Frequent headache is defined as headaches 15 days/month and daily. Course of Frequent/Daily Headache in the General Population and in Medical Practice

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1 DISEASE STATE REVIEW Course of Frequent/Daily Headache in the General Population and in Medical Practice Egilius L.H. Spierings, MD, PhD, Willem K.P. Mutsaerts, MSc Department of Neurology, Brigham and Women s Hospital, Harvard Medical School, and Craniofacial Pain Center, Tufts University School of Dental Medicine, Boston, MA Frequent headache is defined as headaches 15 days/month and daily headache operationally as headaches 5 days/week. In this article, we review the outcome of frequent/daily headache in the general population and in medical practice. In the general population, within 1 year fewer than half of those with frequent/daily headache will still have frequent/daily headache, with a gradual further decrease over subsequent years. In medical practice, the results of studies suggest a one-third reduction in headache days/month over 6 to 12 months, with nearly % of patients with frequent/daily improving 5% in headache days/month over the same time period (5% responder rate). In terms of predictors of poor outcome, no clear picture emerges. [Rev Neurol Dis. 1;7(4):13-11 doi: 1.399/rind9] 1 MedReviews, LLC Key words: Frequent headache Daily headache Headache days Headache course General population Medical practice Headache practice Outcome predictors Frequent headache is defined as headaches 15 days/month and daily headache operationally as headaches 5 days/week. Approximately 1 out of every adults in the general population has frequent/daily headache; in medical practice, it may affect as many as half of all headache patients. In this article, we review the outcome of frequent/daily headache in the general population and in medical practice, including the headache practice of Dr. Egilius Spierings (the first author of this article). Dr. Spierings is a neurologist with specialty training in headache management. We present the results of prospective studies in which the number of headache days was at least 1 of the outcome variables. The studies are presented separately for the general VOL. 7 NO. 4 1 REVIEWS IN NEUROLOGICAL DISEASES 13

2 Course of Frequent/Daily Headache continued population, for medical practice, and for Dr. Spierings headache practice. Only medical practice studies are reviewed that did not look at specific treatments as was also the case with the study conducted in Dr. Spierings headache practice. Where available, the information regarding prognostic predictors is presented as well. Population In an epidemiologic study in the United States, 99 English-speaking subjects between the ages of 18 and 65 years were identified with headaches 18 days/year. 1 Up to 1 attempts were made to interview the subjects again by telephone approximately 11 months after the initial interview; 49% could not be reached and an additional 7% refused participation or were not eligible due to age, incompatible schedule, or mental status. Of the remaining 1134 subjects, 495 (44%) still reported headaches 18 days/year. Remission to headaches 52 days/year (1 day/week) was positively associated with elapsed time between interviews, a history of diagnosed diabetes, and increased level of education; negative associations were found with baseline headache frequency and having been previously married (ie, currently widowed, divorced, or separated). The mean age of the subjects at the follow-up interview was 41 years and the mean duration of frequent/daily headache was 7 years. The development of frequent/daily headache occurred within 1 week in 29% and within 1 month in 8%; in the remaining 63%, it occurred more gradually. In an epidemiologic study in Taiwan, 18 subjects aged 15 years were identified who had headaches 15 days/month, of whom 16 had headaches daily ( days/month). 2 In all, 72% were women; the mean age was 37 years for the women and 44 years for the men. A total of 34% met the criteria for medication overuse (ie, simple analgesics taken 5 days/week, combination analgesics 3 days/week, or ergots or opioids 2 days/week); 57% of the In a public middle school study in Taiwan, 122 adolescents (32 boys and 9 girls), aged 12 to 14 years, were identified with headaches 15 days/ month. At 1-year follow-up, % of them still had frequent/daily headache, at 2-year follow-up % still had frequent/daily headache, and at 8-year follow-up 12% still had frequent/daily headache. 18 subjects had consulted physicians for their headaches in the previous year. In all, 16 subjects (98%) were successfully followed, and after 2 years 37 (35%) still had headaches 15 days/month. Predictors of persistence of frequent/daily headache were found to be age years, frequent/daily headache onset Percent Baseline age 32 years, frequent/daily headache duration 6 years, medication overuse, and daily headache ( days/month). In a public middle school study in Taiwan, 122 adolescents (32 boys and 9 girls), aged 12 to 14 years, were identified with headaches 15 days/month. 3,4 At 1, 2, and 8 years later, 112, 12, and 13 adolescents, respectively, were successfully reached. At 1-year follow-up, % of them still had frequent/daily headache, at 2-year follow-up % still had frequent/daily headache, and at 8-year follow-up 12% still had frequent/daily headache (Figure 1). Significant baseline predictors of frequent/daily headache persistence at 8-year follow-up were: migraine with or without aura, medication overuse, frequent/daily headache onset before age 13 years, headache duration 2 years, and persistence of frequent/daily headache at 1-year follow-up. Baseline psychiatric comorbidities such as anxiety or depression, age, and sex were not found to be predictors of frequent/ daily headache persistence. A stepwise, multivariate Cox proportional analysis only found frequent/ daily headache onset before age Figure 1. Natural history of frequent/daily headache ( 15 days/month) in 122 adolescents, 32 boys and 9 girls, aged 12 to 14 years. Data from Wang SJ et al. 4 1-year follow-up 2-year follow-up 8-year follow-up 14 VOL. 7 NO. 4 1 REVIEWS IN NEUROLOGICAL DISEASES

3 Course of Frequent/Daily Headache 13 years to be an independent risk factor for persistence of frequent/ daily headache at 8-year follow-up. In an epidemiologic study in China among registered residents 65 years, 6 subjects were identified with headaches 15 days/month for 6 months in the previous year. 5,6 Only 23% of these 6 subjects had sought medical help from physicians in the previous year; one-fourth overused medications, defined as simple analgesics taken 5 days/week, combination analgesics 3 days/week, or ergots or opioids 2 days/week. At 2-, 4-, and 13-year follow-up, 7, 16, and 34 subjects, respectively, had either developed dementia or had died. Of the remaining subjects, the participation rates were 96%, 84%, and 1%, respectively. At 2-year follow-up, 61% still had frequent/daily headache, at 4-year follow-up 73% still had frequent/daily headache, and at 13-year follow-up 27% still had frequent/ daily headache. Univariate Cox proportional hazard models showed that none of the following variables predicted persistent frequent/daily headache at 13-year follow-up: female sex, medication overuse at baseline, lifetime migraine history, or baseline geriatric depression score 8. Medical Practice Saper and colleagues 7 followed 421 patients with intractable headache who were mailed a questionnaire 6 months after initiation of treatment. The questionnaire was returned by only 218 of the patients (52%; 59 men and 159 women), aged 14 to 75 years (mean age, 38.6 years). The majority of the patients (84%) had received outpatient treatment only, whereas 16% required both inpatient and outpatient services. In the 218 patients who responded, the mean headache frequency in days per week decreased from to ; the mean frequency of severe/incapacitating headaches decreased from to days/week. Bøe and associates 8 withdrew 1 patients (26 men and 74 women) aged 18 to 7 years with probable medication-overuse headache from all headache or pain medications. Medication-overuse headache was defined as headaches 15 days/month for 3 months and intake of analgesics or acute migraine drugs 1 or 15 days/month, depending on the substance overused. The number of headache days during the days before medication withdrawal (baseline) was.4. The researchers successfully contacted these patients 1 year later and included 8 of them in the analysis: 4 did not succeed in withdrawal, 3 did not want to participate, 7 received another diagnosis, and data were missing for 6. 9 A total of 29 of the 8 patients (36%) had an improvement in the number of headache days compared with baseline of 5%; the remaining 64% had an improvement of 5%. If, for a conservative estimate, the patients who were not included in the analysis are assumed not to have improved, the numbers are 29% and 71%, respectively, for the patients with 5% and 5% improvement in the number of headache days compared with baseline. Anxiety and depression scores at baseline did not predict outcome; however, patients with moderate or severe depression were excluded from the initial study. In contrast, low sleep quality and bodily pain were found to possibly predict a lower response to withdrawal therapy. Hagen and coworkers 1 conducted a 1-year, randomized, multicenter, open-label study of medication withdrawal, preventive treatment, and no specific treatment in 56 patients between 18 and 7 years of age with medication-overuse headache, defined as headaches 15 days/month for 3 months, combined with intake of simple analgesics 15 days/ month or combination analgesics, ergots, triptans, or opioids 1 days/ month. In the 3 treatment groups (withdrawal, preventive treatment, Hagen and coworkers conducted a 1-year, randomized, multicenter, openlabel study of medication withdrawal, preventive treatment, and no specific treatment in 56 patients between 18 and 7 years of age with medicationoveruse headache... In the original preventive treatment group, the mean decrease in headache days per month was 7.3 at the 5-month follow-up and 1.3 at the 12-month follow-up. and no specific treatment), 58% to 65% of the patients were women and the mean age ranged from 38.7 to 42.1 years. The mean number of headache days per month was 24.1,.2, and 26.8, respectively, and the mean number of days per month with analgesics was 22.9, 23.5, and 23.7, respectively. At the 3-month followup, the mean decrease in headache days per month was 4.2, 7.2, and 1.6, respectively. The patients in the withdrawal group were offered preventive treatment at the 3-month follow-up, and those in the control group were offered treatment optimal for them at the 5-month follow-up. In the original preventive treatment group, the mean decrease in headache days per month was 7.3 at the 5-month follow-up and 1.3 at the 12-month follow-up. VOL. 7 NO. 4 1 REVIEWS IN NEUROLOGICAL DISEASES 15

4 Course of Frequent/Daily Headache continued Patients y -29 y -39 y -49 y 5-59 y 6-69 y Willem Mutsaerts (the second author of this article) studied the course of daily headache in the private headache practice of Dr. Spierings. Daily headache was operationally defined as headaches occurring 5 days/week. In the practice, all patients were routinely requested to keep a headache calendar from the first consultation onward to record the occurrence of headache on a daily basis. The patients were asked to record the occurrence of headache by indicating the intensity of the pain on a 3-point scale (mild, moderate, or severe). A guideline to rate the intensity of the pain was provided on the calendar: mild able to function; moderate unable to function but bed rest not necessary; and severe bed rest necessary. The patients who kept a daily headache calendar for a total of at least 2 months of the 6 months following the first consultation were included in the study. On the calendar, the patients also recorded the location of the headache in terms of left or right and whether the headache was associated with nausea or vomiting. They noted, on a daily basis, their (abortive and preventive) medication 7-79 y Figure 2. Distribution of the age at first consultation of the 196 patients in the headache practice study. intake, as well as (for women) the occurrence of menstruation. At the first consultation, the patients were subjected to a semistructured headache interview, as well as a physical and neurologic examination. Neurodiagnostic imaging was only obtained when indicated by the history and/or examination. The history was written out in a report, which was coded by Willem Mutsaerts and entered into a spreadsheet program. The coding included the following items: age and sex of the patient, abrupt or gradual onset of the daily headaches, and duration of time of daily headache presence. The headache calendars for up to 6 months after the first consultation were subsequently analyzed on a monthly basis (-31 days) for headache days and headache units per month. The number of headache units was determined by counting each headache day as 1, 2, or 3, depending on the pain intensity being indicated as mild (1), moderate (2), or severe (3). The means and standard deviations were calculated using the spreadsheet program. A total of 196 patients were identified who fulfilled the inclusion criteria for the study. The distribution of the age at first consultation is shown in Figure 2. There were 27 men (13.8%) and 169 women (86.2%); their mean age was (standard deviation) years. Of the patients, 38 (19.4%) related an abrupt onset of the daily headaches and 155 (79.1%) a gradual onset; in 3 patients (1.5%), the pattern of development of the daily headaches was not clear. The duration of daily headache presence was 1 year in 54 patients (27.6%) and 1 year in 142 (72.4%) (Figure 3). Figure 3. Distribution of the time of daily headache presence for the 196 patients in the headache practice study. Patients y 1-5 y 6-1 y y 16- y y 16 VOL. 7 NO. 4 1 REVIEWS IN NEUROLOGICAL DISEASES

5 Course of Frequent/Daily Headache Headache days Month 1 Month 2 Month 3 Month 4 Month 5 The results of the analysis of the daily headache calendars for the study group as a whole are shown in Figures 4 and 5. Figure 4 shows the results in headache days for the 6 months following the first consultation and Figure 5 those for headache units. Over the 6-month follow-up, the average number of headache days per month decreased to 19.; the average number of headache units decreased to These numbers were not different when a last-observation-carriedforward approach was used to compensate for missing data. From a manual review of the data, it was evident that there were responders and nonresponders to whatever treatment was provided. Responders were defined as those who improved 5% following the treatment, using as the index the number of headache days in month 6. Because the vast majority of the patients had headaches every day at the first consultation, 15 days per month was taken as the determination point. Using this approach, 79 of the 196 patients (.3%) turned out to be responders and 117 (59.7%) nonresponders. The responders had 15 Month 6 Figure 4. Outcome of daily headache over the 6 months following the first consultation in headache days/month. headache days in month 6 of the follow-up period and the nonresponders 15 days. The average number of headache days and the average number of headache units per month for the 6 months following the first consultation, separately for the responders and nonresponders, are shown in Figures 6 and 7, respectively. The average number of headache days per month remained around in the nonresponder group, whereas it gradually decreased to 9.5 in the responder group. The average number of headache units per month remained at approximately 45 in the nonresponder group, whereas it gradually decreased to 17. in the responder group. In a preliminary attempt to separate responders from nonresponders, the results for the study group were analyzed as a whole per sex, for the age groups years (n 7), the age groups to 49 years (n 7), and the age groups 49 years (n 56), for abrupt versus gradual onset of the daily headaches, and for duration of time of daily headache presence 1 year (n 54), 1 year (n 28), 2 to 5 years (n 54), 6 to 1 years (n ), and 1 years (n 35). No differences were observed among the various subgroups in average number of headache days or average number of headache units per month, with the exception of the duration of daily headache presence, where there appeared to be a slight inverse relationship (ie, the longer the time of daily headache presence the better the improvement), which became more pronounced as the follow-up progressed. Figure 8 shows the average number of headache days per Figure 5. Outcome of daily headache over the 6 months following the first consultation in headache units/month. Headache units Month 1 Month 2 Month 3 Month 4 Month 5 Month 6 VOL. 7 NO. 4 1 REVIEWS IN NEUROLOGICAL DISEASES 17

6 Course of Frequent/Daily Headache continued Headache days Headache units 5 1 Month 1 Month 2 Month 3 Month 4 Month 5 Responders (n 79) Nonresponders (n 117) Month 6 Figure 7. Outcome of daily headache over the 6 months following the first consultation in headache units/month for the treatment responders and nonresponders. Headache days Month 1 Month 2 Month 3 Month 4 Month 5 Month 1 Responders (n 79) Nonresponders (n 117) Month 6 Figure 6. Outcome of daily headache over the 6 months following the first consultation in headache days/month for the treatment responders and nonresponders. Month 2 Month 3 Month 4 Month 5 Month 6 1 year (n 54) 1 year (n 28) 2-5 years (n 54) 6-1 years (n ) 1 years (n 35) Figure 8. Outcome of daily headache over the 6 months following the first consultation in headache days/month in relation to time of daily headache presence. month and Figure 9 shows the average number of headache units per month. Discussion The results of the population studies are summarized in Table 1. They suggest that after a 1-year period, fewer than half of patients will still have frequent/daily headache, with a gradual further decrease over the subsequent years. Age does not seem to have much impact on the course of frequent/daily headache over time. In the medical practice studies, Saper and colleagues 7 showed a decrease in headache days per month over 6 months from approximately 21 to approximately 13 ( 38% improvement). In their best group (the preventive-treatment group) Hagen and associates 1 showed a decrease in headache days per month from approximately to approximately 18 at 3 and 5 months ( 28% improvement) and to approximately 15 at 12 months ( % improvement). In our own research, we showed a decrease in headache days per month from approximately to 19 at 6 months ( 24% improvement). In terms of headache days per month in the 5% responders, Bøe and coworkers 9 found this to be 36% at 12 months and we found it to be % at 6 months. Because different outcome variables were used in the epidemiologic studies (percentage of subjects with frequent/daily headache) and in the medical practice studies (headache days per month and 5% responders in headache days per month), a comparison is difficult to make; however, the impression is that the outcome of frequent/daily headache is relatively good in the general population (fewer than half still have frequent/daily headache at 1 year) and relatively poor in medical practice (one-third reduction in headache days per month over 6-12 months and a 5% responder rate in 18 VOL. 7 NO. 4 1 REVIEWS IN NEUROLOGICAL DISEASES

7 Course of Frequent/Daily Headache Headache units Month 1 Month 2 Month 3 Month 4 Month 5 Month 6 1 year (n 54) 1 year (n 28) 2-5 years (n 54) 6-1 years (n ) 1 years (n 35) Figure 9. Outcome of daily headache over the 6 months following the first consultation in headache units/month in relation to time of daily headache presence. Table 1 Percentage of Subjects With Persistent Frequent/Daily Headache in the Population Studies Age 1 Year 2 Years 4 Years 8 Years 13 Years Study (y) (%) (%) (%) (%) (%) Wang SJ et al. 3 and Wang SJ et al. 4 Lu SR et al Scher AI et al Wang SJ et al. 5 and Fuh JL et al. 6 headache days per month of close to % over the same time period). As predictors of poor outcome, baseline headache frequency, long frequent/daily headache duration, medication overuse, and (in terms of comorbidities) poor sleep quality are suggested, but no clear picture emerges. Therefore, if the prognosis is in fact better in the general population than in medical practice, the reason would be entirely speculative. One of the most prominent differences between frequent/daily headache in the general population and frequent/daily headache in medical practice is the association with severe headaches, generating the diagnosis of chronic migraine as opposed to chronic tension-type headache. In the general population, these 2 diagnoses are relatively equally distributed among those with frequent/daily headache, whereas in medical practice the vast majority of patients have chronic migraine, that is, experience severe headaches in addition to the frequent/daily headaches and do so more frequently, generating a much more severe headache presentation. References 1. Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors associated with the onset and remission of chronic daily headache in a population-based study. Pain. 3;16: Main Points Frequent headache is defined as headaches 15 days/month and daily headache operationally as headaches 5 days/week. Approximately 1 out of every adults in the general population has frequent/daily headache; in medical practice, it may affect as many as half of all headache patients. The results of the population studies suggest that after a 1-year period, fewer than half of subjects will still have frequent/daily headache, with a gradual further decrease over the subsequent years. Age does not seem to have much impact on the course of frequent/daily headache over time. In the medical practice studies, a decrease in headache days per month of one-third over 6 to 12 months was shown. As predictors of poor outcome, baseline headache frequency, long frequent/daily headache duration, medication overuse, and (in terms of comorbidities) poor sleep quality are suggested, but no clear picture emerges. VOL. 7 NO. 4 1 REVIEWS IN NEUROLOGICAL DISEASES 19

8 Course of Frequent/Daily Headache continued 2. Lu SR, Fuh JL, Chen WT, et al. Chronic daily headache in Taipei, Taiwan: prevalence, followup and outcome predictors. Cephalalgia. 1; 21: Wang SJ, Fuh JL, Lu SR, Juang KD. Outcomes and predictors of chronic daily headache in adolescents: a 2-year longitudinal study. Neurology. 7;68: Wang SJ, Fuh JL, Lu SR. Chronic daily headache in adolescents: an 8-year follow-up study. Neurology. 9;73: Wang SJ, Fuh JL, Lu SR, et al. Chronic daily headache in Chinese elderly: prevalence, risk factors, and biannual follow-up. Neurology. ;54: Fuh JL, Wang SJ, Lu SR, et al. A 13-year long-term outcome study of elderly with chronic daily headache. Cephalalgia. 8;28: Saper JR, Lake AE 3rd, Madden SF, Kreeger C. Comprehensive/tertiary care for headache: a 6-month outcome study. Headache. 1999;39: Bøe MG, Mygland A, Salvesen R. Prednisolone does not reduce withdrawal headache: randomized, double-blind study. Neurology. 7; 69: Bøe MG, Salvesen R, Mygland A. Chronic daily headache with medication overuse: predictors of outcome 1 year after withdrawal therapy. Eur J Neurol. 9;16: Hagen K, Albretsen C, Vilming ST, et al. Management of medication overuse headache: 1-year randomized multicentre open-label study. Cephalalgia. 9;29: VOL. 7 NO. 4 1 REVIEWS IN NEUROLOGICAL DISEASES

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