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February 22, 2011; 76 (8) Articles

Rates, predictors, and consequences of remission from chronic migraine to episodic migraine

A. Manack, D.C. Buse, D. Serrano, C.C. Turkel, R.B. Lipton
First published January 26, 2011, DOI: https://doi.org/10.1212/WNL.0b013e31820d8af2
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Abstract

Objectives: This study has 3 objectives: 1) to estimate remission rates in a population-based sample of subjects with chronic migraine (CM); 2) to identify potential predictors of CM remission; and 3) to assess the influence of CM remission on headache-related disability.

Methods: The American Migraine Prevalence and Prevention study is a prospective, population-based, mailed questionnaire survey, which included questions regarding headache frequency, symptomatology, demographics, comorbidities, health care utilization, and headache-related disability. Three years of longitudinal data were analyzed to determine rates of CM remission and assess predictors of remission using logistical regression models. The consequence of remission was measured by changes in disability, as measured by the Migraine Disability Assessment, over time.

Results: A total of 383 respondents had CM in 2005 and follow-up data in 2006 and 2007. Over 2 years, among those with CM at baseline, approximately 34% (n = 130) had persistent CM while 26% (n = 100) had remitted CM. In our final multivariate model, predictors of remission included baseline headache frequency (15–19 vs 25–31 headache days/month; odds ratio [OR] 0.29; 95% confidence interval [CI] 0.11 to 0.75) and absence of allodynia (OR 0.45; 95% CI 0.23 to 0.89). Preventive medication use was associated with lower remission rate (OR 0.41; 95% CI 0.23 to 0.75), but this effect lost significance when headache frequency was included. Over 2 years, those with persistent CM demonstrated increased disability while those with remitted CM demonstrated decreased disability.

Conclusions: These findings have clinical practice implications, as it is important to consider that remission rates are variable. However, the benefit of remission goes beyond symptom reduction and may translate to marked decreases in headache-related disability.

Migraine is a common and disabling neurologic condition with a spectrum of severity and a broad-ranging attack frequency. Chronic migraine (CM) represents the most severe end of the spectrum, with headaches on ≥15 days/month.1,2 Studies have shown that each year approximately 2.5% of those with episodic migraine (EM) develop CM.3

One important goal in treatment is reducing attack frequency4 so that CM remits to EM. Because EM includes persons with a broad headache frequency range, from <1 to 14 days/month, this group has been subdivided into low-frequency EM (LFEM): 0–9 headache days/month; and high-frequency EM (HFEM): 10–14 headache days/month. These changes have been conceptualized as transitions among 3 states—LFEM, HFEM, and CM—and occur in the direction of increasing and decreasing frequency dividing into progression or remission, respectively.5 Because headache frequency can vary, there are no concrete definitions for CM remission or persistence. However, migraine is considered in remission when symptoms cease over a prolonged period, while persistence is defined by relative clinical stability with no markers of progression.5

Though predictors of migraine progression have been studied, data are limited on the rates and predictors of CM remission and persistence.5 Additionally, preventive treatment is intended to facilitate the transition from CM to EM, but the real-world benefits of this remission have yet to be quantified. Herein, longitudinal data were utilized to 1) estimate CM remission rates; 2) assess potential predictors of remission from CM to EM; and 3) assess the impact of CM remission on headache-related disability.

METHODS

Study design.

The American Migraine Prevalence and Prevention (AMPP) study is a longitudinal, population-based study whose 2-phase methodology has been detailed elsewhere.6 Briefly, in phase 1, a self-administered screening questionnaire was mailed to a stratified random sample of 120,000 households, selected to be representative of the US population. Households were drawn from a 600,000-household nationwide panel maintained by National Family Opinion Inc., a survey-sampling firm.

Of the 162,562 respondents to the screener, 30,721 reported at least one severe headache in the past year. A random sample of 24,000 adults (≥18 years of age) with severe headache was selected to participate in phase 2, a 5-year longitudinal study with annual follow-up. Each year, respondents are asked to complete a self-administered questionnaire assessing variables including, but not limited to, sociodemographics, headache characteristics, and health care utilization. Reasons for nonparticipation were not assessed during screening or at annual follow-up.

Study population.

Eligible participants were 2005 AMPP respondents who had CM in 2005 and 2 years of consecutive follow-up data (2006 and 2007 surveys). To be classified as CM within this study, individuals had to report an average of ≥15 headache days/month over the previous 3 months and meet International Classification of Headache Disorders (ICHD)–21 criteria for migraine. These criteria are a variation of the ICHD-2R definition of CM, which requires 15 or more headache days/month and at least 8 days/month with migraine either by meeting criteria for migraine with aura or by demonstrating a treatment response to migraine-specific medications.2

Assessments.

Headache-related medication use was assessed in the annual questionnaire. Respondents were provided a comprehensive list, including generic and brand names, of acute and preventive medications used to treat headaches and identified medications they currently used for their head pain. For each acute medication, individuals reported number of days of use per month. Preventive medication was assessed as a dichotomous variable (currently using/not currently using). Over-the-counter (OTC) and prescription medication overuse were included as independent variables. OTC overuse was defined as ≥10 days of use in the past month for at least one of the following groups: nonsteroidal anti-inflammatory drugs (NSAIDs), OTCs, and combined OTCs like Excedrin® (acetaminophen, aspirin, and caffeine). Prescription overuse was defined as ≥10 days of use in the past month for at least one of the following acute medications: triptans, ergotamines, Midrin, barbiturates, or opioids.

Headache-related disability was assessed with the Migraine Disability Assessment (MIDAS) questionnaire. Scores were classified into 5 severity grades: little or none (0–5), mild (6–10), moderate (11–20), severe (21–40), and most severe (41+).7,8 Depression was measured using the Patient Health Questionnaire–depression module,9 a validated self-report measure of major depressive disorder based on DSM-IV criteria.10 Respondents scoring ≥15 were categorized as having depression. The 12-item Allodynia Symptom Checklist (ASC)11 was used to assess the frequency of cutaneous allodynia symptoms. ASC score ≥3 indicated presence of allodynia, while allodynia severity was treated as an ordered variable and categorized as none (0–2), mild (3–5), moderate (6–8), or severe (≥9).11

Headache frequency groups.

To assess potential predictors of remission, 3 CM subgroups were defined by headache status at follow-up5:

  • Persistent CM: met CM criteria in every year (2005–2007).

  • Remitted CM: met CM criteria in 2005 and either LFEM, no headache, probable episodic migraine, episodic tension-type headache, or other episodic headache in 2006–2007.

  • Transitioning CM: met CM criteria in 2005 and either CM, HFEM, LFEM, chronic or episodic tension-type headache, no headache, probable migraine, or other episodic headache in subsequent years and did not meet criteria for remitted or persistent CM.5

Data analyses.

All statistical analyses were conducted using SAS system v9.1.3. Descriptive statistics such as means, standard deviations (SD), and percents were computed using the MEANS and FREQ procedures. A p value ≤0.05 was considered significant. The study was approved by the Albert Einstein College of Medicine Institutional Review Board.

Analysis was based on 4 stages, each addressing a study objective. The overall rates of persistent CM and remitted CM were calculated; then those with persistent CM and remitted CM were contrasted on sociodemographics, headache characteristics, and health care utilization using χ2 tests of equivalent marginal proportions.

The 2005 data were then evaluated to identify potential predictors of remission. These analyses used logistic regression to estimate the relative odds of having remitted CM from a series of multivariate models. Multivariate logistic regression models first adjusted for sociodemographics, then added candidate predictors one at a time. Additionally, multivariate models assessed effects of covariates of interest. A series of 4 models were examined. Model 1 included sociodemographic variables. Model 2 added effects of headache characteristics and depression to model 1. Model 3 removed depression and added effects of medication to model 2. Model 4 removed age at onset and several nonsignificant variables. Effects retained in subsequent models were identified via a forward-selection process by which effects in a preceding model were retained in subsequent models so long as p values were approximately ≤0.1.

To assess disability impact, those with persistent CM and remitted CM were contrasted in the years subsequent to remission on MIDAS scores. The 2005 assessment served as the baseline and the 2007 assessment as the follow-up. As a continuous variable, MIDAS was modeled using the general linear model with Gaussian errors. The repeated measures design was analyzed via linear mixed models (SAS Proc Mixed) to examine the nature of the relationship between remitted CM and persistent CM. Examined effects were difference between overall mean score, trend for scores over time, and interaction between these effects indicating the extent to which the trend differed.

RESULTS

Of 24,000 respondents with headache surveyed in 2005, 18,514 returned complete questionnaires (77.1% response rate). In the 2006 follow-up, 20,639 questionnaires were fielded, of which 14,540 were returned (70.4% response rate). A total of 20,489 questionnaires were fielded for the 2007 follow-up, and 14,069 of these were returned (68.7% response rate). Respondents included 383 individuals with CM in 2005 who contributed data in 2006 and 2007.

Remission rates.

Of individuals with CM in 2005, 52.7% (n = 238) had CM in at least 1 year of follow-up and 64.6% (n = 292) had either CM or HFEM in at least 1 year of follow-up. Approximately 33.9% (n = 130) had CM in all 3 years (i.e., persistent CM), while 26.1% (n = 100) had CM in 2005 but had other headache conditions (i.e., LFEM, no headache, probable migraine, episodic tension-type headache, or other episodic headache) in both 2006 and 2007 (i.e., remitted CM) (figure 1).

Figure 1
Figure 1 Two-year transition rates relative to chronic migraine (CM) status in 2005 (baseline)

Persistent CM: met CM criteria in every year from 2005 to 2007. Remitted CM: met CM criteria in 2005 and low-frequency episodic migraine (LFEM: 0–9 headache days/month), no headache, probable migraine, episodic tension-type headache, or other episodic headache in 2006–2007. Transitioning CM is defined as CM at baseline and CM, high-frequency episodic migraine, LFEM, chronic or episodic tension-type headache, no headache, probable migraine, or other episodic headache in subsequent years and not meeting criteria for remitted or persistent CM.

Comparisons between remitted CM and persistent CM.

The sociodemographic profiles were similar between remitted CM and persistent CM (table 1). With regard to headache characteristics, there were no significant group differences in age at onset, MIDAS grades, or depression status between the 2 populations. However, there were differences in allodynia when measured by grade (p = 0.02) or as a dichotomous variable (presence or absence) (p = 0.01). Persistent CM had the largest percent with severe allodynia (37.4%) whereas remitted CM had the largest with no allodynia (35.6%). Additionally, distribution of headache frequency was different between persistent CM and remitted CM (p < 0.001), with the persistent CM group having a larger proportion with 25–31 days/month. Health care utilization, including acute medication use and OTC/prescription overuse, did not significantly differ between persistent CM and remitted CM (table 1).

View this table:
Table 1

Baseline demographic characteristics and headache features among respondents with CM in 2005 by outcome status in 2006 and 2007: Results from the AMPP study

Predictors of remission.

Table 2 summarizes candidate predictor models adjusted for age, gender, race, population density, geographic region, and household income. Those with CM with allodynia were less likely to remit (odds ratio [OR] [95% confidence interval (CI)] = 0.41 [0.20 to 0.83]; p = 0.014). Those in the highest frequency group (25–31 days/month) were much less likely to remit (OR [95% CI] = 0.20 [0.08 to 0.52]; p < 0.001) than those in the low-frequency CM group (15–19 days/month). Additionally, preventive medication use significantly predicted remission, so those with CM utilizing a preventive medication were half as likely to remit (OR [95% CI] = 0.41 [0.23 to 0.75]; p = 0.003) (table 2). Depression, headache-related disability, body mass index, age at onset, medication utilization by class, and OTC/prescription overuse did not significantly predict remission of CM.

View this table:
Table 2

Exploratory remission analysis of potential predictors for CM remission

Significant predictors and key candidates were examined in a series of multivariate models. Results are presented in table 3. In model 1, effects of sociodemographic covariates were not significant. In model 2, headache frequency and allodynia were significant predictors of remission after controlling for effects of demographics, age at onset, and depression. Those with CM who reported 25–31 days/month at baseline were much less likely to remit than those with 15–19 days/month (OR [95% CI] = 0.28 [0.11 to 0.75]). Remission rates for those with higher headache frequency were reduced by nearly 75%. Additionally, the odds of remission for those with allodynia at baseline were nearly 50% lower than those without allodynia (OR [95% CI] = 0.49 [0.24 to 0.97]). Neither depression nor age at onset was a significant predictor of remission. Consequently, only allodynia and headache frequency were retained for model 3.

View this table:
Table 3

Multivariate models for potential predictors of CM remissiona

In model 3, after controlling for demographics, prescription overuse, and OTC overuse covariates, effect of headache frequency remained significant. Additionally, preventive medication use was significant and associated with lower rates of remission (OR [95% CI] = 0.51 [0.27 to 0.96]). The effect of allodynia lost statistical significance, though the magnitude of the OR was unchanged. However, its p value was below the forward-selection entry criterion (0.1); therefore, even though it lost significance, allodynia moved into model 4. In model 4, headache frequency and allodynia remained significant predictors of remission, though the effect of preventive medication failed to reach statistical significance (table 3). Each of these significant predictors was associated with lower rates of remission.

Consequences of remission.

The overall within-group effect for MIDAS scores was different between 2005 and 2007 (p = 0.04). The between-group effect was also different (95% CI = −48.6 [−62.4 to −34.9], p < 0.001). In 2005, those with persistent CM had a mean score of 52.0 (severe disability) that increased to 66.1 (severe disability) (Δ = +14.1) in 2007. Those with remitted CM had a 2005 baseline mean score of 50.9 (severe disability) that decreased to 12.0 (moderate disability) in 2007 (Δ = −38.9) (figure 2). Interaction effect indicated that, over time, those with persistent CM demonstrated increases in MIDAS scores, while those with remitted CM demonstrated decreases in MIDAS scores (95% CI [−32.98 to −17.93], p < 0.001) (figure 2).

Figure 2
Figure 2 Difference in Migraine Disability Assessment (MIDAS) means between persistent chronic migraine (CM) and remitted CM over time

DISCUSSION

Findings indicate that, in the population, CM is a relatively fluid state. One-third (33.9%) of sufferers with CM in a baseline year continue persistent over the subsequent 2 years of follow-up. Conversely, true remission to >10 headache days is not typical, occurring in only 26% of those with CM. Nearly one-half of those with CM (52.7%) had CM in at least 1 year of follow-up; most (64.6%) had either CM or HFEM in at least 1 year of follow-up (figure 1). However, recognition that results do not reflect the natural disease course, but rather the clinical course, in a CM population that may be on treatment is important.

Given that CM sometimes persists and sometimes remits, factors predicting remission were evaluated. In models adjusting for sociodemographic variables, most modeled variables did not significantly predict remission of CM (table 2). However, significant predictors included use of preventive medication, allodynia, and headache frequency. When these were examined in a series of multivariate models, the results demonstrated various patterns, as discussed below.

Preventive medication use was associated with a lower rate of remission. Several factors might contribute to this result. Persons with CM who receive preventive medication may be more likely to have other factors, such as high attack frequency, associated with a reduced chance of remission. Results of multivariate modeling support this hypothesis. The effect of preventive medication lost significance when effect of headache frequency was included in the final model (model 4 in table 3), which would be the result of confounding by indication. In other words, frequent headache confounds the association between preventive treatment and remission.12 This hypothesis is further supported by exploratory analyses demonstrating that when headache frequency was removed from the multivariate model, preventive medication use remained significant (models 3 and 4 in table 3). Preventive medications may also increase remission rates, but effects may be offset by other unmeasured or inadequately measured confounders. In addition, the apparent lack of effect may be the result of treatment not being optimized in terms of choice of drug, dose, or patients not adhering to the recommended regimen. Finally, individuals with CM using preventive medications may have remitted prior to the baseline year; thus, selection bias could contribute to an underestimate of the influence of treatment on remission. All of these factors could have attenuated the effect of treatment on remission.

To understand the nature of the allodynia effect, which maintained a consistent magnitude of effect yet fluctuated in significance across models 2–4, a sensitivity analysis was conducted to determine the basis of what we assumed was a suppression effect caused by one of the covariates included in model 3. Covariates examined were depression, age at onset, medication overuse, and preventive medication use. Allodynia was significant in all refit models, indicating that effects of depression and age at onset or any one of the medication overuse and preventive medication use covariates were capable of suppressing the allodynia effect. However, because the depression, age at onset, and overuse medications covariates did not meet the forward-selection criterion in model 3 and were thus omitted from model 4, their ability to suppress the allodynia effect was not observed in model 4. Allodynia was significant in the final model (OR [95% CI] = 0.45 [0.23 to 0.89]).

Headache frequency was an independent predictor of remission, with higher headache frequency associated with lower rates of remission. The headache frequency variable was used both as a predictor and outcome variable, creating the possibility of circularity. For example, when comparing individuals with 15 headache days/month to individuals with 28 headache days/month, those with more frequent headaches must experience a much greater reduction in frequency to remit. This was addressed in part by defining CM remission conservatively—as having 0–9 days/month rather than <15 days/month. Essentially, if the symptom constellation of CM is more severe at baseline (i.e., higher headache frequency, presence of allodynia), then the less likely CM is to remit even after controlling for effects of interest.

With regard to the consequences of remission, this study showed that persistence and remission preferably influence disability. Those with persistent CM demonstrated increases in headache-related disability while those with remitted CM demonstrated decreases in headache-related disability (figure 2). Thus, treatments that reduce headache frequency should also substantially reduce headache-related disability if treatment results in remission. Improvements in disability can translate into significant improvement of ability to function in aspects of life negatively impacted by migraine, including occupational, academic, social, family, and personal arenas.13 Reduction of headache frequency may also translate into improvements in health-related quality of life14,–,18 and may be related to a reduction in comorbid psychological conditions, including depression and anxiety, having far-reaching positive effects on the lives of patients with headache.19,–,22

When discussing the remission of CM, it is important to consider it in context with new-onset (or incident) CM. Because the prevalence of CM is relatively stable, it may appear that the remission rate must be equivalent to the incidence rate. However, because the pool of those with EM available to develop CM is much larger than the pool of those with CM eligible to remit to EM, we would predict the incidence rate for CM to be lower than the remission rate because of these asymmetric denominators. An additional complexity is that both CM and EM include subpopulations at greater or lesser risk of transition, because follow-up is incomplete, diagnosis is fallible, or outcomes other than CM and EM occur.

Several limitations may influence interpretation of results. First, CM classification was based on self-reported data rather than clinical assessment. The questionnaire has been validated for CM diagnosis and has an acceptable degree of sensitivity and specificity; however, some degree of diagnostic error exists.23,24 Daily diaries may provide the best approach to measuring headache frequency. Additionally, medication overuse was defined by self-reported days of use by medication class. The proposed criteria for medication overuse headache are difficult to assess without a daily diary, which is nearly impossible to implement in a large population-based study. Furthermore, results are from population-based data; therefore, in headache subspecialty care, remission rates for CM are likely to be lower due to factors that led to care-seeking in these settings.

Clinical experience indicates that CM may fluctuate between CM and HFEM; thus, if an individual had CM at baseline, HFEM in 2006, and then CM in 2007, could their disorder be considered persistent CM? To address this limitation, we ran models with a broader persistence criterion (i.e., met CM criteria in 2005 and criteria for CM or HFEM in 2006–2007). Using this definition, results were substantially unchanged. Strengths of this study include the representative sample of patients with CM, 3-year longitudinal follow-up, and depth of predictor and outcome data.

AUTHOR CONTRIBUTIONS

Statistical analysis was conducted by Dr. D. Serrano.

DISCLOSURE

Dr. Manack is a full-time employee of Allergan, Inc., in which she holds stock/stock options. Dr. Buse serves on scientific advisory boards for Iroko Pharmaceuticals and MAP Pharmaceuticals, Inc.; and has received honoraria from Allergan, Inc., Merck Serono, and Endo Pharmaceuticals. Dr. Serrano reports no disclosures. Dr. Turkel is a full-time employee of Allergan, Inc., in which she holds stock/stock options. Dr. Lipton serves/has served on scientific advisory boards for and received funding for travel from Bayer Schering Pharma, Merck Serono, GlaxoSmithKline, Endo Pharmaceuticals, Kowa Pharmaceuticals America, Inc., Allergan, Inc., Neuralieve Inc., Ortho-McNeil-Janssen Pharmaceuticals, Inc.; has received funding for travel from the American Headache Society and the Diamond Headache Center; serves as Associate Editor of Cephalalgia and on the editorial boards of Neurology® and Headache; receives royalties from publishing Headache in Clinical Practice (Isis Medical Media, 2002), Headache in Primary Care (Isis Medical Media, 1999), Wolff's Headache (Oxford University Press, 2001, 2008), Managing Migraine: A Physician's Guide (BC Decker, 2008), and Managing Migraine: A Patient's Guide (BC Decker, 2008); has received speaker honoraria from the National Headache Foundation, the University of Oklahoma, the American Academy of Neurology, the Annenberg Foundation, Merck Serono, GlaxoSmithKline, and Coherex Medical; receives research support from the American Headache Society, National Headache Foundation, the Migraine Research Foundation, and the NIH; and holds stock options in Minster Pharmaceuticals plc.

ACKNOWLEDGMENT

The authors thank IntraMed Educational Group for editorial support in the formatting and styling of this manuscript.

Footnotes

  • Study funding: The American Migraine Prevalence and Prevention (AMPP) Study is funded through a research grant to the National Headache Foundation from Ortho-McNeil Neurologics, Inc., Titusville, NJ. Additional analyses were supported by Allergan, Inc., Irvine, CA.

  • Editorial, page 682

  • Supplemental data at www.neurology.org

  • AMPP
    American Migraine Prevalence and Prevention
    ASC
    Allodynia Symptom Checklist
    CI
    confidence interval
    CM
    chronic migraine
    DSM-IV
    Diagnostic and Statistical Manual of Mental Disorders, 4th edition
    EM
    episodic migraine
    HFEM
    high-frequency EM
    ICHD
    International Classification of Headache Disorders
    LFEM
    low-frequency EM
    MIDAS
    Migraine Disability Assessment
    NSAID
    nonsteroidal anti-inflammatory drug
    OR
    odds ratio
    OTC
    over-the-counter

  • Received May 4, 2010.
  • Accepted October 1, 2010.

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