Abstract
Background
Cutaneous allodynia is a common clinical feature of migraine that has been associated with reduced efficacy of acute migraine treatments and an increased risk of disease progression.
Objective
Identify factors associated with allodynia in a sample of adults with migraine.
Methods
An online survey panel was used to identify adults with migraine who averaged at least 1 monthly headache day over the previous 3 months. Data on sociodemographics, headache frequency, headache pain intensity, migraine symptom severity, medication use, depression and anxiety, and cutaneous allodynia (via the Allodynia Symptom Checklist) were obtained. Binary logistic modeling predicted the presence of allodynia. Odds ratios and 95% confidence intervals (CI) were calculated.
Results
In total, 15,133 individuals with migraine met the eligibility criteria. Mean age was 43.1 years, 73.0% were female, and 81.0% were Caucasian. Allodynia was present in 39.9%. The fully adjusted model, controlling for sociodemographics and headache features, demonstrated that allodynia was significantly associated with a higher migraine symptom severity score (odds ratio 1.17, confidence interval 1.15, 1.19) and more severe pain intensity (odds ratio 1.11, confidence interval 1.08, 1.14); probable depression and/or anxiety (odds ratio 1.83, confidence interval 1.67, 2.00); and overuse of acute medication (odds ratio 1.23, confidence interval 1.09, 1.38). A higher number of monthly headache days increased the likelihood of allodynia, but the effect was attenuated in the fully adjusted model.
Conclusion
In a representative sample of US adults with migraine, there were significant associations between allodynia and headache frequency and intensity, anxiety and/or depression, symptom severity, and acute medication overuse.
Keywords
Introduction
Cutaneous allodynia, defined as pain provoked by ordinarily nonpainful stimulation of the skin (e.g. combing hair, wearing a hat or hairclip), is a common feature of migraine. Although the phenomenon has long been recognized in people with migraine (1), interest expanded when it was demonstrated that cutaneous allodynia results from central sensitization of second and third-order trigeminovascular neurons, occurs in two thirds of people with migraine during attacks, and predicts a poor acute treatment response to triptans (2–6). Subsequent studies have shown that allodynia predicts a poor acute treatment response to other classes of medication, including nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and barbiturate combination products (7,8). Allodynia is a risk factor for migraine attack recurrence and disease progression from episodic migraine to chronic migraine (5,9–11). Among those with migraine, the risk of experiencing allodynia may be associated with unilateral pain, throbbing pain, and nausea, as well as illness duration, attack frequency, and disability (12).
The objective of this cross-sectional study was to identify the factors associated with allodynia in a US sample of adults with migraine.
Methods
Study design
Details of the methods employed in the Migraine in America Symptoms and Treatment (MAST) Study are available elsewhere (13). In brief, MAST is a study of US adults who participate in a nationally representative internet research panel. Baseline data collection occurred between October 2016 and January 2017. The study used stratified sampling to ensure a final sample that was demographically representative of the US adult population for sex, age, household income, race, marital status, and US Census region. Sampling demographics were maintained within 5% of those reported in the 2015 US Census. Data from the longitudinal phase of the study are not presented in this manuscript.
Recruiting and inclusion criteria
A nationally representative sample of panel members (from Research Now, Plano, TX, USA) was invited to participate in a survey about health. Volunteers provided sociodemographics and if they endorsed headache or migraine from a list of health problems, the American Migraine Study (AMS)/American Migraine Prevalence and Prevention (AMPP) Study migraine diagnostic module (14) was administered to assess migraine criteria. The module captures the International Classification of Headache Disorders, 3rd edition (beta version) (ICHD-3 beta) criteria for migraine, including headache pain characteristics (unilateral location, pulsating/throbbing quality, moderate to severe intensity); exacerbation by routine activity; and associated symptoms (nausea, phonophobia, and photophobia) (15). The criteria used for migraine are the same as outlined in ICHD-3 beta (15), with the exception of Criterion A (a lifetime history of ≥5 migraine attacks). The module has sensitivity of 100% and specificity of 82% for migraine (14). To minimize false positives, respondents also had to satisfy headache frequency criteria of 3 or more monthly headache days (MHDs) in the past 3 months and at least 1 MHD in the past 30 days. Respondents meeting migraine symptom criteria and headache frequency criteria (N = 15,133) were included in the current analysis.
The MAST Study protocol was reviewed by Ethical and Independent Review Services (Independence, Missouri), which granted an exemption under (45 CFR 46.101(b)) and certified the exemption status (#16106-01) on August 31, 2016.
Assessments
Respondent sex (male, female); age (years); marital status (yes or no); education (<4-year college degree or ≥ 4-year college degree); race (Caucasian or not Caucasian); employment status (full- or part-time employment); health insurance status (yes vs. no); and total household income (<$25,000, $25,000–$49,999, $50,000–$74,999, $75,000–$99,999, ≥$100,000) were obtained from single, self-report items. Current smoking status was determined by asking respondents if they had smoked at least 100 cigarettes (lifetime recall) and if they smoked at the time the survey was administered. Body mass index (BMI) was calculated using the standard formula (16) and respondents were categorized as underweight (<18.5), normal weight (18.5–24.9), overweight (25.0–29.9), or obese (≥30.0). Respondents were considered prevention medication users if they endorsed the use of “daily oral prescription medication, taken daily to prevent/reduce headaches.”
Monthly Headache Day (MHD) frequency was calculated from responses about the number of headache days over the past 3 months (affected by headache for all or part or the day) and then dividing this number by 3. The MHD variable was used to stratify respondents into the following groups: 1 to 4 MHDs, 5 to 9 MHDs, 10 to 14 MHDs, or 15 or more MHDs.
Probable depression and/or anxiety was based on 2-week recall and measured with the validated 4-item Patient Health Questionnaire (PHQ-4) (17), which has good sensitivity and specificity and screens for major depressive disorder and generalized anxiety disorder using the first 2 criteria for each from the DSM-IV criteria. Response options for PHQ-4 were not at all (none = 0), several days (mild = 1), more than half the days (moderate = 2), and nearly every day (severe = 3). A sum score that ranges from 0 to 12 is calculated by assigning scores of 0 to 3 to each of the response categories. This variable was analyzed as a dichotomous variable. Respondents with scores in the moderate or severe range (a score of ≥ 6) were considered to have probable depression and/or anxiety.
The Migraine Symptom Severity Scale (MSSS) is a composite index that incorporates information about 7 ICHD-3 headache criteria (unilateral pain, pulsatile pain, moderate or severe pain intensity, routine activities worsen pain, nausea, photophobia, and phonophobia). Respondents were asked to “describe the pain and other symptoms you have with your headaches,” and response options included never, less than half the time, half the time or more, or all or nearly all the time. The overall MSSS score ranges from 0 to 21 and was calculated by adding scores ranging from 0 to 3 for each of the 7 headache features assessed. MSSS was evaluated as a continuous score.
Headache pain intensity was assessed with the question from the Migraine Disability Assessment Scale (MIDAS) (18): “On a scale of 0 to 10 (where 0 = no pain at all and 10 = pain as bad as it can be), on average how painful are your headaches?” Mean pain intensity ratings were calculated from these data.
Medication overuse was defined according to ICHD-3 beta criteria (15) and was considered present if respondents reported using a triptan, opioid, barbiturate, combination analgesic, ergot alkaloid, or a combination of these on at least 10 days in the past month or used an NSAID or simple analgesic on 15 or more days in the past month.
Cutaneous ictal allodynia was identified using the Allodynia Symptom Checklist (ASC-12), a validated 12-item questionnaire (12). Response options were never, rarely, less than half the time, and half the time or more. Scores range from 0 to 24, and a sum score cut point of at least 3 was used to define the presence of cutaneous allodynia. Respondents with ASC-12 scores below 3 were classified as not having allodynia.
Statistical analysis
Percentages were used to describe dichotomous variables (sex, marital status, education, race, health insurance status, presence of probable depression and/or anxiety, employment, current smoking, medication overuse, and preventive medication use) and categorical variables (BMI, household income, and MHDs). Means (SD) were used to report continuous variables (age, pain intensity, BMI, and MSSS). Chi-square was used to test differences (
Eight binary logistic models were run with the presence (ASC-12 score of ≥ 3) or absence (ASC-12 score of 0, 1, or 2) of allodynia as the binary outcome. An initial model (not presented) included sociodemographics only (age, sex, BMI, marital status, education, income, race, health insurance status, household income, smoking status, employment status), and non-contributing variables were eliminated. The remaining variables were included in Model 1. In Model 2, MHDs were added to the remaining sociodemographics followed by a single model (Model 3) that included headache characteristics (pain intensity and MSSS), probable depression and/or anxiety, and medication overuse. (An exploratory version of Model 3 that included these variables along with oral preventive medication use was also run.) In addition, given the association between MHDs and allodynia, 4 separate Models (4 through 7) were run to better understand the individual contributions of pain intensity, MSSS, probable depression and/or anxiety, and medication overuse on presence of cutaneous allodynia. In order to identify potential differences between men and women on predictors of allodynia, a fully adjusted model was repeated separately in sex-stratified samples. Odds ratios (OR) and 95% confidence intervals (CI) are provided.
Results
Analysis sample
There were 117,150 returned surveys, 95,821 provided usable data, and 15,133 met migraine symptom and frequency inclusion criteria.
Sociodemographics
Sociodemographic and headache features of respondents with and without cutaneous allodynia as defined by ASC-12.
BMI: body mass index; ASC-12: Allodynia Symptom Checklist.
Mean (SD)
Independent samples t-test
Headache features
Respondent characteristics and headache features are shown in Figure 1. Those with allodynia were more likely to have probable depression and/or anxiety than those without allodynia (33.3% vs. 17.1%, Headache features among respondents with migraine. MSSS: Migraine Symptom Severity Scale.
Relative odds of cutaneous allodynia as determined by ASC-12 among respondents with migraine by sociodemographic features, headache characteristics, and psychiatric comorbidity.
ASC-12: Allodynia Symptom Checklist; MHD: monthly headache day; MSSS: Migraine Symptom Severity Scale.
Note: Table 2 provides regression model results estimating the relative odds of allodynia, first adding significant demographic characteristics, then MHD category and then the other 4 covariates together. Each covariate is then added alone to the model with demographics and MHD frequency category.
Women (Ref = men); monthly headache days (Ref = 1–4 MHD); Caucasian (Ref = non-Caucasian); current smoker (Ref = non-smoker); unemployed (Ref = employed).
An exploratory version of Model 3 added oral preventive medication use. The results were as follows: age OR .99 (CI 0.98, 0.99); women OR 1.76 (CI 1.61, 1.92); household income OR 1.00 (CI 0.97, 1.03); Caucasian OR 1.16 (CI 1.05, 1.27); current smoker OR 1.33 (CI 1.18, 1.49); unemployed OR 1.15 (CI 1.06, 1.26); 5–9 MHD OR 1.21 (CI 1.10, 1.33); 10–14 MHD OR 1.18 (CI 1.02, 1.35); ≥ 15 MHD OR 1.35 (CI 1.18, 1.55); preventive medication use OR 1.32 (CI 1.18, 1.48); medication overuse OR 1.12 (CI 1.01, 1.24); MSSS OR 1.17 (CI 1.15, 1.18); pain intensity OR 1.10 (CI 1.07, 1.13); and probable anxiety and/or depression OR 1.83 (CI 1.68, 2.00).
Models 4 to 7 assess the role of each covariate (medication overuse, MSSS, pain intensity and depression and/or anxiety) alone in attenuating the impact of MHD frequency category on the odds of allodynia.
Model 2 added MHD categories to the significant sociodemographic variables. As MHD category increased, the likelihood of allodynia increased compared with respondents in the 1 to 4 MHD reference group: 5 to 9 MHDs (OR 1.49, CI 1.36, 1.62); 10 to 14 MHDs (OR 1.64, CI 1.44, 1.86); and 15 or more MHDs (OR 2.09, CI 1.86, 2.35). With the addition of MHDs to the model, race and household income were no longer statistically significant (Table 2).
Model 3 simultaneously added other headache and respondent characteristics to MHD and sociodemographics (Table 2). Each 1-point increase in MSSS was associated with a 17% increase in likelihood of having allodynia (OR 1.17, CI 1.15, 1.19). Similarly, each 1-point increase in pain intensity was associated with an 11% increase in the likelihood of having allodynia (OR 1.11, CI 1.08, 1.14). Respondents with probable depression and/or anxiety were 83% more likely to have allodynia (OR 1.83, CI 1.67, 2.00), and respondents overusing acute medication were 23% more likely to have allodynia (OR 1.23, CI 1.09, 1.38). In this fully adjusted model, the effect for women was slightly attenuated compared with the sociodemographics-only model, with women being 70% more likely to have allodynia than men (OR 1.70, CI 1.56, 1.86). Smokers were 37% more likely to have allodynia (OR 1.37, CI 1.22, 1.55), and respondents not currently employed full or part time were 19% more likely to experience allodynia (OR 1.19, CI 1.08, 1.30). Higher MHD frequency was also associated with an increased likelihood of allodynia. With each increasing MHD category versus the 1 to 4 MHD reference group, the OR for 5 to 9 MHDs was 1.23 (CI 1.12, 1.36); for 10 to 14 MHDs the OR was 1.22 (CI 1.05, 1.41) and for 15 or more MHDs the OR was 1.36 (CI 1.18, 1.57).
At this stage of the analysis (exploratory Model 3), we also added daily oral preventive medication use to the model and found that respondents with allodynia were 32% more likely to be using preventive therapy (OR 1.32, CI 1.18, 1.48). When headache frequency categories and preventive medication use were analyzed together, the ORs for the sociodemographic characteristics did not change. This was also true for MSSS, pain intensity and probable depression and/or anxiety covariates, while the OR for medication overuse decreased slightly (OR 1.23 vs 1.12). The ORs for MHD frequency categories were attenuated slightly and remained significant (see Table 2). Given the association and potential confounding by indication for headache frequency and preventive medication use, and to avoid over-adjustment, we elected not to include preventive medication use in the assessment of individual headache characteristics.
To better understand the role of individual headache characteristics, we ran 4 additional models, entering medication overuse, MSSS, pain intensity, and probable depression and/or anxiety alone, while retaining the sociodemographic and MHD categories. Models 4 through 7 showed that the greatest attenuation of the 15 or more MHD category occurred with the inclusion of medication overuse (without medication overuse OR 2.09, with OR 1.61). The greatest attenuation of the 5 to 9 MHD and 10 to 14 MHD categories was observed when MSSS was included alone (5 to 9, without MSSS OR 1.49, with MSSS OR 1.31; 10 to 14) without medication overuse OR 1.64, with MSSS OR 1.37. The greatest attenuation of the 15 or more MHD category was observed when medication overuse was included in the model alone (without medication overuse OR 2.09, with medication overuse 1.61). Compared with the fully adjusted model (Model 3), when assessed separately, the ORs were higher for medication overuse, MSSS, pain intensity, and probable depression and/or anxiety, suggesting shared variance in predicting allodynia for these variables (Table 2).
Relative odds of cutaneous allodynia defined by ASC-12 in men and women.
ASC-12: Allodynia Symptom Checklist; MHD: monthly headache day; MSSS: Migraine Symptom Severity Scale.
Discussion
The current MAST Study analysis was conducted to identify the respondent and headache characteristics associated with increasing or decreasing odds of cutaneous allodynia in persons with migraine. Respondents with cutaneous allodynia comprised 40% of this sample of people with migraine. In bivariate comparisons, respondents with allodynia were younger and more likely to be female than those free of allodynia. Respondents with allodynia were more likely to smoke, overuse acute medications, use oral preventive medication, have probable depression and/or anxiety, have lower household incomes and less likely to have a 4-year college degree. The risk of allodynia was also higher as headache frequency and migraine symptom severity increased.
In logistic regression models, the risk of having allodynia was significantly increased among women, smokers, and the unemployed. Adding MHD frequency categories demonstrated a dose-response effect where increases in MHD category had a greater association with the presence of allodynia. This relationship was attenuated when oral preventive medication use and additional headache and respondent characteristics were added (medication overuse, MSSS, headache pain intensity, probable depression and/or anxiety), indicating these variables are also associated with headache frequency.
Additional models with each of these variables entered separately showed the greatest attenuation between allodynia and the highest MHD frequency category (≥15) when medication overuse was entered in the model alone and attenuation for the 5–9 and 10–14 MHD categories when MSSS was entered alone. The finding that medication overuse attenuated the odds of presenting with allodynia compared with MHD category alone, in particular for the high frequency headache category (≥15 MHDs) is not surprising, as persons with more frequent attacks are also more likely to meet criteria for medication overuse. Adding headache features (MSSS, pain intensity) to the analysis attenuated the predictive effects of headache frequency on allodynia. The same was true when probable depression and/or anxiety was added to the model.
It is interesting to note that smoking was significantly more common in respondents with allodynia than those with no allodynia. This significant relationship was retained in the fully adjusted model (OR 1.37), suggesting that smoking has an independent effect. However, the relationship between smoking and allodynia becomes stronger with the independent addition of medication overuse (OR 1.61), MSSS (OR 1.52), pain intensity rating (OR 1.46), and the depression/anxiety composite measure (OR 1.47), suggesting effect measure modification of these variables with smoking, which is hard to tease apart. It is possible that nicotine has an effect on gene expression and receptor plasticity that increases the risk of allodynia in this patient population (20).
Our results have similarities and important differences relative to prior studies. Although allodynia was common among MAST Study respondents (40%), the rate was lower than in some previous studies. Allodynia rates of up to 80% have been reported among people with migraine (4,9,10,12,21–23). The reason(s) for these differences among similar studies using ASC-12 is not clear.
Other studies have examined risk factors for allodynia. In another large population-based sample from the AMPP Study, allodynia was present in 62% of subjects. Similar to our findings, allodynia was significantly associated with migraine symptom frequency, pain severity, and headache frequency (12). In a subsequent analysis from the AMPP Study population, allodynia was also found to be associated with female sex and depression, as well as increased BMI and migraine-related disability (11). In a longitudinal population-based sample (LUMINA), allodynia was present in 70% of the participants (9). While this is substantially higher than the rate in our study, allodynia in the LUMINA study was determined to be present with a positive response to 2 items on the ASC-12 rather than the sum score of 3 or more used here. As in our study, depression, female sex, and high MHDs were independent risk factors for the presence of allodynia, as was younger age at onset and longer disease duration. The use of migraine prophylaxis was also significantly associated with the presence of allodynia, most likely due to confounding by indication.
The results from the MAST Study further highlight the need to query migraine patients about symptoms of allodynia. In prior research, the presence of allodynia has been shown to increase the likelihood of an inadequate response to acute treatment (7–9), particularly if treatment is delayed (2,5), and to be associated with the risk of progression from episodic to chronic migraine (9). The current analysis suggests that persons with migraine who are younger, less educated, currently smoking, and with probable depression and/or anxiety are also at elevated risk for allodynia.
The causal direction of the association between allodynia and other factors cannot be determined from this study. Among patients in whom allodynia is known to be present, the results indicate that they are more likely to have more severe migraine symptoms, and more days with migraine or headache. These results also confirm previous research (7) indicating that people with migraine who experience allodynia are more likely to be overusing acute medications, which in turn increases the risk of disease progression to chronic migraine. These factors underscore the need for a personalized treatment plan in patients with allodynia. The relationship between depression, anxiety, and allodynia is of interest. While it assumes that chronic pain leads to depression and anxiety, these mood disorders have been shown to significantly increase the risk of new onset chronic migraine and chronic pain, both of which are associated with central sensitization and are part of a group of disorders that have become known as central sensitivity syndrome (24–26). The underlying biology of this relationship remains to be elucidated, but a shared underlying genetic basis or a loss of descending pain inhibition are potential mechanisms (27,28). The relationship of allodynia to medication overuse is also of particular interest. As this is a cross-sectional study, allodynia may be a risk factor for medication overuse, medication overuse may be a risk factor for allodynia, or each problem may augment the other. In this process, allodynia may result in less effective treatment and more medication taking, and medication taking may result in central sensitization and more allodynia (29,30).
In sex-stratified models, the effect of medication overuse was highly significant in men but not in women, suggesting that medication overuse has a sex-specific effect on the presence of allodynia or that allodynia is a sex-specific driver of medication taking (31). In addition, the effect of MHD category is significant in men but not in women in the fully adjusted sex-stratified models. Reasons for these sex differences are uncertain. Perhaps there may be sex differences in the relationship of MHDs to medication taking. For example, if men are more prone to overuse medications at higher headache frequencies than women, the effect of medication overuse may be stronger than the effect of MHDs in men but not in women. There may be sex differences in the types of medication that are overused. Finally, sex hormones may influence the development of allodynia. Women are more likely to have allodynia than men in this and in other studies. One explanation for this may be the recent finding that prolactin, which potentiates the release of calcitonin gene related peptide in female animals but not males, also sensitizes dural nociceptors in female but not male animals (32). The fact that prolactin receptors are expressed in dural sensory nerve fibers exclusively in female animals may in part explain the sex-specific differences in migraine prevalence in general, as well as the propensity for women to be more at risk of sensitization and allodynia. Therefore, if the threshold for developing allodynia is lower in women than in men, men may require a stronger stimulus to develop allodynia, such as medication overuse.
Strengths of this study include the use of a large, generally representative sample of US adults, and the identification of persons with migraine based on ICHD-3 beta criteria using a validated screening instrument. The study also employed validated assessments of relevant respondent characteristics and criteria-based determination of medication overuse. Limitations of this study include retrospective self-report with no corroborating data from outside sources, such as physicians, claims data, or electronic health records. Regression modeling is useful to establish an association between cutaneous allodynia and relevant respondent characteristics, but cross-sectional data are not sufficient to establish a causal relationship.
Conclusion
Cutaneous allodynia during headache was present in 40% of MAST Study respondents and was associated with increasing MHD frequency, probable depression and/or anxiety, headache pain intensity, symptom severity, and medication overuse. In a fully adjusted model, allodynia was 83% more likely in respondents with probable depression and/or anxiety and 23% more likely in respondents overusing acute medication. Increases in symptom severity and average pain intensity were associated with corresponding increases in allodynia as well. Respondents in the high MHD group were 36% more likely than the low frequency group to have allodynia. In sex-stratified models, medication overuse was significantly associated with allodynia in men, and employment and MHD frequency was associated with allodynia in women. Additional investigations are required to determine causality and potential physiologic links between these factors and cutaneous allodynia, as well as the impact of allodynia severity on migraine related features and burden.
Clinical implications
A higher number of MHDs is associated with allodynia, but the effect is attenuated or mediated by headache features (pain intensity, symptom severity) and patient characteristics (psychological symptoms, medication overuse). Allodynia is associated with income, race, and medication overuse in men with migraine and with employment and attack frequency in women with migraine.
Footnotes
Acknowledgement
Medical writing services were provided by Christopher Caiazza.
Declaration of conflicting interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Five-year disclosure: DWD reports the following conflicts from within the past 48 months: Personal fees: Amgen, Autonomic Technologies, Axsome, Allergan, Alder, Biohaven, Charleston Laboratories, Dr. Reddy's Laboratories/Promius, Electrocore LLC, Eli Lilly, eNeura, Neurolief, Novartis, Ipsen, Impel, Satsuma, Supernus, Sun Pharma (India), Theranica, Teva, Vedanta, WL Gore, Zosano, ZP Opco, Foresite Capital, Oppenheimer. CME fees or Royalty payments Healthlogix, Medicom, Medlogix, Mednet, Miller Medical, PeerView, WebMD/Medscape, Chameleon, Academy for Continued Healthcare Learning, Universal Meeting Management, Haymarket, Global Scientific Communications, UpToDate, Oxford University Press, Cambridge University Press, Wolters Kluwer Equity (stock options): Aural Analytics, Healint, Theranica, Second Opinon/Mobile Health, Epien, GBS/Nocira, Matterhorn/Ontologics, King-Devick Technologies. Board of Directors: Aural Analytics, Epien, Matterhorn/Ontologics, King-Devick Technologies. Patent :17189376.1-1466:vTitle: Botulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis. Professional society fees or reimbursement for travel: American Academy of Neurology, American Brain Foundation, American Headache Society, American Migraine Foundation, International Headache Society, Canadian Headache Society. Other: Use agreement through employer: Myndshft.
MLR is an employee of Vedanta Research, which has received support funded by Allergan, Amgen, Colucid, Dr. Reddy’s Laboratories, Eli Lilly, NuPathe, Novartis, and Ortho-McNeil, via grants to the National Headache Foundation.
KMF is an employee of Vedanta Research, which has received support funded by Allergan, Amgen, Colucid, Dr. Reddy’s Laboratories, Eli Lilly, NuPathe, Novartis, and Ortho-McNeil, via grants to the National Headache Foundation.
SM is an employee of Dr. Reddy’s Laboratories and owns stock in the company.
AA is an employee of Dr. Reddy’s Laboratories and owns stock in the company.
DCB has received grant support and honoraria from Allergan, Avanir, Amgen/Novartis, Biohaven, Eli Lilly, Promius, and Teva. She serves on the editorial boards of
TJS has received grant support from the National Institutes of Health, the United States Department of Defense, the Patient Centered Outcomes Research Institute, the American Migraine Foundation, the Mayo Clinic, and Arizona State University. He is a consultant for Alder, Allergan, Amgen, ATI, Avanir, Eli Lilly, Ispen Bioscience, Nocira, Novartis, Promius Pharma, and Teva. He holds stock options in Aural Analytics, Nocira, and Second Opinion. He receives royalties from UpToDate. He serves on the editorial boards for
RBL has received grant support from the National Institutes of Health, the National Headache Foundation, and the Migraine Research Fund. He serves as consultant, serves as an advisory board member, or has received honoraria from Alder, Allergan, American Headache Society, Autonomic Technologies, Biohaven, Eli Lilly, eNeura Therapeutics, Merck, Novartis, Pfizer, and Teva, Inc. He receives royalties from
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded and sponsored by the Dr. Reddy’s Laboratories group of companies, Princeton, NJ 08540, USA. SM and AA are employed by and own stock in Dr. Reddy’s Laboratories; DWD, MLR, KMF, DCB, TJS, and RBL were paid consultants of Dr. Reddy’s Laboratories. DRL Publication #832.
Ethics or Institutional Review Board approval
The MAST Study protocol was reviewed by Ethical and Independent Review Services (Independence, Missouri), which granted an exemption under (45 CFR 46.101(b)) and certified the exemption status (#16106-01) on 31 August 2016.