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Medication Overuse and Headache Burden

Objective To estimate the relative frequency of acute medication overuse (AMO) among people with episodic migraine and chronic migraine, to characterize the types of acute medications overused for migraine, and to identify factors associated with AMO. Methods We analyzed data from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study (ClinicalTrials.gov, NCT01648530), a cross-sectional and longitudinal internet study that included a systematic sampling of the US population. From September 2012 to November 2013, the CaMEO Study respondents participated in different modules to collect data on the clinical course of migraine, family burden, barriers to care, endophenotypes, and comorbidities. Among people who met the criteria for migraine consistent with the International Classification of Headache Disorders, third edition (ICHD-3), we evaluated types and frequency of medications used for headache/migraine, selected comorbidities, and emergency department (ED) and urgent care (UC) use. AMO was defined by days per month of medication use as specified by ICHD-3 criteria for medication overuse headache (MOH) without the requirement for ≥15 monthly headache days (MHDs). Nested, multivariable binary logistic regression modeling was used to identify factors associated with an increased risk of AMO. Results Of 16,789 CaMEO respondents with migraine, 2,975 (17.7%) met the AMO criteria. Approximately 67.9% (2,021/2,975) of AMO respondents reported <15 MHDs. Simple analgesics, combination analgesics, and opioids were the medication classes most commonly overused. Factors associated with AMO in the final multivariable logistic regression model included ≥15 MHDs, moderate to severe disability, severe migraine interictal burden, use of preventive medication, and an ED/UC visit for headache within 6 months. Conclusions Approximately two-thirds of respondents with AMO reported <15 MHDs and therefore did not meet the criteria for MOH. Those with AMO had greater disease burden and increased ED/UC utilization relative to people with migraine but not AMO.

Migraine is a prevalent chronic neurologic disease characterized by painful, debilitating attacks. [1][2][3] The goal of acute treatment is to relieve symptoms and restore function. 4 Current acute treatments are often inadequately effective, contributing to the need for more frequent dosing and overuse, thereby substantially increasing migraine burden as well as the risk of disease progression. [5][6][7][8][9][10] Medication overuse headache (MOH) is defined by the International Classification of Headache Disorders, third edition (ICHD-3) as headache occurring ≥15 days per month in individuals with a preexisting headache disorder and regular overuse of acute medications for more than 3 months. 11 MOH implies that overuse of medication is causally related to headaches, representing a secondary headache disorder. By contrast, acute medication overuse (AMO) refers to taking specific medications ≥10 days per month for most medications or ≥15 days per month for simple analgesics. Consequently, some people with AMO may not meet the headache-day criteria for MOH. In addition, some people may use medications on headache-free days in anticipation of migraine or for other pain disorders. 12 Thus, the number of days taking migraine acute medications can exceed the number of migraine or headache days. 13 The goal of this analysis of the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study data was to estimate the relative frequency of AMO and to characterize the types of acute medications overused. We also sought to identify sociodemographic features, headache characteristics, emergency health care resource utilization, and migraine-related burden in people with and without AMO.

Study Design
CaMEO was a cross-sectional and longitudinal web-based survey that included a systematic sampling of the US population as previously described. 14 From September 2012 to November 2013, the CaMEO Study respondents participated in different modules to collect data on the clinical course of migraine, family burden, barriers to care, endophenotypes, and comorbidities.
The present cross-sectional analysis used data from the baseline screening module, core module, and endophenotype module. The baseline screening module covered sociodemographic information (age, body mass index [BMI], sex, employment, income, race/ethnicity, education, and marital status) and health information related to medical conditions, including headaches, pain disorders, and other conditions. The core module addressed headache frequency over the last 3 months (number of days). The frequency of medication use over the last 30 days (number of days and how many times per day the medication was used) was addressed by the question "Which of these medications (if any) are you currently using (or typically keep on hand) to treat your headaches?". The core module also addressed the type of medication used to treat headache, emergency health care resource use in the past 6 months (number of times each resource was used), number of nights spent in the hospital in the past 6 months related to headaches, and Generalized Anxiety Disorder 7-Item Scale (GAD-7), 9-Item Patient Health Questionnaire (PHQ-9), Migraine Interictal Burden Scale (MIBS-4), and Migraine Disability Assessment (MIDAS) questionnaire results. The endophenotype module assessed migraine features, including the presence of allodynia (using the 12-Item Allodynia Symptom Checklist [ASC-12] and 5-point frequency allodynia screener) and other comorbidities (appendix e-1, links.lww.com/CPJ/A259).

Study Respondents and Outcomes
Study respondents who met the modified ICHD-3 migraine criteria, assessed using the validated American Migraine Study (AMS)/American Prevalence and Prevention (AMPP) migraine diagnostic module, were entered into the study (note: the AMS/ AMPP diagnostic module was based on ICHD-2 migraine criteria, 14,15 but no significant changes occurred among the ICHD-2, 15 ICHD-3-beta, 16 and the final ICHD-3 11 criteria related to classification of migraine). Responses to the core module were used to categorize respondents who met the AMO criteria for any single class of medications or for multiple classes. Respondents were categorized according to monthly headache frequency (calculated from a 3-month report period) of 0-4 days, 5-9 days, 10-14 days, or ≥15 MHDs. Headache characteristics were assessed in the AMO and non-AMO groups.
Emergency health care resource utilization as determined by frequency of emergency department (ED) and urgent care (UC) facility use for headache in the past 6 months was assessed in the AMO and non-AMO groups. The self-reported medical diagnosis of comorbidities reported in the endophenotype module was organized by system organ classes of the Medical Dictionary for Regulatory Activities, and comorbidities that occurred in more than 5% of the CaMEO respondents were reported by AMO status within MHD groups.

Defining AMO
To establish an operational definition for overuse by acute medication class, we chose medication use days per month criteria consistent with medication use rates in ICHD-3 criteria for MOH; AMO was identified from ICHD-3 criteria for single medication class and multiple medication class overuse. The single-class AMO group included respondents who met the AMO criteria for at least 1 class of medication: (1) use of naproxen sodium, aspirin, ibuprofen, acetaminophen, or prescription nonsteroidal anti-inflammatory drugs (NSAIDs) for ≥15 days per month or (2) use of any ergotamine, triptan, opioid, or combination analgesics (including Excedrin, barbiturates, and Midrin) for 10 or more days per  month. The multiple-class AMO group included respondents who did not meet any single-class AMO criteria but met the criteria when multiple medication classes were considered: (1) use of 2 or more classes of medication (ergotamines, triptans, simple analgesics, and opioids) but not any single medication, for 10 or more days, and (2) use of 2 or more simple analgesics (acetaminophen, aspirin, NSAID, or other) cumulatively, but not any single medication, for ≥15 days per month. Respondents could meet single-class AMO criteria for 1 or more classes of medication. Respondents meeting any criteria for AMO were categorized into the AMO subgroup, whereas those who failed to meet any criteria were categorized into the non-AMO group.

Standard Protocol Approvals, Registrations, and Patient Consents
The Albert Einstein College of Medicine Institutional Review Board approved the CaMEO Study and waived written informed consent for study volunteers, who had the right to accept or refuse participation in the survey. Data included in this analysis are from the CaMEO Study, which is registered on ClinicalTrials.gov (NCT01648530).

Statistics
Medication class use by AMO and non-AMO respondents, sociodemographics, headache frequency, depression, anxiety, migrainerelated disability, migraine interictal burden, ED/UC use, and selfreported medical diagnosis of comorbidities were compared in a cross-sectional analysis. Medication class use was analyzed by counts reported in each medication class for each group.
The χ 2 test was used for testing between-group differences in categorical variables. Continuous variables including MHDs and PHQ-9, GAD-7, MIDAS, MIBS-4, and MSSS total scores were represented with medians and interquartile ranges (IQRs: Q1 and Q3). Between-group differences for continuous variables were assessed using the Mood median test between independent groups.
A series of nested multivariable binary logistic regression models was run with AMO vs non-AMO as the outcome. Covariates were entered in sequential blocks: sociodemographics, headache and respondent characteristics, psychiatric comorbidity, 6-month ED/ UC use for headache or any reason, and preventive medication use. Separate models were run for any AMO, and AMO due to opioid use, triptan use, or NSAID use. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for each variable. After each block was entered, nonsignificant variables were trimmed from the model; significance level was p < 0.05. No correction for multiple testing was applied. All analyses were performed using IBM SPSS Statistics Version 24.0 (IBM, Armonk, NY; 2011).

Results
Baseline Characteristics and Patterns of Acute Medication Use Of 16,789 total CaMEO respondents with migraine, 14,936 (89.0%) reported using any acute medication to treat their

Headache-Related Burden and Comorbidities
Compared with respondents without AMO, respondents with AMO were more likely to have moderate to severe   1A). To evaluate the independent impact of both AMO status and headache frequency, the AMO and non-AMO groups were subdivided into those with <15 MHDs and those with ≥15 MHDs ( figure 1B). AMO was consistently associated with a substantial increase in depression, anxiety, headache-related disability, migraine interictal burden, and ED/UC use for headache across both MHD subgroups.
Respondents with ≥15 MHDs had higher rates of depression, anxiety, headache-related disability, migraine interictal burden, and ED/UC use for headache compared with those reporting <15 MHDs in both the AMO and non-AMO subgroups. The observed impact of ≥15 MHDs was greater in those without AMO than in those with AMO.
Within both MHD subgroups, the percentage of respondents with self-reported medical diagnosed comorbidities tended to be greater in those with AMO compared with those without AMO (table 3). Within the <15 MHDs subgroup, the relative frequency of musculoskeletal and connective tissue disorders including neck pain, chronic back pain, arthritis, and chronic pain showed some of the largest differences between AMO groups, being approximately 2-3 times more frequent in those with AMO. Within the ≥15 MHDs subgroup, the AMO-associated differences tended to be smaller than in the <15 MHDs subgroup.

Factors Associated With AMO Based on Multivariable Binary Logistic Regression Models
To identify possible predictors of AMO status, a series of nested multivariable binary logistic models was run with nonsignificant variables removed at each step; the fully adjusted models for AMO and select acute medications are shown in

Discussion
Approximately 17.7% of the CaMEO Study respondents with migraine met the criteria for AMO. Opioids and combination analgesics were the most likely medications to be overused by respondents reporting use of those medications. Overall, respondents with AMO had greater headache-related disability, anxiety, depression, and ED/UC use for headache than those without AMO. Respondents with both AMO and ≥15 MHDs showed the highest total burden, but there was also a substantial negative impact of AMO in those with <15 MHDs. The differences in the relative frequency of selfreported medical diagnosed comorbidities between AMO and non-AMO respondents were greatest in the <15 MHDs subgroups, with many pain-related comorbidities exhibiting the largest differences in the AMO subgroup compared with the non-AMO subgroup. This greater relative frequency of pain-related comorbidities may contribute to the high level of medication use in those with <15 MHDs. Higher rates of anxiety may also contribute to AMO in that group. Finally, results of the nested multivariable binary logistic models show positive relationships between AMO status and migraine-related disability, interictal burden, and ED/UC use for headache.
The findings of this study are consistent with other studies evaluating AMO in people with migraine. Results from the Migraine in America Symptoms and Treatment study showed that survey respondents with AMO were more likely to be obese, have allodynia, have depression and/or anxiety, and report ≥15 headache days per month. 17 European studies demonstrated that female sex, headache frequency, comorbid pain conditions, comorbid psychiatric conditions, and type of overused medication are associated with Abbreviations: AMO = acute medication overuse; GERD = gastroesophageal reflux disease; HCP = health care professional; IBS = irritable bowel syndrome; MHD = monthly headache day; PMS = premenstrual syndrome; TMD = temporomandibular joint dysfunction. All data are n (%). a Comparison between the AMO and non-AMO groups in respective headache frequency category with the χ 2 test. b Calculations are based on the total sample number, not female respondents only.
AMO. [18][19][20][21] Migraine is associated with multiple comorbidities, which could contribute to increased medication use. 22 The many pain comorbidities of migraine could contribute to increased use of analgesics. 23 A cross-sectional, schoolbased study found an overall prevalence of probable MOH of 0.9%, with similar prevalence in boys and girls. 24 An overall prevalence of probable MOH of 2.0% was reported in a Saudi Arabian study, with a greater occurrence in females and participants 46-55 years of age. 25 Additional studies in Asia found that headache disorders (including MOH) are associated with a substantial overall burden, with unmet treatment needs including high rates of over-the-counter medication use. 26,27 Taken together, the results of these studies show a pronounced disease-related burden in those who overuse acute medications for migraine.
AMO is associated with the risk of migraine disease progression from episodic migraine (EM) to chronic migraine (CM). 9,13,28,29 In the AMPP study, triptan overuse alone was associated with risk of disease progression from EM to CM depending on the baseline frequency of MHDs; however, triptan use in combination with NSAIDs was not associated with an increased risk of progression, and NSAID use may be protective of progressing from EM to CM depending on MHDs. 13,28,30 In addition, opioids and barbiturate analgesics are associated with dose-dependent increased risk of CM onset across a range of frequencies. 8,13,31 Although the relationship between medication use and disease progression is not straightforward across all acute medication classes, the suboptimal treatment of migraine attacks is a risk factor for progression. Abbreviations: AMO = acute medication overuse; AMOH = acute medication overuse headache; ASC = Allodynia Symptom Checklist; CI = confidence interval; ED = emergency department; GAD-7 = Generalized Anxiety Disorder 7-Item Scale; MHDs = monthly headache days; MIBS = Migraine Interictal Burden Scale; MIDAS = Migraine Disability Assessment; NSAID = nonsteroidal anti-inflammatory drug; PHQ-9 = 9-item Patient Health Questionnaire; UC = urgent care.
Only variables that were included in at least 1 final model are shown; race, income, and college degree were not included in any of the final models. "-" indicates variable trimmed from the model because of nonsignificance. a The reference group was 0-4 MHDs. b Specialist was defined as a neurologist, pain, or headache specialist. c Reference is no interictal burden (MIBS score of 0). d Variable is nonsignificant in final model.
The true burden related to AMO/MOH may be underestimated in practice, as diagnostic criteria for MOH require 15 MHDs. 11 The analyses reported herein demonstrate that 68% of participants with AMO had <15 MHDs, and these respondents demonstrated substantial burden. In addition, 49% of respondents who reported AMO also reported <10 MHDs, suggesting that these respondents are taking migraine medication on days when they do not have a headache, or taking multiple different acute medications to treat each headache, thus meeting the criteria for AMO with combination use of multiple classes. In addition, some people with migraine may take acute medication preemptively to try to avoid onset of a migraine attack and/or to manage associated anxiety. This practice would be counted as a medication day, but not as a headache day, leading to respondents exhibiting AMO but failing to meet ICHDdefined criteria for MOH. 11 Health care professionals should review the frequency of acute medication use in all patients with migraine, regardless of the monthly headache frequency and especially in those with comorbid pain conditions.
Because AMO is common and associated with high disease burden in people with migraine, it is an important target for prevention and treatment. Approaches for avoiding and treating AMO and MOH include using effective acute treatments, using patient and clinician education about limiting intake of acute medications, and initiating and optimizing pharmacologic and nonpharmacologic preventive treatments. 32 Nonpharmacologic approaches include cognitive behavioral therapy that is specifically focused on AMO treatment and reducing the factors that lead to overuse of the acute medication. 20,33 Improved efficacy and outcomes for elimination of AMO are achieved when behavioral therapies are included as part of treatment. 34 Although most acute treatments can cause AMO, emerging evidence suggests that gepants, a novel class of small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists, may not. In a preclinical model of MOH, repeated administration of pharmacologically active doses of ubrogepant (a CGRP receptor antagonist) did not produce MOH-like latent sensitization in female rats. 35 In long-term safety studies, frequent use of gepants over the course of a year was associated with a reduction and not an increase in monthly migraine days. 36 Unlike most oral acute treatments for migraine for which an MOH warning is required, the prescribing information for the US Food and Drug Administration-approved gepants (ubrogepant and rimegepant) does not include a warning for MOH as is required for most oral acute treatments for migraine. [37][38][39] Although it is promising that the CGRP receptor antagonists might not be associated with AMO, more research is needed to fully understand the relationship between their use and MOH, especially in individuals with a high frequency of migraine days. 40 Strengths of this study include the large sample size (16,789 CaMEO respondents with migraine) and the ability to collect detailed medication use information across a spectrum of individuals with varying migraine frequency. However, as this was a cross-sectional study, the data can only report the frequency of medication use and headache frequency separately; causality cannot be determined. The data collected are self-reported by survey respondents who met the AMO criteria. Participation bias could influence the results. Finally, due to the design of the questionnaire, we could not assess the reason for each reported medication use by respondents and could not differentiate between acute medication use to treat a headache/migraine or preemptive use in anticipation of a headache.
Respondents with AMO had more headache-related disability, anxiety, depression, and ED/UC use for headache than those without AMO in both MHD frequency groups (i.e., <15 MHDs and ≥15 MHDs). These same factors were identified as showing a significant relationship with AMO via multivariable binary logistic regression analysis. Use of comprehensive migraine treatment plans that include improved acute treatment options as well as considering guideline-based preventive treatments, including both pharmacologic and nonpharmacologic modalities, combined with appropriate education may help to reduce the relative frequency of AMO and the associated burden from possible MOH.