colleagues (Mellegård, Grossi, &
Soares, 2001) found that women with fibromyalgia reported greater levels of catastrophizing and use of analgesics and sedatives than women with either neck/shoulder or back pain. In a study of episodic, tension-type headache patients, pain catastrophizing was related to headache impact, including such behaviors as avoiding pleasurable activities (Hursey & Jacks, 1992).
Pain catastrophizing is particularly relevant to this population because of two correlates, chronicity and gender. Phillips and Jahanshahi (1985) reported that pain- related behavior increased over time in a sample of headache patients, even while headache symptoms remained constant. In addition, studies that have examined gender differences in the pain experience concluded that the tendency for women to report more frequent and intense experiences of pain than men is largely a function of pain catastrophizing (Keefe et al., 2000; Sullivan, Tripp, & Santor, 2000; Sullivan et al.,
2001). As a whole, these studies suggest that pain behaviors, such as use of medication and coping strategies, are associated with pain catastrophizing, which may indirectly affect treatment response in this population of women with chronic, frequent, and severe migraine attack. 87
There is scant research that compares acute migraine treatment responders to nonresponders, especially in regards to psychological functioning. Research suggests that between attacks migraine patients experience poorer psychological general well- being when compared to age and gender matched controls (Dahlöf and Dimenäis, 1995;
Tietjen et al., 2003). These findings suggest that migraineurs quality of life during symptom free periods might impact treatment outcomes (Likater, Solomon, and Genzen,
1997). To explore this hypothesis, Litaker and fellow researchers (1997) explored the association between sumatriptan response and pretreatment quality of life (n=235).
They found that nonresponders to sumatriptan reported lower pretreatment general health
(p=0.01) and physical functioning (p=0.016) as measured by the Short-Form-36 (SF-36)
Health Survey, which characterizes health-related quality of life. No other variable was significantly associated with response in the univariate analyses, including medical comorbidity, headache frequency, duration of disease, and presence of aura. This research implies that diminished perception of mental and physical health reduces benefits obtained from acute migraine treatment. Overall, research suggests that pain catastrophizing, and psychological well-being impact acute treatment response.
Response and Gynecologic Factors
Gynecologic problems are common in women with migraine and, thus, might affect menstrual migraine treatment outcomes. Female migraineurs have been found to experience a higher frequency of endometriosis (Tietjen, Conway, Utley, & Herial,
2003), menorrhagia (Tietjen et al., 2003), irregular periods (Hotovy et al., 1997), and dysmenorrhea (Hotovy et al., 1997; Silberstein & Merriam, 1999) when compared to 88 nonheadache controls. In addition, Ferrero and colleagues (2004) found that the prevalence of migraine is higher in women with endometriosis (n=51, 38.3%; CI 30.1-
47.2, p<.001) than controls (n=25; 15.1%; CI 10.0-21.4). When compared to women with nonmenstrual migraines, women with migraines associated with menstruation also report a higher frequency of premenstrual symptoms (e.g., mood changes, backache, breast tenderness, hot flashes, water retention; Facchinetti et al., 1993; Epstein, Hockday and
Hockday, 1975).
Despite the association of hormonally related events with migraines in women, few studies have explored the role of gynecologic problems with migraine outcomes or acute treatment response. In a study of twenty-one menstruating women with migraines,
Martin and associates (Martin et al., 2002; Martin et al., 2005) found that the degree of premenstrual symptoms was moderately correlated with the severity (r=0.46, p=0.0001) and disability (r=0.48; p=0.0001) of migraine headache. Likewise, Kibler and fellow researchers (2005) found that menstrual distress was greater in all phases of the menstrual cycle in migraineurs (n = 17) than controls (n = 6), and that the level of menstrual distress was directly correlated with migraine activity and disability. In another study of 50 female migraineurs, Teitjen and colleagues (2003) reported that menorrhagia was not correlated to the headache disability score. Interestingly, Meckling and fellow researchers (2001) found that women who exhibited nonresponse to sumatriptan were actually less likely to affirm the statement, greater than 25% of their headache were related to menstruation (p=0.003). Because of the limited scope of 89 research in this area, however, there is insufficient data to draw conclusions about the role of gynecologic problems in acute treatment outcomes.
Recurrence Following Acute Treatment
Although research indicates that headache recurrence occurs up to 47% of the time following initial acute treatment (Ferrari et al., 1994; Plosker and McTavish, 1994;
Rapoport et al., 1995), few studies have explored risk factors for migraine recurrence following acute treatment (Visser et al., 1996). In their exploratory analysis of risk factors (n=336), Visser and colleagues (1996) focused on differences in demographic factors, characteristics of the migraine attacks, long-term use and effects of sumatriptan, and previous experience of headache recurrence after other antimigraine drugs. Few differences were noted between patients who always have headache recurrence and patients who never have headache recurrence; most of these differences involved clinical features, as previously described. In addition, patients who reported that they experienced menstrually associated attacks with every menstrual period tended to demonstrate more frequent headache recurrence after treating the attack with subcutaneous sumatriptan than women reporting nonmenstrual migraines (p<0.004; the authors reported significant difference at p<0.001 and a tendency between
0.001 Summary and Overview of Present Study Ample research exists that associates female reproductive events with migraines. In addition, a significant proportion of female migraineurs report that their migraines occur regularly during the perimenstrual period. However, the pathophysiology of menstrually related and nonmenstrual migraines appears similar, suggesting a common etiology with similar types of headache features and response to the same classes of medication. Research assessing differences in headache features and acute treatment response between menstrually related and nonmenstrual migraine has been hindered by failure to diagnose prospectively and to differentiate women with migraines that occur regularly during the perimenstrual period (i.e., pure menstrual and menstrually related migraine) from women with migraines that occur by chance during this time. Because consistent criteria for menstrually related migraines were lacking, it is also difficult to compare results from different studies. The available research, though, suggests that headache features are more severe for menstrually related migraines than nonmenstrual migraines, although these findings might involve clinical sample selection bias. In addition, both NSAIDS and triptans have been shown to be effective in treating migraines associated with the perimenstrual period; effectiveness appears comparable to nonmenstrual migraines. Yet, these results need to be replicated for women with prospectively diagnosed menstrually related migraines using recently proposed criteria (IHS, 2004). Although as many as 20% of migraineurs fail to respond and 50% experience headache recurrence, there is a paucity of research investigating risk factors for acute 91 treatment nonresponse and headache recurrence. Current research indicates that patient- related, rather than attack-related, characteristics are associated with acute treatment nonresponse and headache recurrence in acute treatment of migraines. Because of their association with migraines, psychological factors and, in women, gynecologic factors might influence acute treatment response. Overall, research suggests that pain catastrophizing and psychological well-being impact acute treatment response. Scant research on the relationship of gynecologic factors and migraine treatment response exist, but these limited studies support an association. Because of limited research in this area for migraines, in general, and no research involving women with prospectively diagnosed menstrually related migraines, research examining potential contributors to nonresponse and headache recurrence, such as psychological factors and gynecologic factors, is needed to identify risk factors for acute migraine treatment nonresponse and headache recurrence. This study proposes to examine several research questions regarding menstrually related migraines and its features and acute treatment outcomes in a frequent migraine population. Based on evidence found in the literature, several hypotheses are proposed: 1. Migraine headaches are significantly more likely to occur during the perimenstrual period (i.e., days 2 to +3, with the first day of menstruation as day 1 and the preceding day as day 1); 2. Headache features will not differ qualitatively (i.e., no differences in proportion of migraine-associated symptoms) for menstrually related and nonmenstrual migraines in women with frequent migraines; 92 3. Headache severity will be greater in menstrually related than nonmenstrual migraines, including more severe pain, longer headache duration, greater disability, and more severe migraine-associated symptoms; 4. Because birth control medication suppresses the complex hormonal changes of the endogenous menstrual cycle, the IHS (2004) recommends that research separately assess women with endogenous menstrual cycles and women using hormonal treatments. Based on previous studies, it is hypothesized that menstrual migraine frequency, severity, and treatment response (i.e., more severe pain, higher level of migraine-associated symptoms, longer headache duration, greater disability, two and four hour pain-free treatment response, recurrence after pain free, use of acute and rescue medication) will not be associated with birth control medication use; 5. Treatment response following acute treatment will be less favorable for menstrually related migraines than for nonmenstrual migraines; specifically, menstrually related migraines will have a significantly lower rate of two and four hour pain-free response and greater number of analgesic pills and rescue medication doses taken per migraine attack than nonmenstrual migraines. However, research findings indicate equivalent treatment response to triptans for menstrually related and nonmenstrual migraines; therefore, the number of doses of triptans taken per migraine attack will not significantly differ for the two types of migraines; 93 6. The proportion of menstrually related and nonmenstrual migraines treated with each treatment regimen (i.e., analgesics only, triptans only, or triptans in combination with analgesics) will not significantly differ. Participants were not instructed to treat the two types of migraines differently; therefore, no differences in the proportion of each treatment regimen used with menstrually related and nonmenstrual migraines are predicted. 7. The proportion of migraines that exhibit recurrence within 24 hours of acute treatment will be significantly greater for menstrually related migraines when compared to nonmenstrual migraines; and 8. Treatment response will be associated with less pain catastrophizing and higher quality of life; there are inadequate research findings to make hypotheses related to treatment response and gynecologic factors. In addition, predictors of treatment recurrence within 24 hours will be exploratory in nature because of a paucity of research in this area. METHOD Participants Participants were subjects in an ongoing National Institutes of Health and Ohio University Study for frequent, disabling migraines (i.e., Treatment of Severe Migraine Study, TSM). Participants in the Treatment of Severe Migraine Study were mostly female (81%), employed full time (67%), married (59%), reported family incomes of $40,000 or more (64%), and were non-Hispanic white (83%) with an average age of 38.1 years (SD 10.2). The sample reported an average of 14.8 years (S.D. 2.4) years of 94 education and completion of a high school degree or equivalent, with 63% of participants obtaining post-secondary education. Of the original sample of 238 subjects, 107 women met criteria for menstrually related migraine as proposed by the Headache Classification Subcommittee of the IHS (see Figure 4; IHS, 2004). To comply with these criteria, migraine attacks must occur on day 1 + 2 (i.e., days 2 to +3, with the first day of menstruation as day 1 and the preceding day as day 1) of menstruation in at least two out of three menstrual cycles, as well as occurring additionally at other times during the cycle, and report symptoms that meet the requirements for Migraine Without Aura (IHS, 1988; see Table 1). In addition, participants met the inclusion and exclusion criteria for the ongoing study as described in Table 4 and did not receive exogenous estrogen hormones continually throughout their menstrual cycle. Twenty-three TSM study participants dropped out of the ongoing study before adequate data was collected to determine if migraines were menstrually related using the proposed criteria (IHS, 2004). Differences in demograpic characteristics between eligible participants and TSM dropouts were determined using �2, Fisher exact tests, and t-test for independent samples (see Table 5). No significant differences were found in age, ethnicity, income level or marital and employment status. Eligible participants, however, were significantly better educated than TSM dropouts (68% vs. 33% post- secondary degree, p=.003). The sample for this study was composed primarily of non-Hispanic white (85%) female migraineurs in their late thirties (M=35.4, S.D.=8.9, range=20-53 years; see Table 95 Figure 4. Participant flow in the study. a Women in TSM Study with Phase 1 Data n=193 Inadequate Data: Dropped Out of TSM Study n=23 TSM Participants with Adequate Data for b MRM Determination n=170 Excluded: Excluded: Irregular Nonmenstruating Periods n=42 n=5 Excluded: Excluded: Birth Control Migraines not Medication without Menstrually Related Cycling of Estrogen n=6 n=8 Eligible Participants with MRM n=107 ______ aTSM=Treatment of Severe Migraine bMenstrually Related Migraine 96 6). Other ethnic groups represented in the sample included African Americans (13%) and Hispanics (2%). All participants graduated from high school and the majority of participants (81%) had completed one or more years of college (M=15.0+2.4). Most participants were married or living with a significant other (59%) and employed full-time (64%). 97 Table 4. Inclusion and Exclusion Criteria for Treatment of Severe Migraine Study. Inclusion Criteria Exclusion Criteria (1) Between the ages of 18 to 65 years (1) Unable to tolerate all triptans (e.g., Imitrex old and Maxalt) or all prophylactic medications (e.g., propranolol and (2) Diagnosed with migraine headaches nadalol) used in the ongoing study with or without aura by a board certified neurologist and an (2) Experience more than 20 headache days independent project clinician using per month 1988 IHS diagnostic criteria (see Tables 1 and 5) (3) Diagnosis of probable medication overuse headache (3) Suffer from at least 3 severe, disabling migraines per month for (4) Major psychiatric disorder 1 of sufficient at least six months that occur severity to compromise participation minimally on 3 days per month (5) Appear intellectually unable or are (4) Agree to be randomized to one of unwilling to complete daily headache four treatment conditions recordings (6) History of an exclusionary medical condition 2 (7) Pregnant, breast-feeding, planning a pregnancy or unwilling to use adequate contraception during the study period 1 Meets DSM IV criteria for schizophrenia, primary affective disorder with severe depression [Beck Depression Index-II (BDI-II; Beck, Steer, and Brown, 1996) >24], acute suicidal ideation [Primary Care Evaluation for Mental Disorder (PRIME-MD; Spitzer et al., 1994.)], organic brain syndrome, or alcohol or narcotic dependence. 2 For example, medication hypersensitivity, cardiovascular disease, epilepsy, kidney disease, hepatic or renal impairment, stroke, ischemic abdominal syndromes, peripheral vascular disease, diabetes mellitus (insulin dependent), Raynauds disease, tuberculosis, or bronchiospastic disease. 98 Table 5. Demographic Characteristics of the Eligible Participants vs. Treatment of Severe Migraine Study Drop-Outs. Eligible TSM p Participants Dropouts (n=107) (n=23) Age (Mean, S.D., y) 35.4+8.9 32.6+11.1 .19 Ethnicity White 85.0% 78.3% .531 Other 15.0% 21.7% Highest grade completed Grades 10-12 18.7% 43.5% Grades 13-15 34.6% 30.4% .03 Grades 16-22 46.7% 26.1% Highest Degree High School 32.0% 66.7% .003 Post-Secondary 68.0% 33.3% Income level (US$) 1-40,000 41.0% 47.4% 40,000-80,000 33.0% 26.3% .83 >80,000 26.0% 26.3% Marital Status Married 57.1% 57.9% .95 Not married 42.9% 42.1% Employment Full-time 64.2% 52.4% Part-time 17.0% 23.8% .55 Not working for pay 18.9% 23.8% Results for Age from t-test for independent samples, for Highest Grade Completed and Employment from Fishers Exact Test, and for other discrete variables from �2 analysis. 99 Table 6. Demographic Characteristics of Participants with Menstrually Related Migraines. n=107 Age (Mean, S.D.) 35.4 8.9 Ethnicity (%, n) White, not Hispanic 85% 91 Black, not Hispanic 13.1% 14 Hispanic 1.9% 2 Highest Grade Completed (Mean, S.D.) 15.0 2.4 Education (%, n) H.S. diploma/GED 32.0% 33 Trade School 22.3% 23 Part College 34.0% 35 4-year College Degree 7.8% 8 Masters or Post-Degree 3.9% 4 Income (%, n) 0-20,000 14.0% 14 21,000-40,000 27.0% 27 41,000-60,000 20.0% 20 61,000-80,000 13.0% 13 More than 80,000 26.0% 26 Marital Status (%, n) Single 31.1% 33 Married 52.8% 56 Living with Significant Other 6.6% 7 Separated .9% 1 Divorced 8.5% 9 Employment (%, n) Not working for pay 18.7% 20 Part-time 16.8% 18 Full-time 63.6% 68 100 Diagnosis criteria of the International Headache Society (IHS) criteria (Headache Classification Committee of the IHS, 2004) were applied in classifying migraine attacks. Of the 107 participants, 12 met all IHS (2004) criteria for the diagnosis of Migraine without Aura except for frequency of migraine attacks. According to 2004 guidelines, these participants were diagnosed with Chronic Migraine because they experienced 15 or more migraine headache days per month. Of the remaining participants, all participants were diagnosed with Migraine without Aura, while 23% of participants were additionally diagnosed with Migraine with Aura (see Table 7). Forty-two percent of participants were also diagnosed as experiencing episodic tension-type headaches. The participants averaged 6 migraine episodes (SD = 2.34), 9 migraine headache days (S.D. = 4.0), and 6 disability days (S.D. = 3.5) day per month, with an average of 1 tension-type headache day (S.D.=1.7) per month (see Table 7). Most migraine headaches were associated with disability (75.1%) and migraine-associated symptoms (i.e., nausea and/or vomiting, photophobia, phonophobia; 90.3%). Migraine headaches accounted for approximately 90% of all headaches. Participants averaged 2 mentrually related migraine attacks (S.D.=1.0) and 3 menstrually related migraine days (S.D.=1.9) during the total number of diary days recorded (M=43.0, S.D.=11.4). Participants reported experiencing problem headaches for an average of 13 years (S.D. = 8), with 4 years (S.D. = 4) of migraines at the current frequency. Descriptive statistics for gynecological variables are given in Table 8. The average age of menarche for this sample was approximately 13 years (M=12.8 years, S.D.=1.6). Twenty-one percent reported that their migraines began within two years of 101 Table 7. Headache Diary Characteristics for Participants with Menstrually Related Migraines. Participants with Menstrually Related Mean SD Range Migraines (MRM; n=107) Total number of diary days 43.0 11.4 23-81 Headaches per 30 days 10.12 4.45 3-28 Migraine headache days per 30 days 9.13 3.98 3-20 Migraine headaches per 30 days 6.01 2.34 3-16 Tension-type headache days per 30 days .97 1.67 0-10 Disability days per 30 daysa 6.54 3.49 0-17 Total number of MRM headache daysb 3.07 3.00 1-10 Total number of MRM headachesb 1.94 1.00 1-4 IHSc Headache Diagnosis (IHS, 1988) Migraine without aura 100% Migraine with aura 22.4% Tension-type 42.1% Length of Cycle (days) Median, 25-75% range (all participants) 28 26-32 Frequency (%, n; nonusers of birth control medication; n = 69) Less than 21 10% 7 21-25 20% 14 26-30 38% 26 31-35 19% 13 More than 35 13% 9 a Disability days per 30 days = Average of total number days recorded with DEHS (i.e., Disability Equivalent Hours or sum of all missed activity, including unpaid work, paid work, recreational and social activities, sleep, plus sum of impaired hours divided by two) recorded per participant divided by 30. b Total number of MRM days (or attacks) = Average of number of days (or attacks) per participant in which participant recorded a migraine headache occurring during the interval from 2 days to +2 day days of the first day of menses. c International Headache Society 102 Table 8. Self-reported Descriptive Statistics for Gynecological Variables. Age of Menarche (M, S.D.) 12.8 1.65 Migraines Began + 2 years of Menarche (%, n) 21.2% (21/99) Length of Period (days; M, S.D.) 5.2 1.6 Length of Cycle (days; %, n) Less than 21 39.8% (35/88) 21-25 25.0% (22/88) 26-30 29.5% (26/88) 31-35 2.3% (2/88) More than 35 3.4% (3/88) Regularity of Cycle (days; %, n) Always within + 2 48.9% (44/90) Always within + 3-6 31.1% (28/90) Always within + 1-2 11.1% (10/90) Varies by more than 2 8.9% (8/90) Bleeding between Periods (months per year; %, n) 0 77.7% (73/94) 1-3 18.1% (17/94) 4-6 2.1% (2/94) More than 6 2.1% (2/94) Pain Disability with Periods (%, n) No limitation, pain absent 28.7% (27/94) Some loss of work efficiency, mild pain 47.9% (45/94) In bed part of the day, occasional loss of work, moderate pain 17.0% (15/94) In bed 1 or more days, incapacitation, severe pain 6.4% (6/94) Endometriosis (%, n) 7.8% (8/102) Estimated Menstrual Blood Loss (mL; median+25%) 119 50-211 Menorrhagia (>130 mL blood loss; Janssen 1996; %, n) 48.1% (25/52) Birth Control Medication 35.5% (38/107) 103 Table 8: continued Migraine Change with Period (%, n) (1-7, 4=no change) 1 (worse) 48.4% (46/95) 2 11.6% (11/95) 3 12.6% (12/95) 4 (no change) 24.2% (23/95) 5 2.1% (2/95) 6 0% (0/95) 7 (better) 1.1% (1/95) History of Pregnancy (%, n) 65.7% (67/102 Migraine Change with Pregnancy (%, n) (1-7, 4=no change) 1 (worse) 12.3% (7/57) 2 7.0% (4/57) 3 7.0% (4/57) 4 (no change) 47.4% (27/57) 5 1.8% (1/57) 6 5.3% (3/57) 7 (better) 19.3% (11/57) Menstrual Distress Questionnaire (MDQ; Mean, S.D.) Total 39.7 28.3 Arousal 2.6 3.6 Control 1.6 2.9 Total (Arousal + Control) 35.5 24.2 Presence of Endometriosis and/or Menorrhagia (%, n) 29.4% (30/102) Influence of Hormones on Migrainesa (%, n) 31.4% (32/102) aPresence of improvement with pregnancy and/or migraines starting within two years of menarche. 104 their menarche. The average length of their menstrual period was 5 days (S.D.=1.6). The majority of participants reported a menstrual cycle length between 21 and 30 days (54%), with days between periods occurring regularly within plus or minus six days (80%) and with no bleeding between periods (78%). More participants reported menstrual cycles less than 26 days in length and reported greater variance in length of cycle when compared to the headache diary data (median = 28 days, 25-75% range = 26-32 days; see Table 7). Most participants reported no or mild pain associated with menstruation (77%), with a median menstrual blood loss of 119 mL (median 50% range = 50-211 mL). A majority subjectively reported that their migraines were worse during the menstrual cycle (73%). A minority of participants reported use of birth control medication (36%), the presence of menorrhagia (48%), or endometriosis (8%). Of the 66% who reported a history of pregnancy, 47% reported no change in their headache with pregnancy, with an equivalent number reporting that their headaches were either worse or better with pregnancy (26%). The sample mean for the Menstrual Distress Questionnaire (MDQ; see Appendix C, question 4c; Moos, 1968) total score was 40 (S.D.=28). When the arousal and control subscale scores were subtracted from the total, the resultant mean score was 36 (S.D.=24). According to Clare (1983), scores on MDQ can be used to classify women as nonsufferers (i.e., respondent rates all symptoms from 0 to 2) or sufferers (i.e., respondent rates at least one symptom as 3 or greater). When this classification was 105 applied to the MDQ responses of the participants, 9.6% (n = 10) classified themselves as nonsufferers and 90.4% (n = 94) categorized as sufferers of menstrual distress. Table 9 details the descriptive statistics for psychological variables. On the average, participants reported minimal depressive symptoms (M = 6.4, S.D.= 6.5; Beck Depression Inventory-II, BDI-II; Beck, Steer, and Brown, 1996; see Appendix B). Participants total responses on the Pain Catastrophizing Scale (M = 19.1, S.D. = 9.9; PCS; see Appendix F, Sullivan, Bishop & Pivik, 1995) were roughly equivalent to previously published total scores found in nonclinical populations (M = 20.3, S.D., 4.1, DEon, Harris, and Ellis, 2004; M = 20.1, S.D. = 5.1, Sullivan et al., 1995). The average for the total sum for the responses on the Migraine Specific Quality of Life Questionnaire (M = 40.0, S.D. = 11.2; MSQ; Jhingran, Osterhaurs et al., 1998; see Appendix E) indicated that the participants quality of life was comparable or better than other groups of migraine patients at pretreatment (Study 1: M = 45.1, S.D. 8.7; Study 2: M = 52.1, S.D. 9.0; Study 3: M = 49.1, S.D. 10.9; lower scores are associated with higher quality of life; Kosinski, Bjorner, Ware, Batenhorst, & Cady, 2003). 106 Table 9. Descriptive Statistics for Psychological Variables. N Mean SD Range Beck Depression Inventory-IIa 107 6.4 6.5 0-30 Pain Catastrophizing Scaleb 107 19.1 9.9 3-40 Migraine Specific Quality of Lifec 107 40.0 11.2 17-77 a Beck, et al., 1996. b Sullivan et al., 1995. c Jhingran, Osterhaus et al., 1998; Jhingran, Davis et al., 1998; Martin et al., 2000. ______ Procedure Data collection for this project began in May 2001 and was completed in November 2004. Recruitment was primarily directed at the communities surrounding Columbus and Athens, Ohio. Recruitment efforts also targeted minorities and women. Recruitment responders were provided information about the study and, if interested, screening was administered over the telephone. If a potential participant appeared to meet screening criteria for the study, a pretreatment visit with both a project therapist and a neurologist was scheduled. During the pretreatment evaluation, a detailed explanation of the study and the participants role in the study was provided and the participants informed consent was obtained (see Appendix G and H). Basic demographic information was also gathered at pretreatment and reviewed for clarification. To acquire information about the 107 individuals headache activity and headache-related disability, the therapist interviewed the patient using the Structured Diagnostic Interview for Headache (Penzien & Holroyd, 1990; see Appendix I, questions 1-2) and the Migraine Disability Assessment (MIDAS; Stewart, Lipton, Kolodner, Liberman, & Sawyer, 2000; see Appendix I, questions 3-4). If the participant did not disqualify during this interview, the study neurologist next determined whether the participant met eligibility criteria by collecting a thorough physical history and completing a physical and neurological examination. Participants who met eligibility criteria were prescribed abortive migraine medications and were instructed to use an acute medication treatment protocol that is individualized for the patient (see Appendix J for an example) to manage migraines. In general, initial treatment decisions are based on an assessment of the characteristics of acute attacks, associated symptoms, and disability. The individual protocol specified a recommended migraine medication (i.e., triptan, analgesic, and/or antinausea medication) and dosage instructions. If the migraine failed to respond to initial treatment, participants were requested to either repeat the dose or select another medication (e.g., triptan) if the maximum recommended number of doses had not been exceeded. Participants could take a rescue medication if previous medications failed to bring relief. In addition, participants were provided with a Hand-held Computer Headache Diary (HCHD; see Appendix A) and its operating manual in return for a 50-dollar deposit to be given back to the patient when the hand-held computer was returned. Detailed instructions on how to complete and submit the HCHD were also given by the project staff to the participant. The participant was requested to contact the project staff via 108 telephone after one week, in order to ensure that there were no problems or questions regarding the HCHD. At two weeks, the project neurologist telephoned each subject to discuss medication concerns. In addition, participants were given a list of potential medication side effects (see Appendix L) and requested to contact the project neurologist in case of serious adverse effects. At four weeks, another visit was scheduled to assess acute migraine treatment outcomes. During the pretreatment and treatment visit, data from the participants Hand-held Computer Headache Diary (HCHD) was uploaded into the study database (See Appendix A). Also, participants completed several psychological questionnaires, including Beck Depression Index, 2nd edition (BDI-II; Beck et al., 1996; see Appendix B), Migraine- Specific Quality of Life Index (MSQ; Jhingran, Osterhaus, Miller, Lee & Kirchoerfer, 1998; Jhingran, Davis, LaVange, Miller, and Helms, 1998; Martin et al., 2000; see Appendix E), and Pain Catastrophizing Scale (PCS; Sullivan et al., 1995; see Appendix F). The Gynecological History, Long Form, was collected at the pretreatment visit and the Gynecological History, Short Form, was administered during the treatment visit (Janssen, Scholten, and Heintz, 1995; Moos, 1968; see Appendixes C - D). In order to assess eligibility and psychiatric co-morbidity, the Primary Care Evaluation for Mental Disorder (PRIME-MD; Spitzer et al., 1994; see Appendix K) was administered during the pretreatment visit. To confirm eligibility for this study, additional HCHD data were reviewed to evaluate the occurrence of menstrually related migraines in two out of three consecutive menstrual cycles. 109 Measures (see Table 10 for summary) Eligibility Assessment Measures Structured Headache Interview The Structured Headache Interview (Penzien and Holroyd, 1990; see Appendix I, questions 1-2) is a clinician administered structured interview based on International Headache Societys (IHS) diagnostic criteria (Classification Committee of the IHS, 1988). During the interview, the clinician asked the patient a series of questions about his or her most problematic and other headache. First, the patients description of the headache was recorded verbatim. Then, this information was clarified by asking the patient to identify or rate descriptors of his or her headaches, including location, type of pain, severity, associated symptoms, effects of activity, presence of aura, duration, frequency, and chronicity. In addition, the patient identified suspected precipitating factors for his or her headache. Migraine Disability Assessment The Migraine Disability Assessment (MIDAS; Stewart et al., 1999; see Appendix J, questions 3-4) is a five-item self-administered questionnaire that captures the influence of headache on everyday activities over the preceding three months. To minimize problems with accurate recall, participants in this study responded to each question for the last month. Items 1 and 2 explored paid work, enquiring as to the number of days off work and additional days in which activity was significantly reduced (defined as at least 50% reduced productivity) due to headache and the number of days where productivity was 110 Table 10. Summary of Study Measures. Purpose Study Predictor of Eligibility Outcome Treatment Measure Determination Measure Response or Recurrencea Beck Depression Inventory-IIb X Gynecological History, Long Form X [includes pictoral blood loss chartc & Menstrual Distress Questionnaire (MDQ)e] Gynecological History, Short Form X (includes MDQd) Headache Diary X Migraine Disabiity Assessment X (MIDAS)e Migraine Specific Quality of Life X (MSQL)f Pain Catastrophizing Scaleg X Primary Care Evaluation of Mental X Disorder (PRIME-MD)h Structured Diagnostic Interview for X Headachei a Treatment response=2 hr. and/or 4 hr. pain free response after acute treatment and/or use of rescue medication; Treatment recurrence=Recurrence of a migraine attack after 4 hr. pain free response and/or any time interval within 24 hrs. after initial acute treatment following a pain free response. b Beck, et al., 1996. c Higham, OBrien, & Shaw, 1990; Janssen, Scholten, & Heintz, 1995. d Moos, 1968. eStewart, Lipton, Kolodner, Liberman, & Salyer, 1999. f Jhingran, Osterhaus et al., 1998; Jhingran, Davis et al., 1998; Martin et al., 2000. i Sullivan et al., 1995. hSpitzer et al., 1994. i Penzien & Holroyd, 1990. 111 reduced by half or more. Items 3 and 4 investigated the same questions about household work. Item 5 asked about missed days of recreational, social and family activities. The MIDAS score is simply the summed score of the individual responses. In this studys one-month version, responses were multiplied by three to yield the overall score. This overall score is categorized into four disability grades: grade I, minimal or infrequent disability, corresponds to a MIDAS score of 0-5; grade II, mild or infrequent disability, corresponds to a MIDAS score of 6-10; grade III, moderate disability, corresponds to a MIDAS score of 11-20; and grade IV, severe disability, corresponds to a MIDAS score of 21 or greater. The MIDAS has demonstrated acceptable internal consistency, test-retest reliability, and validity in population-based studies of migraine sufferers (Stewart, Lipton, Dowson, & Sawyer, 2001; Stewart, Lipton, Kolodner et al., 2000; Stewart, Lipton, Kolodner et al., 1999; Stewart, Lipton, Whyte, Dowson, Kolodner et al., 1999). The Cronbach alpha ranged from 0.76 to 0.83 in a United States population and was 0.73 in a population from the United Kingdom, indicating satisfactory internal consistency (Stewart, Lipton, Kolodner et al., 1999; Stewart, Lipton, Whyte et al., 1999). Test-retest reliability for an approximately three-week interval is also adequate. Test-retest Pearson correlation ranged from 0.54 (reduced productivity at work) to 0.68 (missed work days) in a United States sample and from 0.52 (missed nonwork days) to 0.82 (missed days of household work) in a sample from the United Kingdom (Stewart, Lipton, Whyte et al., 1999). Spearman correlations were similar, indicating no substantial influence by outliers (Stewart, Lipton, Kolodner et al., 1999; Stewart, Lipton, Whyte et al., 1999). 112 Convergent validity of the MIDAS was evaluated by comparison with a 90-day headache diary. The Spearmans r for the MIDAS total score and the equivalent diary measure was 0.63, demonstrating moderate concurrence (Stewart, et al., 2000). The face validity was also determine by assessing whether MIDAS scores were associated with physicians perceptions of pain, disability, and need for medical care (Lipton, Stewart, Sawyer, & Edmeads, 2001). The physicians clinical judgment of the need for medical care correlated with the MIDAS score (r=0.69). In addition, estimates of pain and disability were directly correlated with increasing MIDAS scores. The MIDAS score has been used extensively to assess headache impact and disability in studies of both migraine patients and other primary chronic headache sufferers (Bigal, Rapoport, Bordini et al., 2003; Bigal, Rapoport, Lipton, Tepper, and Sheftell, 2003; Brandes, 2002; DAmico et al., 2003; Harpole, Samsa, Jurgelski, Shipley, Bernstein, and Matchan, 2003; Lipton, Stewart, et al., 2000; MacGregor, Brandes, and Eikermann, 2003; Mathew, Kailasam, and Meadors, 2002; Stewart and Lipton, 2002). Beck Depression Inventory II The Beck Depression Inventory-II (BDI-II; Beck, et al., 1996; see Appendix B) is a 21-item self-report inventory that assesses depressive symptomatology in both normal and psychiatric populations (see Appendix B). It is an update of the original BDI (Beck, Ward, Mendelson, Mock, and Erlbaugh, 1961), which was changed to match criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association, 1994) for major depressive disorder and to improve the content validity of the instrument. Like the original BDI, the BDI-II measures affective, 113 behavioral, cognitive, and physiological symptoms often associated with depression. Each item consists of four statements that reflect a continuum of depressive symptom severity (e.g., I do not feel sad, I feel sad much of the time, I am sad all the time, and I am so sad or unhappy that I cant stand it). For each item, respondents choose the statement that best describes how they have been feeling during the last two weeks using a four-point scale. The ratings are summed, yielding a total score that can range from 0-63. With college students (Beck et al., 1996; Dozois, Dobson & Ahnberg, 1998; Sprinkle et al., 2002) and adult psychiatric outpatients (Beck et al., 1996; Steer, Ball, Ranieri, and Beck, 1999), the BDI-II has demonstrated content validity, high internal consistency, excellent test-retest reliability, and moderate to high convergent validity (Beck et al., 1996; Osman et al., 1997; Dozois et al., 1998.) The Cronbachs coefficient alpha was .93 among college students and .92 among outpatients (Beck et al., 1996). The correlation of the total BDI-II score with other psychometrically sound measures of depression ranges from .42 to .77 (Beck et al., 1996; Osman et al., 1997). In addition, the short-term (average=3.2 days) test-retest correlation in a sample of college students indicated excellent test-retest reliability (r=.96). With primary care medical patients, the BDI-II was also found to yield good reliability and validity (Arnau, Meagher, Norris, and Bramson, 2001). In this population, the internal consistency of BDI-II was excellent (Cronbachs � = 0.94) and the convergent validity was acceptable [correlations between BDI-II total scores and factor scores on the Short-Form General Health Survey (SF-20; Stewart, Hayes, & Ware, 1988) 114 ranged from 0.19 to 0.65], with BDI-II total and SF-20 factor scores correlated more strongly with the Mental Health subscale than with any of the other SF-20 subscales (Arnau et al., 2001). Criterion-related validity was also established, with a substantially higher BDI-II score for a depressive diagnosis group than a non-depressive diagnosis group (t(333) =15.3, p < .001), with a diagnostic sensitivity of 94% and a specificity of 92%, as determined by receiver operating characteristics (ROC) analysis (Arnau et al., 2001). The BDI is commonly used to assess treatment outcomes with chronic pain patients, including recurrent headache sufferers (Kinder, Curtiss, & Kalichman, 1992; Penzien, Rains, & Holroyd, 1993; Saper, Lake, and Tepper, 2001; Saper, Winner, and Lake, 2001). Primary Care Evaluation for Mental Disorders Primary Care Evaluation for Mental Disorders (PRIME-MD, see Appendix K; Spitzer et al., 1994) consists of modules designed to aid the diagnosis of psychiatric disorders commonly seen in medical settings. It includes a patient-completed screening questionnaire of key symptoms and a clinician-administered structured interview. The Mood, Anxiety, Alcohol, and Eating Modules were used in this study, yielding the diagnosis of the most commonly encountered mood (major depressive disorder, dysthymia, and minor depressive disorder), anxiety (panic disorder, generalized anxiety disorder, anxiety disorder not otherwise specified [NOS]), alcohol (abuse or dependence), and eating (binge eating disorder, bulimia nervosa) disorders. The PRIME- MD was validated in a sample of 1000 patients (Spitzer et al., 1994). Two diagnoses (minor depression and anxiety disorder NOS) have slightly more liberal diagnostic 115 criteria in the PRIME-MD than in the DSM-IV. Yet, the PRIME-MD exhibits good agreement between its diagnoses and those of independent mental health professionals (Spitzer et al., 1994; �= 0.71; overall accuracy rate=86%). In Lipton and colleagues (Lipton, Hamelsky, Kolokner, Steiner, & Stewart, 2000) population-based study, the PRIME-MD was useful in diagnosing psychiatric comorbidity in a migraine population. Outcome Measure Hand-held Computer Headache Diary Participants were provided a handheld computer (i.e., Visor) to complete a daily Hand-held Computer Headache Diary (HCHD) with information about headache activity, headache-associated symptoms, headache-related disability, medication usage, and menstrual flow onset (see Appendix A). Study participants were asked to log onto the HCHD daily and were asked three dichotomous (yes/no) questions about the following domains: use of prophylactic medication, occurrence of a headache, and menstrual cycle onset (females only). Follow-up questions appeared if the participant indicated that he or she experienced a headache that day. Specifically, the participant was asked to identify the type of headache (migraine, tension-type, other, unknown), start and end time and date of the headache, maximum severity of the headache (none, mild, moderate, or severe), severity (not present, mild, moderate, or severe) of associated symptoms (e.g., nausea, phonophobia, photophobia), presence of vomiting, and types and amounts of medications taken for the headache. The participant was also queried about the type and number of units taken for each acute migraine medication. For analgesic and abortive medications (e.g., Imitrex or Maxalt), 116 the units enumerated were pills, spray, injections, or melts. Rescue medication was defined as medication that could be taken if analgesic and abortive medications failed to provide headache satisfactory relief after the allowable number of repeat dosages. For rescue medication, the participant identified the class of medication (e.g., narcotic, nausea suppository, steroid, or other) and number of doses taken. In addition, several headache-related disability questions followed. In particular, the participant was asked to specify hours of missed unpaid work (e.g., housework, childcare, volunteer, or schoolwork), paid work, recreational or social activities, and sleep due to headache activity. Further, the participant was asked to detail the number of hours of unpaid work, paid work, and recreational or social activities that were completed while he or she was more than 50% impaired by the headache. Migraine attacks were considered a single multiday attack if less than 24 pain-free hours separated headaches. In characterizing this migraine, the highest rating of symptoms (e.g., maximum severity, migraine-associated symptoms) was used; the number of pills or doses for each type of medication was summed. Several medication usage and headache activity variables were calculated from this revised HCHD data, including: 1) Menstrually related migraines were defined as migraines that occurred on the first day of the menstrual cycle plus two days before and after the onset of menstrual flow [MacGregor, 1996; Headache Classification Committee of the International Headache Society (IHS), 2004]. Menstruation was be defined as endometrial bleeding resulting 117 from either the normal menstrual cycle or from withdrawal of exogenous progestogens, as in the case of combined birth control medication; 2) Two and four hour pain-free states were defined as a pain intensity score of none within the specified time period (International Headache Society Clinical Trials Subcommittee (IHS), 2000; Goldstein, Offen, & Moster, 1999); 3) Associated symptom score is the sum of the nausea (e.g., range = 0, 1, 2, 3), photophobia (e.g., range = 0, 1, 2, 3), phonophobia (e.g., range = 0, 1, 2, 3), and vomiting scores (e.g., range = 0 or 4); 4) Recurrence after pain-free was defined as a return of pain within 24 hours of the initial dosing after the patient has achieved a pain-free state (IHS, 2000; Goldstein et al., 1999); 5) Recurrence after pain-free at two and four hours was defined as a return of pain within 24 hours of the initial dosing after the patient has achieved a pain-free state within the specified time period (IHS, 2000; Goldstein et al., 1999); 6) Disability Equivalent Hours was defined as the sum of all missed activity (e.g., unpaid work, paid work, recreational and social activities, sleep) plus the sum of one-half the impaired hours (e.g., performance of unpaid or paid work, recreational and social activities, sleep reduced by half or more) related to headaches (Lipton, Stewart, & von Korff, 1995); and, 7) Use of rescue medication was noted if a narcotic, nausea suppository, steroid, or other rescue medication was taken after taking analgesics and/or triptans. 118 Treatment Response and Recurrence Predictor Measures Gynecological History: Long and Short Forms The Gynecological History, Long Form, is a self-report measure administered to women participants that collects detailed information about a womans gynecological history, including specific information about her menstrual cycle and premenstrual symptoms (Appendix C). Women participants are asked their menstrual status, age of menarche, age of first migraine, and prior pregnancy history and changes, if any, on headaches. In addition, they are asked several questions that described characteristics of current menstrual cycles, including length of cycle, regularity of periods, frequency of bleeding between periods, disability due to menstrual pain, pattern of migraines with menstrual periods, comparison of severity for migraine pain during menstrual periods, and self-perceived change in headache frequency immediately before or at the beginning of their period. Questions address present and past birth control medication and hormone therapy use, including current status, type of medication, and medication effect on headaches. Menstrual blood loss was assessed using a pictorial chart developed by Higham and colleagues (Higham, OBrien, and Shaw, 1990) and refined by Janssen and her fellow researchers (Janssen et al., 1995; see Appendix C, question 4b). In this pictorial chart, women were asked to note the number of pads and tampons used on each day of their last period in a block that corresponds to the picture representing the amount of soiling of their pads or tampons. This enabled the calculation of a score by multiplying the number of lightly, moderately and heavily soiled pads and tampons by fixed factors. 119 Multiplication factors of 1, 5, and 20, and 1, 5, 10, were used for pads and tampons, respectively. To compensate for differences in absorbencies when compared to the standards used by Janssen and colleagues, corrections were applied for the absorbency of the pad (regular=.75; maxi=1.0; super maxi=1.25) and tampon (lite=.5, regular=.75, super=1.0, super plus=1.25). The pictorial chart method was validated by comparing the pictorial rating of blood loss to blood loss as measured with the alkaline hematin extraction method using a Receiver Operating Characteristic (ROC) curve (Hallberg and Nilsson, 1964; Newton, Barnard, and Collins, 1977; van Eijkeren, Scholten, Christiaens, and Alsbach, 1986). The diagnostic specificity and sensitivity for menorrhagia was greater than 80% (Higham et al., 1990; Janssen et al., 1995), with a positive predictive value of 85.9% and a negative predictive value of 84.8% (Janssen et al., 1995). Janssen (1996) recommended a cut off score of 130 mL for menorrhagia as providing the value at which the specificity and sensitivity is highest (specificity=81.9%, sensitivity=91%, as compared to a menstrual blood loss of 80 ml). Test-retest differences for the amount of blood loss in two consecutive menstrual cycles using this pictorial rating method were not significant (m=43.9; p>.25, Wilcoxon matched-pairs signed-rank test; Janssen et al., 1995) and exhibited a very high consistency (i.e., 85%; Janssen, 1996). The refined Higham pictorial chart (Higham et al., 1990; Janessen et al., 1995) has been used frequently to estimate menstrual blood loss in gynecological treatment outcome studies (Barrington, Arunkalaivanan, and Abdel-Fattah, 2003; Crosignani et al., 1997; Fernandez, Kobelt, and 120 Gervaise, 2003; Grigorieva, Chen-Mok, Tarasova, Mikhailov, 2003; Vercellini et al., 1997; Wyatt, Dimmock, Walker, & OBrien, 2001). Premenstrual symptoms were explored using the Menstrual Distress Questionnaire (MDQ; see Appendix C, questions 4c; Moos, 1968.) This is a self-report instrument in which women are asked to rate their experience with various symptoms before or during their last period. Symptoms are assessed on a six-point scale from 0 (no experience) to 5 (extremely disabling/intense experience.) All but one (change in eating habits) of the 47 symptoms can be factored into one of eight empirically intercorrelated clusters: pain, concentration, behavioral change, autonomic reactions, water retention, negative affect, arousal, and control (Moos, 1968). The total and subscale scores are obtained by adding together the scores for all symptoms or each symptom on that subscale. Most subscales demonstrate a cyclical variation with the menstrual cycle, except for arousal and control (Moos, 1968; Woods, Most, and Dery, 1982). The symptoms empirically correlated with each scale are as follows: (1) Pain: muscle stiffness, headache, cramps, backache, fatigue, general aches and pains; (2) Concentration: insomnia, forgetfulness, confusion, lowered motor judgment, difficulty concentrating, distractible, accidents, lowered coordination; (3) Behavioral change: lowered school or work performance, take naps/stay in bed, stay at home, avoid social activities, decreased efficiency; 121 4) Autonomic reactions: dizziness, faintness, cold sweats, nausea, vomiting, hot flashes; (5) Water retention: weight gain, skin disorders, painful breasts, swelling; (6) Negative affect: crying, loneliness, anxiety, restlessness, irritability, mood swings, depression, tension; 7) Arousal: affectionate, orderliness, excitement, feelings of well- being, burst of energy, activity; (8) Control: feeling of suffocation, chest pains, ringing in the ears, heart pounding, numbness, tingling, blind spots, fuzzy vision. The Menstrual Distress Questionnaire demonstrates acceptable internal consistency (i.e., split half rs premenstrual range from .89 - .93; Markum, 1976) and test-retest validity (i.e., subscale test-retest correlations range from .39 to .90; Moos, 1968; premenstrual total score test-retest correlations range from .83 - .96; Markum, 1976). This measure has been used extensively to assess premenstrual distress (Berger, Schaffner, Meier, & Brattstrom, 2000; Marvan and Escobedo, 1999; Monagle, et al., 1993; Oinonen and Mazmanian, 2001), including the evaluation of premenstrual distress in headache patients (Facchinetti et al., 1993; Tarabusi, Caputo, Volpe, & Facchinetti, 1997). The Gynecological History, Short Form (see Appendix D) is an abbreviation of the long form. This form asked participants to assess premenstrual symptoms as previously described using the Menstrual Distress Questionnaire (MDQ: Moos, 1968). In addition, the questionnaire asked participants to indicate if they experienced a 122 migraine from two days before to two days after the start of their last period and to note any changes in their periods, menopause symptoms, birth control medication, or female hormone replacement therapy. Migraine-Specific Quality of Life Questionnaire The Migraine-Specific Quality of Life Questionnaire (Version 2.1, MSQ v2.1; Jhingran, Osterhaus et al., 1998; Jhingran, Davis et al., 1998; Martin et al., 2000; see Appendix E) was developed to assess the effect of migraine and migraine treatment on patients health-related quality of life. Research suggests that disease-specific quality of life measures are more sensitive to changes during treatment (Blumenfeld and Tischio, 2003) and that they are less influenced by comorbid conditions than general health quality of life measures (Zuan, Kirchdoerfer, Boyer, and Norwood, 1999). The MSQ v2.1 questionnaire consists of 14 questions and measures three dimensions: role-function- restrictive (RR), role function-preventive (RP), and emotional function (EF). It was developed from the MSQ v1.0 (Jhingran, Osterhaus et al., 1998); its content was improved by rewording of different items for greater clarification and shortened for easier administration. The MSQ v2.1 is intended to measure the health status and treatment outcomes related to the physical and emotional limitations typically associated with migraine. The MSQ v2.1 dimensions have acceptable internal consistency, test-retest reliability, content, construct, convergent, and discriminant validity. The Cronbach � for the MSQ v2.1 ranged from 0.86 to 0.96 (Martin et al., 2000; RR, � = 0.96; RP, � = 0.93; EF, � = 0.86). The test-retest measures of reliability [intraclass correlation coefficient 123 (ICC), Pearson correlation coefficient (r)] for medically stable subjects at a four-week interval exceed the generally accepted test-retest criteria of 0.50 (Martin et al., 2000; RR, ICC=0.57, r=0.62; RP, ICC=0.60, r=0.63; EF, ICC=0.63, r=0.65.) Content validity on MSQ v1.0 (Jhingran, Osterhaus et al., 1998) was established by identifying prospective items from the literature and by including only those items that were meaningful to both patients and headache specialists. Subsequent changes in the MSQ have improved content validity. Comments provided by clinicians and patients who participated in clinical trails and one-on-one interviews resulted in revisions, such as changing the instrument to reduce wording ambiguity and to increase respondent understanding and acceptance by creating standardized response categories in the form of a six-point Likert-type scale (Martin et al., 2000). Further evaluation of the MSQ v1.0 by confirmatory factor analysis lead to a statistically improved factor structure with the elimination of two questions, yielding the 14-item MSQ v. 2.1 (Martin et al., 2000). Construct validity was evaluated using several different approaches (Martin et al., 2000), including the multitrait-multimethod developed by Campbell and Fiske (1959). This method explores relationships with other variables (i.e., migraines symptoms) that are logically related to the MSQ v2.1 dimensions, and examines hypothesized differences between groups (stable vs. new patients). These analyses indicate that the MSQ v2.1 has three distinct dimensions, although two of these dimensions, RR and RP, are closely related (EF:RP and EF:RR, r = 0.60; RP:RR, r = 0.81), and that these dimensions are distinct from general health quality of life components. Further evidence for construct validity was demonstrated by the negative correlation of MSQ v2.1 scores with migraine 124 symptomatology, with fewer occurrences of symptoms associated with higher MSQ v2.1 scores. Additional support for construct validity was exhibited by significantly higher scores for all MSQ v2.1 dimensions obtained with stable, treated patients as compared to first-time patients. Evidence for convergent and discriminant validity was suggested by the correlation matrix between the two component scores of the Medical Outcomes Study 36-item Short Form (SF-36; physical component (PCS) and mental component (MCS); McHorney, Ware, Lu, Rogers, Raczek, & Lu, 1992; McHorney, Ware, & Raczek, 1993; Ware & Sherbourne, 1992) and the MSQ v. 2.1 (Martin et al., 2000). Low to moderate correlations between the MSQ v2.1 and SF-36 component scores indicate that the MSQ v2.1 measures produce related, but distinct, constructs from the SF-36. However, significant differences were noted with one dimension of the MSQ v2.1. The EF dimension of the MSQ correlated higher with the MCS component than the PCS component of the SF-36, providing evidence for discriminant validity. The MSQ v2.1 has been used in several migraine treatment outcome studies (Adelman et al., 1998; Blumenfeld and Tischio, 2003; Jhingran et al., 1996; Solomon, Skobieranda, and Genzen, 1995). Results of these studies indicate that the MSQ v2.1 is sensitive to the effects of sumatriptan on aspects of health measured by each of the measures dimensions. Pain Catastrophizing Scale The Pain Catastrophizing Scale (PCS; Sullivan et al., 1995; see Appendix F) is a self-report measure of catastrophic thinking related to pain. It consists of 13 items 125 describing various thoughts and feelings that persons may experience when they are in pain. The PCS yields a total score and three subscale scores evaluating rumination, magnification, and helplessness. The PCS has been shown to have high internal consistency (coefficient alphas for undergraduate student population: total PCS = 0.87, rumination = 0.87, magnification = 0.66, helplessness = 0.78; Sullivan et al., 1995; coefficient alphas for adult outpatient sample: total = .92, rumination = 0.85, magnification = 0.75, helplessness = 0.86; Osman et al., 2000). Also, the PCS total score shows strong temporal stability and construct validity (Sullivan et al., 1995). For example, test-retest reliability estimates for 6 weeks (r = .75) and 10 weeks (r = .70) indicated strong evidence for stability of responses on the PCS. Evidence for convergent validity was demonstrated by the moderate correlation of the PCS total scores with scores on self-report measures of anxiety (r = .32, p < .001), negative affectivity (r = .32), and a large correlation with scores on a self-report measure of fear of pain (r = .80). Criterion-related validity has also been suggested in that the PCS total score was clinically useful in differentiating between pain outpatient and community samples (OR = 1.07; CI = 1.04, 1.11; Osman et al., 2000.) In this administration, the word headache was substituted for the more global word of pain, and asked participants to reflect on past painful headaches, instead of pain experiences in general. Individuals were to indicate the degree to which they experience each of the 13 thoughts or feelings when experiencing a headache on five-point scales with the endpoints (0) not at all and (4) all the time. Psychometric properties of this instrument involving these changes have not been determined. 126 Statistical Analysis Descriptive statistics were performed on demographic, clinical, and headache characteristics in order to characterize the sample. Demographic variables included age, income level, education level, highest degree completed, employment status, and ethnicity. Clinical characteristics described were migraine classification [i.e., with or without aura or both, IHS diagnosis (2004)], comorbid episodic tension-type headache diagnosis, disease duration, total diary days recorded per subject, total migraine days per month, average menstrually related migraine episodes and days per subject and per month, gynecologic factors, and psychological symptomology. Migraine episodes were described separately for menstrually related and nonmenstrual migraines and were compared for headache features (i.e., maximum severity, presense of severe pain migraines, presence of migraine-associated symptoms, migraine-associated symptom score, presence and score of individual migraine-associated symptoms, including nausea, photophobia, and phonophobia, duration in hours, presence of disability, disability equivalent hours), medication use (i.e., analgesics, triptans, rescue medications), and treatment outcomes (i.e., two hour pain-free, four hour pain-free, and recurrence within 24 hours after pain-free at two, four, and all intervals withing 24 hours). In addition, headache features, medication use, and treatment outcomes were further classified and described by use and nonuse of birth control medication. Descriptive statistics for demographic variables, including age, income level, education level, highest grade completed, employment status, and ethnicity, were performed on variables from the Treatment of Severe Migraine Study dropouts who were 127 menstruating, female participants and, therefore, potential candidates for this study. Variable categories were collapsed, when necessary, to allow for adequate cell size for inferential statistical analyses. Appropriate inferential statistical tests were performed to determine sigificant differences in comparison to the eligible participants of this current study, including the t-test for independent samples (i.e., age), the Fishers Exact Test (i.e., highest degree completed), and �2 analysis (i.e., other discrete variables). To determine the distribution of migraine and tension-type headaches by day of the menstrual cycle, the percent of patients on each day of the menstrual cycle with a migraine or tension-type headache was graphically represented by day of the menstrual cycle. A headache was counted as occurring on each day that a woman reported a migraine or tension-type headache. Logistic regression was used to estimate the odds ratio (OR) and confidence interval for women to experience a migraine or tension-type headache during the interval between two days prior through two days after the first day of the menstrual cycle. Repeated measures logistic regression [i.e., generalized estimating equations (GEE regression)] was performed to account for intrasubject correlation (Liang & Zeger, 1986; Zeger and Liang, 1986). In order to test for significant differences between menstrually related and nonmenstrual migraines, the working correlation matrix parameters were estimated using the exchangeable correlation, or compound symmetry, matrix so that all days within a menstrual cycle window (i.e., menstrual or nonmenstrual) would be considered equal. For each headache feature, medication, and treatment outcome, the odds of a significant difference between menstrually related migraines and nonmenstrual 128 characteristics were determined using logistic regression to estimate the odds ratio (OR) and confidence interval (CI). Repeated measures logistic regression [i.e., generalized estimating equations (GEE regression)] was performed to account for intrasubject correlation (Liang & Zeger, 1986; Zeger and Liang, 1986). Parameters for the working correlation matrix for the repeated measures logistic regression analysis was estimated using the autoregressive correlation matrix because of an assumption of time dependence for the association of repeated measures within the menstrual cycle. Headache features compared were: (1) maximum headache severity, presence of severe pain migraines, (2) presence of migraine-associated symptoms, migraine- associated symptom score for symptom positive headaches, presence and score of each individual migraine-associated symptom when migraine was positive for each symptom (i.e., nausea, photophobia, phonophobia, vomiting), (3) duration, and (4) presence of disability and disability equivalent hours for migraines with disability. Medication parameters compared were (1) use of analgesics and number of analgesic pills used for migraines treated with analgesics, (2) use of triptans and number of triptan doses for migraines treated with triptans and (3) use of rescue medication and number of rescue medication doses taken for each migraine treated. The primary treatment outcome was the two hour pain-free response (Goldstein et al., 1999; International Headache Society Clinical Trails Subcommittee, 2000). Secondary treatment outcomes were the four hour pain-free response, and recurrence within 24 hours after pain-free at two, four, and all time intervals within 24 hours following acute migraine treatment. 129 Participants were divided into dichotomous groups based on the use of birth control medication status. Descriptive statistics for demographic variables, including age, income level, education level, highest degree obtained, employment status, and ethnicity, were performed on these two subsamples. Appropriate inferential statistical tests were performed to determine significant subsample demographic differences, including the t- test for independent samples for age and education level, the Fishers Exact Test for highest degree obtained, income level, marital status, and ethnicity, and �2 analysis for employment status. To determine the distribution of migraines by birth control medication use and nonuse by day of the menstrual cycle, the percent of patients on each day of the menstrual cycle with a migraine headache was graphically represented by day of the menstrual cycle. Logistic regression was used to estimate the odds ratio (OR) and confidence interval for women to experience a migraine during the interval between two days prior through two days after the first day of the menstrual cycle. In addition, differences in the likelihood of birth control users and nonusers to experience a migraine during this defined menstrual cycle window were determined using logistic regression. Repeated measures logistic regression [i.e., generalized estimating equations (GEE regression)] was performed to account for intrasubject correlation (Liang & Zeger, 1986; Zeger and Liang, 1986). In order to test for significant differences between menstrually related and nonmenstrual migraines, the working correlation matrix parameters were estimated using the exchangeable correlation, or compound symmetry matrix, so that all 130 days within a menstrual cycle window (i.e., menstrual and nonmenstrual) would be considered equal (Hardin & Hilbe, 2003). Each headache feature, medication, and treatment outcome previously described in the comparison of menstrual and nonmenstrual migraines was regressed using multivariate regression models with birth control medication use, menstrually related migraines, and the interaction of birth control medication use and menstrully related migraines as independent variables. Logistic regression was used for all dichotomous variables; multiple regression was used for variables with a normal distribution (i.e., migraine associated-symptom score) or that were transformed into a normal distribution (i.e., duration, disability equivalent hours, number of analgesic pills and triptan doses); multinomial regression was used for categorical variables or variables with a small number of discrete levels (i.e., maximum severity, number of doses of rescue medication). Because each individual can contribute multiple observations to the analysis, repeated measures logistic, linear, or multinomial regression (i.e., GEE) was performed. Parameters for the working correlation matrix in the repeated measures logistic regression analyses were estimated using the autoregressive correlation matrix because of an assumption of time dependence for the association of repeated measures within the menstrual cycle (Hardin & Hilbe, 2003). The working correlation matrix could not be estimated for the multiple and multinomial regression models and was set to the independence or identity working correlation matrix, which uses the following structure: Corr(Yi j, Yi j) = 1 j = k ; 0 j � k 131 Exploratory analyses for both psychological and gynecological predictors of menstrually related migraine acute treatment response (i.e., four hour pain free response, use of rescue medications) and recurrence after pain-free at any time interval within 24 hours following acute migraine treatment were performed using logistic regression analyses. There was inadequate power (<70%) to reliably predict two hour pain-free treatment response following acute treatment because of low rate of occurrence (13 of 193). Because each individual could contribute multiple observations to the analyses, repeated measures logistic regression (i.e., GEE) was used. Treatment regimen and use of birth control medication were included in the model when found to significantly covary with the treatment response or recurrence variable of interest. Additional analyses indicated that depressive and anxiety symptoms were not predictors of treatment outcomes (see Appendix M); therefore, these variables were not included in models of psychological predictors for treatment outcomes. Gynecological factors evaluated included (1) presence of menorrhagia and/or endometriosis, (2) presence of significant influence of reproductive hormones on migraines (i.e., migraines beginning within two years of menarche and/or noted improvement of migraines with pregnancy), and (3) degree of premenstrual symptoms (i.e., MSQ score total score minus arousal and control subscales). Psychological factors regressed comprised (1) level of pain catastrophizing (i.e., PCS score) and (2) level of quality of life (i.e., MSQL score). All descriptive statistical analyses were performed with the SPSS, version 12.0 (SPSS, 2003). All repeated measures logistic, multiple, and 132 multinomial regression analyses were performed using the Statistical Analysis System (SAS), version 8.2 (SAS, 2001). Power Analysis Post-hoc power analyses were performed to determine the power of detecting significant differences between values of the independent variables with a sample size of 107. To determine the power for a two-fold increase in the odds ratio (OR) at the 5% level using repeated measures logistic regression analyses, the following equation was used (Brown and Prescott, 1999): 2 2 n = 2(z1-�/2 + z�) v{1 + (m 1)�}/m� , where v = �a/b, a = denominator term for b inomial data, b = expected variance, e.g. µ(1 µ) for binary data, � = dispersion parameter, m = number of repeated measures, � = correlation between observations on same patient � = change in odds ratio. In determining the power for this sample, a = 1, a dispersion parameter of one and a correlation of � = 0.50 were assumed; at the 5% significance level, z1-�/2 = 1.96. The difference in logit [log (odds ratio); �] required for a doubling of the OR is log (2) log(1) = 0.693. The expected variance [e.g. µ(1 µ) for binary data] was calculated separately for each variable of interest. Summaries of the results of the power analyses 133 are presented in the results section. In general, inferential statistics were not presented when power analyses revealed levels below 75%, unless a significant relationship between the independent and dependent variables was found or otherwise noted. RESULTS Prevalence of Headache per Day of the Menstrual Cycle The percent of participants with migraine headaches (see Figure 5) peaked on the first day of the menstrual cycle (i.e., Day 0), with participants 1.9 times more likely to experience a migraine during the interval of 2 days prior through 2 days after the first day of the cycle than at other times during the month (OR=1.91, 95% CI 1.59, 2.30). No significant association between percent participants with tension-type headaches and menstrual cycle was evident (OR=1.02, 95% CI .71, 1.46). However, whereas power analysis for migraines yielded a value of 77%, the likelihood of detecting a Type I error at the .05 significance level for tension-type headaches was less than 50% because of the low prevalence of tension-type headaches in this sample. 134 Figure 5. Percent of participants with migraine or tension-type headache per day of the menstrual cycle. 60.0 MIGRAINE HA ORMRM = 1.91**** TENSION HA 50.0 40.0 30.0 ent of ent Participants Perc 20.0 10.0 ORMRHA = 1.02 0.0 8 2 4 6 8 0 2 14 12 10 - -6 -4 -2 0 1 1 - - - Y Y Y Y Y Y Y Y A Y Y DA DAY DAY DAY D A AY DA DA DA DA D DA DA DA D Day of Menstrual Cycle Note: MRM=Menstrually Related Migraine; HA = Headache; MRHA=Menstrually Related Tension-type Headache. **** p<.0001, N = 107 clusters, Generalized Estimating Equation Modelling Menstrully related migraine headache days = 273 Nonmenstrually related migraine headache days = 922 135 Comparison of Menstrually Related and Nonmenstrual Migraines The 107 participants recorded a total of 684 nonmenstrually related migraines (NMRM) and 208 menstrually related migraines (MRM). Descriptive statistics for migraine features, medication use, and treatment outcomes are given in Tables 11, 13, and 15 for both nonmenstrual and menstrually related migraines. Significant differences in headache features (see Table 12), medication use per migraine (see Table 14), and response following acute medication (see Table 16) were associated with time of occurrence during the menstrual cycle. Power analysis indicated that the ability to detect a type I error for comparisons of menstrually related and nonmenstrual migraines was 81%. Headache Features As presented in Tables 11 and 12, menstrually related migraines were of longer duration [23.4 vs. 16.1 hours, Odds Ratio (OR) 1.01, 95% Confidence Interval (CI) 1.01- 1.02], rated as slightly more painful (2.1 vs. 2.0, scale 0-3, OR 1.24, 95% CI 1.02-1.51), and were more likely to be associated with disability (85.6% vs. 75.6%, OR 1.82, 95% CI 1.27-2.58) that persisted longer (7.4 vs. 6.3 hours, OR 1.02, 95% CI 1.00-1.04) than nonmenstrual migraines (see Figures 6 and 8). Migraine-associated symptoms (i.e., phonophobia, photophobia, nausea, vomiting) were present in 95.1% of mentrually related migraines and 89.2% of nonmenstrual migraines, with no significant differences found in the proportion of headaches with at least one migraine-associated symptom (OR 1.51, 95% CI .92-2.48) or with each symptom when evaluated individually (e.g., 95% CI included 1.00; see Tables 11 and 12; Figures 6, 7, and 8). When present, participants 136 rated the average severity of migraine-associated symptoms as moderate, which did not differ from ratings of nonmentrually related migraines when combined together as an Associated Symptom Score (3.8 vs. 3.7, OR 1.02, 95% CI .96-1.09) or when each symptom was evaluated individually (e.g., 95% CI did not include 1.00 ; see Tables 11 and 12; Figure 6). Numerically, status migrainosus, [i.e., severe, disabiling migraine headache lasting 72 hours or more with no or brief re m ittance of sym ptoms a ssociated with sleep or treatm ent (IH S, 2004)], occurr ed more fr eque n ytl with menstrually re la dte migraines than non-mentrual migraines (5.3 v s 2.5 % ,), but this dif fe rence wa s n ot statistically significant (OR 2.19, 95% CI .97 -4.97; s ee Tables 11 and 12; Figure 6 and 8). 137 Table 11. Descriptive Statistics for Migraine Features. aNonmenstrually bMenstrually Related Migraines Related Migraines Headache Features Maximum severity (0-3)c (M, SD) 2.0 .8 2.1 .7 (n=684) (n=208) Proportion with severe pain (%, n) 27.6% (189/684) 29.3% (61/208) Migraine-associated symptoms Proportion with symptoms (%, n) 89.2% (610/684) 95.1 % (193/208) Score (1-10)d (M, SD) 3.7 2.4 3.8 2.4 (n=610) (n=193) Proportion with nausea (%, n) 53.5% (366/684) 58.7% (122/208) Proportion with phonophobia (%, n) 63.0% (431/684) 65.4% (136/208) Proportion with photophobia (%, n) 79.4% (543/684) 81.7% (170/208) Proportion with vomiting (%, n) 7.0% (48/684) 7.2% (15/208) Duration (hours; M, SD) 16.1 20.9 23.4 33.5 (n=684) (n=208) Disability Equivalent Hourse Proportion with disability (%, n) 75.6% (517/684) 85.6% (178/208) Hours with disability (M, SD) 6.3 7.0 7.4 8.0 (n=517) (n=178) Status migrainosusf (%, n) 2.5% (17/684) 5.3% (11/208) a MRM = Menstrually related migraine; b NMRM = Nonmenstrually related migraine. c Maximum severity = rating of maximum pain (0=none, 1=mild, 2=moderate, 3=severe) d Migraine-associated symptom score = Sum of phonophobia (0-3), photophobia (0-3), nausea (0-3), and vomiting (0 or 1) scores. e Disability Equivalent Hours = Sum of all missed activity (e.g., unpaid work, paid work, recreational and social activities, sleep) plus sum of impaired hours divided by two. f Status migrainosus = Severe, disabiling migraine lasting 72 hours or more with no more than brief remittance with sleep or treatment (IHS, 2004). 138 Figure 6. Proportion of migraines with headache feature by type of migraine. % Migraines Note: MRM = Menstrually related migraine; NMRM = Nonmenstrually related migraine; % Severe = % Maximum pain severity rating of 3 or severe; % Associated Symptoms = % with migraine-associated symptom score of >1 [Sum of phonophobia (0-3), photophobia (0-3), nausea (0-3), and vomiting (0 or 1) scores]; % Disability = % with Disability Equivalent Hours of >1 [Sum of all missed activity (e.g., unpaid work, paid work, recreational and social activities, sleep) plus sum of one-half impaired hours (i.e., performed at > 50% reduced productivity). 139 Figure 7. Headache feature scores by type of migraine. Note: MRM = Menstrually related migraine; NMRM = Nonmenstrually related migraine; Maximum severity = rating of maximum pain (0=none, 1=mild, 2=moderate, 3=severe); Migraine-associated symptom score = Sum of phonophobia (0-3), photophobia (0-3), nausea (0-3), and vomiting (0 or 1) scores; Disability Equivalent Hours = Sum of all missed activity (e.g., unpaid work, paid work, recreational and social activities, sleep) plus sum one-half impaired hours (i.e., performed at > 50% reduced productivity); fStatus migrainosus = Severe, disabiling migraine lasting 72 hours or more with no more than brief remittance with sleep or treatment (IHS, 2004). 140 Table 12. Summary of Repeated Measures Logistic Regression Analysis for Headache Features: Menstrually Related Migraine versus Nonmenstrual Migraine (N = 107 a clustersGEE ). Feature � SEa � e�a CIa e� �2 df Maximum severity b Severe rating .116 .174 1.12 .80-1.58 .45 1 Rating (0-3 scale) .218 .099 1.24 1.02-1.51 4.87* 1 Associated symptomsc Symptoms present .411 .253 1.51 .92-2.48 2.64 1 Score (1-10) .023 .031 1.02 .96-1.09 .56 1 Duration (hours) .012 .003 1.01 1.01-1.02 14.16*** 1 DEHSd (hours) Disability present .596 .178 1.82 1.27-2.58 11.16*** 1 Hours with disability .021 .010 1.02 1.00-1.04 4.06* 1 Status migrainosuse .786 .417 2.19 .97-4.97 3.55 1 a GEE = Generalized Estimating Equations. SE = Standard error. CI = Confidence interval. eB = exponentiated �. b Maximum Severity = rating of maximum pain (0=none, 1=mild, 2=moderate, 3=severe); c Associated symptom score = Sum of phonophobia (0-3), photophobia (0-3), nausea (0-3), and vomiting (0 or 1) scores. d DEHS = Disability Equivalent Hours or sum of all missed activity (e.g., unpaid work, paid work, recreational and social activities, sleep) plus sum of impaired hours divided by two; e Status migrainosus = Severe, disabiling migraine lasting 72 hours or more with no more than brief remittance with sleep or treatment (IHS, 2004). p<.10, *p < .05, **p < .01, ***p<.001. 141 F 8. Odds ratio with 95% confideigure nce interval of headache feature for menstrually related migraines. 5 4 3 2.19 2 Odds Ratio 1.24 1.02 1.01 1.02 1 0 AssociatedMaximum DEHSDuration Status Pain Symptom Migrainosus Severity Score Feature * * Maximum Pain Severity = rating of maximum pain (0=none, 1=mild, 2=moderate, 3=severe); Associated symptom score = Sum of phonophobia (0-3), photophobia (0-3), nausea (0-3), and vomiting (0 or 1) scores; DEHS = Disability Equivalent Hours or sum of all missed activity (e.g., unpaid work, paid work, recreational and social activities, sleep) plus sum of impaired hours divided by two; Status migrainosus = Severe, disabiling migraine lasting 72 hours or more with no more than brief remittance with sleep or treatment (IHS, 2004). Odds Ratio (95% confidence interval) excludes 1.0. 142 Medication Use per Migraine Drugs for acute treatment of migraine attacks were taken in 94% (842 of 892) of migraine attacks. Triptans were used in the treatment of 68% (604 of 892) of migraine attacks, alone in 28% (249 of 892) and in combination with analgesics (i.e., nonsteroidal antiimflammatory drugs) in 40% (355 of 892 ) of mig ra ines attacks. A nalgesi cs alone were used in the treatment of 27% (238 of 89 2) of mi graine headaches. Rescue medication (i.e., narcotic, anti-nausea suppos itory, ste r oid, or other m edicati on) was used to treat only 6.7% (60 out of 892) of migraine headaches No differences in the proportion of headache s tr eated with an algesic s, tr iptans, or rescue medication were found between menstrually related or nonmenstrual migraines (i.e., 95% CI included 1.00; see Tables 13 and 14; Figure 9). However, differences existed in the number of triptan and rescue medication doses taken for the two types of headaches (see Table 14; Figure 10). Menstrually related migraines were associated with significantly more triptan [2.0 vs. 1.6 doses (596 out of 892 migraines treated), OR = 1.19, 95% CI 1.07-1.33) and rescue medication [2.3 vs. 1.7 doses (60 out of 892 migrai n e s treated), OR = 1.42, 95% CI 1.08-1.85] per headache than nonmentrually related migraines (see Tables 13 and 14; Figure 11). No significant differences (OR = 1.06, 95% CI .98-1.14) in the number of analgesic pills taken per headache were found between the two types of migraines (MRM = 3.3, NMRM = 3.0; see Tables 13 and 14; Figure 11). 143 Table 13. Descriptive Statistics for Medication Use per Migraine and Treatment Outcome. aNonmenstrually bMenstrually Related Migraines Related Migraines Medication Use Per Migraine Analgesics Proportion treated (%, n) 66.1% (452/684) 67.3% (140/208) Average number of pills (M, SD) 3.0 2.3 3.3 2.6 n=452 n=140 Triptans Proportion treated (%, n) 65.8% (450/684) 70.2% (146/208) Average number of doses (M, SD) 1.6 1.2 2.0 1.8 n=450 n=146 Rescue medications Proportion treated (%, n) 6.0% (41/684) 9.1% (19/208) Average number of doses (M, SD) 1.7 .96 2.3 1.88 n=41 n=19 Figure 9. Proportion of migraines treated by type of medication and type of migraine. % Migraines Note: MRM = Menstrually related migraine; NMRM = Nonmenstrually related migraine. 144 Figure 10. Participant medication use by type of medication and type of migraine. Number Note: MRM = Menstrually related migraine; NMRM = Nonmenstrually related migraine. Table 14. Summary of Repeated Measures Logistic Regression Analysis for Use of Migraine Medications: Menstrually Related Migraines vs. Nonmenstrual Migraines (N = a 107 clustersGEE ). Medication use per Migraine � SEa � e�a CIa e� �2 df Analgesics Proportion treated (N=107) .054 .157 1.06 .77-1.44 .12 1 Number of pills (N=93) .059 .038 1.06 .98-1.14 2.49 1 Triptans Proportion treated (N=107) .289 .150 1.34 .99-1.79 3.70 1 Number of doses (N=103) .178 .054 1.19 1.07-1.33 10.72** 1 Rescue medication Proportion treated (N=107) .444 .279 1.56 .90-2.69 2.54 1 Number of doses (N=28) .348 .136 1.42 1.08-1.85 6.52* 1 Note: a GEE = Generalized Estimating Equations. SE = Standard error, CI = Confidence interval. eB = exponentiated �. *p < .05, **p < .01, ***p<.001. 145 F 11. Odds ratio with 95% conigure fidence interval of amount of medication use for menstrually related migraines. 2.00 1.75 1.50 1.42 1.25 1.19 Odds Ratio 1.06 1.00 0.75 0.50 Analgesics Rescue medicationTriptans Medication * * Analgesics = number of pills; Triptans = number of doses; Rescue medication = number of doses. Odds Ratio (95% confidence interval) excludes 1.0. 146 Acute Treatment Outcomes Significant differences in treatment response between menstrually related and nonmenstrual migraines also were found. Based on the primary outcome measure of two hour pain-free response (Goldstein et al., 1999; International Headache Society Clinical Trials Subcommittee, 2000), drugs for the acute treatment of migraines were less effective for menstrually related migraines than migraines occurring at other times during the menstrual cycle (see Tables 15 and 16). While observed in only 12% (105 of 892) of migraines treated with acute therapy, a two hour pain-free response following acute treatment was half as likely with menstrually related than with nonmentrual migraines (6.7% vs. 13.4%, OR .45, 95% CI .26-.80; see Tables 15 and 16; Figures 12 and 13). However, by four hours following initial acute tr eatment, no d ifferen ce w as demonstrated in pain-free response between menstrually related and nonmenstrual migraines (see Tables 15 and 16; Figure 13). Thirty-seven percent of migraines were reported as pain-free at 4 hours after dosage ( 38.5% MR M vs. 36 .2% NMRM ), with no significant differences between menstrually r elated an d nonmenstrua l migrain es (OR 1.10, 95% CI .81-1.51; OR .86, 95% CI .60-1.21, respectively). Significant differences in headache recurrence within 24 hours following acute treatment were exhibited between menstrually related and nonmenstrual migraines (see Tables 15 and 16; Figures 12 and 13). After a four hour pain-free response, menstrually related migraines were 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, recurrence following a pain-free response at any time interval within 24 hours following acute 147 treatment was more frequent with menstrually related migraines (37.3%, 66 of 177) than nonmenstrually related migraines (23.2%, 140 of 602; OR 1.88, 95% CI 1.34-2.66). Numerically, recurrence within 24 hours after a pain-free response at 2 hours also was geater for menstrually related migraines (38.5%) than nonmenstrual migraines (14.9%); however, there was inadequate power to reliably detect a significant difference at the .05 level (power < 70%). Table 15. Descriptive Statistics for Treatment Outcomes. aNonmenstrually bMenstrually Related Migraines Related Migraines Treatment Outcomes Two-hour pain-free (%, n) 13.4% (87/647) 6.7% (13/195) Four-hour pain-free (%, n) 36.2% (234/647) 38.5% (75/195) Recurrence within 24 hours after pain-free (%, n) 23.2% (140/602) 37.3% (66/177) Recurrence within 24 hrs. after pain-free at 2 hrs. (%, n) 14.9% (13/87) 38.5% (5/13) Recurrence within 24 hrs. after pain-free at 4 hrs. (%, n) 19.6% (46/234) 36.0% (27/75) 148 Figure 12. Headache acute treatment outcomes by type of migraine. % Migaines * Note: MRM = Menstrually related migraine; NMRM = Nonmenstrually related migraine. * Two hour pain-free = Pain-free two hours following acute treatment; Four hour pain- free = Pain-free four hours following acute treatment; Recur after pain-free = Reccurence within 24 hours after a pain-free response following acute treatment; Recur after pf @ 4 hours = Reccurence within 24 hours after pain-free at four hours following acute treatmen t; Recur after pf @ 2 hours = Recurrence within 24 hours after pain-free at two hours following acute treatment. 149 Table 16. Summary of Repeated Measures Logistic Regression Analysis for Treatment Outcomes: Menstrually Related Migraines versus Nonmenstrual Migraines (N = 107 a clustersGEE ). Acute Treatment Response � SEa � e�a CIa e� �2 df Two-hour pain-free -.789 .288 .45 .26-.80 7.50** 1 Four-hour pain-free .010 .158 1.10 .81-1.51 .40 1 Recurrence within 24 hours .633 .175 1.88 1.34-2.66 13.05*** 1 after pain-free Recurrence within 24 hrs. .752 .260 2.12 1.27-3.53 8.33** 1 after pain-free at 4 hrs. Note: a GEE = Generalized Estimating Equations. SE = Standard error, CI = Confidence interval. eB = exponentiated �. *p < .05, **p < .01, ***p<.001. 150 Figure 13. Odds ratio with 95% confidence interval of treatment outcomes for menstrually related migraines. 4 3 2.12 Odds Ratio 2 1.88 1.10 1 0.45 0 2-Hour Pain 4-Hour Pain Recur after Recur after pf Free Free pain free (pf) @ 4 hours Outcome * * Two hour pain-free = Pain-free two hours following acute treatment; Four hour pain- free = Pain-free four hours following acute treatment; Recur after pain-free = Reccurence within 24 hours after a pain-free response following acute treatment; Recur after pf @ 4 hours = Reccurence within 24 hours after pain-free at four hours following acute treatment; Recur after pf @ 2 hours = Recurrence within 24 hours after pain-free at two hours following acute treatment. Odds Ratio (95% confidence interval) excludes 1.0. 151 Birth Control Medication and Menstrually Related Migraines Thirty-eight of the 107 participants reported using birth control medication for three weeks out of the month, with a one-week hiatus followed by menstruation. Of users of birth control medication, 57% reported using com bine d, m onop hasic low-do se (i.e., <30 micrograms) estrogen oral birth control medication. Except for two participants, other birth control users reported using combined , mu ltiph asic lo w- dose estrogen oral birth control. One woman each report ed using a con traceptive ring and transdermal patch. Differences in demograpic and headache characteristics between birth control medication users and non-users were determined using �2, Fisher exact tests, and t-test for independent samples (see Tables 17 and 18). No signif ic ant diffe r ences wer e fou nd in age, ethnicity, education level, income level, or marital and employment status. However, differences were found in the level of academic degrees obtained by women taking birth control med ication versus nonusers [�2 (4, 10 3) = 12. 60, p= .009 ]; descriptive a nalysis indicated that this difference was prim ari ly as sociate d wi th a high er percentage of college degrees in birth control users when compared to woman currently not using birth control medication (19% vs. 8%). Headache characteristics were similar for birth control medication users and non-users, and no significant statistical differences were found between the groups (p>.05; see Table 18). 152 Table 17. Demographic Characteristics of Participants with Menstrually Related Migraines by Birth Control Medication Use. Birth Co n trol M edica tion No (nBC=No=69) Yes (nBC= Yes=38) p Age (M, S.D.) 3 .15 4 3 68. .0 9.9 .64 Ethnicity (%, n) .18 White, not Hispanic 81.2 56 92.1 35 Black, not Hispanic 17.4 5 .12 3 2 Hispanic 1 2.6 11.4 Highest Grade Completed (M, S.D.) 14.9 2 1 5.5 .2 2.3 .62 Education (%, n) .01 H.S. diploma/GED 35.8 24 25.0 9 Trade School 25.4 1 617 .7 6 Part College 31.3 21 38.9 14 4-year College Degree 1.5 1 19.4 7 Masters or Post-Degree 6.0 4 0 0 Income (%, n) .85 0-20,000 15.6 10 11.1 4 21,000-40,000 29.7 19 22.2 8 41,000-60,000 18.8 12 22.2 8 61,000-80,000 12.5 8 13.9 5 More than 80,000 23.4 15 30.6 11 Marital Status (%, n) .64 Single 33.8 23 26.3 10 Married 51.4 35 55.3 21 Living with Significant Other 7.4 5 5.3 2 Separated 1.5 1 0 0 Divorced 5.9 4 13.2 5 Employment (%, n) .07 Not working for pay 25.0 17 7.9 3 Part-time 17.6 12 15.8 6 Full-time 57.4 39 76.3 29 Results for Age and Grade Completed from t-test for independent samples, for Highest Grade Completed, Income, Marital Status and Ethnicity from Fishers Exact Test, and for Employment from �2 analysis. 153 Table 18. Headache Characteristics for Users and Nonusers of Birth Control Medication. Headache Characteristic Birth Control Medication Users Non-users M SD M SD df t p Headaches per 30 days 10.6 4.2 9.8 4.6 105 .810 .420 Migraine headache days per 30 days 9.3 4.0 9.0 4.0 105 -.371 .711 Migraine headaches per 30 days 6.2 2.6 5.9 2.2 105 -.353 .725 Tension-type headache days per 30 days 1.2 1.9 .8 1.5 105 -1.406 .163 Disability days per 30 daysa 6.2 3.1 6.7 3.7 105 .659 .511 Menstrually related headache days per 2.2 1.3 2.2 1.5 105 -.039 .969 30 daysb Menstrually related headaches per 30 1.4 .8 1.4 .8 105 .550 .583 daysb a Disability days per 30 days = Average of total number days recorded with DEHS (i.e., Disability Equivalent Hours or sum of all missed activity, including unpaid work, paid work, recreational and social activities, sleep, plus sum of impaired hours divided by two) recorded per participant divided by 30. b Total number of MRM days (or attacks) = Average of number of days (or attacks) per participant in which participant recorded a migraine headache occurring during the interval from 2 days to +2 day days of the first day of menses. 154 Prevalence of Migraines Across the Menstrual Cycle The percent of migraine headaches per day peaked on the first day of the menstrual cycle (i.e., Day 0) for both groups (see Figure 14). Participants taking birth control medication were 2.1 times more likely to experience a migraine during the interval of 2 days before through 2 days after the first day of the cycle than at other times during the month (OR 2.12, 95% CI 1.63-2.74), while women not on birth control medication were 1.8 times more likely to experience a migraine during this same interval when compared to other days of the month (OR 1.81, 95% CI 1.42-2.31). No significant differences were noted between groups using and not using birth control medication in the percent of women experiencing migraines during this window of premenstrual days when compared to other days of the month (OR 1.18, 95% CI .83-1.69; 81% power at .05 significance level). 155 Figure 14. Percent of participants with migraine headaches per day of the menstrual cycle by birth control medication use. 70 OR = 2.1**** 60 OR = 1.8**** 50 % M i g r a i n e BC = No % M i g r a i n e BC = Yes 40 Percent of Participants 30 20 10 0 4 2 0 8 6 4 2 0 2 4 6 8 0 2 - - - - Y Y 1 1 Y Y Y Y AY AY AY -1 DA DA DA DA DA DA D D DAY AY AY D DAY -1DAY -1 D D Day of Period Note: **** p<.0001, Generalized Estimating Equation Modelling BC = Birth control medication nmigraine days, BC = yes = 533, nclusters = 38 nmigraine days, BC = no = 2422, nclusters = 69 156 Headache Features Headache features were comparable for birth control medication users and nonusers, and no significant differences were found (e.g., CI i ncluded 1.0; see Tables 19 and 20). In addition, headache featu res di d not differ for menstrually related migraines based on birth control medication use statu s (e.g., CI includ ed 1 .0). I nfre quent (i.e., status migrainosus, presence of vom iting) or c ommon headache features (i.e., presence of migraine-associated symptoms) lacke d ad equate pow er (po wer < 70% ) to discern significant differences at the .05 leve l; t herefore , th e r s wesult er not se h own. 157 Table 19. Descriptive Statistics for Migraine Features by Migraine Type and Birth a a Control Medication Use (nNMRM =684, nMRM =208). Headache feature BCb = NO (n= 571) BC = Y ES (n= 321 ) NMRM MRM Total NMRM MRM Total Maximum Severity 2.0 2.1 2.0 1.96 2.1 2.0 (0-3)c (M, SD) (.8) (.7) (.8) (.7) (.7) (.7) Severe pain (%, n) 30.3 30.4 30.3 23.1 27.1 24.0 131/433 42/138 173/571 (58) (19) (77) Migraine-associated symptoms With symptoms (%, n) 88.9 92.8 89.8 89.6 92. 9 90.3 385/433 128/138 513/571 225/251 65/70 290/321 Score (1-10)d (M, SD) 3.8 3.9 3.8 3.8 3.5 3.5 (2.5) (2.5) (2.5) (2.1) (2.2) (2.1) With nausea (%, n) 52.9 57.2 53.9 54.6 61. 4 56.1 229/433 79/138 308/571 137/251 43/70 180/321 With phonophobia (%, n) 64.7 66.7 65.1 60.2 62.9 60.7 280/433 92/138 372/571 151/251 44/70 195/321 With photophobia (%, n) 79.2 80.4 79.5 79.7 84.3 80.7 343/433 111/138 454/571 200/251 59/70 259/321 With vomiting (%, n) 7.9 8.7 8.1 5.6 4.3 5.3 34/433 12/138 46/571 14/251 3/70 17/321 Duration (hours) 16.1 22.9 17.7 16.1 24.6 18.0 (21.2) (36.1) (25.7) (20.6) (28.0) (22.6) e DEHS With disability (%, n) 77.4 86.2 79.5 72.5 84. 3 75.1 335/433 119/138 454/571 182/251 59/70 241/321 Hours with disability 6.5 7.8 6.8 5.9 6.7 6.1 ) (M, SD) (6.9) (8.7) (7.4) (7.2) (6.5 ) (7.0) Status migrainosusf (%, n) 2.8 5.1 3.3 2.0 5.7 2.8 12/433 7/138 19/571 5/251 4 /7 0 9/321 a NMRM = Nonmenstrually Related Migraine, MRM = Menstrually Related Migraine. b BC= Birth Control Medication. c Maximum Severity=rating of maximum pain (0=none, 1=mild, 2=moderate, 3=severe). d Associated symptom score = sum of phonophobia (0- 3), photophobia (0-3), nausea (0-3), and vomiting (0 or 1) scores. e DEHS = disability equivalent hours or sum of all missed activity (e.g., unpaid work, paid work, recreational and social activities, sleep) plus sum of impaired hours divided by two. f Status migrainosus = Severe, disabiling migraine lasting 72 hours or more with no more than brief remittance with sleep or treatment (IHS, 2004). 158 Table 20. Summary of Repeated Measures Logistic Regression Analysis for Migraine a a Features by Birth Control Medication Use and Menstrual Status (N= 107 clustersGEE ). Headache feature � SEa � 95% CI � �2 df p Maximum severityb Average rating (0-3) BCa .079 .255 .421-.579 .10 1 .757 MRM .315 .236 -.147-777 1.72 1 .182 BC*MRM -.076 .291 -.648-.495 .07 1 .793 Severe rating (3) BCa -.099 .347 -.780-.581 .08 1 .775 MRM .311 .344 -.364-.986 .81 1 .367 BC*MRM .292 .395 -.482-1.067 .55 1 .459 Migraine-associated symptomsc Score (1-10; log) BC -.401 .389 -1.163-.361 1.06 1 .302 MRM .162 .267 -.362-.686 .37 1 .544 BC*MRM -.090 .336 -.748-570 .07 1 .790 Duration (hours; log) BC .048 .093 -.133-.230 .27 1 .602 MRM .176 .079 -.020-.330 4.93 1 .026 BC*MRM .054 .091 -.124-.231 .35 1 .555 DEHSd Presence of disability BC -.359 .398 -1.138-.421 .81 1 .367 MRM .440 .242 -.034-.914 3.31 1 .069 BC*MRM -.065 .320 -.693-.562 .04 1 .838 Hours of disability (log) BC -.062 .085 -.229-.105 .53 1 .464 MRM .085 .074 -.061-.230 1.30 1 .253 BC*MRM .018 .086 -.150-.185 .04 1 .837 a GEE = Generalized Estimating Equations. MRM = Menstrually related migraine. BC = Birth Control Medication. bMaximum Severity=rating of maximum pain (0=none, 1=mild, 2=moderate, 3=severe). cAssociated symptom score = sum of phonophobia (0- 3), photophobia (0-3), nausea (0-3), and vomiting (0 or 1) scores. dDEHS = disability equivalent hours or sum of all missed activity (e.g., unpaid work, paid work, recreational and social activities, sleep) plus sum of impaired hours divided by two. eStatus migrainosus = Severe, disabiling migraine lasting >72 hours (IHS, 2004). 159 Medication Use per Migraine Although no differences in the proportion of migraines treated with analgesics were found between groups, significant differences in the amount of analgesics used per migraine existed between users and non-use rs of birth c ontrol medication (see Tables 21 and 22). Birth control users took an average of 3.5 analgesic pills (SD 2.8) per m igraine compared to an average of 2.8 analge sic D pills 2.0) (S per mi [graine� 2 (1, 93) =1 0.82, p= .001] by women not using b irth co ntro l med icat ion. In add ition, there was a significance difference [�2 (1, 9 3) = 5.62, p = . 018] in the num ber o f analgesi c pill s use d in treating menstrually related migraines for birth control medication users (4.0, S.D. 2.7) and nonusers (2.9, S.D. 2.5). No othe r sig nifican t differences i n acu te mi grain e treatment were found. However, numeric n oally n us o fers b irt con trh o l m aedict ion used re scue medication more frequently (10.1%, 14 of 138) and used more doses of rescue medication (M= 2.6 doses, SD 2.1) than users of birth control medication (7.1%, 5 of 70; M = 1.4 doses, SD .5) when treating menstrually related migraines; however, there was inadequate power to reliably detect a significant difference at the .05 level because of the infrequent use of rescue medication (60 of 892 migraine episodes, 60 of 842 treated migraines; power < 70%). 160 Table 21. Descriptive Statistics for Medication Use by Migraine Type and Birth Control Medication Use. Medication Use per BCb = NO (n=534) BC = YES (n =451) Migraine NMRM MRM Tl ota NMRM M RM Total Analgesics Proportion treated (%, n) 69.7 68.0 69.3 69.7 79.1% 71.8 283/406 87/12 8 370/534 168/241 53/67 221 /308 Ave. no. of pills (M, SD) 2.8 2.9 2.8 3.3 4.0 3.5 (1.9) (2.5 ) (2.0) (2.9) (2.7) (2.8) Triptans Proportion treated (%, n) 70.2 75.0 71.3 68.5 74.6 69.8 285/406 96/128 381/534 165/241 50/67 215 /308 Ave. no. of doses (M, SD) 1.7 2.0 1.8 1.6 2.1 1.7 (1.3) (1.9) (1.5) (1.0) (1.4) (1.1) Rescue medication Proportion treated (%, n) 5.5 10.1 6.7 6.8 7.1 6.9 24/433 14/13 8 38/57 1 17/251 5/70 22/3 21 Ave. no. of doses (M, SD) 1.7 2.6 2.0 1.6 1.4 1.6 (1.1) (2.1) (1.6) (.8) (.5) (.7) a NMRM = Nonmenstrually Related Migraine, MRM = Menstrually related migra in e, BC = Birth Control Medication. 161 Table 22. Summary of Repeated Measures Logistic Regression Analysis for Medication Use with Birth Control Medication and Menstrually Related Migraine. Medication use per migraine � SEa � 95% CI � � df p Analgesics Use in treatment (n=107clusters) BCa .090 .395 -.684-.864 .05 1 .819 MRMa -.018 .149 -.310-.273 .01 1 .901 BC X MRM -.094 .234 -.552-.364 .16 1 .687 Number of pills (log; n=93clusters) BC .124 .038 .050-.198 10.82 1 .001 MRM .084 .032 .022-.145 7.02 1 .008 BC X MRM .088 .037 .015-.161 5.62 1 .018 Triptans Use in treatment (n=107clusters) BC .090 .323 -.543-.722 <.01 1 .781 MRM .265 .296 -.316-.845 .64 1 .371 BC X MRM .093 .364 -.619-.806 <.01 1 .798 Number of doses (log; n=103clusters) BC .048 .033 -.017-.112 2.10 1 .148 MRM .082 .026 .032-.132 10.24 1 .001 BC X MRM .049 .031 -.111-.012 2.50 1 .115 Rescue medication Use in treatment (n=107clusters) BC -.118 .557 -1.209-.974 .04 1 .833 MRM .200 .377 -.539-.940 .28 1 .596 BC X MRM -.259 .486 -1.211-.693 .28 1 .594 Number of doses (log; n=28clusters) BC 1.302 1.013 -.728-3.322 1.59 1 .206 MRM .493 .802 -1.079-2.065 .37 1 .539 BC X MRM -1.645 .995 -3.595-.305 2.72 1 .098 a MRM = Menstrually related migraine, BC = Birth Control Medication. 162 Acute Treatment Outcomes Birth control medication use was associated with a higher proportion of migraine recurrences [38.6% (85 of 220)] following a pain-free interval within 24 hours after initial dosing of acute medicati on tha n non -use [ 22.7% (121 of 53 4); �2 (1, 107) = 4.97, p=.026; see Tables 23 and 24; Figu re 15]. N o other sign if icant differe nces in ac ute treatment outcomes fo r migraines, in general , or menstru a lly related m igraines , in particular, between birth control m e dication u sers and non -users wer e found. Recurrences of menstrually related migraines within 24 hours after being pain-free at 4 hours was numerically g reater f or bi rth con trol medication users (6 6.0% , 13 o f 29 ) than nonusers of birth control medic ation (30.4%, 14 of 46) ; how ever, there was i nadeq uate power (<70%) to detect a si nificg an t differe nc e between gr oups at t he .05 leve l. 163 Table 23. Descriptive Statistics for Treatment Outcomes by Migraine Type and Birth a a Control Medication Use (nNMRM =647, nMRM =195). Treatment Outcome BCa = NO (n=534) BC = YES (n=308) NMRM MRM Total NMRM MRM Total Two-hour pain-free 12.8 6.3 11.2 14.5 7.5 13.0 (%, n) (52/406) (8/128) (60/534) (35/241) (5/67) (40/308) Four-hour pain-free 35.7 35.9 35.8 36.9 43.3 38.3 (%, n) (145/406) (46/128) (191/534) (89/241) (29/67) (118/308) Recur within 24 27.0 42.8 30.7 30.7 73.2 38.6 hours after pain-free (85/315) (36/84) (121/399) (55/179) (30/41) (85/220) (%, n) Recur within 24 11.5 37.5 15.0 20.0 40.0 22.5 hours after pain-free (6/52) (3/8) (9/60) (7/35) (2/5) (9/40) at 2 hrs. (%, n) Recur within 24 17.2 30.4 20.4 23.6 66.0 28.8 hours after pain-free (25/145) (14/46) (39/191) (21/89) (13/29) (34/118) at 4 hrs. (%, n) a NMRM = Nonmenstrually Related Migraine, MRM = Menstrually related migraine, BC = Birth Control Medication. 164 Figure 15. Headache acute treatment outcomes by type of migraine and birth control medication use. % Migaines * Note: MRM = Menstrually related migraine; NMRM = Nonmenstrually related migraine. BC = Birth Control. Med = medication * Two hour pain-free = Pain-free two hours following acute treatment; Four hour pain- free = Pain-free four hours following acute treatment; Recur after pain-free = Reccurence within 24 hours after a pain-free response following acute treatment; Recur after pf @ 4 hours = Reccurence within 24 hours after pain-free at four hours following acute treatment; Recur after pf @ 2 hours = Recurrence within 24 hours after pain-free at two hours following acute treatment. 165 Table 24. Summary of Repeated Measures Logistic Regression Analysis for Treatment Outcomes with Birth Control Medication and Menstrually Related Migrainea (N = 107 b a clusters GEE ). Treatment Outcome � SE a � 95% CI � � df p 4 hr pain-free Birth control medication .308 .308 -.300-.911 1.00 1 .317 Menstrually related migraine .265 .280 -.285-.814 .79 1 .345 Birth control X MRM .255 .351 -.433-.943 .28 1 .467 Recur within 24 hours after pain-free (at any time) Birth control medication .733 .328 .089-1.376 4.97 1 .026 Menstrually related migraine 1.021 .330 .375-1.667 9.61 1 .002 Birth control X MRM .624 .388 -.137-1.385 2.59 1 .108 Recur within 24 hours after four-hour pain-free Birth control medication .692 .455 -.201-1.584 2.31 1 .129 Menstrually related migraine .928 .408 .128-1.727 5.15 1 .023 Birth control X MRM .295 .528 -1.330-.740 .31 1 .577 a GEE = Generalized Estimating Equations. MRM = Menstrually Related Migraine. b Included 842 observations receiving acute treatment. 166 Exploratory Analyses: Predictors of Response and Headache Recurrence Following Acute Treatment of Migraines The use of rescue medication (17 of 193) following nonresponse to acute drug treatment for menstrually related migraines was more likely to occur (OR 1.1, 95% CI 1.02-1.18) with higher levels of pain catastrophizing [Pain Catrastrophizing Scale = 27.1(users of rescue medication) vs. 18.0 (nonusers of rescue medication)]; see Tables 30 and 32). In addition, menstrually related migraines in women whose migraines were associated with reproductive events (i.e., m igrai nes started within tw o yea rs of menarch e and/or migraines improved with pregnancy) were significantly less likely (OR = .11, 95% CI .01-.84) to be treated with rescue medication (1.6%) following nonresponse to acute migraine treatment than menstrually related migraines without reproductive event association (13.6%; see Tables 29 and 32). There was inadequate power (i.e., power <70%) to infer lack of association for nonsignficant findings for use of rescue me dicat ion with other psychological and gynecological predict ors (see T ab le 32). No sig nificant psychological or gynecological predictors for fou r-hour pa in-free respons e were fo und (95% CI included 1.00; see Tables 29, 30, 31). In the presence of birth control use and treatment regimen (see Tables 25,26,27,28), no significant psychological or gynecological predictor for migraine recurrence within 24 hours after being pain-free was found (95% CI included 1.00; see Tables 29, 33, 34). 167 Table 25. Descriptive Statistics for Treatment Outcomes by Birth Control for Mentrually Related Migraines Treated with Acute Medication (n=193). Birth Control Birth Control Medicatio n = No Medicat ion = Yes % n % n Treatment Outcomes Four-hour pain-free 35.9 4 6/128 43.1 28/65 Recurrence within 24 hours after 31.6 36/114 56.2 29/61 Pain-free Use of rescue medications 10.2 13/128 6.2 4/65 Table 26. Descriptive Statistics for Treatment Outcomes by Treatment Regimen for Mentrually Related Migraines Treated with Acute Medication (N=193). Triptans Triptans Analgesics Only Alone with Analgesics % n % n % n Treatment Outcomes Four-hour pain-free 40.9 18/44 38.2 21/55 37.2 35/94 Recurrence within 24 hours after 19.5 8/41 38.1 16/42 48.8 41/84 Pain-free (any time interval) Use of rescue medications 0 0 9.1 5/55 12.8 12/94 168 Table 27. Summary of Repeated Measures Logistic Regression Analysis for Treatment Outcomes with Birth Control Medication Use for Menstrually Related Migraines Treated a with Acute Medication (N = 105 clustersGEE ). � SEa � e�a 95% CIa e� df �2 Four-hour pain-free Birth control .279 .346 1.3.67-2.6 2 0 1 .65 medication Recurrence after pain-free (any time interval) Birth control .765 .338 2.15 1.11-4.17 1 5.11* medication Use of rescue medication Birth control -.354 .645 .70 .20-2.49 1 .30 medication Note: a GEE = Generalized Estimating Eq u ations, SE = Standard error, CI = Confidence interval. eB = exponentiated �. p<.1, *p < .05, **p < .01, ***p<.001. 169 Table 28. Summary of Repeated Measures Logistic Regression Analysis for Treatment Outcomes with Treatment Regimen for Menstrually Related Migraines (N = 105 a clustersGEE ). � SEa � e� 95% CI e� df �2 Four-hour pain-free Analgesics vs. -.260 .397 .77 .35-1.6 8 1 .42 Triptans + Analgesics Triptans vs. -.014 .349 .98 .50-1.95 1 <.01 Triptans + Analgesics Recurrence after pain- free (any time inverva l) Analgesics vs. 1.258 .4 37 3. 52 1.49-8.29 1 8.29** Triptans + Analgesics Triptans vs. .654 . 327 1.92 1 .0 1-3.65 1 4.00* Triptans + Analge sics Use of rescue medication Triptans vs. -.745 .5 69 .47 .16-1.45 1 1.72 Triptans + Analgesics Note: a GEE = Generalized E stimating Equations. SE = Standard error, CI = Confidence interval, eB = exponentiated �. p<.1, *p < .05, **p < .01, ***p<.001. 170 Table 29. Descriptive Statistics for Gynecological Predictors of Response and Recurrence Following Acute Treatment for Menstrually Related Migraines (N=193). Independent Menstrual Hormone Endometriosis Variable Distressa Influenceb and/or n=188 n=180 Meno rr hagia n=182 No Yes No Yes Four-hour pain-free response No M SD n 62.7% 61.3% 60.7% 63.8% 33.6 24.6 116 n=7 4 n =38 n=8 2 n=30 Yes M SD n 37.3% 3 8 .7% 39.3 % 36.2% 33.3 22.7 72 n=44 n=24 n=5 3 n=17 Use of recue medications No M SD n 86.4% 98.4% 91.1 % 89.4% 32.8 22.6171 n=102 n =61 n=3 12 n=42 Yes M SD n 13.6% 1.6% 8.9% 10.6% 41.1 33.3 17 n=16 n=1 n=12 n=5 Recurrence within 24 hours after pain-free (any time interval within 24 hours) No M SD n 71.2% 66.1% 67.4% 72.3% 33.6 24.2 126 n=84 n=41 n=91 n=34 Yes M SD n 28.8% 33.9% 32.6% 27.7% 33.2 23.2 62 n=34 n=21 n=44 n=13 a Menstrual Distress Questionnaire; Moos, 1968. b Improvement with pregnancy and/or migraines starting within 2 years of menarche. 171 Table 30. Descriptive Statistics for Psychological Predictors of Response Following Acute Treatment for Menstrually Related Migraines (N=193). Independent MSQLa PCSb Variable M SD n M SD n Four-hour pai r espon sen-free No 39.1 12.5 119 17.8 9.9 198 Yes 39.6 10.0 74 20.3 9.5 74 Use of rescue m atedic ion No 38.7 10.9 176 18.0 9.417 6 Yes 1 1 7 27 .1 10 .445.45.6 17 Recurrence within 24 hours after pain-free (any time interval within 24 hrs) No 40.1 12.2 128 19.6 9.812 8 Yes 1 6 5 17 .3 9 .837.70.0 65 a Migraine Specific Quality of Life; Jhingran, Osterhaus et al., 1998; Jhingran, Davis et al., 1998; Martin et al., 2000. b Pain Catastrophizing Scale; Sullivan et al., 1995. 172 Table 31. Summary of Repeated Measures Logistic Regression Analysis for Predictors of Four Hour Pain-free Response after Acute Drug Treatment for Menstrually Related Migraines (N = 105 clustersGEE). Independent na � SEa � e�a CIa e� df � 2 Variable Migraine specific quality of 105 .001 .014 1.00 .97-1.03 1 <.01 lifeb Pain Catastrophizingc 105 .024 .017 1.02 99-1.06 1 2.01 Menstrual distressd 102 .002 .006 1.00 .99-1.01 1 .07 Hormone influencee 100 -.073 .360 .93 .46-1.88 1 .04 Endometriosis and/or 100 .085 .362 1.09 .54-2.21 1 .05 Menorrhagia Note: a GEE = Generalized Estimating Equation. SE = Standard error, CI = Confidence interval. e B = exponentiated �. *p < .05, **p < .01, ***p<.001. b Migraine Specific Quality of Life; Jhingran, Osterhaus et al., 1998; Jhingran, Davis et al., 1998; Martin et al., 2000. c Pain Catastrophizing Scale; Sullivan et al., 1995. d Menstrual Distress Questionnaire; Moos, 1968. e Improvement with pregnancy and/or migraines starting within 2 years of menarche. 173 Table 32. Summary of Repeated Measures Logistic Regression Analysis for Predictors of Use of Rescue Medication after Acute Drug Treatment for Menstrually Related Migraines. Independent na � SEe a � �a I C a e� df �2 Variable Migraine specific quality of 105 .036 .0 1. .93004 8-1.10 1 1.44 lifeb Pain Catastrophizingc 105 .094 .038 1.10 1.02-1.18 1 6.18* Menstrual distressd 105 .014 .010 1.01 1.00-1.03 1 2.29 Hormone influencee 105 -2.236 1.0 .5011 .01-.84 1 4.53* Endometriosis and/or 105 .415 .6 1.5 .181 45-5.08 1 .45 Menorrhagia a Note: n=number of clusters for Generalized Estimating Equations. SE = Standard error, CI = Confidence interval. eB = exponentiated �. *p < .05, **p < .01, ***p<.001. b Migraine Specific Quality of Life; J h ing ran, Os ter haus et a l., 1 99 8; Jhingran, D av is et al., 1998; Martin et al., 2000. c Pain Catastrophizing Scale; Sullivan et al., 1995. d Menstrual Distress Questionnaire; Moos, 1968. e Improvement with pregnancy and/or migraines starting within 2 years of menarche. 174 Table 33. Summary of Repeated Mesures Logistic Regression Analysis for Gynecological Predictors of Recurrence within 24 Hours Following a Pain-free Response after Acute Drug Treatment for Menstrually Related Migraines. Independent na � E SeCa � �a I a e� df �2 Variable Model 1: Menstrual distressb 102 <-.001 .007 1.00 .99-1.01 1 <.01 Birth Control .3 2 .251 .14-4.44 1 5.81048 .43* Analgesics vs. -1.371 .4 97 . 25 .10-.67 1 7.62* Triptans+analgesic * Triptans vs. Triptans .3 . 60 3 1-1.18 1 2-.50743 .19 + analgesic Model 2: Hormone influencec 100 .222 .3 1.25 .34 64-2.40 1 .44 Birth Control .656 .3 51 1 .93 .97-3.80 1 3 .50 Analgesics vs. -1.31 .512 . 27 .10-.73 1 6.55* Triptans+analgesic Triptans vs. Triptans .3 . 66 . 34-1.27 1 1-.41634 .56 + analgesic Model 3: Endometriosis 100 -.209 .417 .81 .36-1.84 1 .25 and/or Menorrhagia Birth Control .662 .361 1.93 .96-3.93 1 3.34 Analgesics vs. -1.190 .470 .30 .12-.76 1 6.40* Triptans+analgesic Triptans vs. Triptans -.487 .338 .61 .32-1.19 1 2.07 + analgesic Note: an=number of clusters for Generalized Estimating Equations. SE = Standard error, CI = Confidence interval, eB = exponentiated �. *p < .05, **p < .01, ***p<.001. b Menstrual Distress Questionnaire; Moos, 1968. c Improvement with pregnancy and/or migraines starting within 2 years of menarche. 175 Table 34. Summary of Repeated Measures Logistic Regression Analysis for Psychological Predictors of Recurrence within 24 Hours Following a Pain-free Response after Acute Drug Treatment for Menstrually Related Migraines. Independent n � SEa � e�a CIa e� �2 Variables df Model 4: Migraine specific 105 -.024 .015 .97 .95-1.00 1 2.58 quality of lifeb Birth Control .668 .342 1.95 1.00-3.81 1 3.80 Analgesics vs. -1.352 .451 .26 .11-.62 1 9.00** Triptans+analgesic Triptans vs. Triptans -.627 .349 .53 .27-1.06 1 3.24 + analgesic Model 5: Pain Catastrophizingc 105 -.031 .019 .97 .93-1.01 1 2.61 Birth Control .638 .346 1.89 .96-3.72 1 3.42 Analgesics vs. -1.393 .450 .25 .10-.60 1 9.55** Triptans+analgesic Triptans vs. Triptans -.617 .356 .54 .27-1.08 1 3.03 + analgesic Note: n=number of clusters for Generalized Estimating Equations. aSE = Standard error, CI = Confidence interval. eB = exponentiated �. *p < .05, **p < .01, ***p<.001. b Migraine Specific Quality of Life; Jhingran, Osterhaus et al., 1998; Jhingran, Davis et al., 1998; Martin et al., 2000. c Pain Catastrophizing Scale; Sullivan et al., 1995. 176 DISCUSSION There are several strengths of the current study. Foremost, this is the first study to employ prospective diagnosis of menstrually related migraines using the proposed criteria of the IHS (2004). Currently, there are no published studies investigating headache frequency, migraine characteristics, and acute treatment outcomes of menstrually related migraines that have used all of the proposed diagnostic criteria proposed by IHS (2004). Therefore, this study makes a significant contribution to validation of the proposed criteria for the classification of menstrually related migraines. This study is also the first to use a hand-held computer to record headache diary information across the menstrual cycle migraine to assess migraine prevalence by day and acute treatment outcomes. The hand-held computer is portable, easy to use, and is purported to increase accuracy of diary entries by increasing the probability of correctly entering data in a timely manner (Holroyd & Chen, 2001; Heckman, Waller, Cottrell, Holroyd, & Chen, 2001). For example, using the hand-held computer largely overcomes the criticism for using recurrence as an indicator of treatment outcomes (Aurora, 2002). Another overall strength of this study is the exclusion of participants who were currently taking migraine prophylactic treatment or any drug potentially able to prevent migraine attacks (e.g., beta-blockers, calcium antagonists, antidepressants, antiepileptic drugs). Only one other study (Granella et al., 2004) reported the exclusion of participants who were taking migraine preventive medication. Thus, this study eliminated a potential confound whose affect on migraine acute treatment outcomes is only beginning to be explored (Becker et al., 2005; Dodick, Hulihanm, & Wu, 2005). 177 Another overall strength of this study is its population size. Previous studies of migraine frequeny across the menstrual cycle, headache features and acute migraine treatment outcomes assessed a smaller sample size (i.e., 13-81; Dalton, 1973; Granella et al., 2004; Johannes et al., 1995; MacGregor et al., 1990; MacGregor & Hackshaw, 2004; Martin et al., 2000, 2002; Stewart et al., 2000; Waters & OConnor, 1971). The larger sample size of the current study increased power to detect significant differences in headache features and treatment outcomes between menstrually related and nonmentrual migraines. In addition, analyses of the larger population revealed differences in treatment outcomes for birth control users and nonusers where previous studies with fewer participants (Granella et al., 2004; Johannes et al., 1995) found no differences. Summary of Findings The primary purpose of this research was to describe and compare menstrually related migraines to migraines that occur at other times in the menstrual cycle in a population of female migraineurs with frequent, disabling migraines. Migraines were compared by frequency per day of the menstrual cycle, headache features, use of abortive and rescue medications, and acute migraine treatment outcomes. In addition, exploratory analyses were performed to assess the affects of birth control on treatment outcomes and to identify psychological and gynecological predictors of acute treatment response and headache recurrence within 24 hours following acute migraine treatment for menstrual migraines. Findings of this research indicated that the frequency of migraines increased significantly during the perimenstrual period, and that menstrually related migraines are 178 of longer duration and greater frequency with longer lasting disability than nonmenstrual migraines. In addition, this study found that participants reported using more doses of triptans and rescue medication for menstrually related migraines than for migraines occurring at other times during the month. This research also identified less favorable acute migraine treatment outcomes for menstrually related migraines than for nonmentrual migraines. A pain-free response at two hours after acute treatment was half as likely with menstrually related than with nonmenstrual migraines. In addition, menstrually related migraines were twice as likely to recur within 24 hours as nonmenstrual migraines after a four hour pain-free response. Exploratory analyses yielded significant findings. This study found that birth control medication use influences the rate of migraine recurrence. Specifically, birth control medication use was associated with a higher proportion of migraine recurrences after pain-free within 24 hours following initial dosing of acute medication than non-use. In addition, this study identified psychological and gynecological predictors for treatment response following acute migraine treatment. Use of rescue medication was associated with greater pain catrastrophizing and the lack of reproductive event influences on migraines. Comparison to Previous Findings Frequency of Menstrually Related Migraine As with previous headache diary studies (Dalton, 1973; Granella et al., 2004; Johannes et al., 1995; MacGregor et al., 1990; MacGregor & Hackshaw, 2004; Pinkerman & Holroyd, 2003; Stewart et al., 2000; Waters & OConnor, 1971), this study 179 found an increased likelihood that migraines occur during the perimenstrual period when compared to other times during the menstrual cycle. Other headache diary studies, however, did not use all of the proposed IHS (2004) criteria when selecting participants, such as the occurrence of migraines in the time window from two days before menses to the third day of menstruation in two of three menstrual cycles (Dalton, 1973; Johannes et al., 1995; MacGregor et al., 1990; MacGregor & Hackshaw, 2004; Stewart et al., 2000; Waters & OConnor, 1971) or the use of prospective data in diagnosis (Granella et al., 2004). Therefore, this is the first study to support the IHS (2004) proposed criteria for classification of menstrually related migraine. This study adds to the growing body of knowledge that supports the robust finding that migraines are precipitated by perimenstrual hormonal changes, resulting in an increased frequency of migraines during this time window when compared to other days of the menstrual cycle. This finding has been reported in community-based (Johannes et al., 1995; Stewart et al., 2000; Waters & OConnor, 1971) and clinic-based (Dalton, 1973; Granella et al., 2004; MacGregor et al., 1990; MacGregor & Hackshaw, 2004; Pinkerman & Holroyd, 2003) headache diary studies. This finding has not only been found in studies of women identified with migraines associated with the menstrual cycle (Dalton, 1973; Granella et al., 2004) but in studies of female migraineurs, in general (Johannes et al., 1995; MacGregor et al., 1990; MacGregor & Hackshaw, 2004; Pinkerman & Holroyd, 2003; Stewart et al., 2000; Waters & OConnor, 1971). As a whole, this research supports the conclusion that menstruation is a potent, frequent precipitant, or trigger, for migraine episodes in women. 180 This study also found that the frequency of migraines was significantly increased during the perimenstrual period in both women who used birth control medication, as well as those who did not use this form of contraception, and that the likelihood of the increase in migraines perimenstrually did not differ between the two groups. Previous researchers have noted an increase in headaches in women using combination oral contraceptives during the drug-free interval of the cycle when estrogen levels are rapidly declining (Carroll, 1971; Dalton, 1976; Kudrow, 1975; Phillips, 1968; Whitty et al., 1986); yet, no migraine diary study has compared the frequency of migraines across the menstrual cycle in users versus nonusers of birth control medication. Lack of research in this area may be related, in part, to lack of power. Previous studies (Dalton, 1973; Johannes et al., 1995; Stewart et al., 2000; Waters & OConnor, 1971) evaluated a smaller sample size (i.e., 52-81 participants) than this current study, decreasing the power to detect significant differences between subsamples within the population. As noted by Massiou and MacGregor (2000), additional research is needed to evaluate the influence of birth control medication on the frequency of migraines, and, in particular, the frequency of migraines during the perimenstrual period. Headache Features of Menstrually Related Migraines In agreement with previous clinic-based studies (Granella et al., 2004; McGregor & Hackshaw, 2004; Martin et al., 2000, 2002), this study found statistically and clinically significant differences in the severity of headache features perimenstrually when compared to the other days of the month. Menstrually related migraines were of longer duration and were associated with more disability that, when present, persisted longer 181 than nonmenstrual migraines. In contrast to other clinic-based studies (Granella et al., 2004; McGregor & Hackshaw, 2004; Martin et al., 2000, 2002), participants in the current study rated menstrually related migraines as only slightly more painful, and this difference was not clinically, though statistically, significant. Two explanations for this difference in findings are proposed: 1) lack of sensitivity of a 4-point pain rating scale and 2) differences in treatment regimens in the study populations. First, this study used a 4-point rating scale (i.e., none, mild, moderate, or severe) to assess the maximum severity of each migraine attack. In other studies that found clinically significant differences in pain severity, pain was rated using a more detailed scale, including a 5-point scale (i.e., none, mild, moderate, severe, or very severe; Granella et al., 2004) and an 11-point rating scale (i.e., 0-10; Martin et al., 2000, 2002). Such an expanded scale could potentially allow individuals to describe the level of pain with a higher degree of discrimination, which might allow discrimination of the most severe migraines, and thus, potential pain severity differences. Second, the majority of participants in this study used triptans for acute treatment of migraines (i.e., 68%), which has been proposed as the treatment of choice for moderate to severe migraines (Lipton, Bigal, & Goadsby, 2004; Lipton, Stewart et al., 2000). In addition, participants were encouraged to identify and treat migraines early in the course of an attack, which has also been shown in several studies (e.g., Cady, Elkind, & Goldstein, 2004; Scholpp, Schellenberg, Moeckesh, & Banik, 2004; Mathew, Kailasam, & Meadors, 2004) to be more efficacious than treating migraines when the pain is moderate to severe. Studies reporting a clinically significant difference in 182 maximum pain severity (Granella et al., 2004; MacGregor & Hackshaw, 2004) drew participants from clinic populations that included considerably varied treatment protocols, with as few as 26% of patients treated with triptans (Granella et al., 2004). Therefore, it is possible that the early treatment of migraines, especially with triptans, reduced the frequency of severe menstrually related and nonmenstrual migraines, and, thus, the likelihood of detecting a clinically significant difference in maximum pain severity. Interestingly, Stewart and colleagues (2000) also found a statistically significant, but not clinically significant, difference in pain severity for menstrually related versus nonmenstrual migraines in a population-based sample. Differences in methodology, however, limit the ability to make meaningful comparisons between the two studies. For example, Stewart and colleagues (2000) assessed the average pain intensity for each phase of the menstrual cycle, instead of the maximum pain intensity per migraine as evaluated in the current study and clinic-based studies (Granella et al., 2004; MacGregor and Hackshaw, 2004). In addition, Stewart and fellow researchers (2000) used each specific day of the menstrual cycle as the unit of analysis, instead of the individual migraineur. This essentially reduced the data to daily averages, which is not comparable to the current study, which used maximum pain severity per individual per migraine episode. In agreement with Granella et al. (2004) and Stewart et al. (2000), this study found that the types of migraine-associated symptoms were similar in both menstrually related and nonmenstrual migraines. Although differences in severity of symptoms were 183 noted, no significant differences were found in the frequency of occurrence of any type of migraine-associated symptom. Taken together, these findings suggest that menstrually related migraines are qualitatively identical, yet quantitatively different, to nonmenstrual migraines. This current study, nevertheless, unlike a previous study (Granella et al., 2004) found no differences in the frequency of diagnosis of status migrainous between menstrually related and nonmenstrual migraines. This divergence in finding might be explained by the overall low incidence of status migrainous in this sample (nonmenstrual migraine=2.5%, menstrually-related migraine=5.3%), with associated inadequate power to detect statistically significant differences. Unlike Granella and colleagues study (2004), participants in this study treated the majority of migraines with triptans and were encouraged to treat their attacks early when the pain was mild if the pattern of prodromal symptoms predicted a migraine. Early treatment of migraine attacks with triptans has been associated with better treatment outcomes (e.g., Cady et al., 2000, Mathew et al., 2004; Scholpp, Schellenberg, Moeckesch, & Banik, 2004; Sheftell et al., 2000). As recommended by IHS (2004), this study compared migraine headache features separately in women who were users and nonusers of birth control medication. This study found no quantitative or qualitative differences in headache features, including maximum pain severity and migraine-associated symptoms associated with the use of birth control medication with migraines, in general, or with mesntrually related migraines. These results concurred with previous findings found in another headache diary study of a clinical sample (Granella et al., 2004). 184 However, the findings of both of these studies should be considered with caution. It is probable that the previous study (n=64; Granella et al., 2004) lacked power to detect differences in headaches features between users and nonusers of birth control medication. In the current study, there was inadequate power to detect significant differences in infrequent (i.e., status migrainosus, vomiting) or common (i.e., migraine-associated symptom score) features. Numerical differences between users and nonusers of birth control medication in the proportion of migraine features were noted. For example, women who used birth control medication rated migraines, in general, as less severe, including less severe pain and fewer headaches with migraine-associated vomiting. Additional headache diary studies are needed to support the findings of this limited research before conclusions about the affect of birth control medication on migraine features can be discerned. Use of Abortive and Rescue Medications per Migraine The number of pills or doses of acute migraine medication used to treat a migraine episode can be an indicator of severity of the migraine (Granella et al., 2004). Participants in this study were given an individual protocol that provided medication recommendations (i.e., analgesic, triptan, antinausea, or rescue medication) and dosing instructions for treating each migraine. In agreement with recommendations of the US Headache Consortium (Matchar et al., 2000) and several other medical groups (Diener, Kaube, & Limmroth, 1998; Pryse-Phillips et al., 1997), participants were instructed to use triptans for severe migraines, for migraines whose features typically predicted a severe headache, or for migraines that failed to respond satisfactorily to NSAIDs or 185 combination analgesics. Use of resuce medication (e.g., narcotic, nausea suppository, steroid, or other) was reserved for migraines that did not respond to repeated doses of analgesic or triptans. Considering these instructions, the amount of triptans and/or rescue medication taken per headache may be an indicator of the number of moderate to severe migraines treated, while the amount of analgesics taken may be related to the number of mild migraines treated. Although there were no differences between menstrually related and nonmentrual migraines in the proportion of migraines treated with analgesics, triptans, or rescue medication, the number of triptan and rescue medication doses were significantly greater for menstrually related than nonmenstrual migraines. Given the aforementioned instructions, use of more doses of triptans and rescue medication could indicate more severe migraines. In the only other study reporting drug dosages, Granella and colleagues (2004) reported that the average number of symptomatic drug doses taken per migraine attack was higher in perimenstrual migraines than nonmenstrual migraines. These findings support the conclusion that menstrually related migraines are associated with higher severity. The current study also found differences for medication taken by birth control users in contrast to nonusers. Although no differences in the proportion of migraines treated with analgesics or triptans were found, birth control users, in general, took significantly more analgesic pills than nonusers did. In addition, women using birth control medication treated menstrually related migraines with significantly more analgesic pills than women not using birth control medication did. If women treated 186 milder migraines more frequently with analgesics than triptans, these results suggest that birth control use is associated with less severe migraines. No other study has reported findings related to acute migraine medication use in birth control users; therefore, additional research is needed to aid in interpretation of these findings. Acute Migraine Treatment Outcomes In contrast to the preponderance of the literature (e.g., Al-Waili, 2000; Massiou et al., 2000; Nett et al., 2003; Salonen & Saiers, 1999, review; Silberstein et al., 1999, 2000, 2002), this study found that menstrually related migraines were less responsive and more likely to recur after a pain-free response following acute treatment than nonmenstrual migraines. However, a clinic-based study (Granella et al., 2004) reported comparable findings (see Table 35). In assessing this disagreement with the overwhelming number of studies reporting a more favorable response, it may be useful to compare and contrast this current study with the research by Granella et al. (2004) and examine factors that could potentially explain the divergent findings of these studies from the majority of treatment outcomes reported in the literature. Similarities between the two studies include the following factors: 1) The current and Granellas et al. (2004) research studies used participant inclusion criteria that diagnosed menstrually related migraines as migraines that occur regularly with menstruation (e.g., in 2 out of 3 menstrual cycles), not just migraines that happened to occur perimenstrually at the time of data collection. In constrast, treatment trials for menstrually related migraines have typically been similar in design; studies compared migraines that occurred during the perimenstrual period treated with active medication or 187 Table 35. Comparison of Acute Migraine Treatment Outcomes for Menstrually Related Migraines: Current Study vs. Granella et al. (2004). Current Study Granella et al. (2004) Perimenstrual: Premenstrual: Menstrual: 2 days before to 2 days before menses days 1 and 2 of cycle Measure day 3 of cycle Pain-free at 2 hrs. 6.7% 23.1% 13.5% OR=.45 OR=.70 OR= .41 95% CI=.26-.80 95% CI = .41-1.20 95% CI=.22-.76 Recurrence after 52.4% 61.5% 67.6% pain-free within 24 OR=1.88 OR=1.96 OR=2.15 hoursa 95% CI=1.34-2.66 95% CI=1.46-2.63 95% CI=1.67-2.78 Note: OR=Odds Ratio, CI=Confidence Interval. a Current study: pain- free within 24 hours; Granella et al. (2004): pain-free at 2 hours. placebo, with no attempt to select women who were diagnosed with menstrually related migraines or whose migraines occurred regularly with menstruation (Facchinetti et al., 1995; Loder & Silberstein, 1999; Massiou, Silberstein et al., 2000; Pitei & Hettiarachchi, 2000; Silberstein et al., 1999, 2000, 2002). Defining menstrually related migraines based in regular occurrence with the menstrual cycle may not be pivotal, however. In one clinical study that initiated the trial using retrospective diagnosis of menstrually related migraines, the diagnosis of menstrually associated migraines was confirmed in only 52% of participants. Yet, the participants with confirmed menstrually associated migraine diagnosis had similar treatment response as those participants whose diagnosis lacked confirmation. 2) The current and Granellas et al. (2004) study used similar days in the menstrual cycle to define menstrually related migraines. The time window used in defining menstrually 188 related migraines varied considerably between studies, including 3 to +5 (Facchinetti et al., 1995, Gross et al., 1995), -3 to +3 (Massiou & Silberstein, et al., 2000; Silberstein et al., 2000, 2002), -2 to +3 (Loder & Silberstein, 1999), -2 to +4 (Nett et al., 2003), -1 to +4 (Solbach & Waymer, 1993), and 0 to +1 (Al-Waili, 2000) days from onset of menstruation. In addition, one study evaluated the efficacy of acute migraine treatment for migraines that occurred only during menstruation (Silberstein et al., 1999). However, the time window selected may not be the distinguishing factor between studies; Granella et al. (2004) studied various time windows and found significant treatment differences in several time windows ranging from 2 to +7, although attacks were found to be least responsive to acute treatment during the first two days of the menstrual cycle. 3) Participants in the current and Granellas study were excluded if they were currently taking prophylactic treatment for migraine or any drug potentially able to prevent migraine attacks (e.g., beta-blockers, calcium antagonists, antidepressants, antiepileptic drugs). In other studies, participant selection criteria either did not specify whether the patients were taking prophylactic medication (Al-Waili, 2000; Fracchinetti et al., 1995; Gross et al., 1995; Loder & Silberstein, 1999; Massiou, Silberstein et al., 2000) or explicitly stated that participants were not excluded who were taking preventive migraine medication (Nett et al., 2003; Silberstein et al., 2000, 2002; Solbach & Waymer, 1995). Thus, the potential confound of prophylactic medication existed in the majority of studies that investigated the acute treatment response of menstrual migraines. 4) The current study and the study by Granella et al. (2004) were not randomized control studies, and, therefore, the results must be treated with caution. However, only two 189 studies (Facchinetti et al., 1995; Gross et al., 1995) for treatment outcomes for perimenstrual migraines were randomized control trials. In addition, one study used a within-subject cross-over with placebo design (Al-waili, 2000). Other studies were posthoc analysis of previous studies that were not randomized for menstrually related migraines (Loder & Silberstein, 1999; Massiou, Silberstein et al., 2000; Siblerstein et al., 1999, 2000, 2002; Solbach & Waymer, 1993). Because of the diversity of methodologies in previous studies, there is little support for differences in study design as an explanation for the divergence of findings for acute migraine treatment response in the current study. Factors that differ between the current and Granellas et al. (2004) may have less influence on acute migraine treatment response than common factors. These factors include the following: 1) The majority of participants in the current study treated their migraines with triptans (i.e., 68%), while the majority of participants in Granella and colleagues (2004) study treated migraines with NSAIDs (i.e., 74%), although the protocol of both studies incorporated multiple acute treatment regimens. In other studies, acute treatment outcomes for menstrually related migraines are comparable for triptans (e.g., Salonen & Saiers, 1999, review; Loder & Silberstein, 1999; Massiou, Silberstein et al., 2000; Silberstein et al., 2000, 2002) and NSAIDs (Al-Waili, 2000; Granella et al., 2004; Silberstein et al., 1999). In addition, studies that directly compared analgesic and triptan response for migraines, in general, reported that NSAIDs alone or in combination are as effective as or more effective than sumatriptan (Di Monda et al., 2003; Dowson et al., 2000; Freitag et al., 2001; Goldstein et al., 2005; Tfelt-Hansen, 2000; Tfelt-Hansen et al., 190 1995). Overall, research evidence suggests that acute treatment response of triptans and analgesics are not significantly different, and, therefore, played a minor, if any, role in the discrepancy between the current studys results and the majority of findings. 2) The current study included migraineurs with 3-16 migraine attacks per month (M= 6.01, S.D.= 2.34), whereas Granellas et al. (2004) participants demonstrated 2-6 migraines per month (Granella et al., 2004). However, Granellas et al. (2004) participant selection criteria were similar to other studies reporting favorable treatment outcomes for migraines associated with menstruation (Al-Waili, 2000, Granella et al., 2004; Silberstein et al., 1999). Two studies with divergent findings did enroll participants with more frequent migraines (i.e., up to 8 migraines per month; Silberstein et al., 2000, 2002). Considering the similarity of headache severity and frequency criteria from these studies with divergent findings, it is unlikely that sample bias related to severity and frequency of migraines explains the divergence of findings from the majority of studies (Al-Waile, 2000; Facchinetti et al., 1995; Gross et al., 1995; Loder & Silberstein, 1999; Massious, Silberstein et al., 2000; Pitei & Hettiarachchi, 2000; Silberstein et al., 1999, 2000, 2002; Solbach & Waymer, 1993). 3) In contrast to other menstrually related migraine acute treatment studies (Al-Waili, 2000; Facchinetti et al., 1995, Gross et al., 1995; Loder & Silberstein, 1999; Massiou & Silberstein et al., 2000; Silberstein et al., 2000, 2002; Nett et al., 2003; Solbach & Waymer, 1993; Silberstein et al., 2000, 2002), the current study uniquely recorded headache diary data using a hand-held computer. Real-time data recording could potentially be associated with acute treatment outcome differences, especially recurrence 191 after pain-free following acute treatment. However, similar outcome data for recurrence after pain-free following acute migraine treatment when using either the hand-held computer or pen-and-paper entries (Granella et al., 2004) minimizes this difference as a reason for divergence in findings for acute treatment outcomes as reported in the majority of studies (Al-Waile, 2000; Facchinetti et al., 1995; Gross et al., 1995; Loder & Silberstein, 1999; Massious, Silberstein et al., 2000; Pitei & Hettiarachchi, 2000; Silberstein et al., 1999, 2000, 2002; Solbach & Waymer, 1993). To summarize, exclusion of participants who were currently using migraine preventive medication is the main feature distinguishing studies that failed to differentiate perimenstrual and nonmenstrual migraines studies treatment outcomes (Al- Waile, 2000; Facchinetti et al., 1995; Gross et al., 1995; Loder & Silberstein, 1999; Pitei & Hettiarachchi, 2000; Silberstein et al., 1999, 2000, 2002; Solbach & Waymer, 1993) from the current and Granella et al (2004) studies. Few studies have investigated the affects of migraine preventive medication on the course of migraines treated with abortive drugs (Becker et al., 2005; Dodick, Hulihanm, & Wu, 2005). Becker and colleagues (n=55; 2005) found that topiramate, a migraine preventive medication, reduced the frequency of migraine attacks per month, but did not increase the proportion of participants that were pain-free at two hours following acute treatment with triptans. In a post-hoc analysis of two randomized, placebo-controlled studies, Dodrick et al. (n=445; 2005) reported that participants receiving topiramate to prevent migraines reported significant reductions in migraine symptoms when compared to baseline following use of triptans, including reductions in pain severity (p=.007), nausea 192 (p=.045), and sensitivity to light and sound (p<.02); no acute treatment outcomes responses were reported. Additional research is needed to elucidate the affects of prophylactic medication on acute migraine treatment responses for migraines, in general, and for menstrually related migraines. Exploratory Analyses: Predictors of Response and Headache Recurrence As with previous studies investigating predictors of acute migraine treatment response (Christoph-Diener et al., 2004; Likater et al., 1997; Meckling et al., 2001; Visser, Burggraaf et al., 1996) and recurrence after treatment response (Sheftell et al., 2000; Visser, Jaspers et al., 1996), few predictors of response and of migraine recurrence following acute migraine treatment were identified. No psychological or gynecological predictor was associated with four hour pain-free treatment response or recurrence after pain-free following initial treatment. Only the use of rescue medication, an indicator for lack of response, was predicted by psychological and gynecological factors; higher levels of pain catastrophizing and positive report of the influence of reproductive events on migraines (i.e., migraines started within two years of menarche and/or migraines improved with pregnancy) were associated with use of rescue medication. No previous study of migraine acute treatment response predictors has assessed use of rescue medication as an indicator of treatment response. However, two studies evaluated the association between use of analgesics and pain catastrophizing. In one study, greater patient requests for analgesics during the first three post-operative days after breast cancer surgery were significantly associated with pain catastrophizing (Jacobsen & Butler, 1996). Likewise, Mellegård and colleagues (2004) found that 193 women with fibromyalgia reported greater catastrophizing and use of analgesics and sedatives than women with either neck/shoulder or back pain. Neither study design, though, permited inferences of causation. Although pain catatrophizing may result in a predeliction to use rescue medication, pain catastrophizing may also be a consequence of a history of treatment nonresponse, despite adequate treatment. Thus, pain catastrophizing in the present study may be the consequence of lack of response to state- of-the-art acute migraine treatment. Coping strategies, including use of rescue medication, may differ relative to the degree of pain catastrophizing in recurrent headache patients (Wittrock & Myers, 1998). Pain catastrophizing is associated with greater use of passive coping strategies, including praying/hoping (Mellegård et al., 2001) and use of analgesics and sedatives (Jacobsen & Butler, 1996; Mellegård et al., 2001). Consequently, pain catastrophizing and use of rescue medication may represent a passive coping style in managing migraine attacks. In addition, use of rescue medication may suggest use of a pain avoidance mechanism, which allows dissociation of the pain sensation from the pain experience and pain behavior. Phillips (1987) views such avoidance behavior as reducing the individuals perceived control over pain. This behavior subsequently results in withdrawal from normal activities and escalating pain catastophizing and ensuing intolerance of further pain; this would increase, in turn, the likelihood of using rescue medication. Surprisingly, use of rescue medication was less likely for migraine attacks in which women reported an influence of estrogen on reproductive events. Based on results 194 of previous studies (Meckling et al., 2001; Tatrow and Blanchard, 2002), two possible explanations are proposed. Biological differences may exist between women with menstrually related migraines; a subset of women with menstrually related migraines whose migraines are closely linked with reproductive events might exhibit greater acute migraine treatment response, which reflects a difference in biological mechanisms underlying their attacks. Meckling et al. (2001) suggested that biological mechanisms underscore their finding that significantly greater number of sumatriptan responders than nonresponders indicated that > 25% of their headaches were related to their menstrual cycle. In addition, Tatrow and Blanchard (2002) found that women with menstrually related migraines were less severely distressed by their headaches than women with nonmenstrual migraines, suggesting greater influence of biological than emotional factors. Conversely, psychological factors may be indirectly related to less use of rescue medication for migraine attacks in women who reported an influence of estrogen on reproductive events. Women who associate migraines with reproductive events may attribute their migraines to biological factors rather than personal deficits or external stressors. This explanatory style (Peterson & Seligman, 1984) may reduce uncertainty and produce a personal feeling of control (Amirkhan, 1998), and subsequently, reduce migraine-associated distress and decrease the need to use rescue medication. In a related study, Tatrow and Blanchard (2002) also suggested that a belief in a biological basis for migraines may lessen the perceived impact of stressors that might otherwise trigger a 195 migraine. Further research is needed to confirm these results and explore possible explanatory factors. Caution is warranted in interpreting and generalizing negative predictor findings for acute migraine treatment outcomes because of concerns about adequate power to detect the contributions to variance of these predictors. Also of note, the two hour pain- free response for menstrually related migraines in this sample was low (i.e., 6.7%), and therefore, there was inadequate power (i.e., <70%) to discern significant differences at the .05 level for predictors of this outcome measure. As such, this study was unable to determine predictors for the recommended (Goldstein et al., 1999) primary acute migraine treatment outcome measure. Samples demonstrating greater responsiveness to acute migraine medications could potentially yield different predictors of treatment outcomes. Implications of Findings Currently, the International Headache Classification Subcommittee members (IHS, 2004) do not recognize menstrual migraine as a unique diagnostic disorder because of insufficient validation for inclusion in the formal classification system. Instead, the IHS (2004) decided to place the definition for menstrually related migraines in the Appendix of the second edition of the International Classification of Headache Disorders (2004) rather than in the main classification section to provide a framework for research to verify or refute the disorder. This study provided data to support the existence of menstrual migraine as a separate, diagnostic category and, ultimately, to support the purpose of classification by providing data related to frequency of migraines by day of 196 the menstrual cycle, headache features, medication use, and acute treatment response for menstrually related migraines using the IHS (2004) criteria,. According to Merikaugas (1993), the purpose of classification is three-fold: 1) to provide valid and reliable definitions to support the success of research; 2) to provide a meaningful description of a disorder to assist in finding the etiological origins of the disease; and 3) to provide communication among health-care providers to support decision-making about treatment and prognosis. Because of significant differences in headache frequency, severity, and treatment outcomes for nonmenstrual and menstrually related migraines, these results support the new IHS (2004) diagnostic criteria for menstrually related migraines. As noted by MacGregor (1996), investigators cannot begin to identify the etiology of menstrual and menstrually related migraines without defining these conditions. Only by defining menstrual and menstrually related migraines can researchers distinguish between the two entities and test various hypotheses related to etiology. Research on the pathophysiology of menstrually related migraines found similar biochemical changes in menstrual and nonmenstrual migraines (see Introduction, section- Migraine Pathophysiology and Menstrually Related Migraines). In agreement with Granella et al. (2004) and Stewart et al. (2000), this study found similar migraine- associated symptoms in both menstrually related and nonmenstrual migraines. When considered with physiological research, the current study, together with previous clinical research on menstrually related migraines (Granella et al., 2004; Stewart et al., 2000), support the conclusion that menstrually related migraines do not have a distinct etiology, 197 but are qualitatively similar, yet with an exaggerated response, yielding headaches that are more severe and less responsive to treatment. Further physiological research directly comparing the biochemical etiologies of nonmenstrual and menstrual migraines is needed to confirm this hypothesis. As mentioned previously, classification allows improved communication among health-care providers to support migraine management and prediction of prognosis. Presently, the acute treatment and prognosis of menstrually related and nonmenstrual migraines is similar, with the possible exception of a recommendation for greater use of nonsteroidal anti-inflammatory drugs (NSAIDs) with menstrually related migraines than nonmenstrual migraines because of the role of prostaglandins in menstrually related symptoms (Loder, 2005). However, less favorable treatment outcome for two hour pain- free response and greater recurrence rate for menstrually related migraines when compared to nonmenstrual migraines suggest that concurrent triptan and NSAID treatment might be warranted. Previous studies demonstrated that concurrent treatment with triptans (Krymchantowski et al., 1999, 2000; Smith et al., 2005) and NSAIDs decrease migraine recurrence and improve two hour treatment response (Smith et al., 2005) when compared to treatment with sumatriptan or analgesic alone, without a significant increase in adverse effects when compared to monotherapy. The efficacy of short-term prophylaxis for menstrual migraines has been demonstrated (see Loder, 2002, and Martin, 2004, for reviews). Although long-term prophylaxis for menstrual migraines is generally recommended for treatment of frequent migraines or headaches that do not respond well to acute medication (Loder, 2005), 198 menstrual migraine treatment response to established long-term preventive medications (e.g., beta-blockers, tricyclic antidepressants, sodium valproate, ethysergide) has not been established. The differences in the current findings and results of Granellas et al. (2004) investigation of acute migraine treatment efficacy for participants not taking preventive medication when compared to studies of those on migraine prophylaxis suggest that migraine preventive treatment might be synergistic with acute medication, particularly triptans. The treatment effects of long-term migraine prophylaxis for menstrually related migraines prescribed alone and with acute migraine treatments warrant further study. Limitations of the Study The current study has several limitations. Foremost, subjects in this study were a highly select group of participants: women who were having 3-20 migraine days with at least 3 days of headache disability per month despite acute migraine treatment. The participants migraine headaches were longstanding, averaging 4 years at the current frequency and 13 years overall. Thus, this population constitutes some of the most severely affected female migraineurs. Although these participants might be typical of patients seen in a tertiary headache clinic, participants of this study are not representative of the general population. Results, therefore, may not be characteristic of the majority of women with menstrually related migraines. This study was limited to women affected by menstrually related migraines only. These results, therefore, apply to women with menstrually related migraines and not to women diagnosed with pure menstrual migraines or migraines occurring at other times during the menstrual cycle. No studies reviewed to date have characterized headache 199 features and acute treatment outcomes for women with pure menstrual migraine. Neither have studies compared migraine characteristics and acute treatment response for menstrually related migraines with pure menstrual migraines. Finally, the results of this study were not obtained by a randomized, controlled clinical trial and, as such, do not convey the same level of confidence as outcomes from a double-blind, placebo-controlled study. In addition, the treatment regimen was not standardized across participants, but depended on the clinical judgment of the neurologist and the participants preferences, with subjects initially treating their migraines with either triptans (i.e., sumatriptan, rizatriptan) or analgesics (e.g., ibuprofen, naproxen sodium), with or without an antiemitic. Routes of administration also varied for triptans (i.e., tablets, melts, intramuscular injection). Although this treatment regimen more closely approximated patient care protocols than typical clinical trials, variance in treatment protocols limits interpretation of subsequent results. Future Directions As the first study to incorporate the proposed IHS (2004) criteria for menstrually related migraines, these findings require confirmation with further research. Preferably, participants in future studies will be more typical of the majority of female migraineurs with menstrually related migraines (e.g., less frequent migraines with a shorter history of migraine attacks). In addition, separate and comparative research of subpopulations of users and nonusers of birth control medication is essential to understand treatment response in women with and without exogenous hormone treatment. As noted in comments in the International Headache Societys (IHS; 2004) proposed criteria for 200 mentrually related migraines, The mechanism(s) of migraine may be different with endometrial bleeding resulting from the normal menstrual cycle and bleeding due to the withdrawal of exogenous progestogens (as occurs with combined oral contraception and cyclical hormone replacement therapy). For example, the endogenous menstrual cycle results from complex hormonal changes in the hypothalamic-pituitary-ovarian axis resulting in ovulation, which is suppressed by use of combined oral contraceptives. Therefore, research should separate these subpopulations. Management strategies may also differ for these distinct subpopulations (p. 212). Currently, the treatment approach for menstrually related migraines is similar to migraines, in general, except for more frequent use of NSAIDs (Loder, 2005). This study, however, found differences in treatment outcomes for menstrually related migraines when compared to migraines that occurred at other times during the month. Consequently, these findings suggest the need for research to explore different treatment approaches that address reduced responsiveness and increased recurrence within 24 hours after a pain-free response. One potential approach is concurrent triptan and analgesic use for the acute treatment of menstrually related migraines. Concurrent use of triptans and analgesics has demonstrated increased two hour pain-free acute treatment response (Smith et al., 2005) and reduced recurrence within 24 hours after pain-free (Krymchantowski et al., 1999, 2000; Smith et al., 2005) for migraines in general. Based on the findings of this study, a prospective, randomized placebo-controlled clinical trial to assess concurrent treatment 201 efficacy in comparison to monotherapy for menstrually related migraines is recommended. The current treatment outcome findings that demonstrate less responsiveness and greater recurrence for menstrually related migraines when compared to nonmenstrual migraines diverge from the preponderance of published results (e.g., Al-Waili, 2000; Massiou et al., 2000; Nett et al., 2003; Salonen & Saiers, 1999, review; Silberstein et al., 1999, 2000, 2002). As previously reviewed, this discrepancy may be explained, in part, by the indiscriminate use of migraine preventive medications (e.g., beta-blockers, tricyclic antidepressants, sodium valproate, ethysergide) or failure to specify prophylaxis status (Al-Waili, 2000; Fracchinetti et al., 1995; Gross et al., 1995; Loder & Silberstein, 1999; Massiou, Silberstein et al., 2000) in clinical trials evaluating the efficacy of acute migraine treatment for menstrually related migraines. Few studies (Becker et al., 2005; Dodick, Hulihanm, & Wu, 2005) have explored this potential confound for migraines in general, and the results of these studies have been mixed. The effects of migraine prophylactic treatment on acute treatment outcomes for menstrually related migraines in not well known. Therefore, further research on the treatment effects of migraine prophylactic medication on acute treatment outcomes of migraines, in general, and menstrually related migraines, in particular, is essential, not only because of its implications for treatment, but also because of its role in insuring the internal validity of acute treatment outcome studies. 202 Further research is also indicated to confirm or refute the proposal that the mechanism for menstrually related migraines is qualitatively similar, yet quantitatively different, from migraines that occur at other times during the menstrual cycle. By clarifying the underlying mechanism, more effective treatment of menstrually related migraines could be proposed (MacGregor, 1996). These studies could be undertaken as a within subjects (i.e., migraines within or outside the menstrual window in the same women) or as a between subjects (i.e., migraines within the menstrual window in women with and without a diagnosis of menstrually related migraines) design. The findings from these studies could be reviewed to assess whether different biochemical mechanisms are involved, or whether menstrually related migraines result from an exaggerated response to a common trigger. Finally, additional research is essential to discern predictors of treatment response for menstrually related migraines. Although acute migraine treatment effectiveness has improved tremendously with the advent of migraine-specific medications, a significant proportion of migraineurs fail to respond (Diener & Limmroth, 2001; Visser, de Vriend, et al., 1996) or experience recurrence of their migraines within 24 hours following acute treatment (Dahlöf, 1992; Ferrari et al., 1994; Visser, de Vriend, et al., 1996) to acute migraine treatment. Individual attributes that may contribute to poor treatment outcomes for menstrually related migraines are not well known. Further exploratory and confirmatory research is required to replicate and augment the results of this study. In particular, predictors of acute treatment response should be determined in a population yielding adequate power (e.g., larger sample size or more treatment responsive sample) to 203 evaluate predictors of the primary treatment outcome measure, two four pain-free response (International Headache Society Clinical Trails Subcommittee, 2000) for menstrually related migraines. Conclusions In summary, this study found several significant findings that distinguished menstrually related migraines from nonmenstrual migraines in a population of women diagnosed with menstrually related migraines using IHS (2004) criteria. Menstrually related migraines varied in frequency, features, medication use, and treatment outcomes when compared to migraines that occur at other times during the month. The frequency of migraines were significantly increased during the perimenstrual period, and menstrually related migraines were of longer duration and associated with the presence of more frequent and longer lasting disability than nonmenstrual migraines. Participants reported using more doses of triptans and rescue medication for menstrually related migraines in comparison to migraines occurring at other times during the month. Menstrually related migraines were also reported to be less responsive and to reoccur more frequently within 24 hours after pain-free following acute migraine treatment than nonmenstrual migraines. This research supports the separate diagnostic classification of menstrually related migraine as proposed by the IHS (2004). This research also explored two areas with little known findings: (1) the effects of birth control on the frequency, features, medications use, and acute treatment outcomes for and (2) psychological and gynecological predictors of menstrually related migraines. Frequency of menstrually related migraines and migraine features did not 204 differ between birth control medication users and nonusers. However, differences in acute treatment outcomes for birth control medication users (i.e., more pills of analgesics used, increased frequency of recurrence within 24 hours following acute treatment) when compared to nonusers were found. Although menstrually related migraines were treated with more analgesic medications than nonmenstrual migraines, other treatment outcomes for menstrually related migraines for users of birth control were not discernable because of inadequate power. In addition, few predictors of acute treatment outcomes were found for menstrually related migraines. Nevertheless, greater pain catrastrophizing and the lack of a history of reproductive event influences on migraines were associated with the use of rescue medication. These findings suggest factors that could potentially influence the acute treatment outcomes for menstrually related migraines and, therefore, warrant further study. 205 REFERENCES Abduljabbar, M., Ogunniyi, A., al Balla, S., Alballaa, S., & as-Dalaan, A. (1996). Prevalence of primary headache syndrome in adults in the Qassim region of Saudi Arabia. Headache, 36, 385-388. Abu-Arefeh, I., & Russell, G. (1994). Prevalence of headache and migraine in schoolchildren. British Medical Journal, 309, 765-769. Adelman, J., Brod, A., Von Seggern, R., Mannix, L., Rapoport, A. (1998). Migraine preventive medications: a reappraisal. Cephalalgia, 18, 605-611. Alders, E., Hentzen, A., & Tan, C. (1996). A community-based prevalence study on headache in Malaysia. Headache, 36, 379-384. Allais, G., De Lorenzo, C., Mana, O., & Benedetto, C. (2004). Oral contraceptives in women with migraine: Balancing risks and benefits. Neurological Science, 25, S211-S214. Al-Waili, N. (2000). Treatment of menstrual migraine with prostaglandin synthesis inhibitor mefenamic acid: Double-blind study with placebo. European Journal of Medical Research, 2000, 176-182. Amirkhan, J. (1998). Attributions as predictors of coping and distress. Personality and Social Psychology Bulletin, 24, 1006-1018. Aylward, M., Holly, F., & Parker, R. (1974). An evaluation of clinical response to piperazine oestrone sulphate ('Harmogen') in menopause patients. Current Medical Research and Opinion, 2, 417-423. American Psychiatric Association. (1994). Diagnostic and Statistical Manual of Mental Disorders. Washington, DC: American Psychiatric Press. 206 Amery, W., & Vandenbergh, V. (1987). What can precipitating factors teach us about the pathogenesis of migraine? Headache, 27, 146-150. Anselmi, B., Baldi, E., Casacci, F., & Salmon, S. (1980). Endogenous opioids in cerebrospinal fluid and blood in idiopathic headache sufferers. Headache, 20, 294-299. Arnau, R, Meagher, M., Norris, M., & Bramson, R. (2001). Psychometric evaluation of the Beck Depression Inventory-II with primary care medical patients. Health Psychology, 20(2), 112-119. Aurora, S. (2002). Headache recurrence as a criterion for assessing efficacy of triptans: A perspective. Headache, 42, 70-79. Barclay, S., & Harding, C. (1990). Differential modulation of monoamine levels and turnover rates by estrogen and/or androgen in hypothalamic and vocal control nuclei of male zebra finches. Brain research, 523, 251-262. Barrington, J., Arunkalaivanan, A., & Abdel-Fattah, M. (2003). Comparison between the levonorgestrel intrauterine system (LNG-IUS) and thermal balloon ablation in the treatment of menorrhagia. European Journal of Obstetrics and Gynecological Reproductive Biology, 108, 72-74. Beck, A., Steer, R., & Brown, G. (1996). Manual for the Beck Depression Inventory-II. San Antonio, TX: Psychological Corporation. Beck, A., Ward, C. ,Mendelson, M., Mock, J., & Erlbaugh, J. (1961). An inventory for measuring depression. Archives of General Psychiatry, 4, 561-571. 207 Beckham, J., Krug, L., Penzien, D., Johnson, C., Mosley, T., Meeks, G., et al. (1992). The relationship of ovarian steriods, headache activity and menstral distress: A pilot study with female migraineurs. Headache, 32, 292-297. Becker, W., Hew, H., Christie, S., Binder, C., Wang, J., & Ledoux, S. (2005). A trial to evaluate the effect of topiramate on subject responsiveness to triptans used for symptomatic migraine treatment. Headache, 45, 818. Benedetto, C., Massobrio, M., Zonica, M., & Melzi, E. (1987). Menstrual migraine: A possible pathogenic implication of platelet function. Gynecological Endocrinology, 1, 345-353. Berga, S., & Yen, S. (1990). Circadian pattern of plasma melatonin concentrations during four phases of the human menstrual cycle. Neuroendocrinology, 51, 606-612. Berger, D., Schaffner, W., Schrader, E., Meier, B., & Brattstrom, A. (2000). Efficacy of Viex agnus castus L. extract Ze 440 in patients with premenstrual syndrome (PMS). Archives of Gynecology and Obstetrics, 264, 150-153. Bergström, S., Carlson, L., Ekelund, L. G., & Oro, L. (1965). Cardiovascular and metabolic response to infusions of prostaglandin E1 and to simultaneous infusions of noradrenaline and prostaglandin E1 in man. Prostaglandin and related factors 35. Acta Physiologica Scandinavica, 64, 332-339. Bethea, C., Pecins-Thompson, M., Schutzer, W., Gundlah, C., Lu, Z. (1998). Ovarian steroids and serotonin neural function. Molecular neurobiology, 18, 87-123. Bigal, M., Rapoport, A., Bordini, C., Tepper, S., Sheftell, F., & Speciali, J. (2003). Burden of migraine in Brazil: Estimate of cost of migraine to the public health system and an 208 analytical study of the cost-effectiveness of a stratified model care. Headache, 43, 742- 754. Bigal, M., Rapoport, A., Lipton, R., Tepper, S., & Sheftell, F. (2003). Assessment of migraine disability using the migraine disability assessment (MIDAS) questionnaire: A comparison of chronic migraine with episodic migraine. Headache, 43, 336-342. Bille, B. (1962). Migraine in school children. Acta Paediatrica Scandinavica, 51, 1-151. Blumenfeld, A., & Tischio, M. (2003). Center of excellence for headache care: Group model at Kaiser Permanente. Headache, 43, 431-440. Bousser, M., Ratinahirana, H., & Darbois, X. (1993). Migraine and pregnancy: A prospective study of 703 women after delivery. Neurology, 40, 437. Brandes, J. (2002). Global trends in migraine care: Results from the MAZE survey. CNS Drugs, 16, 13-18. Breslau, N., & Davis, G. (1993). Migraine, physical health and psychiatric disorder: A prospective epidemiologic study in young adults. Journal of Psychiatric Research, 27, 211-221. Breslau, N., Davis, G., & Andreski, P. (1991). Migraine, psychiatric disorders, and suicide attempts: An epidemiologic study of young adults. Psychiatry Research, 37, 11-23. Breslau, N., Lipton, R., Stewart, W., Schultz, L., & Welch, K. (2003). Comorbidiy of migraine and depression: Investigating potential etiology and prognosis. Neurology, 60, 1308- 1312. Breslau, N., & Rasmussen, B. (2001). The impact of migraine. Neurology, 56, S4-S12. 209 Breslau, N., Shultz, L., Stewart, W., Lipton, R., and Welch, K. (2001). Headache types and panic disorder: Directionality and specificity. Neurology, 56, 350-354. Brown, H., & Prescott, R. (1999). Sample size estimation: Non-normal data. In Applied mixed models in medicine. (p. 258). New York: John Wiley & Sons, Inc. Brun, J., Claustrat, B., & David, M. (1987). Urinary melatonin, LH, oestradiol, progesterone excretion during the menstrual cycle or in women taking oral contraceptives. Acta Endocrinologica, 116, 145-149. Brun, J., Claustrat, B., Saddier, P., & Chazot, G. (1995). Noctoral melatonin excretion is decreased in patients with migraine without aura attacks associated with menses. Cephalalgia, 15(136-139). Brzezinski, A., Lynch, H., Seibel, M., Deng, M., Nader, T., & Wurtman, R. (1988). The circadian rhythm of plasma melatonin during the normal menstrual cycle and in amenorrheic women. Journal of Clinical Endocrinology and Metabolism., 66, 891-895. Burger, H., Dudley, E., Robertson, D., Dennerstein, L. (2002). Hormonal Changes in the Menopause Transition. Recent progress in hormone research, 57, 257-275. Buzzi, M., & Moskowitz, M. (1992). The trigemino-vascular system and migraine [Abstract]. Retrieved October 15, 2003. Cady, R., Elkind, A., Goldstein, J., & Keywood, C. (2004). Randomized, placebo-controlled comparison of early use of frovatriptan in a migraine attack versus dosing after the headache has become moderate or severe. Current Medical Research and Opinions, 20, 1465-1472. 210 Cady, R., Sheftell, F., Lipton, R., OQuinn, S., Jones, M., Putnam, D. et al. (2000). Effect of early intervention with sumatriptan on migraine pain: Retrospective analyses of data from three clinical trials. Clinical Therapeutics, 22, 1035-1048. Callaghan, N. (1968). The migraine syndrome in pregnancy. Neurology, 18, 197-201. Campbell, D., & Fiske, D. (1959). Convergent and discriminant validation by the multitrait- multimethod matrix. Psychological bulletin, 56(2), 81-105. Cardinali, D., Vacas, M., Keller Sarmiento, M., Etchegoyen, G., Pereyra, E., & Chuluyan, H. (1987). Neuroendocrine integrative mechanisms in mammalian pineal gland: Effects of steroid and adenohypophysial hormones on melatonin synthesis in vitro. Journal of Steroid Biochemistry, 27, 565-571. Carlson, L., Ekelund, L., & Orö, L. (1968). Clinical and metabolic effects of different doses of prostaglandin E1 in man. Prostaglandin and related factors. Acta Medica Scandinavica, 183, 423-430. Carroll, J. (1971). Migraine--general management. British Medical Journal, 2(764), 756-757. Carson, A., Rose, K., Sanford, C., Ephross, S., Stang, P., Hunt, K., et al. (2004). Lifetime prevalence of migraine and other headaches lasting 4 or more hours: The artherosclerosis risk in communities (ARIC) study. Headache, 44, 20-28. Central Intelligence Agency. (2004). The World Factbook. Retrieved April 18, 2004, from http://www.cia.gov/cia/publications/factbook/goes/us.html. Chancellor, A., Wroe, S., & Cull, R. (1990). Migraine ocurring for the first time in pregnancy. Headache, 30, 224-227. 211 Chen, T. C., & Leviton, A. (1994). Headache recurrence in pregnant women with migraine. Headache, 34, 107-110. Christoph-Diener, H., Ferrari, M, & Mansback, H. for the SNAP Database Study Group. Predicting the response to sumatriptan: The sumatriptan naratriptan aggregate patient database. Neurology, 63, 520-524. Chumlea, W., Schubert, C., Roche, A., Kulin, H., Lee, P., Himes, J. et al. (2003). Age at menarche and racial comparisons in US girls. Pediatrics, 111, 110-113. Clare, A.W. (1983). Psychiatric and social aspect of premenstrual complaint. Psychological Medicine, 193 (Supplement 4), 1-58. Claustrat, B., Brun, J., Chiquet, C., Chazot, G., & Borson-Chazot, F. (2004). Melatonin secretion is supersensitive to light in migraine. Cephalalgia, 24, 128-133. Claustrat, B., Brun, J., Geoffriau, M., Zaidan, R., Mallo, C., & Chazot, G. (1997). Nocturnal plasma melatonin profile and melatonin kinetics during infusion in status migrainosus. Cephalalgia, 17, 511-517. Claustrat, B., Loisy, C., Brun, J., Beorchia, S., Arnaud, J., & Chazot, G. (1989). Nocturnal plasma melatonin levels in migraine: A preliminary report. Headache, 29, 241-244. Condon, T., Ronnekleiv, O., & Kelly, M. (1989). Estrogen modulation of the alpha-1-adrenergic response of hypothalamic neurons. Neuroendocrinology, 50, 51-58. Coope, J. (1975). The post-hysterectomy syndrome. Nursing Times, 71, 1285-1286. Couch, J., Taylor, K., & Hilliard, B. (2003). Migraine in the primary care population: Prevalence, severity, and disability [Abstract]. Headache, 43, 570-571. 212 Couturier, E., Bomhof, M., Neven, A., Knuistingh, M., & van Duijn, N. (2003). Menstrual migraine in a represenative Dutch population sample: Prevalence, disability and treatment. Cephalalgia, 23, 302-308. Critchley, M., & Ferguson, F.(1933). Migraine. Lancet, 123-126. Crosignani, P., Parazzini, F., La Vecchia, C., Meroni, S., & Ricci, E. (1997). Clinical overview of hormonal contraception with special emphasis on long-term effects. The European Journal of Contraception and Reproductive Health Care, 2, 117-121. Crosignani, P., Vercellini, P., Mosconi, P., Oldani, S., Cortesi, I., & DeGiorgi, O. (1997). Levonorgestrel-releasing intrauterine device versus hysteroscopic endometrial resection in the treatment of dysfunctional uterine bleeding. Obstetrics & Gynecology, 90, 257- 263. Cull, R., Wells, N., & Miocevich, M. (1992). The economic cost of migraine. British Medical Journal of Economics, 2, 103-115. Cullberg, J. (1972). Mood changes and menstrual symptoms with different gestagen/estrogen combinations. Acta Psychiatrica Scandinavica, 236, 1-86. Cupini, L., Matteis, M., Troisi, E., Calabresi, P., Bernardi, G., Silvestrini, M. (1995). Sex- hormone-related events in migrainous females. A clinical comparative study between migraine with aura and migraine without aura. Cephalalgia, 15, 140-144. Curren, D., Hinterberger, H., Lance, J. (1965). Total plasma serotonin, 5-hydroxyindoleacetic acid and p-hydrowy-m-methoxymandelic acid excretion in normal and migrainous subjects. Brain, 88, 997-1009. 213 Dahlöf, C. (1992). Headache recurrence after subcutaneous sumatriptan and early treatment. Lancet, 340, 909. Dahlöf, C., & Dimenäis, E. (1995). Migraine patients experience poorer subjective well- being/quality of life even between attacks. Cephalalgia, 15, 31-36. Dalessio, D., Brown, D., Solbach, P., Adelman, J., Elkind, A., & Stark, S. (1996). Oral 311C90 is effective in treatment of menstrual migraines. Cephalalgia, 16, 400-401. Dalton, K. (1973). Progesterone suppositories and pessaries in the treatment of menstrual migraine. Headache, 151-159. Dalton, K. (1976). Migraine and oral comtraceptives. Headache, 15, 247-251. D'Amico, D., Usai, S., Grazzi, L., Rigamonti, A., Solari, A., Leone, M., et al. (2003). Quality of life and disability in primary chronic daily headaches. Neurological Science. D'Andrea, G., Hasselmark, L., Cananzi, A., & Alecci, M. (1995). Metabolism and menstrual cycle rhythmicity of serotonin in primary headaches. Headache, 35, 216-221. de Belleroche, J. (1996). Platelet serotonin pathway in menstrual migraine. Cephalalgia, 16, 406. de Lignieres, B., Vincens, M., Mauvais-Jarvis, P., & et al. (1986). Prevention of menstrual migraine by percutaneous oestradiol. British Medical Journal, 293, 1450. Della-Bella, D., Carenzi, A., Casacci, F., Anselmi, B., Baldi, E., Salmon, S. (1982). Endorphines in the pathogenesis of headache. Advances in Neurology, 33, 75-79. DEon, J., Harris, C., and Ellis, J. (2004). Testing factorial validity and gender invariance of the Pain Catastrophizing Scale. Journal of Behavioral Medicine, 27, 361-372. 214 Deleu, D. & Hanssens, Y. (1999). Primary chronic daily headache: Clinical and pharmacological aspects: A clinic-based study in Oman. Headache, 39, 432-436. Dennerstein, L., Morse, C., Burrows, G., Oats, J., Brown, J., Smith, M. (1988). Menstrual migraine: a double-blind trial of percutaneous estradiol. Gynecological endocrinology, 2, 113-20. Diener, H. (for the ASASUMAMIC Study Group). (1999). Efficacy and safety of intravenous acetylsalicylic acid lysinate compared to subcutaneous sumatriptan and parenteral placebo in the acute treatment of migraine. A double-blind, double-dummy, randomized, multicenter, parallel group study. Cephalalgia, 19, 581-588. Diener, H., Kaube, H., & Limmroth, V. (1998). A practical guide to the management and prevention of migraine. Drugs, 56, 811-824. Diener, H., & Limmroth, V. (2001) Advances in pharmacological treatment of mgraine. Expert Opinions in Investigational Drugs, 10, 1831-1845. Di Monda, V., Nicolodi, M., Aloisio, A., Del Bianco, P., Fonzari, M., Grazioli, I., et al. (2003). Efficacy of a fixed combination of indomethacin, prochlorperazine, and caffeine versus sumatriptan in acute treatment of multiple migriane attacks: A multicenter, randomized, crossover trial. Headache, 43, 835-844. Diamond, S., & Damasio, H. (1982). The practicing physician's approach to headache. Baltimore: Williams and Wilkins. The Diclofenac-K/Sumatriptan Migraine Study Group. (1999). Acute treatment of migraine attacks: Efficacy and safety of a nonsteroidal anti-inflammatory drug, diclofenac- potassium, in comparison to oral sumatriptan and placebo. Cephalalgia, 19, 232-240. 215 Digre, K., & Damasio, H. (1987). Menstrual migraine: Differential diagnosis, evaluation, and treatment. Clinical Obstetrics and Gynecology, 30(2), 417-430. Dodrick, D., Hulihan, J., & Wu, (2005). Do migraine preventive medications enhance the efficacy of triptans? Analyses from topiramate migraine trials. Headache,45, 820. Dowson, A., Ball, K., & Hawarth, D. (2000). Comparison of a fixed combination of domperidone and paracetamol (Domperamol) with sumatriptan 50 mg in moderate to severe migraine: A randomixed UK primary care study. Current Medical Research Opinions, 16, 190-197. Dowson, A., Kilminster, S., Salt, R., Clark, M., & Bundy, M. (2005). Disability associated with headaches occurring inside andd outside the menstrual period in those with migraine: A general practice study. Headache, 45, 274-282. Dozois, D., Dobson, K., & Ahnberg, J. (1998). A psychometric evaluation of the Beck Depression Inventory-II. Psychological Assessment, 10, 83-89. Dzoljic, E., Sipetic, S., Vlajinac, H., Marinkovic, J., Brzakovic, B., Pokrajac, M., et al. (2002). Prevalence of menstrually related migraine and nonmigraine primary headache in female students of Belgrade University. Headache, 42(185), 193. Ellis, J., & DEon, J. (2002). Pain, emotion, and the situational specificity of catastrophising. Cognition And Emotion, 16, 519-532. Epstein, M., Hockaday, J., & Hockaday, T. (1975). Migraine and reproductive hormones throughout the menstrual cycle. The Lancet, 543-548. Espey, L., & Lipner, H. (1994). The Physiology of Reproduction. (2nd ed.). New York: Raven. 216 Facchinetti, F., Martignoni, E., Fioroni, L., Sances, G., & Genazzani, A. (1990). Opioid control of the hypothalamus-pituitary-adrenal axis cyclically fails in menstrual migraine. Cephalalgia, 10, 51-56. Facchinetti, F., Neri, I., Martignoni, E., Fioroni, L., Nappi, G., Genazzani, A. (1993). The association of menstrual migraine with the premenstrual syndrome. Cephalalgia, 13, 422- 425. Facchinetti, F., Bonellie, G., Kangasniemi, P., Pascual, J., Shuaib, A. (1995). The efficacy and safety of subcutaneous sumatriptan in the acute treatment of menstrual migraine. Obstetrics & Gynecology, 86, 911-916. Facchinetti, F., Nappi, R., Tirelli, A., Polatti, F., & Nappi, G. (2002). Hormone supplementation differently affects migraine in postmenopausal women. Headache, 42, 924-929. Fanciullacci, M., Alessandri, M., & Del Rosso, A. (2000). Dopamine involvement in the migraine attack. Functional neurology, 15(Suppliment 3), 171-181. Fernandez, H., Kibelt, G., and Gervaise, A. (2003). Economic evaluation of three surgical interventions for menorrhagia. Human Reproduction, 18, 583-587. Ferrari, M., James, M., Bates, D., Pilgrim, A., Ashford, E., Anderson, B. A., et al. (1994). Oral sumatriptan: Effect of a second dose, and incidence and treatment of headache recurrences. Cephalalgia: An International Journal of Headache, 14, 330-338. Ferrero, S., Pretta, S., Bertoldi, S., Anserini, P., Remorgoda, V., Del Sette, M., Gandolfo, C., & Ragni, N. (2004). Increased frequency of migraine among women with endometriosis. Human Reproduction, 19, 2927-2932. 217 Fioroni, L., Martignoni, E., Facchinetti, F. (1995). Changes of neuroendocrine axes in patients with menstrual migraine. Cephalalgia, 15, 297-300. Fioroni, L., D'Andrea, G., Alecci, M., Cananzi, A., & Facchinetti, F. (1996). Plaelet serotonin pathway in menstrual migraine. Cephalalgia, 16(427-430). Fog-Miller, F., Genefke, I., Bryndum, B. (1978). Changes in concentration of catecholamines in blood during spontaneous migraine attacks and reserpine-induced attacks. In Current Concepts in Migraine Research, eds., Greene, R. New York: Raven Press, 115-119. Fotherby, K. (1992). Clinical experience and pharmacological effects of an oral contraceptive containing 20 micrograms oestrogen. Contraception, 46, 477-488. Fotherby, K. (1998). Twelve years of clinical experience with an oral contraceptive containing 30 microg ethinyl-estradiol and 150 microg desogestrel. Contraception, 51, 3-12. Freitag, F., Cady, R., DeSerio, F., Elkind, A., Gallagher, R., Goldstein, J., et al. (2001). Comparative study of a combination of isometheptenemucate, dichloralphenazone with acetaminophen and sumatriptan succinate in the treatment of migraine. Headache, 41, 391-398. Fuseau, E., Petricoul, O., Sabin, A. Pereira, A., OQuinn, S., Thein, S., et al. (2001). Effect of encapsulation on absorption of sumatriptan tablets: Data from healthy volunteers and patients during a migraine. Clinical Therapeutics, 23, 242-251. Galaxo-Wellcome. (1996). Migraine Specific Quality of Life Questionnaire (Version 2.0; pp. 1- 5). 218 Gallai, V., Floridi, A., Mazzotta, G., Codini, M., Tognoloni, M., Vulcano, M., et al. (1996). L- arginine/nitric oxide pathway activation in platelets of migraine patients with and without aura. Acta Neurol Scand, 94, 151-160. Genazzani, A., Petraglia, F., Volpe, A., & Facchinetti, F. (1985). Estrogen changes as a critical factor in modulation of central opioid tonus: Possible correlations with postmenopausal migraine. Cephalalgia, 2, 211-214. Géraud, G., Keywood, C., & Senard, J. (2003). Migraine headache recurrence: Relationship to clinical, pharmacological, and pharmacokinetic properties of triptans. Headache, 43, 376- 388. Gerth, W., Carides, G., Dasbach, E., Visser, W., & Santanello, N. (2001). The multinational impact of migraine symptoms on healthcare utilization and work loss. Pharmacoeconomics, 19, 197-206. Goadsby, P., Lipton, R., & Ferrari, M. (2002). Migraine--current understanding and treatment [Review]. New England Journal of Medicine, 346, 257-270. Göbel, H., Pettersen-Braun, M., & Soyka, D. (1994). The epidemiology of headache in Germany: A nationwide survey of a representative sample on the basis of the headache clasification of the International Headache Society. Cephalalgia, 14, 97-106. Goldstein, D., Offen, W., & Moster, M. (1999). Efficacy definitions for migraine studies [Letter to the Editor]. Cephalalgia, 19, 248-249. Goldstein, J., Silberstein, S., Saper, J., Elkind, A., Smith, T., Gallagher, M., Battikha, J-P. et al. (2005). Acetaminophen, aspirin, and caffeine versus sumatriptan succinate in the early treatment of migraine: Results from the ASSET trial. Headache, 45, 973-982. 219 Goldzieher, J., Moses, L., Averkin, E., Scheel, C., & Taber, B. (1971). Nervousness and depression attributed to oral contraceptives: a double-blind, placebo-controlled study. American Journal of Obstetrics and Gynecology, 111, 1013-1020. Granella, F., Sances, G., Allais, G., Nappi, R., Tirelli, A., Benedetto, C., et al. (2004). Characteristics of menstrual and nonmenstrual attacks in women with menstrually related migraine referred to headache centres. Cephalalgia, 24, 707-716. Granella, F., Sances, G., Zanferrari, C., Costa, A., Martignoni, E., & Manzoni, G. C. (1993). Migraine without aura and reproductive life events: A clinical epidemiological study in 1300 women. Headache, 33, 385-389. Granot, M., & Ferber, S. (2005). The roles of pain catastrophizing and anxiety in the prediction of postoperative pain intensity: A prospective study. Clinical Journal of Pain, 21, 439- 445. Grant, E. (1965). Relation of arterioles in the endometrium to headache from oral contraceptives. Lancet, 1, 1143-1144. Greenblatt, R., & Bruneteau, D. (1974). Menopausal headaches -- psychogenic or metabolic? Journal of the American Geriatrics Society, 22, 186-190. Grigorieva, V., Chen-Mok, M., Tarasova, M., & Mikhailov, A. (2003). Use of a levonorgestrel- releasing intrauterine system to treat bleeding related to uterine leiomyomas. Fertility and Sterility, 79, 1194-1198. Gross, M., Barrie, M., Bates, D., Dowson, A., & Elrington, G. (1995). The efficacy of sumatriptan in menstrual migraine [Abstract]. European Journal of Neurology, 2, 144- 145. 220 Guidetti, V., Galli, F., Fabrizi, P., Giannantoni, A., Napoli, L., Bruni, O., et al. (1998). Headache and psychiatric comorbidity: Clinical aspects and outcome in an 8 year follow-up study. Cephalalgia, 18, 455-462. Guillebaud, J. The 150/30 formulation. Experience in the United Kingdom. Journal of Reproductive Medicine, 28(Suppl. 1), 66-70. Hallberg, Högdahl, Nilsson, & Rybo. (1966). Menstrual blood loss: A population study. Acta Obstretrics and Gynecologyin Scandinavia, 45, 320. Hallberg, L., & Nilsson, L. (1964). Determination of menstrual blood loss. Scandinavian Journal of Clinical and Laboratory Investigation, 16, 244-248. Hardin, J., & Hilbe, J. (2003). Generalized Estimating Equations. Boca Raton: CRC Press. Harpole, L., Samsa, S., Jurgelski, A., Shipley, J., Bernstein, A., & Matchan, D. (2003). Headache management program improves outcome for chronic headache. Headache, 43, 715-724. Hassinger, H., Semenchuk, E., & OBrien, W. (1999). Appraisal and coping responses to pain and stress in migraine headache sufferers. Journal of Behavioral Medicine, 22, 327-340. Headache Classification Committee of the International Headache Society. (1988). Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia, 8(Suppl 7), 1-96. Headache Classification Committee of the Internation Headache Society. (2004). The International Classification of Headache Disorders, 2nd edition. Cephalalgia, 24, 1-160. 221 Heckman, B. D., Waller, S., Cottrell, C., Holroyd, K., & Chen, Y. (2001). A hand-held computer headache diary: An innovative method for the collection of data in a clinical trial of a migraine treatment intervention. Cephalalgia, 21, 440-446. Helm-Hylkema, H., Orlebeke, J., Enting, L., Thijssen, J. H., & van Ree, J. (1990). Effects of behaviour therapy on migriane and plasma �-endorphin in young migraine patients. Psychoneuroendocrinology, 15, 39-45. Heritage, A., Stumpf, W., Sar, M., & Grant, L. (1980). Brainstem catecholamine neurons are target sites for sex steroid hormones. Science, 207, 1377-1379. Higham, J., O'Brien, P., & Shaw, R. (1990). Assessment of menstrual blood loss using a pictorial chart. British Journal of Obstetrics and Gynaecology, 97, 734-739. Hill, Mark. (2005). Human menstrual cycle. Retrieved August 27, 2005, from http://embryology.med.unsw.edu.au/222human/MCycle/MCycle.htm. Holroyd, K. & Chen, Y. (2000). A hand-held computer headache diary program: Monitoring headaches, medication use and disability in real time. Headache, 40, 412. Holroyd, K., & Lipchik, G. (2000). Sex differences in recurrent headache disorders: overview and significance. In R. B. Fillingim (Ed.), Sex, Gender, and Pain in Progress in Pain Research and Management (Vol. 17, pp. 1-29). Seattle: IASP Press. Hotovy, L., Rains, J., Davig, J., & Penzien, D. (1997). Headache and women's health: Gynecologic history of women suffering from chronic headache versus a nonheadache sample [Abstract]. Headache, 37, 314. 222 Hu, X., Markson, L., Lipton, R., Stewart, W., & Berger, M. (1999). Burden of Migraine in the United States: Disability and economic costs. Archives of Internal Medicine, 159, 813- 818. Hursey, K., & Jacks, S. (1992). Fear of pain in recurrent headache sufferers. Headache, 32, 283- 286. Ikeda, T., & Ikenoue, T. (1994). Influence of pregnancy on the vascular response to norepinephrine and serotonin in rat carotid artery. Nippon Sanka Fujinka Gaddai zasshi, 46, 240-246. Abstract retrieved October 2004, from MEDLINE database. International Headache Society Clinical Trials Subcommittee. (2000). Guidelines for controlled trials of drugs in migriane: Second edition. Cephalalgia, 20, 765-786. Jacobsen, P., & Butler, R. (1996). Relation of cognitive coping and catastrophizing to acute pain and analgesic use following breast cancer surgery. Journal of Behavioral Medicine, 19, 17-29. Janssen, C. (1996). A simple visual assessment technique to discriminate between menorrhagia and normal menstrual blood loss. European Journal of Obstetrics Gynecology and Reproductive Biology, 70(1), 21-22. Janssen, C., Scholten, P., & Heintz, A. (1995). A simple visual assessment technique to discriminate between menorrhagia and normal menstrual blood loss. Obstetrics & Gynecology, 85(6), 977-982. Jhingran, P., Cady, R., Rubino, J., Miller, D., Grice, R., & Gutterman, D. (1996). Improvements in health-related quality of life with Sumatriptan treatment for migraine. Journal of Family Practice, 42(1), 36-42. 223 Jhingran, P., Davis, S., LaVange, L., Miller, D., & Helms, R. (1998). MSQ: Migraine-Specific Quality -of-Life Questionnaire: Further investigation of the factor structure. Pharmacoeconomics, 13, 707-717. Jhingran, P., Osterhaus, J., Miller, D., Lee, J., & Kirchdoerfer, L. (1998). Development and validation of the migraine-specific quality of life questionnaire. Headache, 38, 295-302. Johannes, C., Linet, M., Stewart, W., Celentano, D., Lipton, R., & Szklo, M. (1995). Relationship of headache to phase of the menstrual cycle among young women: A daily diary study. Neurology, 45, 1076-1082. Johnson, E., Kamilaris, T., Chrousos, G., & Gold, P. (1992). Mechanisms of stress: A dynamic overview of hormonal and behavioral homeostatsis. Neuroscience and Biobehavioral Review, 16, 115-130. Kappius, R., & Goolkasian, P. (1987). Group and menstrual phase effect in reported headaches among college students. Headache, 27, 491-494. Karli, N., Zarifoglu, M., Calisir, N., & Akgoz, S. (2005). Comparison of pre-headache phases and trigger factors of migraine and episodic tension-type headache: Do they share similar clinical pathophysiologiy? Cephalalgia, 25, 444-451. Katzelnick, D., Kobak, Sands, G., King, M., Greis, J., Mackell, J., et al. (2003). Prevalence and burden of migraine to managed-care patients [Abstract]. Headache, 43, 570. Keefe, F., Brown, G., Wallston, K., & Caldwell, D. (1989). Coping with rheumatoid arthritis pain: Catastrophizing as a maladaptive strategy. Pain, 37, 51-56. 224 Keefe, F., Lefebvre, J., Egert, J., Affleck, G., Sullivan, M., & Caldell, D. (2000). The relationship of gender to pain, pain behavior, and disability in osteoarthritis patients: The role of catastrophizing. Pain, 87, 325-334. Kibler, J., Rhudy, J., Penzien, D., Rains, J., Meeks, G., Bennett, W. et al. (2005). Hormones, menstrual distress, and migraine across the phases of the menstrual cycle. Headache, 45, 1181-1189. Kinder, B., Curtiss, G., & Kalichman, S. (1992). Affective differences among empirically derived subgroups of headache patients. Journal of Personality Assessment, 58(3), 516- 524. Klangkalya, B., & Chan, A. (1988). The effects of ovarian hormones on �-adrenergic and muscarinic receptors in rat heart. Life Science, 42, 2307-2314. Kobak, K., Katzelnick, D., Sands, G., King, M., Greist, J., & Dominski, M. (2005). Prevalence and burden of illness of migraine in managed care patients. Journal of Managed Care Pharmacy, 11, 124-136. Kornstein, S., & Parker, A. (1997). Menstrual migraines: Etiology, treatment, and relationship to premenstrual syndrome. Current Opinions in Obstetrics and Gynecology, 9, 154-159. Kosinski, M., Bjorner, J., Ware, J., Batenhorst, A., & Cady, R. (2003). The responsiveness of headache impact scales scored using classical and modern psychometric methods: A re-analysis of three clinical trials. Quality of Life Research, 12, 903-912. Krymchantowski, A., Adriano, M., & Fernandes, D. (1999). Tolfenamic acid decreases migraine recurrence when used with sumatriptan. Cephalalgia, 19, 186-187. 225 Krymchantowski, A.(2000). Naproxen sodium decreases migraine recurrence when administered with sumatriptan. Arquivos de Neuro Psiquiatria, 58, 428-430. Kryst, S., & Scherl, E. (1994). A population-based survey of the social and personal impact of headache. Headache, 34, 344-350. Kudrow, L. (1975). The relationship of headache frequency to hormone use in migraine. Headache, 15, 36-40. Lackner, J., & Quigley, B. (2005). Pain catastrophizing mediates the relationship between worry and pain suffering in patients with irritable bowel syndrome. Behaviour Research and Therapy, 43, 943-957. Lackner, J, Quigley, B., & Blanchard, E. (2004). Depression and abdomianla pain in IBS patients: The mediating role of catastrophizing. Psychosomatic Medicine, 66, 435-441. Lance, J., & Anthony, M. (1966). Some clinical aspects of migraine. A prospective survey of 500 patients. Archives of Neurology, 15(4), 356-361. Landy, S., Richardson, M., & O'Quinn, S. (2002). Migraine, Midrine, and Imitrex [Letter to the editor]. Headache, 322-323. Lantére-Minet, M., Auray, J., El Hasnaoui, A., Dartigues, J, Duru, G., Henry, P., et al., (2003). Prevalence and description of chronic daily headache in the general population in France. Pain, 102: 143-149. Larsson-Cohn, U., & Lundberg, P. (1970). Headache and treatment with oral contraceptives. Acta Neurol Scand, 46, 267-278. 226 Leone, M., Sacerdote, P., D'Amico, D., Panerai, A., & Bussone, G. (1992). Beta-endorphin concentrations in the peripheral blood mononuclear cells of migraine and tension-type headache patients. Cephalalgia, 12, 154-157. Lethem, J., Slade, P., Troup, J., & Bentley, G. (1983). Outline of a fear-avoidance model of exaggerated pain perception-I. Behavioral & Research in Therapy, 21, 401-408. Liang, K., & Zeger, S. (1986). Longitudinal data analysis using generalized linear models. Biometrika, 73(1), 13-22. Lipton, R., Bigal, M., & Goadsby, P. (2004). Double-blind clinical trials of oral triptans vs other classes of acute migraine medication - a review. Cephalalgia, 24, 321-332. Lipton, R., Bigal, M., Kolodner, K., Stewart, W., Liberman, J., Steiner, T. (2003). The family impact of migraine: Population-based studies in the USA and UK. Cephalalgia, 23, 429- 440. Lipton, R., Hamelsky, S., Kolodner, K., Steiner, T., Stewart, W. (2000). Migraine, quality of life, and depression. A population-based case-control study. Neurology, 55, 629-635. Lipton, R., & Stewart, W. (1993). Migraine in the United States: A review of epidemiology and health care use. Neurology, 48 (Suppl. 3), S6-S10. Lipton, R., & Stewart, W. (1995). Health-related quality of life in headache research. Headache, 37, 447-448. Lipton, R., & Stewart, W. (1998). Migraine headaches: epidemiology and comorbidity. Clinical Neuroscience, 5(1), 2-9. 227 Lipton, R., Stewart, A., Diamond, S., Diamond, M., & Reed, M. (2001). Prevalence and burden of migraine in the United States: Data from the American Migraine Study II. Headache, 41, 646-657. Lipton, R., Stewart, W., & von Korff. (1995). Migraine impact and functional disability. Cephalalgia, 15 (Suppl. 15), 4-9. Lipton, R., Stewart, W., Stone, A., Láinez, M., & Sawyer, J. (2000). Stratified care vs step care strategies for migraine, the Disability in Strategies of Care (DISC) Study: A randomized trial. JAMA, 284, 2599-2605. Lipton, R., Stewart, W., Sawyer, J., & Edmeads, J. (2001). Clinical utility of an instrument assessing migraine disability: The Migraine Disability Assessment (MIDAS) Questionnaire. Headache, 41, 854-861. Litaker, D., Solomon, G., & Genzen, J. (1997). Using pretreatment quality of life perceptions to predict response to sumatriptan in migraineurs. Headache, 37(10), 630-634. Loder, E. (2002). Prophylaxis of menstrual migraine with triptans: Problems and possibilities. Neurology, 59, 1677-1681. Loder, E. (2005). Menstrual Migraine: Clinical considerations in light of revised diagnostic criteria. Neurological Science, 26, S121-S124. Loder, E., Buse, D., & Golub, J. (2005). Headache and combination estrogen-progestin oral contraceptives: Integrating evidence, guidelines, and clinical practice. Headache, 45, 224-231. Loder, E., & Silberstein, S. D. (1999). Efficacy of zolmitriptan in the acute treatment of menstrually associated migraine [Abstract]. Headache, 5, 366. 228 MacGregor, E. (1996). "Menstrual" migraine: towards a definition. Cephalalgia, 16, 11-21. MacGregor, E. (1998). Evaluating migraine during menstruaton and the potential effecacy of oral eletriptan. European Journal of Neurology, 5, S56-S57. MacGregor, A. (2000). Migraine associated with menstruation [Review]. Functional neurology, 15 (Suppl. 3), 143-153. MacGregor, A. (Ed.). (2003). Migraine in women. (Rev. ed.). New York: Martin Dunitz. MacGregor, A., Brandes, J., & Eikermann, A. (2003). Migraine prevalence and treatment patterns: The global migraine and zolmitriptan evaluation survey. Headache, 43, 19-26. MacGregor, E.A., Brandes, J., Eikermann, A., Giammarco, R. (2004). The impact of migraine on patients and their families: The Migraine and Zolmitriptan Evaluation (MAZE) survey- Phase III. Current Medical Research and Opinion, 20, 1143-1150. MacGregor, E., Chia, H., Vohrah, R., Wilkinson, M. (1990). Migraine and menstruation: a pilot study. Cephalalgia, 10, 305-310. MacGregor, E.A., & Hackshaw, A. (2004). Prevalence of migraine on each day of the natural menstrual cycle. Neurology, 63, 351-353. MacGregor, E., Igaashi, H., & Wilkinson, M. (1997). Headache and hormones: Subjective versus objective assessment. Headache Quarterly: Current Research and Treatment, 8, 126-136. Maggioni, F., Alessi, C., Maggino, T., & Zanchin, G. (1997). Headache during pregnancy. Cephalalgia, 17, 765-769. Magness, R., & Rosenfeld, C. (1989). Local and systemic estradiool-17 beta: Effects on uterine and systemic vasodilatation. American Journal of Physiology, 25, E536-E542. 229 Magos, A., Brincat, M., Zilkha, K., & Studd, J. (1985). Serum depamine beta-hydroxylase activity in menstrual migraine. Journal of Neurology, Neurosurgery, and Psychiatry, 49, 328-331. Magos, A., Zilka, K., & Studd, J. (1983). Treatment of menstrual migraine by oetradiol implants. Journal of Neurology, Neurosurgery, and Psychiatry, 46, 1044-1046. Majerus, P. (1983). Arachidonate metabolism in vascular disorders. Journal of Clinical Investigation, 72, 1521-1525. Mannix, L. (2003). Management of menstrual migraine. The Neurologist, 9, 207-213. Marcus, D. (1995). Interrelationships of neurochemicals, estrogen, and recurring headache. Pain, 62, 129-139. Marcus, D., Scharff, L., & Turk, D. (1996). Hormonal and neurochemical changes in menopause and chronic headaches: A conceptual model. Headache Quarterl: Current Treatment and Research, 7(4), 294-305. Marcus, D., Scharff, L., & Turk, D. (1999). Longitudinal prospective study of headache during pregnancy and postpartum. Headache, 39, 625-632. Marcus, D. (2000). Identification of patients with headache at risk of psychological distress. Headache, 40, 373-376. Marcus, D.A. (2001). Estrogen and tension-type headache. Current Pain and Headache Reports, 5, 449-453. Marcus, D.A. (2004). Estrogen and Chronic Daily Headache. Current Pain and Headache Reports, 8, 66-70. 230 Markum, R. (1976). Assessment of the reliability of and the effect of neutral instructions on the symptom ratings on the Moos Menstrual Distress Questionnaire. Psychosomatic Medicine, 38, 163-172. Markush, R., Karp, H., Heyman, A., & O'Fallon, W. (1975). Epidemiologic study of migraine symptoms in young women. Neurology, 25, 430-435. Martin, P., Burnier, A., Segre, E., & Huix, F. (1971). Graded sequential therapy in the menopause: A double-blind study. American Journal of Obstetrics and Gynecology, 111, 178-186. Martin, V. (2004). Menstrual migraine: A review of prophylactic therapies. Current pain and headache reports, 8, 229-237. Martin, V., Wernke, S., Zomma, W., Mandell, K., Lui, J., & Rebar, R. (2000). Does the phase of the menstrual cycle have an influence on headache severity and disability in female migraineurs? [Abstract]. Headache, 40 (5), 420. Martin, V., Wernke, S., Mandell, K., Ramadan, N., Kao, L., Bean, J. et al. (2005). Defining the relationship between ovarian hormones and migraine headache. Headache, 45, 1190- 1201. Martin, V., Zoma, W., Mandell, K., Wernke, S., Liu, J., & Rebar, R. (2002). Does the phase of the menstrual cycle have an effect on headache? [Abstract]. Headache, 45(5), 438-439. Marvan, M., & Escobedo, C. (1999). Premenstrual symptomatology: Role of prior knowledge about premenstrual syndrome. Psychosomatic Medicine, 61, 163-167. 231 Mascia, A., Afra, J., & Schoenen, J. (1998). Dopamine and migraine: A review of pharmacological, biochemical, neurophysiological, and therapeutic data. Cephalalgia, 18, 174-182. Massiou, H. (1999). Is menstrually associated migraine difficult to treat? Cephalalgia, 19(Suppl. 24), 13-18. Massiou, H., & Bousser, M. (2000). Influence of female hormones on migraine. In J. Olesen, Tfelt-Hansen, P., Welch, K. (Ed.), The Headaches (2nd ed., pp. 261-267). Philadelphia: Lippincott Williams & Wilkins. Massiou, H., & MacGregor, E.A. (2000). Evolution and treatment of migraine with oral contraceptives. Cephalalgia, 20, 170-174. Massiou, H., Silberstein, S., McCarroll, K., Allen, C., & Lines, C. (2000). Efficacy of rizatriptan in menstrual migraine: Freedom from pain and associated symptoms at 2-hour and 24- hour sustained pain [Abstract]. Cephalalgia, 20, 338-357. Matchar, D., Young, W., & Rosenberg, J., & al., e. (2000). Evidence-based guidelines for migraine headache: Pharmacological management of acute attacks. Available at: http://www.aan.com/public/practiceguidelines/headache_gl.htm. Mathew, N., Kailasam, J., & Meadors, L. (2002). Prophylaxis of migraine, transformed migraine, and cluster headache with topiramate. Headache, 42, 796-803. Mathew, N., Kailasam, J., & Meadors, L. (2004). Early treatment of migraine with rizatriptan: A placebo-controlled study. Headache, 44, 669-673. Mattsson, P. (2003). Hormonal factors in migraine: A population-based study of women aged 40 to 74 years. Headache, 43, 27-35. 232 McCrory, D., & Gray, R. (2003). Oral sumatriptan for acute migraine. Cochrane Database System Review, CD002915. Abstract obtained from PubMed: 12917936. McHorney, C., Ware, J., & Raczek, A. (1993). The MOS 36-item Short-form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Medical Care, 31, 247-263. McHorney, C., Ware, J., Rogers, W., Raczek, A., & Lu, J. (1992). The validity and relative precision of MOS short- and long-form health status scales and Dartmouth COOP charts. Results from the Medical Outcomes Study. Medical Care, 30(Suppl. 5), MS253-265. Meckling, S., Becker, W., Rose, M., & Dalby, J. (2001). Sumatriptan responsiveness and clinical, psychiatric and psychologic features in migriane patients. Canadian Journal of Neurological Sciences, 28, 313-318. Mellegård, M., Grossi, G., & Soares, J. (2001). A comparative study of coping among women with fibromyalgia, neck/shoulder and back pain. International Journal of Behavioral Medicine, 8, 103-115. Meredith, J., Wait, S., & Brewer, K. (2003). A prospective double-blind study of nasal sumatriptan versus IV ketorolac in migraine. American Journal of Emergency Medicine, 21, 173-175. Merikanges, K. (1993). Background and introduction. Cephalalgia, 13, 5-6. Merikangas, K., Angst, J., & Isler, H. (1990). Migraine and psychopathology. Results of the Zurich cohort study of young adults. Archives of General Psychiatry, 47, 849-853. 233 Miller, V. and Vanhoutte, P. (1990). 17-beta-Estradiol aurgments endothelium-dependent Contractions to arachidonic acid in rabbit aorta. The Americcan Journal of Physiology, 258, R1502-1507. Misakian, A., D, L., Bensenor, I., Cook, N., Manson, J. E., E, B., et al. (2003). Postmenopausal hormone therapy and migraine headache. Journal of Womens Health, 12, 1027-1036. Monagle, L., Dan, A., Krough, V., Jossa, F., Farinaro, E., & Trevisan, M. (1993). Perimenstrual symptom prevalence rates--An Italian-American comparison. American Journal of Epidemiology, 138, 1070-1081. Moos, R. (1968). The development of the Menstrual Distress Questionnaire. Psychosomatic Medicine, 30(6), 853-867. Moskowitz, M. (1993). Neurogenic inflammation in the pathophysiology and treatment of migraine. Neurology, 43, S16-20. Murialdo, G., Fonzi, S., Costelli, P., Solinas, G., Parodi, C., & Marabini, S. (1994). Urinary melatonin excretion throughout the ovarian cycle in menstrually-related migraine. Cephalalgia, 14, 205-209. Murialdo, G., Martignoni, E., De Maria, A., Bonura, M., Sances, G., & Bono, G. (1986). Changes in the dopaminergic control of prolactin secretion and in ovarain steroids in migraine. Cephalalgia, 6, 43-49. Myllyla, V., Havanka, H., Herrala, L., Kangasniemi, P., Rautakorpi, I., Turkka, J., et al. (1998). Tolfenamic acid rapid release versus sumatriptan in the acute treatment of migraine: Comparable effect in a double-blind, randomized, controlled, parallel-group study. Headache, 38, 201-207. 234 Nappi, G., Costa, A., Tassorelli, C., and Santorelli, F. (2000). Migraine as a complex disease: heterogeneity, comorbidity and genotype-phenotype interactions. Functional Neurology, 15, 87-93. Nappi, G., Micieli, G., Sandrini, G., Martignoni, E., Lottici, P., & Bono, G. (1983). Headache temporal paterns: Towards a chronobiological model. Cephalalgia (Suppl. 1), 21-30. Nattero, G. (1982). Menstrual headache. Advances in neurology, 33, 215-226. Nattero, G. (1987). Correlation between platelet sensitivity to prostacyclin and sex hormones in menstrual migraine. Cephalalgia, 7(Suppl. 6), 242-243. Nattero, G., Allais, G., De Lorenzo, C., Benedetto, C., Zonca, M., Melzi, E., et al. (1989). Relevance of prostaglandins in true menstrual migraine. Headache, 29, 232-237. Neri, I., Granella, F., Nappi, G., Manzoni, G., Facchinetti, F., & Genazzani, A. (1993). Characteristics of headache at menopause: A clinico-epidemiologis study. Maturitas, 17, 31-37. Nett, R., Landy, S., Shackelford, S., Richardson, M., & Ames, M. (2003). Pain-free efficacy after treatment with sumatriptan in the mild pain phase of menstrually associated migraine. Obstetrics & Gynecology, 102, 835-842. Nilsson, L., & Solvell, L. (1967). Clinical studies on oral contraceptives--a randomized, doubleblind, crossover study of 4 different preparations (Anovlar mite, Lyndiol mite, Ovulen, and Volidan). Acta Obstetricia Et Gynecologica Scandinavica, 46(Suppl. 8), 1- 31. O'Brien, B., Goeree, R., & Streiner, D. (1994). Prevalence of migraine headache in Canada: A population-based survey. International Journal of Epidemiology, 23, 1020-1026. 235 OConnor, K., Hooman, D., & Holman, J. (2001). Menstrual cycle variability and the perimenopause. American Journal of Human Biology, 13, 465-478. Oinonen, K., & Mazmanian, D. (2001). Effects of oral contraceptives on daily self-ratings of positive and negative affect. Journal of Psychosomatic Research, 51, 647-658. Olson, D., Skinner, K., & Challis, J. (1983). Estradiol-17 beta and 2-hydroxyestradiol-17 beta- induced differential production of prostaglandins by cells dispersed from human intrauterine tissues at parturition. Prostaglandins, 25, 639-651. Olesen, J., Thomsen, L., Lassen, L., & Olesen, L. (1995). The nitric oxide hypothesis of migraine and other vascular headaches. Cephalalgia, 15, 94-100. The Oral Sumatriptan and Aspirin plus Metoclopramide Comparative Study Group. (1992). A study to compare oral sumatriptan with oral aspirin plus oral metoclopramide in the acute treatment of migraine. European Neurology, 32, 177-184. Osman, A., Barrios, F., Gutierrez, P., Kopper, B., Merrifield, T, and Grittmann, L. (2000). The Pain Catastrophizing Scale: further psychometric evaluation with adult samples. Journal of Behavioral Medicine, 22,351-365. Osman, A., Down, W., Barrios, F., A, K., Gutierrez, P., & Chiros, C. (1997). Factor structure and psychometric characteristics of the Beck Depression Inventory-II. Journal of Psychopathology & Behavioral Assessment., 19, 359-376. Pascual, J. (2004). A review of rizatriptan, a quick and consistent 5-HT1B/1D agonist for the acute treatment of migraine. Expert Opinions in Pharmacotherapy, 5, 669-677. Penzien, D., & Holroyd, K. (1990). Structured Diagnostic Interview for Headache. Jackson, MS: Headache Clinic, University of Mississippi. 236 Penzien, D., Rains, J., & Holroyd, K. (1993). Psychological assessment of the recurrent headache sufferer. In C.D. Tollison & R.S. Kunkel (Eds.), Headache: Diagnosis and treatment (pp. 39-49). Baltimore: Williams and Wilkins. Pesa, J., & Lage, M. (2004). The medical costs of migraine and comorbid anxiety and depression. Headache, 44, 562-570. Peterson, C., & Seligman, M. (1984). Causal explanations as a risk factor for depression: Theory and evidence. Psychological Review, 91, 347-374. Petitti, D. (2003). Combination estrogen-progestin oral contraceptives. New England Journal of Medicine, 349, 1443-1450. Phillips, B. (1968). Oral contraceptive drugs and migraine. British Medical Journal, 2, 99. Philips, H. (1987). The effects of behavioural treatment on chronic pain. Behavioral Research and Therapy, 25, 365-377. Philips, J., & Jahanshahi, M. (1986). The components of pain behaviour report. (1986). Behavioral Research and Therapy, 24, 117-125. Pinkerman, B., & Holroyd, K. (2003). Comparison of abortive treatment for mentrually-related and nonmentrual migraines in a frequent migriane population: A preliminary report [Abstract]. Headache, 43, 512-213. Pitei, D., & Hettiarachchi, J. (2000). Efficacy of eletriptan in treating women with menstrually associated migraine and women on oral contraceptives or hormone replacement therapy [Abstract]. Obstetrics & Gynecology, 95(4, Suppl. 1), 32S. 237 Plosker, G., & McTavish, D. (1994). Simatriptan: A reappraisal of its pharmacology and therapeutic ifficacy in the acute treatment of migraine and cluster headache. Drugs, 47, 622-651. Polinsky, R., Brown, R., Lee, G., Timmers, K., Culman, J., Foldes, O., et al. (1987). Beta- endorphin, ACTH, and catecholamine responses in chronic autonomic failure. Annals of Neurology, 21, 573-577. Pryse-Phillips, W., Dodick, D., Edmeads, J., Gawel, M., Nelson, R., Purdy, R., et al. (1997). Guidelines for the diagnosis and management of migraine in clinical practice. Canadian headache society. CMAJ: Canadian Medical Association Journal, 156, 1273-1287. Pryse-Philips, W., Findlay, H., Tugwell, P., Edmeads, J., Murray, T., & Nelson, R. F. (1992). A Canadian population survey on the clinical, epidemiologic and societal impact of migraine and tension-type headache. Canadian Journal of Neurological Sciences, 19, 333-339. Rains, J., Penzien, D., Martin, V. (2002). Migraine and women's health. JAMWA, 57, 73-78. Ramcharan, S., Pellegrin, F., Ray, R., & Hsu, J. (1980). The Walnut Creek Contraceptive Drug Study. A prospective study of the side effects of oral contraceptives. Volume III, an interim report: A comparison of disease occurrence leading to hospitalization or death in users and nonusers of oral contraceptives. The Journal of Reproductive Medicine, 25 (Suppl. 6), 345-372. Ramos, R., Apelo, R., Osteria, T., & Vilar, E. (1989). A comparative analysis of the three different dose combinations of oral contraceptives. Contraception, 39, 165-177. 238 Rapoport, A., Visser, W., Cutler, N., Alderton, C., Paulsgrove, L., Davis, R., et al. (1995). Oral sumatriptan in preventing headache recurrence after treatment of migraine attacks with subcutaneous sumatriptan. Neurology, 45, 1505-1509. Rasmussen, B. (1992). Migraine and tension-type headache in a general population: Psychosocial factors. International Journal of Epidemiology, 21(6), 1138-1143. Rasmussen, B. K. (1993). Migraine and tension-type headache in a general population: Precipitating factors, female hormones, sleep pattern and relation to lifestyle. Pain, 53, 65-72. Rasmussen, B. (1995). Epidemiology of headache. Cephalalgia, 14, 45-68. Rasmussen, B., Jensen, R., Schroll, M., & Olesen, J. (1991). Epidemiology of headache in a general population - a prevalence study. Journal of Clinical Epidemiology, 44(11), 1147- 1157. Rasmussen, B. K., & Olesen, J. (1992). Migraine without aura and reproductive life events: A clinical epidemiological study in 1300 women. Headache, 33, 385-389. Raskin, N. (1988). Headache. In (2nd ed., pp. 396). New York: Churchill Livingstone. Rebar, R., & Spitzer, I. (1987). The physiology and measurement of hot flushes. American Journal of Obstetrics and Gynecology, 156, 1284-1288. Rebaudengo, N., Rainero, I., Parziale, A., Rosina, F., Pavanelli, F., Rubino, E., et al. (2004). Lack of interaction between a polymorphism in the dopamine D2 receptor gene and the clinical features of migraine. Cephalalgia, 24, 503-507. 239 Rothrock, J., Patel, M., Lyden, P., & Jackson, C. (1996). Demographic and clinical characteristics of patients with episodic migraine versus chronic daily headache. Headache, 16, 44-49. Rupprecht, R., Hauser, C., Trapp, T., & Holsboer, F. (1996). Neurosteroids: Molecular mechanisms of action and psychopharmacological significance. Journal of Steroid Biochemistry and Molecular Biology, 56, 163-168. Russell, M., Rasmussen, B., Fenger, K., & Olesen, J. (1996). Migraine without aura and migraine with aura are distinct clinical entities: a study of four hundred and eighty-four male and female migraineurs from the general population. Cephalalgia, 16, 239-245. Ryan, R. (1978). A controlled study of the effect of oral contraceptives on migraine. Headache, 17(6), 250-252. Sakai, F., & Igarashi, H. (1997). Epidemiology of migraine in Japan. Cephalalgia, 17, 15-22. Salvesen, R., & Bekkelund, S. I. (2000). Migraine, as compared to other headaches, is worse during midnigh-sun summer than during polar night. A questionnaire study in an Arctic population. Headache, 40, 824-829. Salonen, R., & Saiers, J. (1999). Sumatriptan is effective in the treatment of menstrual migraine: a review of prospective studies and retrospective analyses. Cephalalgia, 19, 16-19. Salvesen, R., & Bekkelund, S. (2000). Migraine, as compared to other headaches, is worse during midnigh-sun summer than during polar night. A questionnaire study in an Arctic population. Headache, 40, 824-829. 240 Sances, G., Granella, F., Nappi, R., Fignon, A., Ghiotto, N., Polatti, F., et al. (2003). Course of migraine during pregnancy and postpartum: A prospective study. Cephalalgia, 23, 197- 205. Saper, J., Lake, A., Tepper, S.(2001). Nefazodone for chronic daily headache prophylaxis: An open-Label study. Headache, 41, 465-474. Saper, J., Winner, P., Lake, A. (2001). An open-label dose-titration study of the efficacy and tolerability of tizanidine hydrochloride tablets in the prophylaxis of chronic daily headache. Headache, 41, 357-358. Sarchielli, P., Alberti, A., Codini, M., Floridi, A., & Gallai, V. (2000). Nitric oxide metabolites, prostaglandins and trigeminal vasoactive peptides in internal jugular vein blood during spontaneous migraine attacks. Cephalalgia, 20, 907-918. Sarchielli, P., Pini, L., Zanchin, G., Alberti, A., Maggioni, F., Rossi, C. et al., (2005). Clinical- biochemical correlates of migraine attacks in rizatriptan responders and non-responders. Cephalalgia, 0(0), -. doi: 10.1111/j.1468-2982.2005.01016.x. Sarchielli, P., Tognoloni, M., Russo, S., Vulcano, M., Feleppa, M., Mala, M., et al. (1996). Variations in the platelet arginine/nitric oxide pathway during the ovarian cycle in females affected my menstrual migraine. Cephalalgia, 16, 268-275. Schoenen, J., & Sawyer, J. (1997). Zolmitriptan (Zomig, 311C90), a novel dual central and peripherl 5HT1B/1D agonist: An overview of efficacy. Cephalalgia, 17(Suppl. 18), 28- 40. 241 Scholpp, J., Schellenberg, R., Maeckesch, B., Banik, N. (2004). Early treatment of a migraine attack while pain is still mild increases the efficacy of sumatriptan. Cephalalgia, 24, 925- 933. Sheftell, F., OQuinn, S., Watson, C., Pait, D., & Winter, P. (2000). Low migraine headache recurrence with naratriptan: Clinical parameters related to recurrence. Headache, 40, 103-110. Shimomura, T., Murakami, F., Kotani, K., Ikawa, S., & Kono, S. (1999). Platelet nitric oxide metabolites in migraine. Cephalalgia, 19, 218-222. Siddle, N., Sarrel, P., & Whitehead, M. (1987). The effect of hysterectomy on the age at ovarian failure: Identification of a subgroup of women with premature loss of ovarian function and literature review. Fertility & Sterilization, 47, 94-100. Silberstein, S. (1992). Menstrual migraine. Headache, 32, 312-313. Silberstein, S. (1997). Migraine and pregnancy. In N. T. Mathew (Ed.), Neurologic clinics: Advances in headache (Vol. 15, pp. 209-231). Philadelphia: W.B. Saunders. Silberstein, S., Armellino, J., Hoffman, H., Battokha, J., Hamelsky, S., Stewart, W., et al. (1999). Treatment of menstruation-associated migraine with the nonprescription combination of acetaminophen, aspirin, and caffeine: Results from three randomized, placebo-controlled studies. Clinical Therapeutics, 21(3), 475-491. Silberstein, S., Lipton, R., & Goadsby, P. (1998). Headache in clinical practice. St. Louis: Mosby-Year Book. Silberstein, S., & Merriam, G. (1999). Sex hormones and headache 1999 (menstrual migraine). Neurology, 53(Suppl. 1), S3-S13. 242 Silberstein, S., Massiou, H., Le Jeunne, C., Johnson-Pratt, L., McCarroll, K., Lines, C. (2000). Rizatriptan in the treatment of menstrual migraine. Obstetrics & Gynecology, 96(2), 237- 242. Silberstein, S., & Merriam, G. (2000). Physiology of the menstrual cycle. Cephalalgia, 20, 148- 154. Silberstein, S., Massiou, H., McCarroll, K., & Lines, C. (2002). Further evaluation of rizatriptan in menstrual migraine: Retrospective analysis of long-term data. Headache, 42, 917-923. Silberstein, S., & Merriam, G. (1991). Estrogens, progestins, and headache. Neurology, 22, 239- 244. Silberstein, S., Norman, B., Jiang, K., Lines, C., & Block, G. (1999). Rizatriptan is effective in menstrual migraine [Abstract]. Neurology, 52(Suppl. 2), A208. Silberstein, S., Saper, J., & Freitag, F. (2001). Migraine: Diagnosis and treatment. Silberstein, S., Lipton & Dalessio, D., (Eds.), Wolff's headache and other head pain (7th ed., pp. 121- 237). New York: Oxford University Press. Smith, R. (1998). Impact of migraine on the family. Headache, 38, 423-426. Smith, T., Sunshine, A., Stark, S, Littlefield, D., Spruill, S., & Alexander, J. (2005). Sumatriptan and naproxen sodium for the acute treatment of migraine. Headache, 45, 983-991. Solbach, M., & Waymer, R. (1993). Treatment of menstruation-associated migraine headache with subcutaneous sumatriptan. Obstetrics & Gynecology, 82, 769-772. Soloman, S., Lipton, R. (1993). A headache clinic-based approach to field trials of the International Headache Society. Cephalalgia, 13(Suppl. 12), 63-65. 243 Solomon, G., Skobieranda, F., & Genzen, J. (1995). Quality of life assessment among migraine patients treated with sumatriptan. Headache, 35(8), 449-454. Somerville, B. (1971). The role of progesterone in menstrual migraine. Neurology, 21, 853-859. Somerville, B. (1972a). The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology, 22, 355-365. Somerville, B. (1972b). A study of migraine in pregnancy. Neurology, 22, 824-828. Somerville, B. (1975a). Estrogen-withdrawal migraine: I. Duration of exposure required and attempted prophylaxis by premenstrual estrogen administration. Neurology, 22, 239-244. Somerville, B. (1975b). Estrogen-withdrawal migraine II. Attempted prophylaxis by continuous estradiol administration. Neurology, 25, 245-250. Somerville, B. W., & Carey, H. M. (1970). The use of continuous progestogen contraception in the treatment of migraine. The Medical Journal of Australia, 1, 1043-1045. Spitzer, R., Williams, J., Kroenke, K., Linzer, M., deGruy, F., Hahn, S., et al. (1994). Utility of a new procedure for diagnosing mental disorders in primary care: The PRIME-MD 1000 study. Journal of the American Medical Association, 272, 1749-1756. Sprinkle, S., Lurie, D., Insko, S., Atkinson, G., Jones, G., Logan, A., et al. (2002). Criterion validity, severity cut scores, and test-retest reliability of the Beck Depression Inventory-II in a university counseling center sample. Journal of Counseling Psychology, 49, 381- 385. SPSS, Inc. (2003). Version 12.0. [Computer software]. Chicago, IL. SAS Institute, Inc. (2001). Statistical Analysis System (SAS), Version 8.2. [Computer software]. Cary, NC. 244 Stang, P., Von Korff, M., & Galer, B. (1998). Reduced labor force participation among primary care patients with headache. Journal of General Internal Medicine, 13, 296-302. Steer, R., Ball, R., Ranieri, W., & Beck, A. (1999). Dimensions of the Beck Depression Inventory-II in clinically depressed outpatients. Journal of Clinical Psychology, 55, 117- 128. Steer, R., Clark, D., Beck, A., & Ranieri, W. (1995). Common and specific dimensions of self- reported anxiety and depression: A replication. Journal of Abnormal Psychology, 104, 542-545. Stein, G., Morton, J., Marsh, A., Collins, W., Branch, C., Desaga, U., Ebeling, J. (1984). Headaches after childbirth. Acta Neurologica Scandinavica, 69, 74-79. Stein, G. (1981). Headaches in the first post partum week and their relationship to migraine. Headache, 21, 201-205. Stewart, A., Hays, R., & Ware, J. (1988). The MOS short-form General Health Survey: Reliability and validity in a patient population. Medical Care, 26, 724-735. Stewart, W., & Lipton, R. (2002). Need for care and perceptions of MIDAS among headache sufferers study. CNS Drugs, 16, 5-11. Stewart, W., Lipton, R., Kolodner, K., Liberman, J., & Sawyer, J. (1999). Reliability of the migraine disability assessment score in a population-based sample of headache sufferers. Cephalalgia, 19, 107-114. Stewart, W., Shechter, A., & Rasmussen, B. (1994). Migraine prevalence. A review of population-based studies. Neurology, 44(Suppl. 4), S17-S23. 245 Stewart, W., Lipton, R., Kolodner, K., Liberman, J., & Sawyer, J. (1999). Reliability of the Migraine Disability Assessment score in a population-based sample of headache sufferers. Cephalalgia, 19, 107-114. Stewart, W., Linet, M., Celentano, D., Van Natta, M., & Ziegler, D. (1991). Age- and sex- specific incidence rates of migraine with and without visual aura. American Journal of Epidemiology, 134, 1111-1120. Stewart, W., Lipton, R., Celentano, D., & Reed, M. (1992). Prevalence of migraine headache in the United States: Relationship to age, income, race and other sociodemographic factors. Journal of the American Medical Association, 267, 64-69. Stewart, W., Lipton, R., Chee, E., Sawyer, J., & Silberstein, S. (2000). Menstrual cycle and headache in a population sample of migraineurs. Neurology, 55, 1517-1523. Stewart, W., Lipton, R., Dowson, A., & Sawyer, J. (2001). Development and testing of the Migraine Disability Assessment (MIDAS) Questionnaire to assess headache-related disability. Neurology, 56(6, Suppl. 1), S20-28. Stewart, W., Lipton, R., Kolodner, K., Sawyer, J., Lee, C., & Liberman, J. (2000). Validity of the Migraine Disability Assessment (MIDAS) score in comparison to a diary-based measure in a population sample of migraine sufferers. Pain, 88, 41-52. Stewart, W., Lipton, R., & Liberman, J. (1996). Variation in migraine prevalence by race. Neurology, 47, 52-59. Stewart, W., Lipton, W., Whyte, J., Dowson, A., Kolodner, K., Liberman, J., et al. (1999). An international study to assess reliability of the Migraine Disability Assessment (MIDAS) score. Neurology, 53, 988-994. 246 Sullivan, M., Bishop, S., and Pivik, J. (1995). The Pain Catastrophizing Scale: Development and validation. Psychological Assessment, 7, 524-532. Sullivan, M., Rodgers, W., & Kirsch, I. (2001). Catastrophizing, depression and expectancies for pain and emotional distress. Pain, 91, 147-154. Sullivan, J., Thorn, B., Haythornthwaite, B., Keefe, J., Martin, M., Bradley L. et al. (2001). Theoretical perspectives on the relation between catastrophizing and pain. Clinical Journal of Pain, 17, 52-64. Sullivan, M., Thorn, B., Rodgers, W., & Ward, L. (2004). Path model of psychological antecedents to pain experience: Experimental and clinical findings. Clinical Journal of Pain, 20, 164-173. Sullivan, M., Tripp, D., & Santor, D. (2000). Gender differences in pain and pain behavior: The role of catastrophizing. Cognitive Therapy and Research, 24, 121-134. Szekely, B., Botwin, D., Eidelman, B., Becker, M., Elman, N., & Schemm, R. (1986). Nonpharmacological treatment of menstrual headache: Relaxation-biofeedback behavior therapy and person-centered insight therapy. Headache, 26, 86-92. Tarabusi, M., Caputo, A., Volpe, A., Facchinetti, F. (1997). Cardiovascular response to cognitive stress in subjects with menstrually related disorders. Cephalalgia, 17(Suppl. 20), 5-7. Tatrow, K., & Blanchard, E. (2002). Headache activity and psychological functioning in menstrual and nonmenstrual headache sufferers. Headache Quarterly: Current Research and Treatment, 13, 11-18. 247 Tfelt-Hansen, P. (1998). Efficacy and adverse events of subcutaneous, oral, and intranasal sumatriptan used for migraine treatment: A systematic review based on number needed to treat [Review]. Cephalalgia, 18, 532-538. Tfelt-Hansen, P. (2000). The effectiveness of combined oral lysine acetylsalicylate and metoclopramide (Migpriv) in the treatment of migriane attacks. Comparison with placebo and oral sumatriptan. Functional neurology, 15(Suppl. 3), 196-201. Tfelt-Hansen, P., Henry, P., Mulder, L., Scheldewaert, R., Schoenen, J., & Chazot, G. (1995). The effectiveness of combined oral lysine acetylsalicylate and metoclopramide compared with oral sumatriptan for migraine. Lancet, 346, 923-926. Tekle-Haimanot, R., Seraw, B., Forsgren, L., Ekbom, K., & Ekstedt, J. (1995). Migraine, chronic tension-type headache, and cluster headache in an Ethiopain rural community. Cephalalgia, 15, 482-488. Tietjen, G., Conway, A., Utley, C., & Herial, N. (2003). Migraine is associated with menorrhagia and endometriosis [Abstract]. Headache, 43, 548. Toglia, J. U. (1986). Is migraine due to a deficiency of pineal melatonin? Italian Journal of Neurological Sciences, 7, 319-323. Turner, J., & Aaron, L. (2001). Commentary: Pain-related catastrophizing: What is it? Clinical Journal of Pain, 17, 65-71. U.S. Census Bureau, P.D. (2004). U.S. POPClock Projection. Retrieved April 18, 2004. Ukestad, K., & Wittrock, D. (1996). Pain perception and coping in female tension headache sufferers and headache-free controls. Health Psychology, 15, 65-68. 248 Uknis, A., & Silberstein, S. (1991). Review article: Migraine and pregnancy. Headache, 31, 372- 374. van Eijkeren, M., Scholten, P., Christiaens, G., Alsbach, G., & Haspels, A. (1986). The alkaline hematin method for measuring menstrual blood loss--a modification and its clinical use in menorrhagia. European Journal of Obstetrics Gynecology and Reproductive Biology, 22(5-6), 345-351. Vecsei, L., Widerlov, E., Ekman, R., Kovacs, K., Jelencsik, I., Bozsik, G., et al. (1992). Suboccipital cerebrospinal fluid and plasma concentrations of somatostatin, neuropeptide Y and beta-endorphin in patients with common migraine. Neuropeptides, 22, 111-116. Vercellini, P., De Giorgi, O., Aimi, G., Panazza, S., Uglietti, A., Crosignani, P. (1997). Menstrual characteristics in women with and without endometriosis. Obstetrics & Gynecology, 90(2), 264-267. Visser, W., de Vriend, R., Jaspers, N., & Ferrari, M. (1996). Sumatriptan-nonresponders: A survey in 366 migraine patients. Headache, 36(8), 471-475. Visser, W., Burggraaf, J., Muller, L., Schoemaker, R., Fowler, P., Cohen, A., et al., (1996). Pharmacokinetic and pharmacodynamic profiles of sumatriptan in migraine patients with headache recurrence or no response. Clinical pharmacology and therapeutics, 60, 452- 260. Visser, W., Jaspers, N., de Vriend, R., & Ferrari, M. (1996). Risk factors for headache recurrence after sumatriptan: A study in 366 migraine patients. Cephalalgia, 16, 264- 269. 249 Wagner, H., Crutcher, K., & Davis, J. (1979). Chronic estrogen treatment decreases beta- adrenergic responses in rat cerebral cortex. Brain Research, 171, 147-151. Wang, S., Fuh, J., Lu, S., Juang, K., & Wang, P. (2003). Migraine prevalence during menopausal transition. Headache, 43(5), 470-478. Ware, J., & Sherbourne, C. (1992). The MOS 36-item Short-Form Health Survey (SF-36). I. Conceptual frameworks and item selection. Medical Care, 30, 473-483. Waters, W., & O'Connor, P. (1971). Epidemiology of headache and migraine in women. Journal of Neurolgy, Neurosurgery, and Psychiatry, 34, 148-153. Wenzel, R., Sarvis, C., and Krause, M. (2003). Over-the-counter drugs for acute migraine attacks: Literature review and recommendations. Pharmacotherapy, 23, 494-505. Wentz, A. (1985). Contraception and family planning. In: Jones, H.W., Wentz, A.C., Burnett, L.S., eds. Novaks textbook of gynecology, 11th ed. Baltimore: Williams, & Wilkins, 204- 239. Wetterberg, L., Arendt, J., Pounier, L., Sizonenko, P., Donselaar, V., & Heyden, T. (1976). Human serum melatonin changes during the menstrual cycle. Journal of Clinical Endocrinology and Metabolism, 42, 185-188. Whitty, C., Hockaday, J., & Whitty, M. (1986). The effect of oral contraceptives on migraine. Lancet, 1, 856-859. Willoughby, S., Hailey, B., Mulkana, S., & Rowe, J. (2002). The effect of laboratory-induced depressed mood state on responses to pain. Behavioral Medicine, 28, 23-31. 250 Wittrock, D., & Myers, T. (1998). The comparison of individuals with recurrent tension-type headache and headache-free controls in physiological response, appraisal, and coping with stressors: A review of the literature. Annals of Behavioral Medicine, 20, 118-134. Wong, T., Wong, K., Yu, T., & Kay, R. (1995). Prevalence of migraine and other headaches in Hong Kong. Neuroepidemiology, 14, 82-91. Woods, N., Most, A., & Dery, G. (1982). Prevalence of perimenstrual symptoms. American Journal of Public Health, 72, 1257-1264. Wright, G., & Patel, M.(1986). Focal migraine and pregnancy. British Medical Journal, 293, 1557-1558. Wyatt, K., Dimmock, P., Walker, T., & O'Brien, P. (2001). Determination of total menstrual blood loss. Fertility and Sterility, 76, 125-131. Xuan, J., Kirchdoerfer, L., Boyer, J., & Norwood, G. (1999). Effects of comorbidity on health- related quality of life scores: An analysis of clinical trial data. Clinical Therapeutics, 21, 383-403. Yoshimi, T., Strott, C., Marshall, J., & Lipsett, M. (1969). Corpus luteum function in early pregnancy. The Journal of Clinical Endocrinology and Metabolism, 29(2), 225-230. Zeger, S., & Liang, K. (1986). Longitudinal data analysis for discrete and continuous outcomes. Biometrics, 42(1), 121-130. Zwart, J., Hagen, K., Odegard, K., Dahl, A., Bovim, G., & Stover, J. (2003). Depression and anxiety disorders associated with headache frequency. The Nord-Trondelag Health Study. European Journal of Neurology, 10, 147-152. 251 Appendix A Hand-held Electronic Headache Diary Instructions 1. To turn on your electronic diary, open your case and flip up the cover. Press the square green button in the lower left hand corner of your palm pilot. 2. To activate the Headache Diary, tap the Diary icon with the stylus. 3. To begin your diary entry, tap the Start icon on the Welcome screen with the stylus and then tap the OK icon on the next screen. 4. Enter your answers to the following questions by tapping the appropriate answer with your stylus. To move to the next question, tap the Next icon at the bottom of each page. To go back to a previous page, tap the Back icon at the bottom of each page. � Did you take preventive medication for today? Yes or No � Did your menstrual flow begin on the day above? Yes or No (This question will appear only for women) � Do you have a headache to record today? Yes or No 5) If you didnt have a headache that day, you are finished with entering data. The program will automatically show you a table of your headache activity from the time you began collecting the data so you can track your headache progress. 6. If you had a headache that day, tap the arrow � with your stylus next to Headache Type and tap the appropriate type from the list: � Migraine � Tension � Other � Dont know 7. Answer the questions about your headache by tapping the appropriate answer or by tapping the date or time icon with your stylus. Then tap the + or - sign to increase or decrease the value. � Start Date � Start Time � Has this headache ended? Yes or No � End Date � End Time 252 Appendix A: continued 8. To answer the questions about your headache symptoms, tap the arrow � next to each symptom with your stylus. Then tap the appropriate answer to each question. � Max. Severity: None Mild Moderate Severe � Nausea: Not Present Mild Moderate Severe � Phonophobia: Not Present Mild Moderate Severe � Photophobia: Not Present Mild Moderate Severe � Vomiting Yes No 9. Next, answer the questions about your preventive medication by tapping the appropriate answer or by tapping the type of medication icon with your stylus. Then tap the + or - sign to increase or decrease the amount. If your answer to the first question is No, you will advance to the next section. � Did you take any medication for the headache? Yes or No � Analgesic (Pill) � Imitrex (Pill) � Imitrex (Spray) � Imitrex (Injection) � Maxalt (Pill) � Maxalt (Melt) � Anti-Nausea (Pill) � Rescue Med. (Dose) 253 Appendix A: continued 10. Next, answer the questions about how much this headache interfered with various activities by tapping the appropriate answer or by tapping the Hours icon with your stylus. Then tap the + or - sign to increase or decrease the number of hours. If your answer to any question is No, you will advance to the next question. � Did this headache impact your performance of unpaid housework, childcare, volunteer or schoolwork? Yes or No � How many hours of unpaid work did you miss because of this headache? Hours � How many hours of unpaid work did you do while impaired (>50%) by this headache? Hours � Did this headache impact your performance at paid work? Yes or No � How many hours of paid work did you miss because of this headache? Hours � How many hours of paid work did you do while impaired (>50%) by this headache? Hours � Did this headache interfere with any recreational or social activities? Yes or No � How many hours of activities did you miss because of your headache? Hours � How many hours of activities did you do while impaired (>50%) by this headache? Hours � Did this headache affect your sleep? Yes or No � How many hours of sleep did you miss because of your headache? Hours � How many hours of sleep did you do while impaired (>50%) by this headache? Hours 11. After you have answered all questions, the program will automatically show you a table of your headache activity so you can track your headache progress. Appendix B 254 This copy of the Beck Depression Index has been removed due to potential copyright issues. Appendix B 255 This copy of the Beck Depression Index has been removed due to potential copyright issues. Appendix B 256 This copy of the Beck Depression Index has been removed due to potential copyright issues. Appendix B 257 This copy of the Beck Depression Index has been removed due to potential copyright issues. Appendix B 258 This copy of the Beck Depression Index has been removed due to potential copyright issues. 259 Appendix C Gynecological History, Long Form 1. At what age did you start having migraines? ______ 2. At what age did you have your first period? ______ 3. Did your migraines begin at about the same time as you started your periods? No Yes 4. Currently, do you have periods? No Yes (If you answered "No", complete 4a; if you answered, "Yes", complete 4b and 4c.) 4a. If NO, Did your periods stop due to: Menopause (greater than 3 months and less than 12 months since your last period). Postmenopause (12 months or more since your last period). Hysterectomy Other (please specify) ______. 4b. If YES, Please note the number of pads and tampons used on each day of your last period in the block that corresponds to the amount of soiling of your pads or tampons. Below each day, list the absorbency category for the pads (Regular, Maxi, Super Maxi) or tampons (Lite, Regular, Super, Super Plus) used that day. In addition, note the date (month/day/year) of day 1 of your period. This date should be the first day of heavy flow. RECORD DATE OF DAY 1 OF PERIOD: AMOUNT OF SOILING DAY OF PERIOD PAD 1 2 3 4 5 6 7 8 Absorbency of Pad 260 Appendix C: continued AMOUNT OF SOILING DAY OF PERIOD TAMPON 1 2 3 4 5 6 7 8 Absorbency of Tampon Please indicate below the appropriate description of your last period: Length of time since your previous menstrual cycle: < 21 days 21-25 days 26-30 days 31-35 days > 35 days Please indicate below the appropriate description of your periods during the last year: Regularity of your periods: Always within Always within Always within Varied more + 2 days + 3-6 days + 1-2 weeks than 2 weeks Number of months you experienced bleeding between periods: 0 1-3 4-6 Greater than 6 Disability due to menstrual pain: no limitation, some loss of work in bed part of the day in bed 1 or more pain absent efficiency, mild & occasional loss of days and pain work, moderate pain incapacitation, severe pain 261 Appendix C: continued Pattern of migraines with menstrual periods: Regularly Regularly with With some Sometimes with At Unsure with menstruation menstrual menstruation any menstruation and at other periods and at other time only times only times Severity of migraine pain during menstrual periods: About the same as More severe than Less severe than Unsure migraines at other migraines at other times migraines at other times times 4c. If YES, rate your experience with the following symptoms before or during your last period by circling a number from 0 5, with 0 as no experience with the symptom to 5 as a disabling (or extremely intense) experience with the symptom: Extremely No Disabling/In Symptom Experience tense Experience Weight gain 0 1 2 3 4 5 Insomnia 0 1 2 3 4 5 Crying 0 1 2 3 4 5 Lowered school or work 0 1 2 3 4 5 performance Muscle stiffness 0 1 2 3 4 5 Forgetfulness 0 1 2 3 4 5 Confusion 0 1 2 3 4 5 Take naps; stay in bed 0 1 2 3 4 5 Headache 0 1 2 3 4 5 Skin disorders 0 1 2 3 4 5 262 Appendix C: continued Extremely No Disabling/ Symptom Experience Intense Experience Loneliness 0 1 2 3 4 5 Feeling of suffocation 0 1 2 3 4 5 Affectionate 0 1 2 3 4 5 Orderliness 0 1 2 3 4 5 Stay at home 0 1 2 3 4 5 Cramps 0 1 2 3 4 5 Dizziness, faintness 0 1 2 3 4 5 Excitement 0 1 2 3 4 5 Chest pains 0 1 2 3 4 5 Avoid social activities 0 1 2 3 4 5 Anxiety 0 1 2 3 4 5 Backache 0 1 2 3 4 5 Cold sweats 0 1 2 3 4 5 Lowered judgment 0 1 2 3 4 5 Fatigue 0 1 2 3 4 5 Nausea, vomiting 0 1 2 3 4 5 Restlessness 0 1 2 3 4 5 Hot flashes 0 1 2 3 4 5 263 Appendix C: continued Extremely No Disabling/ Symptom Experience Intense Experience Difficulty concentrating 0 1 2 3 4 5 Painful breasts 0 1 2 3 4 5 Feelings of well-being 0 1 2 3 4 5 Ringing in the ears 0 1 2 3 4 5 Distractible 0 1 2 3 4 5 Swelling 0 1 2 3 4 5 Accidents 0 1 2 3 4 5 Irritability 0 1 2 3 4 5 General aches and pains 0 1 2 3 4 5 Mood swings 0 1 2 3 4 5 Heart pounding 0 1 2 3 4 5 Depression 0 1 2 3 4 5 Decreased efficiency 0 1 2 3 4 5 Lowered motor 0 1 2 3 4 5 coordination Numbness, tingling 0 1 2 3 4 5 Tension 0 1 2 3 4 5 Blind spots, fuzzy 0 1 2 3 4 5 vision 264 Appendix C: continued Bursts of energy, 0 1 2 3 4 5 activity 5. Do your headaches change just before or at the beginning of your period? 1 2 3 4 5 6 7 Got worse No change Got better 6. Have you had any of the following problems? (Check all that apply.) Abnormal Pap smear-non-cancerous. Cysts in your ovaries. Abnormal Pap smear-cancerous. Cancer of your ovaries. Fertility problems Breast cancer. (unable to conceive after 12 months) Cancer of your womb. Miscarriage. Other (please list) ______ Endometriosis-overgrowth of the lining of your womb. 7. Have you ever used birth control medication? Yes No 7a. If YES, how long (years)? Less than 1 1-5 6-10 11-15 16-20 More than 20 years 7b. If YES, Did your headaches change when you were taking birth control medication? 1 2 3 4 5 6 7 Got worse No change Got better 8. Are you currently taking birth control medication? Yes No 265 Appendix C: continued 8a. If YES, what type of medication do you use? Combined, monophasic low dose estrogen pill (pill with same dose of estrogen (less than 50 mcg) and progestin is taken for 21 days; for example, Alesse, Brevicon, Desogen, Loestrin, Nordette, Levlen, Lo/Ovral, Ortho-Cyclen, Ovcon- 35, Orthocept, Brevicon, Modicon, Norinyl 1/35, Ortho-Novum 1/35, Genora 1/35, Demulen 1/35) Combined, bi- or tri-phasic low-dose estrogen pill (pill with both estrogen (less than 50 mcg) and progestin is taken for 21 days, with dosage varied for progestin during cycle; for example, Tri-Cyclen, Tri-Norinyl, Ortho-Novum 7/7/7, Ortho- Novum10/11, Triphasil, Tri-Levlen, Desogen) Combined, biphasic low-dose estrogen pill with placebo (pill with both estrogen (20 mcg) and progestin is taken for 21 days, followed by 2 days of placebo and then 5 days of estrogen (10 mcg); for example, Mircette) Combined, monophasic high-dose estrogen pill (pill with both estrogen (50 mcg or more) and progestin is taken every day; for example, Norinyl 1/50, Ortho 1/50, Genova 1/50, Norinyl 1/80, Ortho 1/80, Ovcon 50, Noriestrin 1/50, Norinyl 2, Ortho-Novum 1/50, Enovid-E, Norlestrin 2.5/50, Ovral, Demulen 1/50, Ovulen) Progestin-only pills (Minipills; for example, Micronor, Nor-QD, Ovrette, Noriday, Norod, Micro-Novum, Neogest, Microval, Noregeston, Microlut, Femulen, Exluton) Implant (for example, Norplant) Depo-Provera injection Progesterone T IUD Other; List______ 9. Have you ever been pregnant? Yes No 9a. If YES, Did your headaches change during your pregnancy? 1 2 3 4 5 6 7 Got worse No change Got better 266 Appendix C: continued 10. Have you ever used female hormone replacement therapy (HRT)? Yes No 10a. If YES, Did your headaches changed during your use of female hormone replacement Therapy? 1 2 3 4 5 6 7 Got worse No change Got better 10. Are you currently taking female hormone replacement therapy? Yes No 11a. If YES, What type of hormone replacement therapy do you use? Combined estrogen/progesterone pill, continuous administration (taken every day; for example, PremPro). Combined estrogen/progesterone pill, interrupted administration (taken for 21 days and stopped or a dummy pill taken for 7 days; for example, Premphase.) Estrogen only pill (for example, Premarin, Ogen, Estratab). Combined estrogen/androgen pill (for example, Estratest). Hormone patch (for example, Estraderm). Vaginal cream (for example, Ortho Dienestrol Cream, Estragard Cream) Other. Specify ______. 267 Appendix D Gynecological History, Short Form 1. Did you have a period last month? No Yes (If you answered "No", skip to 2; if you answered, "Yes", complete 1a, 1b, 1c, and 2.) 1a. If YES, rate your experience with the following symptoms before or during your last period by circling a number from 0 5, with 0 as no experience with the symptom to 5 as a disabling (or extremely intense) experience with the symptom: Disabling/ No Intense Symptom Experience Experience Weight gain 0 1 2 3 4 5 Insomnia 0 1 2 3 4 5 Crying 0 1 2 3 4 5 Lowered school or work 0 1 2 3 4 5 Performance Muscle stiffness 0 1 2 3 4 5 Forgetfulness 0 1 2 3 4 5 Confusion 0 1 2 3 4 5 Take naps; stay in bed 0 1 2 3 4 5 Headache 0 1 2 3 4 5 Skin disorders 0 1 2 3 4 5 268 Appendix D: continued Disabling/ No Intense Symptom Experience Experience Loneliness 0 1 2 3 4 5 Feeling of suffocation 0 1 2 3 4 5 Affectionate 0 1 2 3 4 5 Orderliness 0 1 2 3 4 5 Stay at home 0 1 2 3 4 5 Cramps 0 1 2 3 4 5 Dizziness, faintness 0 1 2 3 4 5 Excitement 0 1 2 3 4 5 Chest pains 0 1 2 3 4 5 Anxiety 0 1 2 3 4 5 Backache 0 1 2 3 4 5 Cold sweats 0 1 2 3 4 5 Lowered judgment 0 1 2 3 4 5 Fatigue 0 1 2 3 4 5 Nausea, vomiting 0 1 2 3 4 5 Restlessness 0 1 2 3 4 5 Hot flashes 0 1 2 3 4 5 Difficulty concentrating 0 1 2 3 4 5 269 Appendix D: continued Disabling/In No tense Symptom Experience Experience Painful breasts 0 1 2 3 4 5 Feelings of well-being 0 1 2 3 4 5 Ringing in the ears 0 1 2 3 4 5 Distractible 0 1 2 3 4 5 Swelling 0 1 2 3 4 5 Accidents 0 1 2 3 4 5 Irritability 0 1 2 3 4 5 General aches and pains 0 1 2 3 4 5 Mood swings 0 1 2 3 4 5 Heart pounding 0 1 2 3 4 5 Depression 0 1 2 3 4 5 Decreased efficiency 0 1 2 3 4 5 Lowered motor 0 1 2 3 4 5 Coordination Numbness, tingling 0 1 2 3 4 5 Tension 0 1 2 3 4 5 Blind spots, fuzzy vision 0 1 2 3 4 5 Bursts of energy, activity 0 1 2 3 4 5 Appendix D: continued 270 1b. Did you have a migraine any time from two days before to two days after the start of your last period? No Yes 1c. Note the date of day 1 (month/day/year) of your last period. This date should be the first day of heavy flow. ______ 2. During the last month, have there been any changes in your: a. periods No Yes Not applicable b. menopause symptoms No Yes Not applicable c. birth control medication No Yes Not applicable d. female hormone replacement No Yes Not applicable therapy 2a. If YES, please explain: ______ 271 Appendix E Migraine-Specific Quality of Life Questionnaire Name Date INSTRUCTIONS: While answering the following questions, please think about all migraine attacks you may have had in the past 4 weeks. 1. In the past 4 weeks, how often have migraines interfered with how well you dealt with family, friends and others who are close to you? (Select only one response.) � None of the time � A little bit of the time � Some of the time � A good bit of the time � Most of the time � All of the time 2. In the past 4 weeks, how often have migraines interfered with your leisure activities, such as reading or exercising? (Select only one response.) � None of the time � A little bit of the time � Some of the time � A good bit of the time � Most of the time � All of the time (Continue to the next page.) 272 Appendix E: continued 3. In the past 4 weeks, how often have you had difficulty in performing work or daily activities because of migraine symptoms? (Select only one response.) � None of the time � A little bit of the time � Some of the time � A good bit of the time � Most of the time � All of the time 4. In the past 4 weeks, how often did migraines keep you from getting as much done at work or at home? (Select only one response.) � None of the time � A little bit of the time � Some of the time � A good bit of the time � Most of the time � All of the time 5. In the past 4 weeks, how often did migraines limit your ability to concentrate on work or daily activities? (Select only one response.) � None of the time � A little bit of the time � Some of the time � A good bit of the time � Most of the time � All of the time (Continue to the next page.) 273 Appendix E: continued 6. In the past 4 weeks, how often have migraines left you too tired to do work or daily activities? (Select only one response.) � None of the time � A little bit of the time � Some of the time � A good bit of the time � Most of the time � All of the time 7. In the past 4 weeks, how often have migraines limited the number of days you have felt energetic? (Select only one response.) � None of the time � A little bit of the time � Some of the time � A good bit of the time � Most of the time � All of the time 8. In the past 4 weeks, how often have you had to cancel work or daily activities because you had a migraine? (Select only one response.) � None of the time � A little bit of the time � Some of the time � A good bit of the time � Most of the time � All of the time (Continue to the next page.) 274 Appendix E: continued 9. In the past 4 weeks, how often did you need help in handling routine tasks such as every day household chores, doing necessary business, shopping, or caring for others, when you had a migraine? (Select only one response.) � None of the time � A little bit of the time � Some of the time � A good bit of the time � Most of the time � All of the time 10. In the past 4 weeks, how often did you have to stop work or daily activities to deal with migraine symptoms? (Select only one response.) � None of the time � A little bit of the time � Some of the time � A good bit of the time � Most of the time � All of the time 11. In the past 4 weeks, how often were you not able to go to social activities such as parties, dinner with friends, because you had a migraine? (Select only one response.) � None of the time � A little bit of the time � Some of the time � A good bit of the time � Most of the time � All of the time (Continue to the next page.) 275 Appendix E: continued 12. In the past 4 weeks, how often have you fest fed up or frustrated because of your migraines? (Select only one response.) � None of the time � A little bit of the time � Some of the time � A good bit of the time � Most of the time � All of the time 13. In the past 4 weeks, how often have you felt like you were a burden on others because of your migraines? (Select only one response.) � None of the time � A little bit of the time � Some of the time � A good bit of the time � Most of the time � All of the time 14. In the past 4 weeks, how often have you been afraid of letting others down because of your migraines? (Select only one response.) � None of the time � A little bit of the time � Some of the time � A good bit of the time � Most of the time � All of the time Copyright 1992, 1996, 1998 Glaxo Wellcome Inc. 276 Appendix F: Pain Catastrophizing Scale Everyone experiences painful situations at some point in their lives. Such experiences may include headaches, tooth pain, joint or muscle pain. People are often exposed to situations that may cause pain such as illness, injury, dental procedures or surgery. We are interested in the types of thoughts and feelings that you have when you have a headache. Listed below are thirteen statements describing different thoughts and feelings that may be associated with headache pain. Using the following scale, please indicate the degree to which you have these thoughts and feelings when you are experiencing a headache. 0 not at all 1 to a slight degree 2 to a moderate degree 3 to a great degree 4 all the time ______ When I have a headache 1 I worry all the time about whether the headache will end. 2 I feel I cant go on. 3 Its terrible and I think its never going to get any better. 4 Its awful and I feel that it overwhelms me. 5 I feel I cant stand it anymore. 6 I become afraid that the headache will get worse. 7 I keep thinking of other painful headaches. 8 I anxiously want the headache to go away. 9 I cant seem to keep it out of my mind. 10 I keep thinking about how much it hurts. 11 I keep thinking about how badly I want the headache to stop. 12 Theres nothing I can do to reduce the intensity of the headache. 13 I wonder whether something serious may happen. 277 Appendix G TSM - Human Subjects Informed Consent Form: Assessment & Treatment Phase Title of Research: Drug and Non-Drug Treatment of Severe Migraines Principal Investigators: Kenneth A. Holroyd, PhD; Frank ODonnell, DO; and Gary Cordingley, PhD, MD. I. Thank you for your interest in this research project on ways to treat recurrent headaches. We hope you will be able to participate Exclusions (Reasons You Cannot Be In This Study) If you have any one of the following, you should not participate in this study: a. are pregnant, breast feeding, planning a pregnancy or taking inadequate contraceptives. (Acceptable methods of birth control are: the consistent use of an approved oral contraceptive (birth control pill), an intrauterine device (IUD), hormone implants (Norplant®), contraceptive injection (Depo-Provera®), double barrier methods (diaphragm with spermicidal gel or condoms with contraceptive foam), and sexual abstinence (no sexual intercourse)). b. history (within the prior 1 year) or current evidence of drug or alcohol abuse c. current use of preventive headache therapy - defined as any medication taken every day to prevent the occurrence of migraines (as opposed to acute medication which is taken only when a migraine occurs). d. are unable or unwilling to complete daily headache recordings e. headaches that are a symptom of an underlying organic disorder (secondary headaches), cluster headache, tension-type headache (as primary complaint), post-traumatic headache, headaches associated with excessive analgesic use, or other headaches not appropriately treated with the treatments being evaluated in this study. f. reaction to or serious adverse event in response to sumatriptan (tablet, injection, intranasal, or suppository) or rizatriptan (oral) or contraindication to the use of these medications. g. current use of medications that contraindicate the use of any of the study medications. h. history or clinical evidence of heart disease, such as heart failure, heart attacks, stable or unstable angina i. asthma, brain disorders, diabetes, or other conditions judged to be contraindications for study participation. 278 Appendix G: continued There may be other reasons why you cannot participate which will be discussed with you by the study doctor or a member of the study staff. The reasons that a person cannot be in this study will be reviewed with you by the study doctor or a member of the study staff to ensure that you understand them and that they do not apply to you. If you do decide to participate, federal, university, and clinic regulations require that you sign this Consent Form. First read section II of this Form. If you have any questions please feel free to ask them. Then, if you agree to take part, sign your name at the end of the form. This will mean you understand and agree to the statements below. II. Statement of Procedure: Assessment/Treatment Phase. By this time, a staff member should have described the assessment and treatment procedures for you in detail. The purpose of this assessment is to obtain information about your headache problems and to help us evaluate the treatments we will be providing. Any information you provide to us will be kept in strict confidence. I understand that in the Assessment/Treatment Phase of this study: 1) I will be asked to disclose information about my headache and medical history so staff can assess my headache problems. I also will be asked to complete psychological and research questionnaires. 2) I will be asked to keep daily records of my headaches and medication use throughout a five-week assessment and four-month treatment period. I also will be asked to deposit $50, which will serve as a reminder to complete the daily headache monitoring and to return the hand held computer. This money will be returned to me at the completion of the study or earlier if I cannot complete the study, after I return the palm computer. 3) I will be provided a physical and neurological examination. The project neurologist may also decide to conduct other tests to obtain additional information about my headache problems. 4) If it determined the treatments being evaluated in this study are appropriate for my headaches I will be offered the treatments as described below for my headaches. A.. Acute therapy . All participants will be provided medication for acute treatment of migraine. This medication is to treat migraines when they occur. Acute treatment will include the following types of medication. Analgesic/anti-nausea medication. An analgesic compound containing acetaminophen, aspirin, and caffeine and, if needed, an anti-nausea 279 Appendix G: continued (anti-emetic) medication to control nausea or vomiting (metoclopramide). This combination of medications has been shown to be effective for many people for some or all of their migraines. (Alternative analgesic medications will be provided if the neurologist judges this compound analgesic is not the most appropriate analgesic for you.) Migraine-specific medication. These medications (called 5HT1 agonists or triptans) are designed specifically for migraines, and have been shown to be effective in reducing the duration and severity of migraine attacks. This medication can be sumatriptan (Imitrex) in either pill, injectable or intranasal spray form or rizatriptan (Maxalt) in pill or melt form. I will be provided the medication that works best for me and that I prefer. Rescue medication. If the previous medications fail to relieve a migraine, I may use the analgesic medication I usually use for severe migraines four hours after headache onset. (This medication cannot be provided by the research project.) B. Preventive medication Preventive medication differs from acute medication in that it is taken daily to prevent the occurrence of migraines. I will be randomly assigned (by a computer randomization procedure) to take a preventive medication pill each day. These pills will contain either an active or inactive ingredient. Pills with an active ingredient will contain a beta-blocker medication that has been shown to prevent the occurrence of some migraines for many people. Inactive ingredient pills contain no active medication. I may take a pill containing inactive medication during one phase of the study and a pill taking active medication in another phase of the study. I will not know whether the pills I am taking contain active or inactive ingredients. This is important to make the results of the study as clear as possible. C. Behavioral Migraine-Management . One half of study participants will be randomly selected (by a computer randomization procedure) to also receive migraine management therapy. This involves learning migraine management skills that reduce the occurrence and severity of migraines for many people. If I am randomly selected to receive Behavioral Migraine Management I will also meet with a counselor at 4 clinic visits to receive training in migraine management skills. 6) I will be asked not to use daily medication to prevent my headaches other than the preventive medication that will be provided by the Project Neurologist as part of this 280 Appendix G: continued study. I will be asked to inform the Project Neurologist if I begin taking any new medication, even it is taken for medical conditions that seem unrelated to my headaches. 7) At each clinic visit I will be asked to complete self-report questionnaires that help to evaluate the effectiveness of treatment. 8) If my migraines are not effectively controlled in the five-week assessment period with infrequent use of acute therapy I may continue in the next phase of the study. If my migraines are effectively controlled with infrequent use of acute therapy I will not continue in this study beyond the initial five-week assessment phase. 9) If I have any questions or experience any problems related to my participation in this research project, I may call the project manager Dr. Connie Cottrell at (614) 839-3254 in Westerville or Brenda Pinkerman at (740) 593-1060 in Athens; or the principal investigator, Dr. Kenneth Holroyd at (740) 593-1060; or for medically related questions or problems, Dr. Frank ODonnell at (614) 839-3254 in Westerville or Dr. Gary Cordingley at (740) 594-8147 in Athens. 10) I am free to discontinue my participation in this study at any time, without penalty. Potential Risks of Participation: 1) I may experience side effects from acute therapy medications. The analgesic compound may cause anxiety, nausea, and less often, stomach pain. The anti-emetic may cause nausea, diarrhea, headache, dizziness, drowsiness, dry mouth, restlessness or sleeplessness; in rare instances it may cause muscle spasm or excessive muscle contraction. Only some individuals experience these side effects and most side effects are temporary. 2) I may experience side effects from the migraine-specific medications (sumatriptan or rizatriptan) if I chose to use them. The medication may initially cause flushing (redness of face lasting a short time), dizziness, weakness, nausea, drowsiness, stiffness, or feelings of tingling, heat, pressure or fatigue (If I chose to use the injectable form of this medication I may experience tenderness at the injection site. Unlikely side effects include irregular or fast heartbeat, trouble breathing, itching/rash, swelling, vision changes, and cold, tingling or numb hands and feet. If I develop any of these unlikely symptoms I will inform the Project Neurologist. 3) I may experience side effects from the medication to prevent migraines as my body adjusts to the medication. These may include dizziness, lightheadedness, drowsiness, and blurred vision. My hands and feet may be more susceptible to the cold. These side effects typically pass after a short time. Some individuals develop easy bruising or bleeding, 281 Appendix G: continued swollen hands or feet, confusion, depression or a sore throat. If I develop any of these latter symptoms I will inform the Project Neurologist. The Project Neurologist can adjust the medication dose and, if necessary, change to a second medication to minimize side- effects. 4) I may experience discomfort when answering personal questions during the evaluation. 5) If I stop taking my usual daily medication to prevent my headaches, I may experience an increase in headache activity. Potential Benefits of Participation: 1) I will receive free evaluation of my headaches from health care professionals. 2) I will receive information concerning my headache problems. 3) I may experience a reduction in the frequency, duration, and severity of my headaches. 4) I may experience positive side effects from treatment such as feeling more relaxed and improved sleep. 5) I may be able to reduce the amount of analgesic medication I currently take. 6) I will receive free treatment for my headaches from health-care professionals. Statement of Consent: I certify that I have read and understand the Statement of Procedure and agree to participate as a subject in the research described therein. My participation is given voluntarily and without coercion or undue influence. I understand that I may discontinue participation at any time without penalty or loss of benefit to which I might otherwise be entitled. I agree that all known risks to me have been explained to my satisfaction and I understand that no compensation is available from Ohio University, Orthopedic and Neurological Consultants, Inc., the private practice of Dr. Gary Cordingley, or from their employees for any injury resulting from my participation in this research. I certify that I am at least eighteen years of age. If you have any questions regarding your rights as a research participant, please contact Jo Ellen Sherow, Director of Research Compliance, Ohio University, (740) 593-0664. 282 Appendix G: continued ______ Print Your Name Here Sign Your Name Here Date ______ Witness Date 283 Appendix H TSM Human Subjects Informed Consent Form: Evaluation Phase Title of Research: Drug and Non-Drug Treatment of Severe Migraines Principal Investigators: Kenneth A. Holroyd, PhD; Frank ODonnell, DO; and Gary Cordingley, PhD, MD. I. Thank you for your participation in this research project on ways to treat recurrent headaches. We hope you will also be able to participate in the evaluation phase of the study. If you do decide to participate, federal, university, and clinic regulations require that you sign this Consent Form. First read section II of this Form. If you have any questions please feel free to ask them. Then, if you agree to take part, sign your name at the end of the form. This will mean you understand and agree to the statements below. II. Statement of Procedure: Evaluation phase. By this time, a staff member should have described the treatment evaluation phase of the study for you in detail. The purpose of this phase of the study is to monitor the long-term benefits of treatment. I understand that in the Evaluation Phase of the study: 1) The follow-up phase of the study involves clinic visits 1, 3 & 6 and 12 months following my last treatment visit. At these visits my response to treatment will be evaluated and medication dose adjusted as needed. If I received Behavioral Migraine Management in the treatment phase of the project any questions or problems I have in using migraine-management exercises also will be addressed at these visits. 2) I will be asked to complete self-report questionnaires at each evaluation visit to help assess the effectiveness of the treatments. 3) I will be asked for a blood sample, which will be drawn by the Project Nurse at the 1 month visit. This will allow researchers to determine how I metabolize study medication 4) I will be asked to keep daily records of my headache activity and medication use through the 6-month evaluation. I will also be asked to complete questionnaires I completed in the assessment and treatment phases of the project. At the 1-month visit I 284 Appendix H: continued will receive $30 and at the 6-month visit I will receive $50.00 to partially compensate for the time required for these visits. 5) If I have any questions or experience any problems related to my participation in this research project, I may call the project manager Dr. Connie Cottrell at (614)839-3254 in Westerville or Ms. Brenda Pinkerman at (740) 593-1060 in Athens; the principal investigator, Dr. Kenneth Holroyd (740)593-1060; or for medically related questions or problems, Dr. Frank ODonnell in Westerville at (614) 839-3254 or Dr. Gary Cordingley in Athens at (740) 594-8147. 6) I am free to discontinue my participation in this study at any time without penalty. 7) I will be excluded from the evaluation phase of the study if: a) I fail to keep adequate records of my daily headache activity and medication use. b) I fail to regularly attend scheduled appointments with staff members. 8) At the completion of the 12-month evaluation my involvement in this study will end. However, I will be provided or referred for additional treatment if I wish. Potential Risks of Treatment: 1) I may experience side effects from acute therapy medications. The analgesic compound may cause anxiety, nausea, and less often, stomach pain. The anti-emetic may cause nausea, diarrhea, headache, dizziness, drowsiness, dry mouth, restlessness or sleeplessness; in rare instances it may cause muscle spasm or excessive muscle contraction. Only some individuals experience these side effects and most side effects are temporary. 2) I may experience side effects from the migraine-specific medications (sumatriptan or rizatriptan) if I chose to use them. The medication may initially cause flushing (redness of face lasting a short time), dizziness, weakness, nausea, drowsiness, stiffness, or feelings of tingling, heat, pressure or fatigue (If I chose to use the injectable form of this medication I may experience tenderness at the injection site.) Unlikely side effects include irregular or fast heartbeat, trouble breathing, itching/rash, swelling, vision changes, and cold, tingling or numb hands and feet. If I develop any of these unlikely symptoms I will inform the Project Neurologist. 3). I may experience side effects from the medication to prevent migraines as my body adjusts to the medication. These may include dizziness, lightheadedness, drowsiness, and 285 Appendix H: continued blurred vision. My hands and feet may be more susceptible to the cold. These side effects typically pass after a short time. Some individuals develop easy bruising or bleeding, swollen hands or feet, confusion, depression or a sore throat. If I develop any of these latter symptoms I will inform the Project Neurologist. The Project Neurologist can adjust the medication dose and, if necessary, change to a second medication to minimize side-effects. 4) I may experience side effects from having blood drawn from a vein. These side effects may include pain and/or bruising at the site, lightheadedness, and on rare occasions, infection. Potential Benefits of Treatment: 1) I may experience a reduction in the frequency, duration, and severity of my headaches. 2) I may experience other positive side effects from treatment such as feeling more relaxed and improved sleep. 3) I may be able to reduce the amount of analgesic and/or abortive medication I currently take. 4) I will receive free treatment for my headaches from health-care professionals. 5) My participation in this study may contribute to the development of more effective treatments for severe migraine. Statement of Consent: I certify that I have read and understand the Statement of Procedure and agree to participate as a subject in the research described therein. I agree that known risks to me have been explained to my satisfaction. My participation is given voluntarily and without coercion or undue influence. I understand that no compensation is available from Ohio University, Orthopedic and Neurological Consultants, Inc., or the private practice of Dr. Gary Cordingley, or from their employees for any injury resulting from my participation in this research. I certify that I am at least eighteen years of age. If you have any questions regarding your rights as a research participant, please contact Jo Ellen Sherow, Director of Research Compliance at (740) 593-0664. ______Print Your Name Here Sign Your Name Here Date Witness Date 286 Appendix I: Structured Headache Interview STRUCTURED HEADACHE INTERVIEW Interviewer: Date: ___/___/___ Study Visit#: Pretx1 ______Patient Name: ID #: ______Headache 1 (Migraine HA) 1. During the phone interview, you described your most problematic headache as: (read from phone screen) Is this still an accurate description? I need to ask some specific questions about your headache to ensure that we have the correct information: (migraine) a. Location: ____Unilateral _____Bilateral b. Type: ____Pulsating _____Sharp/Piercing c. Severity: ____Severe _____Moderate d. Associated symptoms: _____Nausea _____Vomiting _____Photophobia _____Phonophobia _____None e. Aggravated by activity: _____Yes _____Sometimes _____No f. Aura: _____Yes _____Sometimes *g. Duration: _____(hrs) Treated _____(hrs) Untreated *h. Frequency: _____(total # of days per month this type of headache occurs _____ (total # of migraine attacks per month) *i. Chronicity: _____ # of months at this frequency ______# of months/yrs of problem headaches *j. Precipitating Factors: _____Stress ____Allergies _____ Menstrual _____ ETOH _____ Dietary ____Caffeine ____Weather ____HA Trauma _____Other 287 Appendix I: continued Headache 2 (Other HA) 2. During the phone interview, you described your other headache as: (read from phone screen) Is this still an accurate description? I need to ask some specific questions about your headache to ensure that we have the correct information: (other headaches) a. Location: ____Unilateral _____Bilateral b. Type: ____Pulsating _____Sharp/Piercing c. Severity: ____Severe _____Moderate d. Associated symptoms: _____Nausea _____Vomiting _____Photophobia _____Phonophobia _____None e. Aggravated by activity: _____Yes _____Sometimes _____No f. Aura: _____Yes _____Sometimes g. Duration: _____(hrs) Treated _____(hrs) Untreated h. Frequency: _____(# of days per month this type of headache occurs) _____(# of headache episode per month) i. Chronicity: _____ (# of months at this frequency) j. Precipitating Factors: _____Stress ____ Allergies _____Menstrual ___ETOH ___ Dietary _____Caffeine _____Weather _____Other 3. How many days in the past month... a. did you miss work or school because of your headaches? _____ b. was your productivity at work or school reduced by half or more because of your headaches? _____ (Do not include days you counted in question 5a where you missed work or school) 288 Appendix I: continued c. did you not do household work because of your headaches? _ ___ d. was your productivity in household work reduced by half or more because of your headaches? _ ___ (Do not include days you counted in question 5c where you missed household work) e. did you miss family, social, or leisure activities because of your headaches? ______ 4. Lets say you had not taken Triptans in those ____ days. How many days in the past month... a. would you have missed work or school because of headaches? _____ b. would your productivity at work or school have been reduced by half or more because of headaches? _____ (Do not include days you counted in question 6a where you missed work or school) c. would you have not done household work because of your headaches? _____ d. would your productivity in household work have been reduced by half or more because of headaches? _____ (Do not include days you counted in question 6c where you missed household work) e. would you have missed family, social, leisure activities because of headaches? ______Disability (MIDAS Sum)X3__ _ **On average, during an entire month, how many of the 31 days in the month do you have a headache (or how many of the 31 days are you pain-free)? ______289 Appendix I: continued 5. Review medication information from Patient Information form (Items 4-17): Tell me more about: 6. If patient reports a history of depression in Screening Interview, inquire into the following: Prior Suicide attempts: Prior Treatment (medications, psychotherapy): Duration of Depression: Other Depressive Episodes (dates): 290 Appendix J TSM Treatment Decision Protocol As a participant in this migraine study you are encouraged to use the following staged approach to treat migraines. This procedure is designed to identify the most effective treatment for your migraine. Four treatment stages are outlined below. Treat the next 2 migraines you experience with the directions checked in Treatment Stage I. You need only go to the next stage if adequate relief was not obtained by using the previous treatment stage. I. TREATMENT STAGE I (Try for your next 2 migraines) Take I or 2 analgesic tablets, wait 1 hour. If not improved go to the next stage. Take 1 or 2 analgesic tablets + 1 metoclopramide tablet, wait 1 hour. If not improved, go to the next stage. . Take 1 Imitrex 50 mg tablet, wait 2 hours. If not improved take a second 50 mg Imitrex tablet and wait 2 more hours. If not improved, go to the next stage. Take 1 Maxalt 5 mg regular or MLT tablet and wait 2 hours. If not improved, take a second 5 mg Maxalt tab or MLT and wait 2 more hours. If not improved, go To the next stage. Take 2 Maxalt 5mg regular or MLT tablets, wait 2 hours. If not improved go to next stage. Administer 1 single spray of Imitrex 20 mg nasal spray, wait 2 hours. If not improved, repeat and wait 2 more hours. If not improved, go to the next stage. Administer 1 Imitrex 6 mg S.Q.injection, wait 2 hours. If not improved, you may administer a second injection. Wait 1 hour, if not improved, go to next stage. Use your rescue medication, wait 6 - 8 hours. If not improved, repeat dose of rescue med and wait 6 - 8 hours. If not improved call the doctor. Other: ______291 Appendix J: continued If a migraine returns within 24 hours after obtaining relief, repeat the treatment in Stage I. If you obtained minimal or no benefit with Treatment Stage I medication above, treat your third migraine using the Stage II treatment. (See checked boxes on the back of this page for Stage II treatment) � TREATMENT STAGE II Take 1 Imitrex 50 mg tablet, wait 2 hours. If not improved, take a second 50 mg tablet and wait 2 more hours. If not improved, go to the next stage. Take 1 Maxalt 5 mg regular or MLT tablet and wait 2 hours. If not improved take a second 5 mg Maxalt regular or MLT tablet and wait 2 more hours. If not improved, go to the next stage. Take 2 Maxalt 5 mg regular of MLT tablets, wait 2 hours. If not improved go to the next stage. Administer one 20mg Imitrex nasal spray, wait 2 hours. If not improved repeat and wait 2 more hours. If not improved go to the next stage. Administer one 6 mg Imitrex S.Q. injection, wait 2 hours. If not improved, a second injection may be administered; wait 2 hours. If not improved, go to the next stage. Use your 1st rescue medication and wait 6 - 8 hours. If not improved, repeat a dose of the 1st rescue medication and wait 6-hours. If not improved, go to the next stage. Use your 2nd rescue medication and wait 6-8 hours. If not improved, call the doctor. Other ______292 Appendix J: continued If a migraine returns within 24 hours after obtaining relief, repeat the treatment in Stage II. If you obtained minimal or no benefit using Stage I and Stage II medications To treat the last 3 migraines go to Stage III to treat your next migraine. (See boxes checked below for Stage III treatment) � TREATMENT STAGE III Administer 1 Imitrex 20 mg nasal spray, wait 2 hours. If not improved repeat and wait 2 more hours. If not improved, go to the next stage. Administer 1 Imitrex 6 mg S.Q. injection, wait 2 hours. If not improved go to the next stage. Administer a 2nd Imitrex 6 mg S. Q. injection, wait 2 hours. Use your rescue medication, wait 6 - 8 hours. If not improved repeat a dose of your of your 1st rescue medication and wait 6-8 hours. If not improved, go to the next stage. Use your 2nd rescue medication and wait 6 -8 hours. If not improved call the doctor. Other ______ For the next migraine, repeat the medication in Stage I, II or III that was the most successful. If relief was not obtained using any of the previous treatments, you may use the treatment in Stage IV (see checked boxes below) 293 Appendix J: continued � TREATMENT STAGE IV Use your 2nd rescue medication and wait 6 -8 hours. If not improved repeat a dose of the 2nd rescue medication and wait 6-8 hours. If not improved, call the doctor. Other ______ IMPORTANT PRECAUTIONS: DO NOT EXCEED THE FOLLOWING MAXIMUM DOSES: 6 X Imitrex 50 mg tablets ( 300 mg total ) in 24 hours. 2 X Imitrex nasal sprays 20 mg each ( 40mg total ) in 24 hours. 2 X Imitrex 6 mg injections (12 mg total ) in 24 hours. 2 X Imitrex 50 mg tablets + 1 X Imitrex 20 mg nasal spray 2 X Imitrex 50 mg tablets + 1 X Imitrex 6 mg injection 6 X Maxalt 5 mg tablets or MLTs (30 mg total) in 24 hours. Do not take Maxalt and Imitrex in the same 24-hour period. 294 Appendix K: Primary Care Evaluation for Mental Disorders 295 Appendix K: continued PRIME-MD 296 Appendix K: continued PRIME-MD 297 Appendix K: continued PRIME-MD 298 Appendix K: continued PRIME-MD 299 Appendix K: continued PRIME-MD 300 Appendix K: continued PRIME-MD 301 Appendix L: Patient Handout on Frequently Asked Medication Questions FAQs about Imitrex and Maxalt ***CONTACT A DOCTOR*** Rash or itching? Stop the medicine and contact the doctor. Shortness of breath? Stop the medicine. Obtain medical care. Chest pain? (Not just a full, congested or flushed feeling.) Stop the medicine and contact the doctor. ***MAYBE CONTACT A DOCTOR*** A full, congested or flushed feeling in the chest, neck or throat? This is a frequent, benign symptom seen especially with injectable Imitrex. If it is not distressing, you can continue taking the medicine. Bad taste? This is a benign side-effect of the nasal spray, but if it is annoying, try sucking on butterscotch candy before using the spray. If the symptom remains annoying, contact the doctor about a possible change in medicine. Symptoms at the injection site, like stinging, burning, or itching? This is common. If it is just mild, you can keep taking the medicine the same way. If it is distressing, try placing an ice cube or cold compress over the injection site. Upset stomach? Try taking it with food, like crackers or a piece of toast. 302 Appendix L: continued FAQs about Reglan (metoclopramide) ***CONTACT A DOCTOR*** Shortness of breath? Stop the medicine. Obtain medical care. ***MAYBE CONTACT A DOCTOR*** Itching or rash? Stop the medicine. Take 1-2 Benadryl pills up to 3-4 times per day as needed to control symptoms. Contact the doctor if it worsens. Involuntary twisting movement of eyes, jaw, neck, trunk, arms or legs? This is an acute dystonic reaction and its occurrence means you shouldn’t take this medicine anymore. The symptom will go away on its own, but if it is too severe, distressing, or interferes with breathing, you should go to an emergency room where they can give you an injection to make it go away faster. Drowsiness? Try using a half-pill next time. 303 Appendix L: continued FAQs about Excedrin (aspirin + acetaminophen + caffeine) ***CONTACT A DOCTOR*** Shortness of breath? Stop the medicine. Obtain medical care. Vomiting blood? Stop the medicine. Contact the doctor. Blood in stool (including tarry, black stools)? Stop the medicine. Contact the doctor. ***MABYE CONTACT A DOCTOR*** Itching or rash? Stop the medicine. Take 1-2 Benadryl pills up to 3-4 times per day as needed to control symptoms. If it worsens, contact the doctor. Nervous, jittery or can’t sleep? This is a benign effect of the caffeine ingredient. If the symptom is just mild, you can keep taking the medicine the same way. If it is distressing, contact the doctor. Upset stomach? Try taking it with food, e.g. crackers or a piece of toast. 304 Appendix L: continued FAQs about Ibuprofen ***CONTACT A DOCTOR*** Itching or rash? Stop the medicine. Contact the doctor. Shortness of breath? Stop the medicine. Seek emergency medical care. Blood in stool or tarry black stools? Stop the medicine. Contact the doctor. Upset stomach? Try taking the medicine with food like a cracker or a piece of toast. 305 Appendix L: continued FAQs about Propranolol and Nadalol ***CONTACT THE DOCTOR*** Itching or rash? Stop the medicine. Contact the doctor. Shortness of breath? Contact the doctor. Swelling in feet or ankles? Contact the doctor. ***MAYBE CONTACT THE DOCTOR*** Fatigue? It it’s just mild, continue the same dose for now, but try taking it at bedtime. If it’s more than mild, contact the doctor. Depression? If you are experiencing more sadness than is usual with the normal ups and downs of life, call the doctor. Constipation? Drink plenty of fluids. Eat roughage like lettuce, or grains like cereal. Take 1-2 stool softeners per day, e.g. Colace pills or Metamucil powder in water. Upset stomach? Try taking it with food. If there is more than one pill per day, try dividing the dose among multiple meals. Sexual dysfunction? Try taking the medicine at a different time of day. Sleepiness? Try taking the medicine at bedtime. 306 Appendix M: Summary of Repeated Measures Logistic Regression for Anxiety and Depressive Symptoms with Treatment Outcomes Treatment Outcome: Four hour pain-free (n = 105 clustersGEE) Independent na � SEa � e�a CIa e� df � 2 Variable Anxiety symptomsa 105 -.015 .035 .98 .92-1.06 1 .17 Depressive symptomsb 105 .001 .027 1.00 .95-1.06 1 <.01 Treastment Outcome: Rescue Medication (n = 105 clustersGEE) Independent na � SE a � e�a CIa e� df �2 Variable Anxiety symptomsa 105 -.029 .080 .97 .83-1.14 1 .13 Depressive symptomsb 105 .044 .038 1.04 .97-1.13 1 1.33 Treatment Outcome: Recurrence within 24 Hours after Pain-free Response (n = 105 clustersGEE) Independent n � SEa � e�a CIa e� �2 Variables df Model 1: Anxiety symptomsa 105 -.011 .037 .99 .92-1.06 1 .09 Birth Control .741 .333 2.10 .92-4.03 1 4.93* Analgesics vs. -1.253 .461 .28 .11-.70 1 7.40** Triptans+analgesic Triptans vs. -.582 .336 .56 .29-1.08 1 2.99 Triptans + analgesic Model 2: Depressive symptomsb 105 .033 .028 1.03 .98-1.09 1 1.38 Birth Control .797 .347 2.22 1.12-4.38 1 5.29* Analgesics vs. -1.319 .465 .27 .11-.66 1 8.06** Triptans+analgesic Triptans vs. -.545 .333 .58 .30-1.11 1 2.69 Triptans + analgesic 307 Appendix M: continued a Beck, A., Epstein, N., Brown, G., & Steer, R. (1988). An inventory for measuring clinical anxiety: Psychometric properties. Journal of Consulting and Clinical Psychology, 56, 893-897. a Beck, A., & Steer, R. (1990). Manual for the Beck Anxiety Inventory. San Antonio, TX: Psychological Corportation. Beck, A., Steer, R., & Brown, G. (1996). Manual for the Beck Depression Inventory-II. San Antonio, TX: Psychological Corporation.