Nyeri kepala dg gangguan psikiatri

1
J Neurol Neurosurg Psychiatry doi:10.1136/jnnp-2013-305197 Migraine

Research paper

Headache-related health resource utilisation in chronic and episodic migraine across six countries
1. 2. 3. 4. 5. 6. 7. 8. 9. Joanna C Sanderson1,2, Emily B Devine1, Richard B Lipton3, Lisa M Bloudek2, Sepideh F Varon2, Andrew M Blumenfeld4, Peter J Goadsby5, Dawn C Buse3, Sean D Sullivan1

+ Author Affiliations 1. 2. 3. 4. 5.
1.
1

Pharmaceutical Outcomes Research & Policy Program (PORPP), University of Washington, Seattle, Washington, USA 2 Global Health Outcomes Strategy and Research, Allergan Inc, Irvine, California, USA 3 Montefiore Headache Center and the Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA 4 The Neurology Center, Encinitas, California, USA 5 Headache Group, Department of Neurology, University of California, San Francisco, San Francisco, California, USA Correspondence to Joanna C Sanderson, Allergan Inc, 2525 Dupont Drive, Irvine, CA 92612, USA; Sanderson_Joanna@Allergan.com Received 20 February 2013 Revised 29 April 2013 Accepted 3 June 2013 Published Online First 29 June 2013

Abstract
Objective To describe headache-related health resource usage in chronic and episodic migraine across six countries. Methods A web-based questionnaire eliciting data on several topics, including health resource usage, was administered to panellists with migraine from the USA, Canada, UK, Germany, France and Australia. Respondents were grouped into episodic and chronic migraine, based on reported headache phenotype and headache-day frequency. ORs were calculated, comparing usage in each country to that in the US, controlling for chronic versus episodic migraine and other factors. Results Relative to the USA, the odds of visiting a provider for headache during the preceding 3months were significantly higher in all countries, except Germany. Respondents in France were more likely to report having a provider they typically visited for headache-related care. The odds of visiting the emergency department for headache were significantly lower in France, the UK and Germany, and hospitalisation for headache was significantly more frequent in Canada and Australia. Respondents from all countries, except Canada, were more likely to report currently using a prescription-acute treatment, and those from France were more likely to report trying more than three acute treatments. Preventive treatment use did not differ significantly. Conclusions Headache-related resource usage differed significantly between the USA and other countries. US respondents were generally less likely to report recent provider visits and use of prescription-acute treatments. They were more likely to report emergency department visits than in European countries, but less likely to report hospitalisation than in Canada and Australia.

Background
Migraine is a brain disorder most clearly manifested by headache. The two major forms are distinguished based on headache frequency: episodic migraine (EM) and chronic migraine (CM). The revised second International Classification of Headache Disorders (ICHD-IIR) defines CM as having 15 or more headache-days per month for 3months, with at least eight headaches per month linked to migraine without aura, either by virtue of meeting a case definition or by response to migraine-specific treatment.1 EM is characterised by headache on <15days per month with one or more attacks fulfilling ICHD-II criteria.2 CM affects approximately 12% of the worldwide population and has a significantly greater effect on quality of life than EM.3 ,4 CM patients are more debilitated and more likely to miss work or have decreased productivity.57 CM patients have more comorbid conditions, including psychiatric and pain disorders.5 ,8 They also use more health resources than EM patients, including emergency department (ED) visits, clinic visits and medications.5 ,9

Although studies have consistently revealed variation in resource usage between CM and EM, less is known about how this compares across countries. The first International Burden of Migraine Study (IBMS-I) revealed that chronic migraineurs used more health resources than episodic migraineurs in the USA, Canada, UK, France, Germany, Italy and Spain.9 ,10 However, these publications focused primarily on comparing CM to EM rather than comparing countries. Gerth et al11 found that migraine-based resource usage was comparable across the 25 countries included in their study. However, sample sizes were small for some countries (eg, <20 cases), and statistical tests were only used to compare usage across large international regions. The study also excluded subjects reporting >8 migraine attacks per month, which may have excluded the majority of those with CM. Finally, the study is over 10years old, and migraine awareness and prevention and treatment strategies may have changed in this time. Healthcare systems vary in many ways that could influence healthcare access and usage, including supply and demand factors, such as type of insurance (public or private), covered benefits, percent of population insured, physician reimbursement, out-of-pocket expenses and accessibility (eg, physician supply and wait times).12 Results from a study investigating access to care revealed that, of 11 countries (Australia, Canada, France, Germany, The Netherlands, New Zealand, Norway, Sweden, Switzerland, the UK and the USA), subjects from the USA were most likely to report that in the last year they: (1) had problems paying medical bills, (2) had out-of-pocket-expenses exceeding US$1000, (3) skipped medication doses due to cost, and (4) did not receive recommended care due to cost. Patients from the USA also reported the least confidence in their ability to pay for medical expenditures. Conversely, US cases were less likely than those from other countries, except Switzerland and Germany, to report waiting for 2months or more to see a specialist.12 While other country-specific factors, such as cultural and economic differences, may influence health resource usage, much of this difference could be accounted for by the contrast between universal government-sponsored healthcare and private insurance-based healthcare. The objective of this research is to describe differences in headache-related resource usage, including both health services and medication use, among chronic and episodic migraineurs in the USA, Canada, the UK, Germany, France and Australia.

Methods
Design and data source
The second international burden of migraine study (IBMS-II) investigated the burden of CM and EM in the USA, Canada, the UK, Germany, France and Australia. A web-based screening survey, used to determine eligibility, was administered to 32782 Lightspeed Research panellists who previously reported experiencing headaches or migraines. This panel consists of individuals from several countries who express interest in and register online to complete health-related surveys for nominal compensation.13 Target sample sizes were equal for CM and EM but differed by country.

Screener respondents (n=16663) were eligible for the main questionnaire if they were 18years of age and reported at least one headache during the prior 3months that was not associated with a cold, flu, head injury, or hangover. Additionally, respondents must have reported symptoms meeting the ICHD-IIR diagnostic criteria for migraine, based on the following two requirements.1 First, they must report that for either their most severe or second most severe headache type, they experienced at least two of the following symptoms half the time or more or less than half the time: (1) moderate to severe pain, (2) throbbing pain, (3) pain worsening with routine physical activity, or (4) unilateral pain. Second, they must report that for either their most severe or second most severe headache type, they experienced at least one of the following symptoms half the time or more or less than half the time: (1) nausea, or (2) photophobia and phonophobia. Eligible respondents (n=1183) were divided into two groups, CM and EM, based on average reported headache-day frequency on the screener survey (EM: <15 headache days per month, CM: 15 headache days per month). The web-based main questionnaire collected data concerning sociodemographic and clinical characteristics, comorbid conditions, attitudes and usage of health resources. Participants reported use of the following resources for headache: provider visits, ED visits, hospital admissions and acute and preventive medications. IBMS-II was approved by a central ethics review board (Institutional Review Board Services, Ontario, Canada). This research was conducted with approval from the Institutional Review Board of the University of Washington.

Statistical analyses
Because CM patients were oversampled and sampling differed by country, we stratified all analyses by CM versus EM and country. Sociodemographic and clinical characteristics were analysed using means and SDs for continuous variables and proportions for categorical variables. We performed inferential analyses to test the association between country and usage of specific health resources. Bivariate inferential analyses allowed for simple descriptions of relationships. We used analysis of variance to determine whether means of continuous variables varied across countries, and 2 tests to determine whether the proportion of respondents reporting use of a given resource differed by country. Multivariate logistic regression was used to determine whether the odds of reporting use of a given resource differed by country, relative to the USA, while controlling for covariates. Outcome variables were dichotomised, if necessary. Models included the following covariates, which were selected a priori: age, gender, income (above or below country-specific median), race/ethnicity (Caucasian, black, Asian, Hispanic, other/prefer not to say), residential population density (urban, suburban, rural), employment status (working, not working, student, homemaker, prefer not to say), Body Mass Index (BMI) category (underweight <18.5, normal 18.524.9, overweight 25.029.9, obese >30.0),

EM versus CM, and number of comorbid conditions. All statistical analyses were completed using STATA V.12 (College Station, Texas, USA).14

Results
Of the eligible screener respondents (n=1183), 1165 (98%) completed the main questionnaire. Tables 1 and 2 present sociodemographic and clinical characteristics of the CM and the EM groups. View this table: In this window In a new window Table 1 Sociodemographic and clinical characteristics of chronic migraineurs by country View this table: In this window In a new window Table 2 Sociodemographic and clinical characteristics of episodic migraineurs by country

Sociodemographic characteristics
For the CM group, mean age ranged by country from 38 to 46years. For EM, mean age was similar, ranging from 41 to 48years. Respondents were predominantly female in all countries and both migraine types (CM and EM). Gender distribution varied significantly by country in EM only; Australia had the lowest proportion that was female (56%) and Canada had the highest (84%). Over 80% of respondents were Caucasian in all countries and both migraine types, except CM respondents in Germany (65%). Race/ethnicity varied significantly by country, but this may have been driven by the proportion of German respondents reporting other or prefer not to say. Reported residential population density also varied significantly by country in both migraine types; USA, UK and Australia reported the most suburban living; Canada and Germany reported more urban living; France was split between urban and rural. CM respondents were less likely to report being currently employed in all countries. Employment status varied significantly by country in EM only; US and Australian respondents were less likely to report working full or part time and more likely to report being a homemaker than those from other countries. In all countries, fewer CM respondents than EM respondents reported an annual income above the country-specific median, but this did not differ significantly by country within migraine types.

Comorbidities and disability

BMI category, number of comorbidities and Migraine Disability Assessment Score (MIDAS) grade did not differ among countries for CM.15 Among respondents with EM, BMI and MIDAS grade differed significantly by country. More CM respondents were classified as obese (BMI>30.0) than EM respondents in all countries, except for the USA and the UK, where the proportion of the obese was similar across migraine types. BMI distribution differed significantly by country in EM respondents, with the highest prevalence of obesity in the USA (40%) and the lowest in France (14%). The number of comorbidities was also higher in CM respondents but did not differ significantly by country. The MIDAS grade was higher, indicating more severe disability, in CM respondents than EM respondents; MIDAS grade distribution varied significantly by country in EM respondents only.

Resource use for headache

Headache-related resource usage is presented in table 3 for CM and in table 4 for EM. Resource usage was generally higher in CM than in EM. The proportion of respondents who reported visiting a healthcare provider for headache in the 3months prior to survey completion differed significant by country in CM only. However, in both CM and EM, respondents from Australia reported the highest proportion of headache-related provider visits in the prior 3months (CM 64%, EM 36%), and respondents from the USA reported the lowest (CM 37%, EM 19%). The proportion of respondents who reported ever visiting the ED for headache differed significantly by country in both CM and EM, with respondents from Canada reporting the highest proportion (CM 52%, EM 35%) and respondents from the UK reporting the lowest (CM 14%, EM 8%). Similarly, the proportion of EM respondents reporting ever being admitted to the hospital for headache differed significantly by country, with Canada having the highest proportion (16%) and the UK having none; hospital admission did not differ significantly in CM. The proportion of respondents who reported having a healthcare provider whom they typically visited for headache-related care did not differ significantly by country in either migraine type. The number of preventive treatments ever tried, and the number currently used, also did not differ significantly by country in either CM or EM (also see figures 1 and 2). Antidepressants were the most commonly reported preventive agent currently used in all countries and both migraine types, except EM respondents from Germany, who reported a higher proportion of current -blocker use. Most respondents reported trying more than three acute treatments, and the number ever tried did not differ significantly by country in either CM or EM. Use of over-the-counter acute treatments was more commonly reported than use of prescription-acute treatments in all countries and migraine types, except CM respondents from Germany, who reported greater use of prescription-acute treatments. The proportion of subjects reporting current use of prescription-acute treatment was lowest in Canada for EM (44%) and in the USA for CM (53%), and highest in the UK for EM (71%), and in Australia for CM (76%). View this table: In this window

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Table 3 Resource utilisation amongst chronic migraineurs by country View this table: In this window In a new window Table 4 Resource usage among episodic migraineurs by country

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Figure 1 Number of migraine preventive therapies ever used by country.

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Figure 2 Number of migraine preventive therapies currently used by country. Table 5 and figure 3 present the type of provider respondents reported typically visiting for headache care. Respondents could report multiple provider types. Primary care providers were the most commonly reported provider of headache care in all countries and migraine types. For CM, Australia had the highest proportion of respondents who reported typically visiting a primary care provider (88%), and Canada had the lowest (56%). For EM, France had the highest proportion of respondents who reported typically visiting a primary care provider (74%), and the USA had the lowest (57%). Neurologists were the second most commonly reported provider of headache care in all countries, except Australia, where chiropractors were reported with equal frequency in CM and greater frequency in EM. In both CM and EM, the proportion of respondents who reported typically visiting primary care providers, chiropractors and internists differed significantly by country. The proportion of respondents who reported typically visiting a neurologist differed significantly in EM only. View this table: In this window In a new window Table 5 Typical provider of headache care in chronic and episodic migraine

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Figure 3 Typical provider of headache care by country. Subjects may be visiting more than one provider type. *Includes obstetrics/gynecology, ophthalmologist, psychiatrist, other and unknown. Table 6 presents the results from the multivariate analyses of resource usage. All ORs are relative to the USA and adjusted for age, gender, income, race/ethnicity, region of residence, employment status, BMI, migraine type and number of comorbid conditions. The odds of visiting a provider for headache in the 3months prior to survey completion were higher in all countries relative to the USA; this was significant for all countries except Germany. Respondents from other countries were also more likely to report having a healthcare provider whom they typically visited for headache-related care, though this was only significant for France. The odds of ever having visited the ED for headache were significantly lower in France, the UK and Germany. Respondents from Canada and Australia did not differ significantly from the USA in ED visits, but they were significantly more likely to report ever being admitted to the hospital for headache. The odds of currently using a prescription-acute treatment were significantly higher in all countries, except Canada, and respondents from France were more likely to report ever trying more than three acute treatments. The number of preventive treatment currently or ever used did not differ significantly from the USA. View this table: In this window In a new window Table 6 Adjusted odds of using resources by country, relative to the USA

Discussion
As in prior studies, we found a female preponderance both for CM and EM.4 ,8 ,16 The CM group was slightly older, reported lower household income, was less likely to be employed, reported a greater number of comorbid conditions and had higher MIDAS scores, signifying more severe headache-related disability. EM respondents were more diverse across countries sociodemographically and clinically than CM respondents. Because chronic migraineurs constitute the most debilitated subset of the migraine population, they may represent a distinct group clinically and, consequently, may share more characteristics than do episodic migraineurs. Resource usage differed significantly by country. By comparison with the USA, respondents from other countries were more likely to report visiting a healthcare provider for headache in the prior 3months, in both unadjusted and adjusted analyses. Similarly, US respondents were less likely to report having a healthcare provider whom they typically visited for headache care, though adjusted results were only significant compared with France. This trend is consistent with IBMS-I, in which 26% of US respondents reported visiting a primary care provider in the past 3months, compared with 48% in Canada, 56% in the UK, 60% in France and 48% in Germany.9 ,10 These differences are likely multifactorial. Many factors may limit healthcare access in the US, such as the lack of universal coverage or the presence of insurance deductibles for preventive services. In general, less access to preventive services could shift health resource usage to emergency services. Consistent with this idea, US respondents were more likely to report ever visiting the ED for headache than respondents from France, the UK and Germany, in both unadjusted and adjusted analyses. However, Canada actually had the highest percent of CM subjects who reported visiting the ED for headache. This aligns with the results of a recent study, which found that, out of 11 countries surveyed, Canada had the highest proportion of cases who reported visiting the ED in the prior 2years.12 Our results also indicate that Canadian and Australian respondents were more likely to report ever being admitted to the hospital for migraine than US respondents. Again, the reason for this difference is unknown. Australians and Canadians have longer average wait times to see specialists than those in the USA; the abovementioned study reported that 41% of respondents in Canada and 28% in Australia waited 2months or more to visit a specialist, compared with 9% in the USA.12 Further research into the impact of healthcare system design on access to and use of primary care, tertiary care and emergency services in the migraine population is warranted. The proportion of respondents who reported ever using migraine preventive therapy ranged from 50% to 76% for CM and from 33% to 45% for EM. Ever use of preventive therapy for EM respondents in the USA was similar to that in respondents from the American Migraine Prevalence and Prevention (AMPP) study, a longitudinal populationbased survey study of US migraineurs (IBMS-II 38%, AMPP 39%).17 The proportion of CM respondents who reported currently using migraine preventive therapy ranged from 35% to 52%, depending on the country. These rates are generally higher than those

reported in IBMS-I, in which 4% to 37% of CM respondents reported current preventive treatment use.9 ,10 However, given that nearly all CM patients qualify for migraine preventive treatment, this remains low. There are a number of possible explanations for low usage, including a lack of medical provider insight into the need for preventive medications and inadequate treatment response or intolerable side effects with currently available treatment options. Studies have shown that adherence with migraine preventive therapy is low in clinical practice.18 Current, or ever use of preventive medications, did not differ significantly by country in unadjusted or adjusted analyses, suggesting that the proportion of migraineurs who receive preventive therapy is similar, despite differences in frequency of outpatient and inpatient visits. Antidepressants were the most commonly reported prophylaxis agents used, except for EM patients in Germany, despite guideline recommendations for using blockers and antiepileptics first line.19 ,20 The reason for this is unknown, though it may be influenced by insurance coverage, physician experience, patient comorbidities (eg, depression or insomnia) or simply poor adherence with guidelines. Additionally, antidepressants are used for tension-type headaches as well, and may be prescribed if the diagnosis is uncertain.21 Finally, due to the crosssectional design, the sample is not limited to those initiating prophylaxis therapy for the first time, so many respondents had tried multiple agents. Use of prescription-acute treatments differed significantly across countries; respondents from France, the UK, Germany and Australia were significantly more likely than those from the USA to report currently using a prescription-acute treatment. This study has several limitations. First, it has limited ability to explain variability because country-level variables were not included in the dataset. For example, it is unclear whether having fewer recent provider visits in one country relative to another is an indication of poor access (eg, because of affordability), better control of migraines, or some other factor that varies across countries. Due to the cross-sectional design, the results include prevalent cases of migraine. Treatment patterns for incident migraine, including time to treatment and treatment duration, cannot be assessed. Additionally, results depend upon respondent recall and report, since data were not verified through external sources. However, misclassification is likely to be non-differential; there is no reason to believe that country of residence is associated with recall of resource usage. Misclassification of headache type may have occurred as well, due to reliance upon patient recall of headache days in the past 3months, and exclusion of the ICHD-IIR criteria requiring eight or more migraine days per month, and absence of medication overuse, headache, or other causative disorder.1 Generalisability to the broader global migraine population may be limited. The sample was selected from a pool of individuals who elected to participate in web-based healthrelated surveys, and likely had a higher average education level than the general population, since literacy and internet access were required. Health status and access to care are strongly associated with education level, so this is a major limitation. However, sociodemographic characteristics of US respondents are similar in many respects to those from AMPP.8 For example, respondents were primarily Caucasian and female in both EM (percent Caucasian: IBMS-II 88%, AMPP 87%; percent female: IBMS-II 80%, AMPP 80%) and CM (percent Caucasian: IBMS-II 87%, AMPP 91%; percent female:

IBMS-II 81%, AMPP 79%). However, though average age was fairly similar between the two studies, IBMS-II respondents were slightly younger in both EM (mean age: IBMS-II 44, AMPP 46) and CM (mean age: IBMS-II 44, AMPP 48). Also, fewer IBMS-II respondents reported being currently employed full or part time in both EM (IBMS-II 55%, AMPP 65%) and CM (IBMS-II 38%, AMPP 49%). Overall, the results presented here suggest that chronic and episodic migraineurs differ across countries sociodemographically, clinically and in resources used. US migraineurs were generally less likely to report recent provider visits and use of prescription-acute treatments. They were also more likely to report ED visits than the European countries, but less likely to report hospitalisation than Canada and Australia. Further research into the sources of this variability, including the influence of healthcare system design, supply and demand features and the impact of this variability on outcomes is warranted.

Acknowledgments
The authors would also like to thank the following individuals for their contributions: G Maglinte (Amgen, Inc) and L Liu (Allergan, Inc) for contributing to experimental design, and L Allen, K Payne, I Proskorovsky, K Yeomans, R Yu (United BioSource Corporation, Bethesda, Maryland, USA) for data collection.

Footnotes

Contributors JCS (guarantor) developed the research question, planned and conducted the data analysis, and drafted and revised the manuscript. EBD, SDS and LMB assisted in research question development and reviewed and revised the analysis plan and manuscript. SFV designed the second International Burden of Migraine Study, assisted in research question development and reviewed and revised the analysis plan and manuscript. RBL, AMB, PJG and DCB designed the second International Burden of Migraine Study and reviewed and revised the manuscript. Funding The study sponsor (Allergan, Inc) was involved in the study design, data collection, data analysis, data interpretation, and the writing of the article. The sponsor and corresponding authors directed the research design and reviewed all major research decisions (ie, study instruments, sampling and analyses). The authors had full access to all data and had final responsibility for the decision to submit for publication. Competing interests JCS is a senior fellow at Allergan, Inc. LMB and SFV are employees of Allergan, Inc. EBD and SDS indicate no conflicts of interest. RBL has received grants or honoraria from Allergan, Inc, Merck, Inc, Neuralieve, Novartis, OrthoMcNeil, the National Headache Foundation, and the National Institute of Health. ABD has received grants or honoraria from Allergan, Inc, Pfizer, Zogenix, Merck, OrthoMcNeil, MAP pharmaceuticals, Forrest, GSK, and Posen. DCB has received honoraria and/or research funding from Allergan, Inc, Merck, Inc, MAP Pharmaceuticals, NuPathe, and Novartis. PJG is on the boards

of Allergan, Colucid, MAP pharmaceuticals, Merck, Sharpe and Dohme, eNeura, Neuroaxon, Autonomic Technologies Inc, Boston Scientific, Eli-Lilly, Medtronic, Linde gases, Arteaus, AlderBio and BristolMyerSquibb. He has consulted for Pfizer, Nevrocorp, Lundbeck, Zogenix, Impax and Dr Reddy, and has been compensated for expert legal testimony. He has grant support from GlaxoSmithKline, MAP, MSD, eNeura and Amgen. He has received honoraria for speaking from MSD, Pfizer, Allergan and Mennarini, and payment for editorial work from Journal Watch Neurology, and for developing educational materials for the American Headache Society. Provenance and peer review Not commissioned; externally peer reviewed. Open Access This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: http://creativecommons.org/licenses/by-nc/3.0/

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Prevalence of migraine and co-morbid psychiatric disorders among students of Cumhuriyet University
Murat Semiz1*, lteri Ahmet entrk2, Hatice Balaban2, Ayegl Kartal Yaz3 and nder Kavak3

* Corresponding author: Murat Semiz drmuratsemiz@hotmail.com

Author Affiliations
1

Department of Psychiatry, Sivas State Hospital, Sivas, TR-58140, Turkey Department of Neurology, Cumhuriyet University Faculty of Medicine, Sivas, Turkey Department of Psychiatry, Cumhuriyet University Faculty of Medicine, Sivas, Turkey

For all author emails, please log on.

The Journal of Headache and Pain 2013, 14:34 doi:10.1186/1129-2377-14-34

The electronic version of this article is the complete one and can be found online at: http://www.thejournalofheadacheandpain.com/content/14/1/34
Receive 23 January d: 2013 Accepte 2 April 2013 d: Publishe 11 April d: 2013

2013 Semiz et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Backround
The aim of this study was to investigate the prevalence of migraine and associated psychiatric disorders among university students at Cumhuriyet University of Sivas in Turkey.

Methods
A total of 1601 university students participated in this study and answered the questionnaires. The study was conducted in three stages: the self-questionnaire, the neurological evaluation, and the psychiatric evaluation. In the first stage, the subjects completed a questionnaire to assess migraine symptoms. In the second stage, the subjects who reported having migraines underwent a detailed neurological evaluation conducted by a neurologist to confirm the diagnosis. In the final stage, the subjects with migraines

completed a psychiatric examination using the structured clinical interview for DSM IVR Axis I.

Results
The self-reported migraine prevalence rate was 13.7%, and the actual prevalence rate of migraine among the university students was calculated to be 10.6% (n=169). When the results obtained with the SCID-I were examined, a current SCID-I psychiatric diagnosis was found in 39 (23.1%) of the 169 subjects with migraines. A total of 73 (43.2%) students with migraines had a lifetime SCID-I psychiatric diagnosis.

Conclusions
The results of this study indicate that migraines were highly prevalent among university students in Turkey with comorbid psychiatric disorders. Treatment strategies must be developed to manage these comorbidities.

Keywords:
Migraine; Prevalence; Psychiatric co-morbidity; University students; Epidemiology

Background
Migraine is an important health problem due to the frequency and accompanying morbidity, which includes disability and the loss of performance [1-3]. Migraine has a lifetime prevalence of 1218%, which has been shown to be both age- and genderdependent in community-based studies worldwide [4]. The one year prevalence of migraine was reported to be between 12.4% and 12.6% in nationwide studies [5,6] Studies have shown consistently that migraineurs report a lower quality of life than do those without migraines and that these reductions extend to physical health, mental health, social functioning and academic performance [7,8]. Migraine-type headaches are also prevalent among university students and have a profound impact on school performance in university students [8]. This impact is more evident among migrainous

students than students with episodic tension-type headaches (ETTH), with a 62,7% decrease in capacity versus 24.4%. Moreover, students with migraine-type headaches missed more school than students with ETTH [9]. These results reveal the importance of migraine headaches in university students. Despite these findings, there are few studies focused on the prevalence of migraine in university students in Turkey [2,10]. An expanding body of literature has suggested that migraine headaches are associated with higher rates of psychiatric disorders. Studies have shown significant associations between migraine and a variety of psychiatric disorders, including major depressive disorder, anxiety disorders and alcohol or drug abuse and dependence [11]. Patients with migraines, anxiety, and chronic depression also had a poor health-related quality of life. In addition, migraine, specific phobias, and panic disorder were important and independent comorbidities predicting a poor health-related quality of life [12,13]. Although migraine is prevalent among university students, previous studies have not adequately assessed comorbid psychiatric conditions among university students [14,15]. Because previous studies utilised the population admitted to the clinic when searching for the psychiatric comorbidities of migraine patients, our knowledge is restricted to migraine patients whom were not on therapy. We selected our study population by field screening to add more patients who were not on therapy for psychiatric comorbidities. Researchers have reported the prevalence of migraines using self-reporting instruments without performing neurological evaluations [2,4,5,9]. Therefore, reliable studies in which individuals diagnosed with migraines are subjected to a detailed evaluation by a neurologist and psychiatrist are needed. Understanding the nature of the association between migraines and psychiatric disorders and other conditions has implications for diagnosis and treatment. Knowledge of the migraine risks factors and pathophysiologic mechanisms is limited, and the occurrence of comorbidities may also provide clues regarding the aetiology of migraine [16]. The aim of this study was to investigate the actual prevalence of migraine and the comorbidity of psychiatric disorders among students at Cumhuriyet University of Sivas in Turkey.

Methods

Participants
Cumhuriyet University (CU) was founded in 1974 in Sivas, which is located in central Anatolia in Turkey. The citys central population was 315 000 according to the census data of 2011. Sivas, having more traditional attitudes, is located in a less-industrialised part of Turkey with low education level and high unemployment rate. CU has nine faculties and three institutes. The total number of students on the Cumhuriyet University campus was 18 904. Of these students, 8332 were female, and 10 572 were male. The subjects for this research were selected from students enrolled in a university program on the Cumhuriyet University Central Campus. The Directorate of the Cumhuriyet University Student Services selected the students according to faculty, university program, and class. Our study population was composed of 18 904 students. Of these 18 904 students, 1650 were selected using randomised stratified sampling (p=0.005, = 0.01 and d=0.05). A simple random sampling method was used to obtain a representative sample of the university population. From the 1650 students who were informed about the study, 32 students (1.9%) declined to participate in the study. Thus, 1618 students participated in the study. Of the study participants, 54.3% (878) were male, and 45.7% (740) were female, and their ages ranged from 1827 years (mean age, 21.32.2 years).

Procedure
The study incorporated three stages. In the first stage, the students were asked to complete a questionnaire to establish a migraine diagnosis during a school visit. The first part of the instrument consisted of questions regarding demographic characteristics, including age, medical history, family history, family structure, family socioeconomic status, smoking habits, and alcohol use. The second part was composed of questions related to the 2004 diagnostic criteria for the International Headache Society (IHS) for migraines [17]. The ID Migraine was also used.

The subjects who reported having migraines in the screening questionnaire participated in the second stage of the study. During this stage, a neurologist conducted a full neurological evaluation to confirm the migraine diagnosis. The neurological evaluation detailed a headache history and a neurological examination. The Turkish version of the Migraine Disability Assessment Scale (MIDAS) questionnaire was then administered to the students to assess failure due to migraine. In the third stage, students with migraines completed a psychiatric examination with the Structured Clinical Interview for DSM-IVR Axis I (SCID-I). The psychiatric examination was performed by two psychiatrists (MS, AKY). Approval by the institutional ethical committee of the Cumhuriyet University Faculty of Medicine was obtained prior to the study and informed consent was obtained from the students.

Measures Socio-demographic data form

Questions were related to the participants age, gender, marital status, family income, tobacco and alcohol use.

Identification of migraine (ID Migraine)

As a widely used screening instrument for identifying migraine at primary health services, the ID Migraine is a three-question screening tool for migraines that has demonstrated good validity [18]. Each of the three items relates to a central diagnostic symptom of migraine: nausea, photophobia, and interference with activities. Each question is scored dichotomously with endorsements of two or more items suggesting probable migraine sensitivity and specificity. A positive predictive value on this test has been defined as 81, 75, and 93%, respectively. The Turkish version of the ID Migraine screening test has previously been validated [19].

Migraine disability assessment scale (MIDAS)

The MIDAS questionnaire is used to gather information on disability in terms of missed days of paid work (or school), housework (chores), and non-work time. Questions are asked regarding either days of missed activity or days during which productivity was reduced by at least 50%. If productivity decreased to 50% or less, the day is considered missed [20]. The 4-point grading system for the MIDAS questionnaire is as follows: Grade I (scores ranging from 0 to 5), little or no disability; Grade II (scores ranging from 6 to 10), mild disability; Grade III (scores ranging from 11 to 20), moderate disability; and Grade IV (scores of 21 or greater), severe disability. The Turkish version of the MIDAS questionnaire was developed by Ertas et al. [21].

The visual analogue scale (VAS)

The VAS is a simple and commonly used method for evaluating variations in pain intensity [22]. The subjects are instructed to indicate the intensity of their pain by marking a 100-mm line anchored with terms that describe the extremes of pain intensity.

The structured clinical interview for DSM-IV-R (SCID-I)

According to the DSM-IV, the SCID-I is a clinical interview comprising six structured modules that are utilised by an interviewer to determine whether an individual has one or more Axis-I disorders. The average application period is 2560 min, and the evaluation is conducted with the patient individually. During the application, the interviewer uses an administration booklet with interview questions and a scoring sheet to record the ratings. The psychiatric diagnosis is determined based on current and lifetime experiences [23]. Developed by First et al. in 1997 into a Turkish reliability study, an adaptation of the SCID-I was conducted by zkrkgil et al. [24]. For all diagnoses, the interviewer agreement was 98.1%, and the kappa coefficient was 0.86. For all diagnostic categories, the kappa coefficients ranged between 0.52 and 1.00 and were significant (p<0.001).

Statistical analyses
The statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) Version 14.00. The data for categorical variables were presented as counts and percentages; the data for continuous variables were presented as the mean and SD. A comparison of variables between the groups was performed using the Independent t test for numeric variables and the chi-square (x2) test for categorical data. In all analyses, p values less than 0.05 were considered significant.

Results
A total of 1618 students participated in the study. Table 1 displays the demographic and social characteristics of these students. Migraine-type headaches were detected in 221 of 1618 (13.7%) subjects using a self-reporting instrument. Of these 221 eligible subjects, 204 accepted further evaluation. Seventeen students declined to participate in the second part of the study. However, only 169 (10.6%) of the 1601 subjects were diagnosed with migraine based on a personal neurological interview. Table 1 displays the demographic and social characteristics of the 169 students. Therefore, 1432 (89.4%) of the 1601 subjects were migraine-free. The self-reported migraine prevalence was 13.7%, whereas the migraine prevalence among the medically evaluated students was 10.6%. Of these 169 subjects with migraines, 123 (72.8%) were female, and 46 (27.2%) were male. The mean age of disease onset was 17.11 years, and the average number of attacks per month was 6.3 (min 1max 15). In addition, 130 (76.9%) of 186 students had migraines without aura, whereas the remaining 39 students (23.1%) had migraines with aura. No significant differences were found between the socioeconomic status of those students with and without migraines (p>0.05). Similarly, the smoking habits and alcohol use did not differ significantly between the groups. Table 2 shows the clinical characteristics of the migraines. Table 1. Demographic characteristics of students Table 2. Clinical characteristics of migraine in students

The MIDAS scores showed that 59 (34.9%) students had minimal disability, with a mean score of 4. Thirty-two (18.9%) students had mild disability, with a mean score of eight. In addition, 38 (22.5%) had moderate disability, with a mean score of 14, and 40 (23.7%) had severe disability, with a mean score of 26 (Table 3). Table 3. MIDAS grades of the students When the results obtained using the SCID-I were examined, a current SCID-I psychiatric diagnosis was found in 39 (23.1%) of the 169 subjects with migraine. Two (5.1%) of these thirty-nine patients had two psychiatric diagnoses (panic disorder and depressive disorder). A total of 73 (43.2%) students with migraine had a lifetime SCID-I psychiatric diagnosis. Nine patients (12.3%) had two psychiatric diagnoses throughout their life. The current and lifetime DSM-IV Axis-I disorders are shown in Table 4. Table 4. Axis I diagnoses of migraine Migraine patients with present and lifelong psychiatric diagnoses had significantly more severe headaches (p<0.01), higher MIDAS points (p<0.01) and more frequent migraine attacks (p<0.05) but showed no differences based on the migraine initiation age and mean attack time (p>0.05) compared with the migraine patients without any psychiatric diagnosis.

Discussion
The present study was conducted among students registered to different faculties of Cumhuriyet University, Sivas, Turkey. To date, there have been university surveys evaluating the prevalence of migraines based on self-reports, but this study appears to be the first reporting the migraine prevalence in university students with a clinical interview for migraine and co-morbid psychiatric diagnoses. Structured diagnostic interviews increase the reliability and power of the prevalence studies. The subjects with migraines were interviewed and evaluated by a neurologist and a psychiatrist in this study. The

diagnosis of migraine was determined using the 2004 IHS criteria, which are utilised in epidemiological studies due to their high sensitivity [17]. The prevalence of migraines was found to be 10.6%. Migraine without aura was the most common type of migraine found in this study. The observed migraine prevalence was similar to those reported in larger population studies that used structured diagnostic interviews. There are few studies focusing on migraines among university students in Turkey showing differences in prevalence. The migraine prevalence ranged from 7.2-21.9% in the university students of Turkey [1,2,9,25] but ranged from 6.4-48.5% in other international studies [26-29]; in some studies, higher frequencies were reported. We think that the differences might be caused by the methodological differences; different self-reporting questionnaires may reflect different findings. We think the use of a self-administered questionnaire might cause the misunderstanding of some questions, which risks subjectivity in the answers. The examination of the subjects by a neurologist for headache confirmed the screening results and excluded the other headache types. We found the migraine prevalence was 13.7% by the questionnaire evaluation but was 10.6% by the clinical evaluation used for confirmation. Migraine is often comorbid with psychiatric disorders, such as mood disorders and anxiety disorders. Muftuoglu et al. found that migraine patients were considerably more depressed and anxious than the healthy controls [29]. We observed at least one psychiatric diagnosis in 23.1% of the migraine patients at the present time and in 43.2% of migraine patients lifelong. A previous study observed depression in 10-40% of the migraine patients and mood disorders in 13.6% of the patients [30]. In population studies, migraine sufferers are between 2.2 and 4.0 times more likely to suffer from a major depressive disorder than non-migraineurs [11]. Innamorati et al. reported that many patients with chronic migraine reported symptoms of depression and stagnation and that investigating the presence of the depressive disorder may be useful for understanding the

psychology of chronic migraineurs [13]. We observed depression as the most frequent psychiatric disorder in the migraine patients, similar to the findings in the literature of 10.1%. The relationship between migraines and bipolar disorder has been studied in clinical studies [31]. Merinkangas et al. observed a 2-fold increase in bipolar disorder in migraine patients compared with non-migraineurs with bipolar disorder observed in 1.2% of their migraine patients [32]. A previous study observed the bipolar disorder prevalence to be 0.43% in Sivas province [33]. Two patients were diagnosed with bipolar disorder (1.3%) in this study. Anxiety disorders are also associated with migraines [34]. Compared with individuals without migraines, migraineurs are at 45 times greater risk for generalised anxiety disorder (GAD), five times greater risk for obsessive compulsive disorder (OCD), and 3 10 times more likely to suffer from panic disorder [35,36]. We observed anxiety disorder in 11.2% of the migraine patients, with panic disorder and posttraumatic stress disorder being the most frequent, in agreement with the literature. There is increasing support in the literature for a strong association between migraine and PTSD in migraine patients [37]. High PTSD prevalence rates of 2250% have been reported in individuals with migraines in previous studies of adult subjects fulfilling the criteria for PTSD [38,39]. The results of the present study showed that PTSD with migraine was as high in university students as in the general population. Guidetti et al. reported that psychiatric comorbidities negatively affected the migraine patients in their 8-year, longitudinal observational study [40]. Another study reported a worse quality of life in the migraine patients with anxiety disorder and depression compared with the control group and found that the psychiatric comorbidities had negative effects on the pain severity and number of episodes [41]. Most migraine sufferers do not treat themselves in anticipation of the headache, and they often returned unused quantities of drugs to physicians. The correct assessment of anxiety, depression, and stress appear critical for developing an adequate preventive treatment strategy [42].

We found no relationship among the migraine initiation age and the psychiatric comorbidities, which might be affected by the self-reporting of the initiation age by the patients. Thirty-two people in the first phase and seventeen in the second phase (total of 49 [2.9%]) refused to join the study or were excluded because of the lack of communication. The second limitation of this study is the lack of assessment of the nonmigraine group for psychiatric diagnoses. The screening for migraines with only a selfreporting scale and enrolled students from different faculties may have influenced the study results. Another limitation of our study was the inability to show the causality of the relationship between psychiatric disorders and headache-related disability because of the cross-sectional structure. Prospective studies are needed to explain this relationship in detail.

Conclusions
In conclusion, in this study, the prevalence rate of migraines among university students at Cumhuriyet University was 10.6%. Psychiatric disorders are common in university students with migraines and correlate with the pain-related disability. The finding that the majority of the students with migraines had not visited a neurologist or a psychiatrist shows that there is a lack of diagnosis and treatment in this population. The identification and treatment of psychiatric disorders in university students with migraines are an important and represent a potentially modifiable health state. Taken together, the results of previous studies with adults and the present study suggest that the treatment of psychiatric conditions positively influence the levels of pain and migraine-related disability in university students. Therefore, most migraine patients need to be followed due to the frequent presence of psychiatric conditions. However, clinicians should share their knowledge with other specialists, and psychiatric treatment must be viewed in a multidisciplinary context to improve both the quality of life and outcome of migraine patients.

Competing interests

The authors have no financial obligations to disclose related to this study.

Authors contributions
MS and HB conceived and supervised the project and drafted the manuscript. MS, A, and AKY were responsible for data collection. OK performed the statistical analyses. All authors read and approved the final manuscript.

Acknowledgments
The authors thank Ayfer Dikici for her assistance.

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Migraine predicts physical and pain symptoms among psychiatric outpatients

Ching-I Hung1, Chia-Yih Liu1 and Shuu-Jiun Wang2*

* Corresponding author: Shuu-Jiun Wang sjwang@vghtpe.gov.tw

Author Affiliations
1

Department of Psychiatry, Chang-Gung Memorial Hospital at Linkou and Chang-Gung University School of Medicine, Taoyuan, Taiwan
2

Neurological Institute, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, No. 201 Shi-Pai Road, Section 2, Taipei 112, Taiwan For all author emails, please log on. The Journal of Headache and Pain 2013, 14:19 doi:10.1186/1129-2377-14-19

The electronic version of this article is the complete one and can be found online at: http://www.thejournalofheadacheandpain.com/content/14/1/19

Receive 16 November d: 2012 Accepte 19 February d: 2013 Publishe 27 February d: 2013

2013 Hung et al; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background
No study has been performed to compare the impacts of migraine and major depressive episode (MDE) on depression, anxiety and somatic symptoms, and health-related quality of life (HRQoL) among psychiatric outpatients. The aim of this study was to investigate the above issue.

Methods
This study enrolled consecutive psychiatric outpatients with mood and/or anxiety disorders who undertook a first visit to a medical center. Migraine was diagnosed according to the International Classification of Headache Disorders, 2nd edition. Three psychometric scales and the Short-Form 36 were administered. General linear models were used to estimate the difference in scores contributed by either migraine or MDE. Multiple linear regressions were employed to compare the variance of these scores explained by migraine or MDE.

Results
Among 214 enrolled participants, 35.0% had migraine. Bipolar II disorder patients (70.0%) had the highest percentage of migraine, followed by major depressive disorder (49.1%) and only anxiety disorder (24.5%). Patients with migraine had worse depression, anxiety, and somatic symptoms and lower SF-36 scores than those without. The estimated differences in the scores of physical functioning, bodily pain, and somatic symptoms contributed by migraine were not lower than those contributed by MDE. The regression model demonstrated the variance explained by migraine was significantly greater than that explained by MDE in physical and pain symptoms.

Conclusions
Migraine was common and the impact of migraine on physical and pain symptoms was greater than MDE among psychiatric outpatients. Integration of treatment strategies for migraine into psychiatric treatment plans should be considered.

Keywords:
Depression; Anxiety; Headache; Pain; Quality of life; Somatization

Background
Migraine, mood disorders, and anxiety disorders are comorbid with each other and interact [1-6]. Many studies have investigated the prevalence and impact of depression and/or anxiety among patients with migraine. These studies show that comorbidity with depression and/or anxiety is common and related to a poorer quality of life, increases the suicide risk, and predicts a poorer outcome among patients with migraine [7-11]. Many other studies, on the contrary, have investigated the frequency and impact of migraine among patients with mood and/or anxiety disorders [12-20]. Most of these studies evaluated the impact of migraine on psychiatric outpatients with depression or major depressive disorder (MDD) [12-16]. Comorbidity with migraine is associated with

more severe depression, anxiety, and somatic symptoms, as well as a poorer healthrelated quality of life (HRQoL) [14-16]. Patients with depression may suffer from impaired multiple functions and have an increased social burden [21]. Major depressive episode (MDE) is one of the worst states of mood disorders and may be most able to reflect functional impairments of depression. Similarly, migraine also causes significant functional impairment in multiple dimensions [22]. To the best of our knowledge, no study has been performed to compare the impacts of migraine and MDE on depression, anxiety and somatic symptoms as well as HRQoL among psychiatric outpatients with mood and anxiety disorders (or non-psychotic outpatients). Understanding the impact of migraine among psychiatric outpatients with mood and/or anxiety disorder is important because the information might alert physicians to note migraine and to integrate the treatment plan for mood disorders, anxiety, and migraine. Therefore, the study aimed to compare the differences in depression, anxiety and somatic symptoms, as well as HRQoL, associated with the presence of migraine or MDE among psychiatric outpatients with mood and/or anxiety disorders. We hypothesized that psychiatric outpatients with migraine have a greater severity of depression, anxiety, and somatic symptoms as well as a poorer HRQoL based on previous studies [12-16]. Moreover, the impacts of migraine on physical and pain symptoms might be as important as those of a current MDE.

Methods

Subjects
This study enrolled subjects between September 2007 and August 2009 in the psychiatric outpatient clinic of Chang Gung Memorial Hospital, a medical center in northern Taiwan. The study participants were consecutive psychiatric outpatients (2060-years-old) who visited our clinic for the first time and had not taken any medications for psychiatric disorders and migraine prevention within the previous 4 weeks. Four exclusion criteria

were established: 1) psychotic disorders, such as schizophrenia, delusional disorder, and other psychotic disorders; 2) mental retardation, delirium, dementia, and mental disorders due to general medical conditions; 3) psychotic symptoms, catatonic features, severe psychomotor retardation, or a current manic episode in the index month, which may cause difficulty in completing self-administered scales or cooperating with the study process; 4) a history of substance dependence or abuse without full remission in the index month. The government-run single-payer compulsory National Health Insurance program in Taiwan enrolls more than 96% of Taiwans population [23]. The insured in Taiwan have complete freedom to choose their health care providers. They can seek care at tertiary care institutions, regardless of the severity of their illness. Only 2.3% of patients in the clinics of a university teaching hospital in Taiwan were referred from primary clinics [24]. Therefore, although our patients were collected from a medical center, they did not differ much in the demographic patterns of those attending primary psychiatric clinics. The study was approved by the Institutional Review Board of Chang Gung Memorial Hospital. A written informed consent, based on the guidelines regulated in the Declaration of Helsinki, was obtained from all subjects prior to study enrollment.

Assessment of the severity of depression, anxiety, and somatic symptoms, and HRQoL
The Hamilton Depression Rating Scale (HAMD), the Depression and Somatic Symptoms Scale (DSSS), and the Hospital Anxiety and Depression Scale (HADS) were used to evaluate depression, anxiety, and somatic symptoms over the previous week [25-29]. The DSSS is a self-administered scale composed of 12 items in the Depression Subscale (DS) and 10 items in the Somatic Subscale (SS), which includes five pain symptoms and five non-pain somatic symptoms. The reliability and validity of the DSSS have been reported in previous studies [25-27].

The HADS comprises 7 items in the anxiety subscale (HADS-A) and 7 items in the depression subscale (HADS-D) and does not include any somatic symptoms [29]. Therefore, the HADS can measure depression and anxiety without being confounded by somatic symptoms. The three scales were used simultaneously to investigate the severity of depression, anxiety, and somatic symptoms. The total scores for each scale or subscale range from 0 to 36 for the DS and 0 to 30 for the SS, 0 to 52 for the HAMD, and 0 to 21 for the HADS-D and HADS-A. A higher score indicates a greater severity. The acute version of the Short-Form 36 (SF-36), which evaluated the HRQoL in the past week with the same items as the SF-36, was used to be compatible with the evaluating period of the three psychometric scales. The SF-36 includes eight domains: physical functioning (PF), role limitations-physical (RP), bodily pain (BP), general health perceptions (GH), vitality (VT), social functioning (SF), role limitations-emotional (RE), and mental health (MH) [30]. A higher score indicates a better HRQoL. The scores of each subscale ranged from 0 (lowest well-being) to 100 (highest well-being). According to the SF-36 Health Survey Manual, a difference of more than 5 points in each subscale of the SF-36 is considered clinically significant. The Taiwanese version of the SF-36 shows good validity and reliability [31]. The DSSS, HADS, SF-36 were self-administered scales. The HAMD was assessed by a psychiatrist, who was blinded to the results of other psychometric scales, psychiatric diagnoses, and headache diagnoses.

Diagnoses of psychiatric disorders

Another psychiatrist, who was blinded to the diagnosis of headache and the results of these scales, used the Structured Clinical Interview for DSM-IV-TR to diagnose mood and anxiety disorders [32]. If patients had mood and anxiety disorders simultaneously, their diagnoses were categorized as bipolar disorders or MDD, not anxiety disorders.

Therefore, this study divided patients into bipolar disorders, MDD, anxiety-only disorders, and others.

Assessment of headache Headache diagnosis

All patients completed a structured headache intake form, designed to meet the operational criteria of the International Classification of Headache Disorders, 2nd edition (ICHD-2) [33] including information for the diagnoses of migraine and other common headaches, such as headache frequency, intensity, features, aura, locations, duration, and precipitating factors, as well as the amount and frequency of use of drugs taken for pain. An experienced headache specialist (neurologist), who was blinded to the results of the psychiatric diagnoses and psychometric scales, interviewed all patients after they had completed the headache intake form and made headache diagnoses based on the ICHD-2. Patients with chronic migraine (CM) with or without medication-overuse headache (MOH) and episodic migraine (EM) (i.e. migraine with or without aura) were categorized as the migraine group. In order to understand the synergic effects of a current MDE and migraine on depression, anxiety, and somatic symptoms, patients were divided into four groups: a current MDE with migraine, a current MDE without migraine, migraine without a current MDE, and others (neither a current MDE nor migraine).

Headache intensity and frequency assessment

Subjects evaluated their average headache intensity during the previous week using a visual analog scale, with 0 representing no headache and 10 representing headache as severe as I can imagine. The total number of headache days in the past week was also collected.

Statistical methods
We used SPSS for Windows 12.0 to perform the statistical analyses. In performing independent t-tests, Bonferroni corrections were used due to multiple comparisons (statistical significance: p<0.01 for HAMD, DS, SS, HADS-D, and HADS-A and p< 0.006 for the eight SF-36 subscales). One-way analysis of variance (ANOVA) with posthoc comparisons by Scheffes method was used to test the differences in continuous variables among groups. The Chi-square and Pearsons correlation tests were used in appropriate situations. To compare the impacts of migraine and MDE, multiple linear regression analyses with forward selection, which could prevent multicolinearity, were performed. The dependent variables were the scores of the depression, anxiety, and somatic symptoms, as well as the SF-36 subscales. All these dependent variables were continuous variables. Therefore, using multiple linear regression analyses was appropriate. The independent variables included migraine, a current MDE, and five demographic variables (age, gender, educational level, marital status, and employment). Moreover, general linear models were used to calculate the estimated difference contributed by either migraine or MDE after controlling for demographic variables. In statistical analyses, a two-tailed p value<0.05 was considered statistically significant.

Results

Subjects
During the study period, 231 patients fulfilled the criteria for enrollment. Of them, 17 patients refused to participate and 214 (92.6%) subjects completed the study. Table 1 demonstrates that 35.0% of these patients had migraine and 15.9% had chronic daily headache (CM with or without MOH or chronic tension-type headache). Table 1. The percentages of headache diagnoses

Table 2 shows the percentages of migraine among psychiatric diagnoses. Patients with bipolar II disorder had the highest percentage of migraine (70.0%), followed by MDD (49.1%), only anxiety disorder, and no mood and/or anxiety disorders. Table 3 shows the demographic variables and demonstrates that female patients had a significantly higher percentage of migraine. There was no significant difference in age, educational years, employment, and marital status between patients with and without migraine. Table 2. The percentage of patients with migraine by individual psychiatric diagnoses Table 3. Comparison of depression, anxiety, and somatic symptoms as well as demographic variables between outpatients with and without migraine and MDE Patients with migraine was associated with a higher risk of being in a current MDE (69.3% vs. 30.9%, odds ratio (OR)=5.05, 95% CI=2.759.28, p<0.001) compared to those without migraine. Similarly, patients with migraine also had a higher risk of a past suicide attempt history than those without (30.7% vs. 13.7%, OR=2.79, 95% CI=1.40 5.57, p<0.01).

Comparisons of depression, anxiety, and somatic severities between patients with and without migraine
Table 3 shows the severities of depression, anxiety, and somatic symptoms between patients with and without migraine and with and without a current MDE. Compared to patients without migraine, those with migraine had a significantly (p<0.01) greater severity of depression (HAMD, HADS-D, DS), anxiety (HADS-A), and somatic symptoms (SS). Compared to patients without a current MDE, patients with a current MDE also had a significantly greater severity of depression, anxiety, and somatic symptoms. After controlling for demographic variables by a general linear model, the estimated difference in the SS score contributed by migraine was slightly greater than that contributed by a current MDE (6.2 vs. 5.3).

Figure 1 shows the scores of depression, anxiety, and somatic symptoms in four subgroups. There was a trend that patients with a current MDE and migraine had the greatest severities of depression, anxiety, and somatic symptoms, followed by patients with a current MDE without migraine, patients with migraine without a current MDE, and patients without a current MDE or migraine, with the exception of the SS.

Figure 1. The severities of depression, anxiety, and somatic symptoms among patients with different diagnoses or comorbidities. Group I=a current major depressive episode (MDE) comorbid with migraine; Group II=a current MDE without migraine; Group III=migraine without a current MDE; Group IV=neither a current MDE nor migraine. HAMD Hamilton Depression Rating Scale, DS depression subscale of the Depression and Somatic Symptoms Scale (DSSS), SS somatic subscale of the DSSS, HADS-D depression subscale of the Hospital Anxiety and Depression Scale (HADS), HADS-A anxiety subscale of the HADS. Significance (p<0.05): Group I vs. II: DS and SS; Group I vs. III: All five subscales; Group I vs. IV: All five subscales; Group II vs. III: HAMD, DS, and HADS-D; Group II vs. IV: All five subscales except for SS; Group III vs. IV: none.

Comparisons of the SF-36 subscales between patients with and without migraine
Table 4 shows the differences in the SF-36 subscales between patients with and without migraine. Patients with migraine had significantly (p<0.006) lower scores (a poorer HRQoL) in the eight subscales as compared with patients without migraine. Similarly, patients with a current MDE also had significantly lower scores in all subscales. After controlling for demographic variables by a general linear model, the estimated differences between migraine vs. non-migraine and between a current MDE vs. no current MDE reached statistical significance and clinical significance (a difference in score>5) in all eight subscales. Of note, the reduction attributed to migraine was slightly greater than that attributed to a current MDE in the PF (11.2 vs. 9.4) and BP (23.5 vs. 20.0) scores. Table 4. Comparison of the Short-Form 36 subscales and headache indices between outpatients with and without migraine and MDE

Correlations of headache parameters to depression, anxiety, somatic severity, and the SF-36
Headache intensity was significantly correlated to the three psychometric scales (the correlation coefficient (r) ranged from 0.49 SS to 0.29 HADS-D, all p<0.01) and the eight SF-36 subscales (r: 0.49 BP to 0.23 SF, all p<0.01). The headache frequency was also significantly correlated to the three psychometric scales (r: 0.54 SS to 0.39 HADSD, all p<0.01) and all the SF-36 subscales (r: 0.47 BP to 0.28 RP, all p<0.05).

The impacts of migraine on depression, anxiety, and somatic symptoms

Table 5 identifies the factors that independently predict depression, anxiety, and somatic severities. After controlling for demographic variables and a current MDE, migraine was still an independent factor predicting the severities of depression, anxiety, and somatic symptoms. The variance of the SS explained by migraine was greater than that of a current MDE. Table 5. Independent factors predicting depression, anxiety, somatic symptoms, and health-related quality of life among psychiatric outpatients

The impacts of migraine on the SF-36 subscales

After controlling for demographic variables and a current MDE, migraine was still an independent factor predicting all the SF-36 subscales, except for VT and MH (Table 5). The variance in the PF and the BP explained by migraine was greater than that of a current MDE.

Discussion
Our study showed that the presence of migraine among psychiatric outpatients was associated with a greater severity of depression, anxiety, and somatic symptoms, and a poorer HRQoL. Comorbidity with migraine explained a higher variance on the physical and pain symptoms compared to a current MDE. Depression and/or anxiety are often considered important factors related to the severity of somatic or pain symptoms;

however, the role of migraine in somatic and pain symptoms in the psychiatric field has long been neglected. This study first pointed out that the importance of migraine was significantly greater than that of a MDE in predicting pain and somatic symptoms in the regression models. Migraine might be a surrogate for somatic and pain symptoms among these patients. This is imperative because pain or somatic symptoms are common residual symptoms, which are related to a poorer prognosis [34], among depressive patients. It is possible that simultaneous prevention of migraine during treatment for mood and anxiety disorders might decrease residual somatic and pain symptoms and improve the prognosis. Therefore, physicians should integrate the treatment of migraine into psychiatric treatment plans. In fact, migraine was common (35.0%) among these psychiatric outpatients. Patients with bipolar II disorder had the highest percentage (70%) of migraine. This result is compatible with Fasmers report (77%) [19]. The percentage of migraine among patients with MDD was 49.1%, which was close to that reported in previous studies [14,19]. The percentage of migraine among patients with only anxiety disorder was 24.5%, which was lower than that reported in the study of Senaratne et al. (67%) in an anxiety disorders clinic [17]. This might partially result from our diagnostic algorithm, i.e., in patients with only anxiety disorder, other psychiatric comorbidities, such as MDD and bipolar disorders, were excluded. Our results that psychiatric outpatients with migraine were associated with more somatic or pain symptoms might be explained by two possible reasons. 1) Imbalance of neurotransmitters, such as serotonin, noradrenalin, and dopamine, is responsible for the pathogenesis of migraine as well as somatic symptoms and depression [35,36]. This is commonly used to explain the close relationship between migraine, depression, and somatic symptoms; 2) Repeated headache attacks might cause a similar effect to central sensitization, which is associated with comorbid pain conditions and a worse headacherelated disability and increases somatic or pain symptoms among psychiatric outpatients with migraine [37].

There are several points, which might be helpful for clinical practice, worth noting. 1) Headache intensity and frequency were significantly correlated to the severity of depression, anxiety, somatic symptoms, and HRQoL. Therefore, headache intensity and frequency could be a useful index to predict these mental symptoms and HRQoL. 2) Depression and migraine independently predicted negative impacts on quality of life in a general population [38]. Our results demonstrated that migraine and a current MDE were independently associated with depression, anxiety, somatic symptoms, and HRQoL among these psychiatric outpatients. 3) The study showed that patients with both a MDE and migraine had the greatest severity of depression, anxiety, and somatic symptoms. This demonstrated the synergic effect of depression and migraine. 4) Psychiatric outpatients with migraine had an increased risk of a suicide attempt history. This result was compatible with previous studies [39]. In fact, migraine has been neglected in terms of evaluating suicide risk among psychiatric outpatients. Our study has the following limitations. 1) Our study enrolled psychiatric outpatients in a medical center with several exclusion criteria to prevent confounding effects. This enrollment process might introduce bias. For example, the study excluded patients with a current manic episode or with psychotic features. Therefore, this study did not enroll patients with bipolar I disorder. 2) The sample size of some diagnoses, such as bipolar II disorder, was small. The study design, mixing different diagnoses of mood and anxiety disorders, had the advantage of reflecting the percentage of migraine among global nonpsychotic outpatients. 3) The headache intensity and frequency in the past week were recalled by patients. Collecting data on the two headache parameters prospectively by headache diary might be more reliable. However, withholding pharmacological treatment while prospectively observing headache parameters might result in ethical problems owing to the suicidal risk. 4) Depression and migraine are associated with an increased suicide risk. In the study, only the past history of suicide attempts was recorded. A comprehensive assessment of suicide risk was not performed.

Conclusions

In conclusion, migraine was common among psychiatric outpatients with mood and/or anxiety disorders. Bipolar II disorder patients had the highest percentage of migraine, followed by MDD. Patients with migraine had a greater severity of depression, anxiety, and somatic symptoms, as well as a poorer HRQoL than those without. Of note, the association of migraine with PF, BP, and somatic symptoms might be greater than that of a current MDE. Because of the high frequency and significant impacts of migraine on physical and pain symptoms, future studies should explore how to integrate the treatment strategies of migraine, mood disorders and anxiety disorders.

Competing interests
All authors declare that they have no competing interests.

Authors contributions
SJW and CIH designed the study and wrote the protocol. CIH and CYL collected the data. SJW and CIH undertook the statistical analysis, and CIH wrote the first draft of the manuscript. All authors read and approved the final manuscript.

Acknowledgements
This study was supported in part by grants from the National Science Council of Taiwan (NSC 95-2314-B-182A-188-MY2), Taipei Veterans General Hospital [VGHUST101-G71-1, V101C-106, V101E7-003], NSC support for Centre for Dynamical Biomarkers and Translational Medicine, National Central University, Taiwan [NSC100-2911-I-008-001], Brain Research Center, National Yang-Ming University, and a grant from Ministry of Education, Aim for the Top University Plan.

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Combat-Related Posttraumatic Headache: Diagnosis, Mechanisms of Injury, and Challenges to Treatment

1. CPT Matthew Kozminski, DO, MC, USA + Author Affiliations 1. Dr Kozminski was a neurology resident at Madigan Army Medical Center in Tacoma, Washington, when he conducted the present study. 1. Address correspondence to CPT Matthew Kozminski, DO, MC, USA, Chief, Neurology Clinic, Darnall Army Medical Center, 36000 Darnall Loop, Fort Hood, TX 76544. E-mail: mpkst17@yahoo.com. Next Section

Abstract

Context: Studies have revealed the rates of posttraumatic stress disorder (PTSD) and concussion among US soldiers returning from combat, but only one study has focused on the subpopulation of soldiers with headache. Objectives: To determine the rate of PTSD among US soldiers with comorbid chronic posttraumatic headache attributed to head injury, to identify common mechanisms of head injury, and to identify the common challenges a healthcare provider must face when treating US soldiers with chronic posttraumatic headache attributed to head injury. Methods: Between July 2007 and December 2008, the author examined 42 US Army soldiers with complaint of chronic headache. In March 2009, the author retrospectively reviewed the outpatient records for diagnoses, mechanisms of injury, and challenges to treatment. Results: The rate of concussion, defined by the Defense and Veterans Brain Injury Center Working Group on the Acute Management of Mild Traumatic Brain Injury in Military Operational Settings, was 95%. The rate of PTSD, as determined either with the PTSD Checklist or by confirming a prior diagnosis by another healthcare provider, was 97.9%. Both rates are remarkably higher than rates reported in the literature. The most common mechanisms of injury were proximity to blast (18 [45.2%]) and direct target of blast (15 [35.7%]). The most common treatment challenges were overuse of headacheabortive medications (10 [23.8%]) and poor patient followup (7 [16.7%]). Conclusion: Physicians should be aware that the rates of PTSD and concussion for US soldiers, most often linked to involvement in or proximity to a blast, are higher for soldiers complaining of chronic headache. Physicians should also be aware of the potential for overuse of medications in this patient population. Previous SectionNext Section Since 2007, evaluating and treating US soldiers returning from combat with a complaint of headache has become an integral component of neurology residency training at Madigan Army Medical Center. At about that time, more formal traumatic brain injury (TBI) screening programs were being established at Fort Lewis for US soldiers returning from combat tours, thus leading to an increased number of neurology consultations for soldiers with headache as a comorbidity. Although studies1-4 have reported rates of posttraumatic stress disorder (PTSD) and concussion or mild TBI for US soldiers returning from combat settings, only one study attempted to focus on a subpopulation of soldiers with a comorbid complaint of headache.2 Furthermore, all were questionnairebased studies of soldiers returning from combat tours. Questionnaire-based studies may have low response rates and therefore may introduce volunteer bias. Based on the hypothesis that the rates of PTSD and concussion or mild TBI are higher in soldiers complaining of chronic headache and that these rates will be higher when data are obtained from direct face-to-face patient interviews, I conducted a retrospective

review of patient records from soldiers with complaint of chronic headache. Records were evaluated for diagnosis, mechanism of injury, and barriers to treatment. A significant portion of these soldiers are transitioning to a civilian life for a variety of reasons; thus, it is imperative that the various aspects of these soldiers lives, particularly the rate of PTSD with TBI, patient follow-up, and medication overuse, are shared with civilian counterpartsprimary care physicians and physician specialists alike. Previous SectionNext Section

Methods
Between July 2007 and December 2008, I completed three separate outpatient clinic rotation blocks as a neurology resident at Madigan Army Medical Center in Tacoma, Washington, during my postgraduate third and fourth years of training. I also completed the required half day per week of continuity clinic. During this time frame, I examined 42 US Army soldiers with a history of a deployment to Iraq or Afghanistan and who had complaint of chronic headache. At each encounter, I attempted to confirm diagnosis of PTSD, if appropriate, and inquired whether headache onset was temporally related to injury or concussive symptoms. I obtained as much detail as possible regarding each soldier's combat-related injury that might have triggered headache. Examinations included medical evaluation board (MEB) consultations and temporary duty retirement list evaluations. In MEB consultations, the consultant assesses the soldier's fitness for duty and determines whether the soldier should be referred to an evaluation board for consideration of medical discharge as a result of his or her medical condition. Temporary duty retirement list evaluations comprise examinations of soldiers who have been medically discharged from the military and who return for annual evaluations to determine whether their conditions have improved enough for possible rein-statement into active-duty military service. Many of the soldiers had a preexisting diagnosis of PTSD from another healthcare provider before I examined them; however, if this was not the case, I conducted an inperson interview, with the PTSD Checklist5 used as a guide to identify the diagnosis (Appendix 1). Each soldier was asked about symptoms of concussion6 as they appear on the Military Acute Concussion Evaluation (MACE) form (Figure 1). If concussive symptoms temporally related to headache onset and injury were in question, I tried to ensure that the soldier met the definition of concussion provided by the Defense and Veterans Brain Injury Center Working Group on the Acute Management of Mild Traumatic Brain Injury in Military Operational Settings (Appendix 2).7 If a soldier met the definition of concussion, noted headache onset temporally related to the event that precipitated the concussion, or noted exacerbation of a prior headache disorder temporally related to the event that precipitated concussion, then a formal diagnosis of chronic posttraumatic headache attributed to mild head injury was given, as

defined by the International Classification of Headache Disorders (ICHD-II) criteria8 (Appendix 3). In March 2009, I retrospectively reviewed the outpatient records of these 42 soldiers. On review, any of the following treatment or management challenges were noted: analgesia or opioid overuse, overuse of prescribed headache-abortive medications, mistrust of providers or frustration with care, poor compliance with patient follow-up, any questionable legitimacy of complaints (eg, possible embellishment of symptoms for secondary gain, possible somatization, factitious disorder), and expressed dislike of taking medications. The diagnosis of PTSD and the description of the reported mechanism of injury as reported in the outpatient record were also noted on retrospective review. If any soldier was referred to a neuropsychologist for a formal evaluation, the encounters were also retrospectively reviewed to determine whether the neuropsychologist thought that any complaints had questionable legitimacy.

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Figure 1. Symptoms of concussion. Source: Item VIII, Military Acute Concussion Evaluation (MACE). Available at http://www.cs.amedd.army.mil/filedownload.aspx?docid=930. Previous SectionNext Section

Results
Of the reviewed soldiers' records, 5 (12%) were strictly one-time consultations for either an MEB or a temporary duty retirement list evaluation. Seven soldiers (17%) were eventually referred for MEB consultation, and 5 (12%) left the military for nonmedical reasons. Overall, 17 soldiers (40.4%) had already transitioned or were transitioning to a civilian life for a variety of reasons; long-term follow-up of these particular soldiers was not possible. However, I followed up with most for the purposes of routine care of their symptoms until they transitioned to a civilian life, were discharged from my care, or until

I graduated from the residency program. Follow-up care is not described in the present study. The most commonly reported mechanism of injury (19 [45.2 %]) leading to a concussion or mild TBI was close proximity to a blast; that is, soldiers reported experiencing the effects of a shock wave secondary to a nearby blast but not being direct targets of an explosive device. In addition, a substantial proportion of soldiers (15 [35.7%]) reported being inside a physical structure or military vehicle that was the direct target of an explosive device. Smaller proportions of soldiers reported vehicle rollovers or crashes (4 [9.5%]) or falls related to combat scenarios unrelated to explosions (4 [9.5%]) (Figure 2). Overall, 40 soldiers (95%) met the definition of concussion7; however, only 15 soldiers (36%) could account for a witnessed period of definite loss of consciousness, and only 15 (36%) could account for a definite blow to the head. For those who could not account for a definite blow to the head, many implied that the combat situation at the time of injury generated such a fearful or stressful response that the details of the head injury could not be recalled. The majority of these individuals at least agreed that although they could not offer an exact or accurate account of possible mild head injury, they did experience the effects of a blast-related shock wave.

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Figure 2. Categories of injuries as reported by US soldiers (N=42) in the present retrospective review. Overall, 41 soldiers (98%) had PTSD, as determined either by prior diagnosis or by an inperson interview with the PTSD Checklist5 used as a guide. According to patient interview and documentation in outpatient records, 3 soldiers (7%) probably had a predeployment history of a primary headache disorder; however, all agreed that their headache disorder was exacerbated by their respective concussion or mild TBI.

Of the many challenges regarding the management of these soldiers, the most common were overuse of headache-abortive medications and overuse of analgesia or opioids (Table). The most commonly overused abortive medications were isometheptene mucate, dichloralphenazone, and acetaminophen; acetaminophen, butalbital, and caffeine; and serotonin receptor agonist medications. Unfortunately, many soldiers with a history of analgesia or opioid overuse took these medications for comorbid painful conditions other than headache. View this table: In this window In a new window Table Common Management Challenges in US Soldiers With Chronic Headache (N=42) * Many soldiers underwent formal consultation by a neuropsychologist, most for complaints of chronic neurocognitive deficits after head injury. Overall, only 2 soldiers (4.8%) were reported as having questionably legitimate complaints (embellishment of symptoms, factitious disorders, or somatization). Previous SectionNext Section

Comment
In the past, concussion was one of the most commonly overlooked symptoms of blastinjured soldiers.9 More recent studies have indicated that the rates of concussion or mild TBI for US soldiers deployed to combat range from 12% to 41%;1-4 the rates of PTSD are reported to be 11% to 43.9%.1-4 These rates of concussion or mild TBI and PTSD are discordant with the rates reported in the present study95% and 97.9%, respectively. A survey-based, cross-sectional study of Iraq or Afghanistan veterans conducted at the Washington DC Veterans Affairs Medical Center reported rates of 12% for mild TBI and 11% for PTSD.1 Evans Army Community Hospital4 reported clinician-confirmed TBI in 22.8% of soldiers, using the responses of the Warrior Administered Retrospective Casualty Assessment (WARCAT)10 and clinician interview. The Walter Reed Army Institute of Research reported injury and loss of consciousness in 4.9% of soldiers and injury and altered mental status in 10.3%.3 Of note, those with reported loss of consciousness had a much higher rate of PTSD than those who did not report loss of consciousness or injuries.3 None of these prior studies examined the subpopulation of soldiers suffering from chronic headache. In addition, all of these studies were reliant on self-administered questionnaires, which may have lead to volunteer bias. For the questionnaire-based studies at the Washington DC Veterans Affairs Medical Center and Walter Reed Army Institute of Research, the rates of nonresponders were 62.9% and 7%, respectively.1,3

A retrospective cohort study2 at Madigan Army Medical Center of 81 US soldiers seen at the neurology clinic for chronic headache demonstrated a history of head or neck trauma with concussion, with or without loss of consciousness, in 41% of soldiers and a high likelihood of PTSD in 6%. Although that study did target soldiers complaining of chronic headache, portions of the data relied on self-administered questionnaires, which again probably led to volunteer bias. For all 42 soldiers described in the present study, the diagnosis of concussion or mild TBI and PTSD was considered by a face-to-face interview with a neurology resident (M.K.) and not reliant on self-administered questionnaires, thus eliminating volunteer bias. In addition, these soldiers were known to have a comorbid complaint of headache in addition to a history of combat-related injury. Previous SectionNext Section

Role of Osteopathic Medicine

Osteopathic medicine provides a patient-centered approach that integrates recognized and rational healing methods, including osteopathic manipulative treatment (OMT), to improve the health and physiological function of patients.11 There is some basis for the belief that physical manipulation, many techniques of which focus on the cervical spine, can be beneficial in treating certain headache disorders. Biondi12 postulated that head pain may frequently arise from or be influenced by various soft tissues and neurogenic or osseous structures of the head, neck, and upper body. Pain elicits a heightened response of the sympathetic nervous system that can cause vasoconstriction, ischemia, chemical changes, more muscle contraction, and pain, creating a vicious cycle.13 Techniques of OMT are believed to improve circulation; release restrictions in joints; reduce tension in the muscles, fascia, and dura mater; decrease nociceptive input; and promote the normalization or calming of the central nervous system.13 Prior literature has emphasized the importance of focus on the occipitoatlantal joint, occipital condyles, and occipitomastoid joint; sphenobasilar syncondrosis in migraine; and use of craniosacral techniques for cervicogenic headache.14-16 In at least one small case series, OMT was shown to be a helpful adjunct therapy to traditional pharmacologic therapies for US soldiers suffering from posttraumatic headache attributed to mild head injury.17 Previous SectionNext Section

Conclusion
Soldiers returning from combat-related deployments to Iraq or Afghanistan with a complaint of chronic headache have higher rates of concussion or mild TBI and PTSD than those who do not complain of chronic headache. The overall rates of concussion or mild TBI and PTSD are probably underreported when based on the results of self-

administered questionnaires; this discrepancy may be related to volunteer bias and, in some cases, nonresponders. The most common treatment challenges for soldiers with chronic posttraumatic headache attributed to head injury are the overuse of typical headache-abortive medications and poor patient follow-up. Although OMT may be a useful adjunct therapy for combat-related chronic posttraumatic headache attributed to mild head injury, further studies need to be performed. Previous SectionNext Section View this table: In this window In a new window Appendix 1 The Posttraumatic Stress Disorder (PTSD) Checklist is a 17-item questionnaire in which each item is scored from 1 to 5. For example, a response of not at all is scored as 1, and a response of extremely is scored as 5. The patient must have a cumulative score of 50 or greater to receive a diagnosis of PTSD. The version shown here is the military version of the checklist. The checklist has been modified for graphic enhancement and minor style issues only. View this table: In this window In a new window Appendix 2 Definition of concussion used in the present study. Source: The Management of ConcussionTBI Working Group. VA/DoD Clinical Practice Guideline for Management of Concussion/Mild Traumatic Brain Injury. Washington, DC: Department of Veterans Affairs and Department of Defense; March 2009. http://www.dvbic.org/images/pdfs/providers/VADoD-CPGConcussion-mTBI.aspx. Accessed August 19, 2010. View this table: In this window In a new window Appendix 3 The International Classification of Headache Disorders (ICHD-II) criteria for chronic posttraumatic headache attributed to head injury. Source: Headache Classification

Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24(suppl 1):9-160. Previous SectionNext Section

Footnotes

Disclaimer: The opinions and assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Army, Department of Defense, or the US Government. Financial Disclosure: None reported. Received September 9, 2009. Revision received November 23, 2009. Accepted May 2, 2010.

Previous Section

References
1. Schneiderman AI, Braver ER, Kang HK. Understanding sequelae of injury mechanisms and mild traumatic brain injury incurred during the conflicts in Iraq and Afghanistan: persistent postconcussive symptoms and posttraumatic stress disorder. Am J Epidemiol. 2008;167(12):1446-1452. Abstract/FREE Full Text 2. Theeler BJ, Erickson JC. Mild head trauma and chronic headaches in returning US soldiers. Headache. 2009;49(4):529-534. Medline 3. Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild traumatic brain injury in U.S. soldiers returning from Iraq. N Engl J Med2008;358(5):453463. CrossRefMedline

4. Terrio H, Brenner LA, Ivins BJ, et. al. Traumatic brain injury screening: preliminary findings is a US Army brigade combat team. J Head Trauma Rehabil. 2009;24(1):14-23. CrossRefMedline 5. Weathers F, Litz B, Herman D, Huska J, Keane T. The PTSD Checklist (PCL): reliability, validity, and diagnostic utility. Paper presented at: Annual Convention of the International Society for Traumatic Stress Studies; San Antonio, TX; 1993.
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Military Acute Concussion Evaluation (MACE). http://www.cs.amedd.army.mil/filedownload.aspx?docid=930. Accessed August 19, 2010.
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Management of Concussion/mTBI Working Group, Department of Veterans Affairs. VA/DoD Clinical Practice Guideline for Management of Concussion/Mild Traumatic Brain Injury. Washington, DC: Department of Veterans Affairs and Department of Defense; March 2009. http://www.dvbic.org/images/pdfs/providers/VADoD-CPGConcussionmTBI.aspx. Accessed August 19, 2010. 8. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24(suppl 1):9-160. FREE Full Text 9. Scott SG, Belanger HG, Vaderploeg RD, Massengale J, Scholten J. Mechanismof-injury approach to evaluating patients with blast-related polytrauma. J Am Osteopath Assoc. 2006;106(5):265-270. Abstract/FREE Full Text
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Soldier Readiness Process Fort Carson TBI Questionnaire, TBI Reassessment (Fort Carson) and Fort Carson TBI Educational Handout. http://www.evans.amedd.army.mil/srp/WARCAT%20DEC%202007.xls. Accessed August 19, 2010. 11.

Kuchera ML. Applying osteopathic principles to formulate treatment for patients with chronic pain. J Am Osteopath Assoc. 2007;107(11 suppl 6):ES28-ES38. Abstract/FREE Full Text 12.

Biondi DM. Physical treatments for headaches: a structured review. Headache. 2005;45(6):738-746. CrossRefMedline 13.

Anderson RE, Seniscal C. A comparison of selected osteopathic treatment and relaxation for tension-type headaches. Headache. 2006;46(8):1273-1280. Medline 14.

Biondi DM. Cervicogenic headache: a review of diagnostic and treatment strategies. J Am Osteopath Assoc. 2005;105(4 suppl 2):S16-S21. Abstract/FREE Full Text 15. Batchelor K, Gamber R. Migraine and OMT. Am Acad Osteopath J. 2008;18(1):30-33. 16. Bernhardi EF. Cranial osteopathy for migraine headaches. Cranial Letter. 1995;48(1):4-6. 17.

Kozminski M, Kozminski T. OMT as an adjunct therapy for post-traumatic headache in U.S. soldiers: a case series. Am Acad Osteopath J. 2009;19 (2): 2324.

5
J Korean Med Sci. 2009 Oct;24(5):936-940. English. Published online 2009 September 23. http://dx.doi.org/10.3346/jkms.2009.24.5.936 Copyright 2009 The Korean Academy of Medical Sciences

Effect of Biofeedback-assisted Autogenic Training on Headache Activity and Mood States in Korean Female Migraine Patients
Eun-Ho Kang,1 Joo-Eon Park,2 Chin-Sang Chung,3 and Bum-Hee Yu 1 1 Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 2 Department of Psychiatry, Keyo Hospital, Euiwang, Korea. 3 Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Address for correspondence: Bum-Hee Yu, M.D. Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-gu, Seoul 135-710, Korea. Tel: +82.2-3410-3583, Fax: +82.2-3410-6957, Email: bhyu@skku.edu Received June 05, 2008; Accepted October 10, 2008. This is an Open Access article distributed under the terms of the Creative Commons Attribution NonCommercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. This article has been cited by 3 articles in This article has been cited by 1 article in KoMCI This article has been cited by 3 articles in Web of Science

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Abstract
Biofeedback with or without combined autogenic training is known to be effective for the treatment of migraine. This study aimed to examine the effect of biofeedback treatment on headache activity, anxiety, and depression in Korean female patients with migraine headache. Patients were randomized into the treatment group (n=17) and monitoring group (n=15). Mood states including anxiety and depression, and psychophysiological variables such as mean skin temperature of the patients were compared with those of the normal controls (n=21). We found greater treatment response rate (defined as 50% reduction in headache index) in patients with biofeedback-assisted autogenic training than in monitoring group. The scores on the anxiety and depression scales in the patients receiving biofeedback-assisted autogenic training decreased after the biofeedback treatment. Moreover, the decrease in their anxiety levels was significantly related to the treatment outcome. This result suggests that the biofeedback-assisted autogenic training is effective for the treatment of migraine and its therapeutic effect is closely related to the improvement of the anxiety level. Keywords:Migraine, Biofeedback, Autogenic Training, Anxiety, Depression.

Go to: INTRODUCTION

Migraine is a highly prevalent illness, and women of reproductive ages are more affected by it than men or women in other age groups (1). Many researchers have supported the view that behavioral interventions such as biofeedback and relaxation, either alone or in combination, can be effective for the treatment of headache (2-7). Especially, thermal biofeedback with or without combined autogenic training is known to be effective for the treatment of migraine headache (5,8). In addition, some studies showed that the effect of the behavioral treatment is durable (9,10). There have been no controlled studies about the efficacy of biofeedback and relaxation training for patients with migraine in Korea, and few studies have been conducted to investigate the direct association between mood states, including anxiety or depression, and headache activity. The mechanism underlying the efficacy of biofeedback treatment and the role of psychological factors in migraine treatment are still unclear, though various mood states, including anxiety and depression, and some cognitive factors are known to be related to pain regulation (11-13). Psychological conditions including anxiety and depression have been reported to have a strong association with migraine (12-14). Thus, in this study, we examined the hypothesis that biofeedback-assisted autogenic training is effective for the treatment of Korean female patients with migraine and that the improvement of psychological factors, such as anxiety and depression, is associated with the reduction of headache activity in migraine patients who are given biofeedback treatment. Go to: MATERIALS AND METHODS
Subjects

Thirty-two patients, who had migraine headache with or without aura, as defined by the International Headache Society criteria (15), participated in this study, from March 2003 until December 2006. The patients were female subjects aged 20 to 40 yr who had a body mass index (BMI) ranging from 18 to 27.5. They were among the migraineurs who visited the Samsung Medical Center. The patients were randomly allocated to one of two patient groups, consisting of a treatment group receiving biofeedback-assistant relaxation treatment (n=17) and a monitoring group in which the headache activities and biofeedback parameters of the patients were simply measured (n=15). These two groups did not show any significant difference in the duration of headache, headache index, duration of medication use, or other headache-related variables at the baseline (Table 1). Twenty-one normal female volunteers were recruited by advertisement and were matched with the migraine patients by age (treatment group: 31.125.49 yr, monitoring group: 31.874.70 yr, normal control group: 29.384.64 yr), and mood states and mean skin temperature of the patients before the biofeedback treatment were compared with those of the normal control subjects. Each subject underwent a comprehensive medical and psychiatric assessment including careful history taking, physical examination, neurological examination, mental status examination, and electrocardiography. Those patients who seemed to suffer from secondary headache due to medical or psychiatric

illnesses were not included in the study. They did not take regular medications for migraine headache, and only pro re nata (p.r.n.) medication such as sumatriptan was permitted during the study. This study was approved by the Institutional Review Board of Samsung Medical Center, and all of the subjects gave their written informed consent.

Procedure& Treatment

The patients in the treatment group received 8 sessions of biofeedback-assisted autogenic training (two sessions per week) during a period of 4 weeks, while those in the monitoring group received no active intervention except for simple biofeedback measurements (1st, 4th, and 8th session) during the treatment-waiting period. Biofeedback treatment was administered with the patient sitting on a comfortable armchair in a quiet room in the psychiatric outpatient clinic of Samsung Medical Center. A Procomp+system and Biograph version 2.1 program (Thought Technology Ltd., Quebec, Canada) were used for the biofeedback treatment and measurements. Each biofeedback-assisted autogenic training session lasted about 45-50 min. The autogenic training procedures consisted of 6 standard exercises combining both relaxation and auto-suggestion (limb heaviness exercise, limb warmth exercise, cardiac exercise, respiration exercise, solar plexus warmth exercise, and "forehead cooling" exercise) (16). During the 1st session, after the baseline profiles were obtained, education in relaxation techniques was given to the patients in the treatment group. During the 2nd to 8th sessions, thermal biofeedback combined with autogenic training was provided. For the first 15-20 min, after collecting the headache diary data, the patients were rated on psychological variables and headache severity. The patients were trained to increase their skin temperature by an experienced biofeedback therapist for about 15 min according to the procedures described in a treatment manual. During the last 15 min, they were instructed to continue the relaxation exercise by themselves, while listening to a prerecorded tape. They were also asked to perform autogenic training as homework between the sessions.

Measuresof pain andpsychologicalvariables

Headache indices were obtained using a daily headache diary over 7 consecutive days. Success was defined as a 50% reduction in the score. The headache severity was rated on a 6-point rating scale with 0 representing "no pain" and 5 representing "pain as severe as it can be". The headache severity was recorded every hour except during sleep. The average frequency, duration, and intensity of pain during the 7 consecutive days were compiled as headache indexes. Headache indexes at baseline, after 2 weeks, and after 4 weeks of biofeedback treatment were used to compare the two groups. Secondary outcomes were evaluated using the MPQ (17) and the Clinical Global Impression severity scale (CGI-S) administered by the therapist. The baseline headache

variables were recorded for the previous 1 week before the treatment and the follow-up headache variables as the mean of the symptoms during the previous week. Due to the possibility of there being a change in the perception of pain according to the menstrual cycle (18), the menstruation phase was determined by asking the subjects the onset of their last menstruation. Before the biofeedback treatment, there were no differences in the headache indices and mood states between the treatment group and monitoring group according to the menstruation phase. The psychological assessments for anxiety and depressive symptoms were performed using the Hamilton Rating Scales for Anxiety (HAM-A) (19) and Depression (HAM-D) (20), and the Spielberger State Anxiety Inventory (STAI-S) (21). The CGI-S, HAM-A, and HAM-D were performed by a well-trained psychiatrist who was blind to the patients' clinical states.

Dataanalyses

To compare the baseline values, chi-square test, Fisher's exact test, and analysis of variance (ANOVA) were used. Treatment outcome analysis in terms of headache index was preformed using chi-square test. Repeated measures ANOVA was performed to analysis mean changes of skin temperature, psychological variables, and secondary pain outcomes. Student's t-test with Bonferroni's correction was performed for post hoc analysis. Univariate and multivariate logistic regression analyses were used to whether the baseline or changes of depression and anxiety level could predict the treatment outcome. All of the analyses were performed using the SPSS 13.0 statistical software. Go to: RESULTS The Fisher's exact test revealed a significant difference in the response rate in terms of headache index between the two groups (2=4.979, df=1, P=0.029). Ten of the 17 patients (58.9%) in the treatment group showed a significant improvement in their headache index corresponding to a 50% or greater reduction in their headache activity, whereas only 3 of the 15 subjects (20%) in the monitoring group achieved a significant improvement (Fig. 1). Repeated measures ANOVA indicated that there were significant interactions between time and group in the MPQ-S (F=6.994, P=0.014), MPQ-A (F=9.978, P=0.006), and CGI-S (F=16.160, P=0.001). Mean resting skin temperatures did not show any differences between the treatment and monitoring group, nor pre- and post-treatment (all P values >0.1). The results of the comparisons of the psychological states of the three groups are shown in Table 2. The anxiety and depression levels in the migraine patients were significantly higher than those in the normal control subjects at the baseline (all P values <0.001). There were no group differences between the biofeedback-assisted autogenic training group and the monitoring group.

Fig. 2 shows the results of the repeated-measures ANOVA in the psychological variables. Significant interactions between time and group were found for the HAM-A (F=10.560, P=0.003), HAM-D (F=8.161, P=0.013), and STAI-S (F=12.320, P=0.002). Post hoc analysis revealed that there were significant between-group differences at the endpoint (P=0.002, 0.032, 0.001, respectively). Age, BMI, the baseline HAM-D, HAM-A, and STAI-S were not associated with treatment response in terms of headache index (all P values >0.1) in the biofeedbackassisted training group. However, the multivariate logistic regression revealed that the greater reduction of the HAM-A score was associated with the treatment response controlling for age, BMI, and the baseline HAM-A in the biofeedback-assisted autogenic training group (OR=1.52, CI=1.01-2.33, P=0.048) whereas the reduction of the HAM-D score nor that of the STAI-S were not (P=0.088 and P=0.080, respectively). Go to: DISCUSSION We found that biofeedback-assisted autogenic training is effective in management of female migraine patients in Korean population. They also exhibited significant differences in their mood states measured by the HAM-A, HAM-D, STAI-S, as compared with the normal healthy women. This finding is consistent with the results of previous studies which showed that migraine patients had high levels of anxiety and depression (12,14,22). It is also consistent with a previous report (23) that negative mood states such as anxiety and depression are related to physical complaints and headache. The anxiety and depression scores in the migraine patients were reduced after 4 weeks of biofeedback treatment. Furthermore, the reduction in anxiety level after the biofeedback treatment was related to the treatment response of the patients. To our knowledge, there have been no reports about the association between mood states, including anxiety and depression, and improvements in headache activity in migraine patients receiving biofeedback treatment. Our result is also consistent with the finding of previous studies (24-27) that mood states might affect the experience of pain through the cognitive processing of nociceptive information, although this hypothesis has not been directly examined in headache patients. The present result is in contrast with the previous report (2) that decreased depression level rather than anxiety was related to the outcome of biofeedback-assisted training in patients with chronic tension-type headache. Taken together, reduction of anxiety may be related to the biofeedback treatment response of migraine headache, whereas reduction of depression may be related to the biofeedback treatment response of chronic tension-type headache. Further studies will be necessary to confirm this difference between migraine and tension type headache. Mean skin temperatures between the pre- and post-treatment changes were not statistically different. Our finding also suggests that the reduction of anxiety rather than depression level is more important in the biofeedback treatment of migraine. This result appears to confirm the previous findings that the treatment mechanism of biofeedback is mediated by an indirect process rather than a direct physiological change (28,29).

19. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959;32:5055.

20. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:5662.

21. Spielberger CD, Gorsuch RL, Lushene RE. Manual for the State Trait Anxiety Inventory. Palo Alto, DA: Consulting Psychologists Press; 1970. 22. de Filippis S, Salvatori E, Coloprisco G, Martelletti P. Headache and mood disorders. J Headache Pain 2005;6:250253.

23. Watson D, Pennebaker JW. Health complaints, stress, and distress: exploring the central role of negative affectivity. Psychol Rev 1989;96:234254.

24. Cornwall A, Donderi DC. The effect of experimentally induced anxiety on the experience of pressure pain. Pain 1988;35:105113.

25. Dougher MJ, Goldstein D, Leight KA. Induced anxiety and pain. J Anxiety Disord 1987;1:259264.

26. Rhudy JL, Meagher MW. Fear and anxiety: divergent effects on human pain thresholds. Pain 2000;84:6575.

27. Robinson ME, Wise EA, Gagnon C, Fillingim RB, Price DD. Influences of gender role and anxiety on sex differences in temporal summation of pain. J Pain 2004;5:7782.

28. Arena JG, Bruno GM, Hannah SL, Meador KJ. A comparison of frontal electromyographic biofeedback training, trapezius electromyographic biofeedback training, and progressive muscle relaxation therapy in the treatment of tension headache. Headache 1995;35:411419.

29. Holroyd KA, Penzien DB, Hursey KG, Tobin DL, Rogers L, Holm JE, Marcille PJ, Hall JR, Chila AG. Change mechanisms in EMG biofeedback training: cognitive changes underlying improvements in tension headache. J Consult Clin Psychol 1984;52:10391053.

30. Breslau N, Schultz LR, Stewart WF, Lipton R, Welch KM. Headache types and panic disorder: directionality and specificity. Neurology 2001;56:350354.

Combat-Related Posttraumatic Headache: Diagnosis, Mechanisms of Injury, and Challenges to Treatment

1. CPT Matthew Kozminski, DO, MC, USA + Author Affiliations 1. Dr Kozminski was a neurology resident at Madigan Army Medical Center in Tacoma, Washington, when he conducted the present study. 1. Address correspondence to CPT Matthew Kozminski, DO, MC, USA, Chief, Neurology Clinic, Darnall Army Medical Center, 36000 Darnall Loop, Fort Hood, TX 76544. E-mail: mpkst17@yahoo.com. Next Section

Abstract
Context: Studies have revealed the rates of posttraumatic stress disorder (PTSD) and concussion among US soldiers returning from combat, but only one study has focused on the subpopulation of soldiers with headache. Objectives: To determine the rate of PTSD among US soldiers with comorbid chronic posttraumatic headache attributed to head injury, to identify common mechanisms of head injury, and to identify the common challenges a healthcare provider must face when treating US soldiers with chronic posttraumatic headache attributed to head injury. Methods: Between July 2007 and December 2008, the author examined 42 US Army soldiers with complaint of chronic headache. In March 2009, the author retrospectively reviewed the outpatient records for diagnoses, mechanisms of injury, and challenges to treatment. Results: The rate of concussion, defined by the Defense and Veterans Brain Injury Center Working Group on the Acute Management of Mild Traumatic Brain Injury in Military Operational Settings, was 95%. The rate of PTSD, as determined either with the PTSD Checklist or by confirming a prior diagnosis by another healthcare provider, was 97.9%. Both rates are remarkably higher than rates reported in the literature. The most common mechanisms of injury were proximity to blast (18 [45.2%]) and direct target of blast (15 [35.7%]). The most common treatment challenges were overuse of headacheabortive medications (10 [23.8%]) and poor patient followup (7 [16.7%]).

Conclusion: Physicians should be aware that the rates of PTSD and concussion for US soldiers, most often linked to involvement in or proximity to a blast, are higher for soldiers complaining of chronic headache. Physicians should also be aware of the potential for overuse of medications in this patient population. Previous SectionNext Section Since 2007, evaluating and treating US soldiers returning from combat with a complaint of headache has become an integral component of neurology residency training at Madigan Army Medical Center. At about that time, more formal traumatic brain injury (TBI) screening programs were being established at Fort Lewis for US soldiers returning from combat tours, thus leading to an increased number of neurology consultations for soldiers with headache as a comorbidity. Although studies1-4 have reported rates of posttraumatic stress disorder (PTSD) and concussion or mild TBI for US soldiers returning from combat settings, only one study attempted to focus on a subpopulation of soldiers with a comorbid complaint of headache.2 Furthermore, all were questionnairebased studies of soldiers returning from combat tours. Questionnaire-based studies may have low response rates and therefore may introduce volunteer bias. Based on the hypothesis that the rates of PTSD and concussion or mild TBI are higher in soldiers complaining of chronic headache and that these rates will be higher when data are obtained from direct face-to-face patient interviews, I conducted a retrospective review of patient records from soldiers with complaint of chronic headache. Records were evaluated for diagnosis, mechanism of injury, and barriers to treatment. A significant portion of these soldiers are transitioning to a civilian life for a variety of reasons; thus, it is imperative that the various aspects of these soldiers lives, particularly the rate of PTSD with TBI, patient follow-up, and medication overuse, are shared with civilian counterpartsprimary care physicians and physician specialists alike. Previous SectionNext Section

Methods
Between July 2007 and December 2008, I completed three separate outpatient clinic rotation blocks as a neurology resident at Madigan Army Medical Center in Tacoma, Washington, during my postgraduate third and fourth years of training. I also completed the required half day per week of continuity clinic. During this time frame, I examined 42 US Army soldiers with a history of a deployment to Iraq or Afghanistan and who had complaint of chronic headache. At each encounter, I attempted to confirm diagnosis of PTSD, if appropriate, and inquired whether headache onset was temporally related to injury or concussive symptoms. I obtained as much detail as possible regarding each soldier's combat-related injury that might have triggered headache. Examinations included medical evaluation board (MEB) consultations and temporary duty retirement list evaluations. In MEB consultations, the consultant assesses the

soldier's fitness for duty and determines whether the soldier should be referred to an evaluation board for consideration of medical discharge as a result of his or her medical condition. Temporary duty retirement list evaluations comprise examinations of soldiers who have been medically discharged from the military and who return for annual evaluations to determine whether their conditions have improved enough for possible rein-statement into active-duty military service. Many of the soldiers had a preexisting diagnosis of PTSD from another healthcare provider before I examined them; however, if this was not the case, I conducted an inperson interview, with the PTSD Checklist5 used as a guide to identify the diagnosis (Appendix 1). Each soldier was asked about symptoms of concussion6 as they appear on the Military Acute Concussion Evaluation (MACE) form (Figure 1). If concussive symptoms temporally related to headache onset and injury were in question, I tried to ensure that the soldier met the definition of concussion provided by the Defense and Veterans Brain Injury Center Working Group on the Acute Management of Mild Traumatic Brain Injury in Military Operational Settings (Appendix 2).7 If a soldier met the definition of concussion, noted headache onset temporally related to the event that precipitated the concussion, or noted exacerbation of a prior headache disorder temporally related to the event that precipitated concussion, then a formal diagnosis of chronic posttraumatic headache attributed to mild head injury was given, as defined by the International Classification of Headache Disorders (ICHD-II) criteria8 (Appendix 3). In March 2009, I retrospectively reviewed the outpatient records of these 42 soldiers. On review, any of the following treatment or management challenges were noted: analgesia or opioid overuse, overuse of prescribed headache-abortive medications, mistrust of providers or frustration with care, poor compliance with patient follow-up, any questionable legitimacy of complaints (eg, possible embellishment of symptoms for secondary gain, possible somatization, factitious disorder), and expressed dislike of taking medications. The diagnosis of PTSD and the description of the reported mechanism of injury as reported in the outpatient record were also noted on retrospective review. If any soldier was referred to a neuropsychologist for a formal evaluation, the encounters were also retrospectively reviewed to determine whether the neuropsychologist thought that any complaints had questionable legitimacy.

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Figure 1. Symptoms of concussion. Source: Item VIII, Military Acute Concussion Evaluation (MACE). Available at http://www.cs.amedd.army.mil/filedownload.aspx?docid=930. Previous SectionNext Section

Results
Of the reviewed soldiers' records, 5 (12%) were strictly one-time consultations for either an MEB or a temporary duty retirement list evaluation. Seven soldiers (17%) were eventually referred for MEB consultation, and 5 (12%) left the military for nonmedical reasons. Overall, 17 soldiers (40.4%) had already transitioned or were transitioning to a civilian life for a variety of reasons; long-term follow-up of these particular soldiers was not possible. However, I followed up with most for the purposes of routine care of their symptoms until they transitioned to a civilian life, were discharged from my care, or until I graduated from the residency program. Follow-up care is not described in the present study. The most commonly reported mechanism of injury (19 [45.2 %]) leading to a concussion or mild TBI was close proximity to a blast; that is, soldiers reported experiencing the effects of a shock wave secondary to a nearby blast but not being direct targets of an explosive device. In addition, a substantial proportion of soldiers (15 [35.7%]) reported being inside a physical structure or military vehicle that was the direct target of an explosive device. Smaller proportions of soldiers reported vehicle rollovers or crashes (4 [9.5%]) or falls related to combat scenarios unrelated to explosions (4 [9.5%]) (Figure 2). Overall, 40 soldiers (95%) met the definition of concussion7; however, only 15 soldiers (36%) could account for a witnessed period of definite loss of consciousness, and only 15 (36%) could account for a definite blow to the head. For those who could not account for a definite blow to the head, many implied that the combat situation at the time of injury generated such a fearful or stressful response that the details of the head injury could not be recalled. The majority of these individuals at least agreed that although they could not offer an exact or accurate account of possible mild head injury, they did experience the effects of a blast-related shock wave.

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Figure 2. Categories of injuries as reported by US soldiers (N=42) in the present retrospective review. Overall, 41 soldiers (98%) had PTSD, as determined either by prior diagnosis or by an inperson interview with the PTSD Checklist5 used as a guide. According to patient interview and documentation in outpatient records, 3 soldiers (7%) probably had a predeployment history of a primary headache disorder; however, all agreed that their headache disorder was exacerbated by their respective concussion or mild TBI. Of the many challenges regarding the management of these soldiers, the most common were overuse of headache-abortive medications and overuse of analgesia or opioids (Table). The most commonly overused abortive medications were isometheptene mucate, dichloralphenazone, and acetaminophen; acetaminophen, butalbital, and caffeine; and serotonin receptor agonist medications. Unfortunately, many soldiers with a history of analgesia or opioid overuse took these medications for comorbid painful conditions other than headache. View this table: In this window In a new window Table Common Management Challenges in US Soldiers With Chronic Headache (N=42) * Many soldiers underwent formal consultation by a neuropsychologist, most for complaints of chronic neurocognitive deficits after head injury. Overall, only 2 soldiers

(4.8%) were reported as having questionably legitimate complaints (embellishment of symptoms, factitious disorders, or somatization). Previous SectionNext Section

Comment
In the past, concussion was one of the most commonly overlooked symptoms of blastinjured soldiers.9 More recent studies have indicated that the rates of concussion or mild TBI for US soldiers deployed to combat range from 12% to 41%;1-4 the rates of PTSD are reported to be 11% to 43.9%.1-4 These rates of concussion or mild TBI and PTSD are discordant with the rates reported in the present study95% and 97.9%, respectively. A survey-based, cross-sectional study of Iraq or Afghanistan veterans conducted at the Washington DC Veterans Affairs Medical Center reported rates of 12% for mild TBI and 11% for PTSD.1 Evans Army Community Hospital4 reported clinician-confirmed TBI in 22.8% of soldiers, using the responses of the Warrior Administered Retrospective Casualty Assessment (WARCAT)10 and clinician interview. The Walter Reed Army Institute of Research reported injury and loss of consciousness in 4.9% of soldiers and injury and altered mental status in 10.3%.3 Of note, those with reported loss of consciousness had a much higher rate of PTSD than those who did not report loss of consciousness or injuries.3 None of these prior studies examined the subpopulation of soldiers suffering from chronic headache. In addition, all of these studies were reliant on self-administered questionnaires, which may have lead to volunteer bias. For the questionnaire-based studies at the Washington DC Veterans Affairs Medical Center and Walter Reed Army Institute of Research, the rates of nonresponders were 62.9% and 7%, respectively.1,3 A retrospective cohort study2 at Madigan Army Medical Center of 81 US soldiers seen at the neurology clinic for chronic headache demonstrated a history of head or neck trauma with concussion, with or without loss of consciousness, in 41% of soldiers and a high likelihood of PTSD in 6%. Although that study did target soldiers complaining of chronic headache, portions of the data relied on self-administered questionnaires, which again probably led to volunteer bias. For all 42 soldiers described in the present study, the diagnosis of concussion or mild TBI and PTSD was considered by a face-to-face interview with a neurology resident (M.K.) and not reliant on self-administered questionnaires, thus eliminating volunteer bias. In addition, these soldiers were known to have a comorbid complaint of headache in addition to a history of combat-related injury. Previous SectionNext Section

Role of Osteopathic Medicine

Osteopathic medicine provides a patient-centered approach that integrates recognized and rational healing methods, including osteopathic manipulative treatment (OMT), to improve the health and physiological function of patients.11 There is some basis for the belief that physical manipulation, many techniques of which focus on the cervical spine, can be beneficial in treating certain headache disorders. Biondi12 postulated that head pain may frequently arise from or be influenced by various soft tissues and neurogenic or osseous structures of the head, neck, and upper body. Pain elicits a heightened response of the sympathetic nervous system that can cause vasoconstriction, ischemia, chemical changes, more muscle contraction, and pain, creating a vicious cycle.13 Techniques of OMT are believed to improve circulation; release restrictions in joints; reduce tension in the muscles, fascia, and dura mater; decrease nociceptive input; and promote the normalization or calming of the central nervous system.13 Prior literature has emphasized the importance of focus on the occipitoatlantal joint, occipital condyles, and occipitomastoid joint; sphenobasilar syncondrosis in migraine; and use of craniosacral techniques for cervicogenic headache.14-16 In at least one small case series, OMT was shown to be a helpful adjunct therapy to traditional pharmacologic therapies for US soldiers suffering from posttraumatic headache attributed to mild head injury.17 Previous SectionNext Section

Conclusion
Soldiers returning from combat-related deployments to Iraq or Afghanistan with a complaint of chronic headache have higher rates of concussion or mild TBI and PTSD than those who do not complain of chronic headache. The overall rates of concussion or mild TBI and PTSD are probably underreported when based on the results of selfadministered questionnaires; this discrepancy may be related to volunteer bias and, in some cases, nonresponders. The most common treatment challenges for soldiers with chronic posttraumatic headache attributed to head injury are the overuse of typical headache-abortive medications and poor patient follow-up. Although OMT may be a useful adjunct therapy for combat-related chronic posttraumatic headache attributed to mild head injury, further studies need to be performed. Previous SectionNext Section View this table: In this window In a new window Appendix 1

The Posttraumatic Stress Disorder (PTSD) Checklist is a 17-item questionnaire in which each item is scored from 1 to 5. For example, a response of not at all is scored as 1, and a response of extremely is scored as 5. The patient must have a cumulative score of 50 or greater to receive a diagnosis of PTSD. The version shown here is the military version of the checklist. The checklist has been modified for graphic enhancement and minor style issues only. View this table: In this window In a new window Appendix 2 Definition of concussion used in the present study. Source: The Management of ConcussionTBI Working Group. VA/DoD Clinical Practice Guideline for Management of Concussion/Mild Traumatic Brain Injury. Washington, DC: Department of Veterans Affairs and Department of Defense; March 2009. http://www.dvbic.org/images/pdfs/providers/VADoD-CPGConcussion-mTBI.aspx. Accessed August 19, 2010. View this table: In this window In a new window Appendix 3 The International Classification of Headache Disorders (ICHD-II) criteria for chronic posttraumatic headache attributed to head injury. Source: Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24(suppl 1):9-160. Previous SectionNext Section

Footnotes

Disclaimer: The opinions and assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Army, Department of Defense, or the US Government. Financial Disclosure: None reported. Received September 9, 2009. Revision received November 23, 2009. Accepted May 2, 2010.

Previous Section

References
1. Schneiderman AI, Braver ER, Kang HK. Understanding sequelae of injury mechanisms and mild traumatic brain injury incurred during the conflicts in Iraq and Afghanistan: persistent postconcussive symptoms and posttraumatic stress disorder. Am J Epidemiol. 2008;167(12):1446-1452. Abstract/FREE Full Text 2. Theeler BJ, Erickson JC. Mild head trauma and chronic headaches in returning US soldiers. Headache. 2009;49(4):529-534. Medline 3. Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild traumatic brain injury in U.S. soldiers returning from Iraq. N Engl J Med2008;358(5):453463. CrossRefMedline 4. Terrio H, Brenner LA, Ivins BJ, et. al. Traumatic brain injury screening: preliminary findings is a US Army brigade combat team. J Head Trauma Rehabil. 2009;24(1):14-23. CrossRefMedline 5. Weathers F, Litz B, Herman D, Huska J, Keane T. The PTSD Checklist (PCL): reliability, validity, and diagnostic utility. Paper presented at: Annual Convention of the International Society for Traumatic Stress Studies; San Antonio, TX; 1993.
6.

Military Acute Concussion Evaluation (MACE). http://www.cs.amedd.army.mil/filedownload.aspx?docid=930. Accessed August 19, 2010.

7.

Management of Concussion/mTBI Working Group, Department of Veterans Affairs. VA/DoD Clinical Practice Guideline for Management of Concussion/Mild Traumatic Brain Injury. Washington, DC: Department of Veterans Affairs and Department of Defense; March 2009. http://www.dvbic.org/images/pdfs/providers/VADoD-CPGConcussionmTBI.aspx. Accessed August 19, 2010. 8. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24(suppl 1):9-160. FREE Full Text 9. Scott SG, Belanger HG, Vaderploeg RD, Massengale J, Scholten J. Mechanismof-injury approach to evaluating patients with blast-related polytrauma. J Am Osteopath Assoc. 2006;106(5):265-270. Abstract/FREE Full Text
10.

Soldier Readiness Process Fort Carson TBI Questionnaire, TBI Reassessment (Fort Carson) and Fort Carson TBI Educational Handout. http://www.evans.amedd.army.mil/srp/WARCAT%20DEC%202007.xls. Accessed August 19, 2010. 11.

Kuchera ML. Applying osteopathic principles to formulate treatment for patients with chronic pain. J Am Osteopath Assoc. 2007;107(11 suppl 6):ES28-ES38. Abstract/FREE Full Text 12.

Biondi DM. Physical treatments for headaches: a structured review. Headache. 2005;45(6):738-746. CrossRefMedline

13.

Anderson RE, Seniscal C. A comparison of selected osteopathic treatment and relaxation for tension-type headaches. Headache. 2006;46(8):1273-1280. Medline 14.

Biondi DM. Cervicogenic headache: a review of diagnostic and treatment strategies. J Am Osteopath Assoc. 2005;105(4 suppl 2):S16-S21. Abstract/FREE Full Text 15. Batchelor K, Gamber R. Migraine and OMT. Am Acad Osteopath J. 2008;18(1):30-33. 16. Bernhardi EF. Cranial osteopathy for migraine headaches. Cranial Letter. 1995;48(1):4-6. 17.

Kozminski M, Kozminski T. OMT as an adjunct therapy for post-traumatic headache in U.S. soldiers: a case series. Am Acad Osteopath J. 2009;19 (2): 2324.

J Korean Med Sci. 2009 Oct;24(5):936-940. English. Published online 2009 September 23. http://dx.doi.org/10.3346/jkms.2009.24.5.936 Copyright 2009 The Korean Academy of Medical Sciences

Effect of Biofeedback-assisted Autogenic Training on Headache Activity and Mood States in Korean Female Migraine Patients
Eun-Ho Kang,1 Joo-Eon Park,2 Chin-Sang Chung,3 and Bum-Hee Yu 1 1 Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 2 Department of Psychiatry, Keyo Hospital, Euiwang, Korea. 3 Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Address for correspondence: Bum-Hee Yu, M.D. Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-gu, Seoul 135-710, Korea. Tel: +82.2-3410-3583, Fax: +82.2-3410-6957, Email: bhyu@skku.edu Received June 05, 2008; Accepted October 10, 2008. This is an Open Access article distributed under the terms of the Creative Commons Attribution NonCommercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. This article has been cited by 3 articles in This article has been cited by 1 article in KoMCI This article has been cited by 3 articles in Web of Science

Go to:

Abstract
Biofeedback with or without combined autogenic training is known to be effective for the treatment of migraine. This study aimed to examine the effect of biofeedback treatment on headache activity, anxiety, and depression in Korean female patients with migraine headache. Patients were randomized into the treatment group (n=17) and monitoring group (n=15). Mood states including anxiety and depression, and psychophysiological variables such as mean skin temperature of the patients were compared with those of the normal controls (n=21). We found greater treatment response rate (defined as 50% reduction in headache index) in patients with biofeedback-assisted autogenic training than in monitoring group. The scores on the anxiety and depression scales in the patients receiving biofeedback-assisted autogenic training decreased after the biofeedback treatment. Moreover, the decrease in their anxiety levels was significantly related to the treatment outcome. This result suggests that the biofeedback-assisted autogenic training is effective for the treatment of migraine and its therapeutic effect is closely related to the improvement of the anxiety level. Keywords:Migraine, Biofeedback, Autogenic Training, Anxiety, Depression.

Go to: INTRODUCTION Migraine is a highly prevalent illness, and women of reproductive ages are more affected

by it than men or women in other age groups (1). Many researchers have supported the view that behavioral interventions such as biofeedback and relaxation, either alone or in combination, can be effective for the treatment of headache (2-7). Especially, thermal biofeedback with or without combined autogenic training is known to be effective for the treatment of migraine headache (5,8). In addition, some studies showed that the effect of the behavioral treatment is durable (9,10). There have been no controlled studies about the efficacy of biofeedback and relaxation training for patients with migraine in Korea, and few studies have been conducted to investigate the direct association between mood states, including anxiety or depression, and headache activity. The mechanism underlying the efficacy of biofeedback treatment and the role of psychological factors in migraine treatment are still unclear, though various mood states, including anxiety and depression, and some cognitive factors are known to be related to pain regulation (11-13). Psychological conditions including anxiety and depression have been reported to have a strong association with migraine (12-14). Thus, in this study, we examined the hypothesis that biofeedback-assisted autogenic training is effective for the treatment of Korean female patients with migraine and that the improvement of psychological factors, such as anxiety and depression, is associated with the reduction of headache activity in migraine patients who are given biofeedback treatment. Go to: MATERIALS AND METHODS
Subjects

Thirty-two patients, who had migraine headache with or without aura, as defined by the International Headache Society criteria (15), participated in this study, from March 2003 until December 2006. The patients were female subjects aged 20 to 40 yr who had a body mass index (BMI) ranging from 18 to 27.5. They were among the migraineurs who visited the Samsung Medical Center. The patients were randomly allocated to one of two patient groups, consisting of a treatment group receiving biofeedback-assistant relaxation treatment (n=17) and a monitoring group in which the headache activities and biofeedback parameters of the patients were simply measured (n=15). These two groups did not show any significant difference in the duration of headache, headache index, duration of medication use, or other headache-related variables at the baseline (Table 1). Twenty-one normal female volunteers were recruited by advertisement and were matched with the migraine patients by age (treatment group: 31.125.49 yr, monitoring group: 31.874.70 yr, normal control group: 29.384.64 yr), and mood states and mean skin temperature of the patients before the biofeedback treatment were compared with those of the normal control subjects. Each subject underwent a comprehensive medical and psychiatric assessment including careful history taking, physical examination, neurological examination, mental status examination, and electrocardiography. Those patients who seemed to suffer from secondary headache due to medical or psychiatric illnesses were not included in the study. They did not take regular medications for

migraine headache, and only pro re nata (p.r.n.) medication such as sumatriptan was permitted during the study. This study was approved by the Institutional Review Board of Samsung Medical Center, and all of the subjects gave their written informed consent.

Procedure& Treatment

The patients in the treatment group received 8 sessions of biofeedback-assisted autogenic training (two sessions per week) during a period of 4 weeks, while those in the monitoring group received no active intervention except for simple biofeedback measurements (1st, 4th, and 8th session) during the treatment-waiting period. Biofeedback treatment was administered with the patient sitting on a comfortable armchair in a quiet room in the psychiatric outpatient clinic of Samsung Medical Center. A Procomp+system and Biograph version 2.1 program (Thought Technology Ltd., Quebec, Canada) were used for the biofeedback treatment and measurements. Each biofeedback-assisted autogenic training session lasted about 45-50 min. The autogenic training procedures consisted of 6 standard exercises combining both relaxation and auto-suggestion (limb heaviness exercise, limb warmth exercise, cardiac exercise, respiration exercise, solar plexus warmth exercise, and "forehead cooling" exercise) (16). During the 1st session, after the baseline profiles were obtained, education in relaxation techniques was given to the patients in the treatment group. During the 2nd to 8th sessions, thermal biofeedback combined with autogenic training was provided. For the first 15-20 min, after collecting the headache diary data, the patients were rated on psychological variables and headache severity. The patients were trained to increase their skin temperature by an experienced biofeedback therapist for about 15 min according to the procedures described in a treatment manual. During the last 15 min, they were instructed to continue the relaxation exercise by themselves, while listening to a prerecorded tape. They were also asked to perform autogenic training as homework between the sessions.

Measuresof pain andpsychologicalvariables

Headache indices were obtained using a daily headache diary over 7 consecutive days. Success was defined as a 50% reduction in the score. The headache severity was rated on a 6-point rating scale with 0 representing "no pain" and 5 representing "pain as severe as it can be". The headache severity was recorded every hour except during sleep. The average frequency, duration, and intensity of pain during the 7 consecutive days were compiled as headache indexes. Headache indexes at baseline, after 2 weeks, and after 4 weeks of biofeedback treatment were used to compare the two groups. Secondary outcomes were evaluated using the MPQ (17) and the Clinical Global Impression severity scale (CGI-S) administered by the therapist. The baseline headache variables were recorded for the previous 1 week before the treatment and the follow-up

headache variables as the mean of the symptoms during the previous week. Due to the possibility of there being a change in the perception of pain according to the menstrual cycle (18), the menstruation phase was determined by asking the subjects the onset of their last menstruation. Before the biofeedback treatment, there were no differences in the headache indices and mood states between the treatment group and monitoring group according to the menstruation phase. The psychological assessments for anxiety and depressive symptoms were performed using the Hamilton Rating Scales for Anxiety (HAM-A) (19) and Depression (HAM-D) (20), and the Spielberger State Anxiety Inventory (STAI-S) (21). The CGI-S, HAM-A, and HAM-D were performed by a well-trained psychiatrist who was blind to the patients' clinical states.

Dataanalyses

To compare the baseline values, chi-square test, Fisher's exact test, and analysis of variance (ANOVA) were used. Treatment outcome analysis in terms of headache index was preformed using chi-square test. Repeated measures ANOVA was performed to analysis mean changes of skin temperature, psychological variables, and secondary pain outcomes. Student's t-test with Bonferroni's correction was performed for post hoc analysis. Univariate and multivariate logistic regression analyses were used to whether the baseline or changes of depression and anxiety level could predict the treatment outcome. All of the analyses were performed using the SPSS 13.0 statistical software. Go to: RESULTS The Fisher's exact test revealed a significant difference in the response rate in terms of headache index between the two groups (2=4.979, df=1, P=0.029). Ten of the 17 patients (58.9%) in the treatment group showed a significant improvement in their headache index corresponding to a 50% or greater reduction in their headache activity, whereas only 3 of the 15 subjects (20%) in the monitoring group achieved a significant improvement (Fig. 1). Repeated measures ANOVA indicated that there were significant interactions between time and group in the MPQ-S (F=6.994, P=0.014), MPQ-A (F=9.978, P=0.006), and CGI-S (F=16.160, P=0.001). Mean resting skin temperatures did not show any differences between the treatment and monitoring group, nor pre- and post-treatment (all P values >0.1). The results of the comparisons of the psychological states of the three groups are shown in Table 2. The anxiety and depression levels in the migraine patients were significantly higher than those in the normal control subjects at the baseline (all P values <0.001). There were no group differences between the biofeedback-assisted autogenic training group and the monitoring group.

Fig. 2 shows the results of the repeated-measures ANOVA in the psychological variables. Significant interactions between time and group were found for the HAM-A (F=10.560, P=0.003), HAM-D (F=8.161, P=0.013), and STAI-S (F=12.320, P=0.002). Post hoc analysis revealed that there were significant between-group differences at the endpoint (P=0.002, 0.032, 0.001, respectively). Age, BMI, the baseline HAM-D, HAM-A, and STAI-S were not associated with treatment response in terms of headache index (all P values >0.1) in the biofeedbackassisted training group. However, the multivariate logistic regression revealed that the greater reduction of the HAM-A score was associated with the treatment response controlling for age, BMI, and the baseline HAM-A in the biofeedback-assisted autogenic training group (OR=1.52, CI=1.01-2.33, P=0.048) whereas the reduction of the HAM-D score nor that of the STAI-S were not (P=0.088 and P=0.080, respectively). Go to: DISCUSSION We found that biofeedback-assisted autogenic training is effective in management of female migraine patients in Korean population. They also exhibited significant differences in their mood states measured by the HAM-A, HAM-D, STAI-S, as compared with the normal healthy women. This finding is consistent with the results of previous studies which showed that migraine patients had high levels of anxiety and depression (12,14,22). It is also consistent with a previous report (23) that negative mood states such as anxiety and depression are related to physical complaints and headache. The anxiety and depression scores in the migraine patients were reduced after 4 weeks of biofeedback treatment. Furthermore, the reduction in anxiety level after the biofeedback treatment was related to the treatment response of the patients. To our knowledge, there have been no reports about the association between mood states, including anxiety and depression, and improvements in headache activity in migraine patients receiving biofeedback treatment. Our result is also consistent with the finding of previous studies (24-27) that mood states might affect the experience of pain through the cognitive processing of nociceptive information, although this hypothesis has not been directly examined in headache patients. The present result is in contrast with the previous report (2) that decreased depression level rather than anxiety was related to the outcome of biofeedback-assisted training in patients with chronic tension-type headache. Taken together, reduction of anxiety may be related to the biofeedback treatment response of migraine headache, whereas reduction of depression may be related to the biofeedback treatment response of chronic tension-type headache. Further studies will be necessary to confirm this difference between migraine and tension type headache. Mean skin temperatures between the pre- and post-treatment changes were not statistically different. Our finding also suggests that the reduction of anxiety rather than depression level is more important in the biofeedback treatment of migraine. This result appears to confirm the previous findings that the treatment mechanism of biofeedback is mediated by an indirect process rather than a direct physiological change (28,29).

Cognitive factors such as increased self-efficacy belief or coping style can affect the success of biofeedback treatment, and anxiety is known to be closely associated with cognitive factors (11). However, since migraine is known to be inter-related to anxiety (30), our tentative finding has the limitation that it does not confirm whether an improvement in anxiety causes a decrease in headache activity. Further studies are needed to examine the relationship among mood states, cognitive factors, and headache. There are several limitations in this study. Firstly, the time period of the study was short. Migraine is an illness with a fluctuating course in which the symptoms wax and wane, and psychophysiological treatment may have a delayed effect. Secondly, the severity of headache in the recruited patients was relatively low and the patients in this study may not represent the general population with migraine headache. Finally, our sample size was relatively small. However, to the best of our knowledge, this is the first controlled study to examine the efficacy of biofeedback treatment and the relationship between mood states and headache activity in Korean migraine patients. In conclusion, biofeedback treatment was found to cause an improvement of headache and mood states such as anxiety and depression in female migraine patients. In addition, the reduction of anxiety level was related to the biofeedback treatment response. These results suggest that biofeedback treatment can be an effective non-pharmacological treatment for migraine patients and that the improvement of the anxiety states afforded by biofeedback treatment may play a key role in reducing headache activity. Go to: Figures

Fig. 1 Greater treatment response rate (defined as 50% reduction in headache index) was observed in patients with biofeedback-assisted autogenic training than in monitoring-only group (58.9% vs. 20%, 2=4.979, d=1, P=0.029).

Fig. 2 Mood states by treatment group (Biofeedback-assisted autogenic training group vs. monitoring-only group). There were significant interactions between the two groups in changes of the HAM-A (F=10.560, P=0.003), HAM-D (F=8.161, P=0.013), and STAI-S (F=12.320, P=0.002). Post hoc analyses revealed that there were significant differences at the endpoint between the two groups in all the mood states (all P values <0.1).

Go to: Tables

Table 1 Sample characteristics Data are given as n (%) or meanS.D. BMI, body mass index; MPQ-S, the McGill Pain Questionnaire-Sensory; MPQ-A, the McGill Pain Questionnaire-affective; CGI-S, the Clinical Global Impression for Severity.

Table 2 Mood states of migraine patients and normal control subjects at baseline Data are given as meanS.D.
*

Significant by one-way analysis of variance (ANOVA). Post hoc analysis revealed that there were no significant differences in the mood states between the treatment and monitoring groups, whereas there was a significant differences between the patient group and normal controls (P<0.01, by Bonferroni's correction). HAM-A, the Hamilton Rating Scale for Anxiety; STAI-S, the Spielberger State Anxiety Inventory; HAM-D, the Hamilton Rating Scale for Depression.

Go to: Notes
This study was supported by a grant from the Korea Health Industry Development Institute and the Ministry of Health and Welfare (02-PJ1-PG1-CH05-0003).

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8. Stetter F, Kupper S. Autogenic training: a meta-analysis of clinical outcome studies. Appl Psychophysiol Biofeedback 2002;27:4598.

9. Grazzi L, Andrasik F, D'Amico D, Leone M, Moschiano F, Bussone G. Electromyographic biofeedback-assisted relaxation training in juvenile episodic tension-type headache: clinical outcome at three-year follow-up. Cephalalgia 2001;21:798803.

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ORIGINAL ARTICLE

Characteristics of Mood Disorders in Japanese Patients with Medication-Overuse Headache

Yoshiaki Kaji and Koichi Hirata Abstract
Objective The importance of psychiatric comorbidity in migraine has long been recognized. There is a growing body of evidence that these psychiatric comorbidities share diverse epidemiological properties, pathophysiological mechanisms, and treatment response. The prevalence of psychiatric comorbidities is high in patients with medication-overuse headache (MOH). Methods To understand the characteristics of mood disorders in MOH in Japanese patients, we studied and evaluated the characteristics of psychiatric comorbidities in MOH. Results The results suggested that mood disorders in MOH are similar to those in endogenous depression but different from those of secondary mood disorders associated with other diseases. Suspicion of depression and intervention are essential for providing medical care for patients with MOH. Conclusion Affective disorders diagnosed in migraine patients might later progress to MOH. In contrast, migraine patients without MOH and healthy subjects had a similar prevalence of mood disorders. Key words: medication-overuse headache, chronic daily headache, MINI International Neuropsychiatric Interview, Hamilton Depression Scale (Inter Med 48: 981-986, 2009) (DOI: 10.2169/internalmedicine.48.1884)

Introduction
The importance of psychiatric comorbidity in migraine has long been recognized (1, 2). There is a growing body of evidence that these psychiatric comorbidities share diverse epidemiological properties, pathophysiological mechanisms, and treatment response (3). The term chronic daily headache (CDH) describes a variety of headache types, of which chronic migraine is the most common (4). Daily headaches are often disabling in type and may be challenging for both diagnosis and treatment. It is common that patients with CDH have a history of episodic migraine that has evolved to a daily headache (transformed migraine: TM). Regardless of the original headache syndrome, overuse of medication occurs in approximately one-third of patients who develop daily headaches (5). Chronic headache due to overuse of medication is termed medication overuse headache (MOH) (6). Patients with CDH, especially MOH, have a poorer quality of life than patients with episodic migraine headaches (7, 8). Psychiatric complications are frequently seen in MOH patients (9). However, research of the possible mechanisms underlying these associations remains limited. As stated above, migraine, especially MOH, is a condition commonly associated

with psychiatric comorbidity, similar to Parkinsons disease (10) and stroke sequelae (11). The aim of the present study was to evaluate and characterize psychiatric comorbidity in patients with MOH.

Materials and Methods

Subjects This prospective study included 24 patients (9 males and 15 females, age 41.516.5 [meanSD] years [range, 41-71]) who visited the Headache Outpatient Clinic of Dokkyo University Hospital (Department of Neurology) between February 2005 and August 2007. All subjects agreed to participate in this study. MOH was diagnosed based on the new appenDepartment of Neurology, Dokkyo Medical University, Mibu Received for publication November 20, 2008; Accepted for publication March 16, 2009 Correspondence to Dr. Koichi Hirata, hirata@dokkyomed.ac.jp

Inter Med 48: 981-986, 2009 DOI: 10.2169/internalmedicine.48.1884

982 Table 1. Gender Differences in Overused Medication

dix criteria open for a broader concept of chronic migraine in all subjects reported by the Headache Classification Committee (12). In addition, to confirm the diagnosis, magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of the head was conducted in all patients. All procedures were approved by our institutional review board. Table 1 shows prescribed drugs used by the participating patients. The control group consisted of 13 patients diagnosed with idiopathic (endogenous) depression (6 cases of major depression; 7 dysthymia), matched for sex and age with MOH patients. They included 5 males and 8 females aged 49.123.7 (range, 18-81) years. The second control group consisted of 40 patients diagnosed with migraine without MOH (migraine with and without aura), matched for sex and age with MOH patients. They included 13 males and 27 females aged 40.613.3 (range, 14-68) years. None of the patients suffered from disturbance of consciousness, and patients with a consciousness score of less than 21 in the Mini Mental State Examination (MMSE) and with neuropsychological disorders, such as aphasia, were excluded from this study. Study protocol For the estimation of affective disorders associated with MOH, we used four types of psychological tests: the Mini International Neuropsychiatric Interview (MINI) (13), Hamilton Depression Scale (HAM-D17) (14), Hamilton Anxiety Scale (HAM-A) (15), and Apathy Score (16). The MINI is a structured interview technique for neuropsychiatric disorders based on the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) (17). We used methods for estimation of depression, dysthymia, panic disorders, generalized anxiety disorders, and agoraphobia in the MINI. Since the MINI does not include an apparent cut-off score for the determination of minor depression, we employed the following diagnostic criterion for MOH-related depression; including major depression, minor depression, and dysthymia, according to a previous report (18): a patient

does not meet the criteria for major depression as diagnosed by the MINI but has a score greater than 10 in HAM-D17. The diagnostic criterion for apathy was an apathy score of 16 or greater (19). Based on the results, we determined the prevalence rate of each affective disorder. We also determined each risk factor (age and sex) of depression, anxiety disorder, and apathy in MOH as markers of HAM-D17, HAM-A, and apathy scores. We compared MOH-related depression and depression using items of HAM-D17 to evaluate these character differences. In addition we estimated the affective disorders of migraine without MOH by the same procedure as that used in MOH. Statistical analysis Descriptive and analytical statistics were computed with the use of a statistical program (Statcel 2, Saitama, Japan). We used the Mann-Whitneys U test for comparison of subitems of depression in MOH group and endogenous depression group. Furthermore, we performed multivariate analysis using HAM-D17, apathy score, HAM-A, age and sex. Multiple regression analysis was performed for depression, apathy and anxiety as dependent variables and sex and age as independent variables. A p value <0.05 was considered significant.

Results
Prevalence of affective disorders in MOH Table 2 lists the results of all subjects. The prevalence of affective disorders in MOH was as follows: 58.2% of the patients had MOH-related depression, including 20.8% with major depression and all patients with major depression also showed melancholic features; 29.2% with apathy; 29.2% with panic disorders; and 4.2% with generalized anxiety disorder and agoraphobia. Of the 24 subjects, 16 (66.7%) had at least one affective disorder. On the other hand, only 2.5% of patients with migraine without MOH had minor depression and had none of the panic disorders. Inter Med 48: 981-986, 2009 DOI: 10.2169/internalmedicine.48.1884
983 Table 2. Prevalence of Mood Disorders in MOH Headache

Risk of affective disorders in MOH Multivariate analysis s showed that females were at higher risk of depression (p=0.0034), apathy (p=0.00151), and anxiety (p=0.0039) than males in MOH. However, there was no correlation between age and depression (p=0.91), apathy (p=0.30), and anxiety (p=0.95). Each R-Square was depression: 0.35, apathy: 0.26, anxiety: 0.34. Difference between MOH-related depression and endogenous depression We calculated the mean and SD of the items of HAM-D17 in patients with MOH and endogenous depression (Table 3). Statistical differences in each item between the two groups were analyzed by the Mann-Whitney U test. The data of the endogenous depression group showed larger variability (larger SD values) than the MOH-related depression group for all 16 items except item anxiety, somatic, and thus, there was no significant difference between the two groups. In contrast, the anxiety, somatic score of MOH-related depression

was significantly (p=0.03) higher than that of endogenous depression.

Discussion
CDH (MOH) is commonly associated with psychiatric comorbidity, such as depression, as well as increased suicidal risk (20, 21). Many studies have reported that physical disorders, in addition to headache, are also associated with depression, but the reported prevalence is different. Our finding, shown in Table 2, demonstrates that depression associated with MOH is more prevalent than that associated with other disorders. In a previous study of post-stroke depression (22), we reported that the prevalence of major depression was 5% and that of minor depression was 15% in 100 consecutive patients suffering from stroke in the subacute phase. In the present study, we used the same diagnostic criteria as those used in the above study. The previous results suggested that MOH-related depression is more prevalent than that associated with other disorders such as stroke (22), although our previous study was based on patients of a different age and a different male: female ratio compared with the present study. Abnormal serotonin metabolism is thought to be one of the underlying mechanisms of migraine (23). Several studies investigated the correlation between migraine and depression and panic disorders, since aberration of serotonin metabolism is a common contributing factor in these disorders (24). Kececi et al (25) reported the results of a questionnaire study on migraine (by using the IHS criteria) and depression (by using DSM-IV) in 943 Turkish patients. Their results showed that 32% of the patients suffered from migraine and major depression, while 13% had migraine but no depression. Overall, the odds ratio of migraine associated with depression was 2.8. Breslau et al (26) observed an association between migraine and major depression in clinical and community samples. They showed that major depression at baseline predicted the first-onset migraine during the 2-year follow-up period. Migraine at baseline predicted the firstonset major depression during follow-up. These data indicate that major depression increased the risk of migraine, and migraine increased the risk of major depression; i.e., a bidirectional association with each disorder increasing the risk for the onset of the other. These data suggest the exisInter Med 48: 981-986, 2009 DOI: 10.2169/internalmedicine.48.1884

984 Table 3. Differences in Prevalence of HAM-D17 Sub-items between Depression in MOH and Endogenous Depression
Items Depression in MOH Endogenous depression p value* Depressed Mood 2.290.99 2.920.64 NS Feeling of guilt 1.381.08 1.230.83 NS Suicide 1.071.14 1.691.38 NS Insomnia, initial 1.140.95 1.310.85 NS Insomnia, middle 1.000.88 1.000.91 NS Insomnia, delayed 0.570.76 0.920.86 NS Work & Interests 2.360.93 2.690.95 NS

Retardation 0.360.50 0.850.80 NS Agitation 0.290.47 0.460.52 NS Anxiety psychic 2.211.19 2.460.78 NS Anxiety, Somatic 2.430.85 1.690.75 0.03 Somatic symptoms. gastrointestinal 0.860.86 0.850.55 NS Somatic symptoms. general 1.500.65 1.310.48 NS Genital symptoms 1.070.92 0.850.80 NS Hypochondriasis 1.211.12 1.540.78 NS Loss of weight 0.570.76 0.460.66 NS Insight 0.000.00 0.150.38 NS

*By Mann-Whitneys U test

tence of a common pathophysiological factor underlying these conditions. Several studies have discussed the correlation between migraine and panic disorders. Radat et al (27) reported that the lifetime prevalence of depression was 3- to 4-fold higher and that of panic disorder was 3- to 7-fold higher in migraine patients than in healthy controls. Swartz et al (28) reported a strong correlation between migraine and major depression/ panic disorders. There are few previous studies discussing the psychiatric comorbidity only in patients with MOH. Jelinski et al (29) assessed depression in 712 patients with headache by using the Beck Depression Inventory II (BDI-II). They reported a prevalence of depression of 17% in migraine patients but 36% in transformed migraine (TM) (but not MOH) patients. Juang et al (30) performed MINI in 152 patients with MOH (TM), and their results showed that 57% had major depression; 11%, dysthymia; 30%, panic disorders, and 8% had generalized anxiety disorder. They also reported that 68% of their patients had at least one affective disorder, and that the association between anxiety and depression was particularly high. Our results showed that 20.8% of the patients had major depression; 37.4% had dysthymia and minor depression, 29.2% had panic disorder, and 4.2% had generalized anxiety disorder. Although our results showed a low prevalence of major depression, the overall prevalence of depression was similar to that reported by Juang et al (30). MOH is typically based on migraine headache, therefore the previous data of prevalence of psychiatric comorbidity in migraine may include not only in migraine but also MOH. Regardless of the common pathophysiological background, the association of migraine and depression was reported to be likely (31) because these conditions share other similarities, e.g., premorbid personalities and temperaments of patients, such as scrupulousness, hypersensitivity to stress, and irritability. Another report (32) suggested the correlation of depression with chronic pain and limbically augmented pain syndrome (LAPS). The latter occurs through the following steps: chronic pain sensitizes pain sensors and their receptor signal, and these modulate the memory of a painful stimulus. Another report (33) suggested that MOH results from migraine due to various factors such as excessive stress due to personal circumstances and social position, personal profile, and analgesic abuse, and that some forms of depression may occur via this process and the LAPS process. It is conceivable that the prevalence of depression may be higher in MOH than in migraine since the duration

of headache and headache attacks in MOH is longer than in migraine. Actually, our results showed that 20.8% of MOH had major depression; 37.4% had dysthymia and minor depression, however, only 2.5% of patients with migraine without MOH had minor depression and no panic disorders. From another perspective, headache is considered a manifestation of endogenous depression since headache as a Inter Med 48: 981-986, 2009 DOI: 10.2169/internalmedicine.48.1884
985

physical symptom in endogenous depression is ranked high in the frequency of occurrence in both men and women, i.e., fourth in men and third in women (34). Our results, in which all patients with major and endogenous depression exhibited melancholic features, and comparison of the HAM-D17 items between MOH-related depression and endogenous depression showed no significant differences, except for anxiety and somatic depression. These features suggest that MOH is probably associated with anxiety as well as depression since anxiety and somatic depression was more common in MOH than in endogenous depression. Juang et al (30) reported a high risk of anxiety/depression in MOH in females, and our results corroborated this result. Females are at higher risk of endogenous depression than males. This finding also suggests the existence of a correlation between MOH and endogenous depression. Apathy is defined as loss or absence of emotions, affection, interest, and concern. Although this is also included in the diagnostic criteria for depression in DSM-IV, it has different clinical features from depression and may have no association with depressed mood or pessimism (35). Research on the association between headache with apathy is limited. Low morale, rather than depressed mood and pessimism, was more common in patients with stroke and Parkinsons disease than in patients with endogenous depression (36, 37), and this symptomatological condition might reflect a tendency toward apathy. In our study of 100 patients with post-stroke depression in the subacute phase (22), the prevalence of apathy was as high as 40.2%, which is twice the prevalence in depression. On the other hand, in this study, the prevalence of apathy was 29.2%. This result might reflect the close relation between MOH-related depression and endogenous depression.

Conclusion
We confirmed the associations among affective disorders in MOH. Affective disorders in MOH are thought to be similar to those in endogenous depression but different from secondary mood disorders associated with other diseases. Our results suggested that the suspicion of depression and intervention are essential for providing medical care for patients with MOH. Affective disorders diagnosed in migraine patients might later progress to MOH.

References
1. Cobb S, Miles HH. Psychiatric conference: migraine and character neurosis. Am Pract Diag Treat 3: 985-990, 1952. 2. Radat F, Swendsen J. Psychiatric comorbidity in migraine: a review.

Cephalalgia 25: 165-178, 2005. 3. Scher AI, Bigal ME, Lipton RB. Comorbidity of migraine. Curr Opin Neurol 18: 305-310, 2005. 4. Silberstein SD, Lipton RB, Solomon S, Mathew NT. Classification of daily and near-daily headaches: proposed revisions to the IHS criteria. Headache 34: 1-7, 1994. 5. Maizels M. The patient with daily headaches. Am Fam Physician 70: 2272-2274, 2004. 6. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders, 2nd edn. Cephalalgia 24 Suppl 1: 9-160, 2004. 7. Castillo J, Munoz P, Guitera V, Pascual J. Epidemiology of chronic daily headache in the general population. Headache 39: 190-196, 1999. 8. Monzon MJ, Lainez MJ. Quality of life in migraine and chronic daily headache patients. Cephalalgia 18: 638-643, 1998. 9. Atasoy HT, Atasoy N, Unal AE, Emre U, Sumer M. Psychiatric comorbidity in medication overuse headache patients with preexisting headache type of episodic tension-type headache. Eur J Pain 9: 285-291, 2005. 10. Cummings JL. Depression and Parkinsons Disease: A Review. Am J Psychiatry 1149: 443-454, 1992. 11. Robinson RG, Starr LB, Kubos KL, Price TR. A two-year longitudinal study of post-stroke mood disorders: findings during the initial evaluation. Stroke 14: 736-741, 1983. 12. Headache Classification Committee, Olesen J, Bousser MG, Diener HC, et al. New appendix criteria open for a broader concept of chronic migraine. Cephalalgia 26: 742-746, 2006. 13. Sheehan DV, Lecrubier Y, Sheehan KH, et al. The MiniInternational Neuropsychiatric Interview (MINI): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59: 22-23, 1998. 14. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 23: 56-62, 1960. 15. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 32: 50-55, 1959. 16. Okada K, Kobayashi S, Yamagata S, Takahashi K, Yamaguchi S. Poststroke apathy and regional cerebral blood flow. Stroke 28: 2437-2441, 1997. 17. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, ed 4. Washington American Psychiatric Association Press, 1994. 18. Roose SP, Sackeim HA, Krishnan KR, et al; Old-Old Depression Study Group. Antidepressant pharmacotherapy in the treatment of depression in the very old: a randomized, placebo-controlled trial. Am J Psychiatry 161: 2050-2059, 2004. 19. Okada K, Kobayashi S, Aoki K, Suyama N, Yamaguchi S. Assessment of motivational loss in poststroke patients using the Japanese version of Starksteins Apathy Scale. Jpn J Stroke 20: 319-323, 1998 (in Japanese). 20. Saper JR, Silberstein SD, Lake AE 3rd, Winters ME. Double-blind trial of fluoxetine: chronic daily headache and migraine. Headache 34: 497-502, 1994. 21. Wang SJ, Juang KD, Fuh JL, Lu SR. Psychiatric comorbidity and suicide risk in adolescents with chronic daily headache. Neurology 18: 1468-1473, 2007. 22. Kaji Y, Hirata K, Ebata A. Characteristics of poststroke depression in Japanese patients. Neuropsychobiology 53: 148-152, 2006. 23. Ferrari MD. Sumatriptan in the treatment of migraine. Neurology 43 Suppl 3: 43-47, 1993. 24. Mller HJ. Are all antidepressants the same? J Clin Psychiatry 61 Suppl 6: 24-28, 2000. 25. Kececi H, Dener S, Analan E. Co-morbidity of migraine and major depression in the Turkish population. Cephalalgia 23: 271-275, 2003.

26. Breslau N, Schultz LR, Stewart WF, Lipton R, Welch KM. Headache types and panic disorder: directionality and specificity. Neurology 56: 350-354, 2001. 27. Radat F, Creach C, Swendsen JD, et al. Psychiatric comorbidity in

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the evolution from migraine to medication overuse headache. Cephalalgia 25: 519-522, 2005. 28. Swartz KL, Pratt LA, Armenian HK, Lee LC, Eaton WW. Mental disorders and the incidence of migraine headaches in a community sample: Results from the Baltimore Epidemiologic Catchment area follow-up study. Arch Gen Psychiatry 57: 945-950, 2000. 29. Jelinski SE, Magnusson JE, Becker WJ; CHORD Study Group. Factors associated with depression in patients referred to headache specialists. Neurology 68: 489-495, 2007. 30. Juang KD, Wang SJ, Fuh JL, Lu SR, Su TP. Comorbidity of depressive and anxiety disorders in chronic daily headache and its subtypes. Headache 40: 818-823, 2000. 31. Gesztelyi G. Primary headache and depression. Orv Hetil 145: 2419-2424, 2004 (in Hungarian). 32. Rome HP Jr, Rome JD. Limbically augmented pain syndrome (LAPS): kindling, corticolimbic sensitization, and the convergence of affective and sensory symptoms in chronic pain disorders. Pain Med 1: 7-23, 2001. 33. Mathew NT, Stubits E, Nigam MP. Transformation of episodic migraine into daily headache: Analysis of factors. Headache 22: 6668, 1982. 34. Sugahara H, Akamine M, Kondo T, et al. Somatic symptoms most often associated with depression in an urban hospital medical setting in Japan. Psychiatry Res 128: 305-311, 2004. 35. Marin RS. Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci 3: 243-354, 1991. 36. Lipsey JR, Spencer WC, Rabins PV, Robinson RG. Phenomenological comparison of poststroke depression and functional depression. Am J Psychiatry 143: 527-529, 1986. 37. Miyoshi K, Ueki A, Nagano O. Management of psychiatric symptoms of Parkinsons disease. Eur Neurol 36: 49-54, 1996.

2009 The Japanese Society of Internal Medicine http://www.naika.or.jp/imindex.html

9
European Review for Medical and Pharmacological Sciences
1546

Abstract. BACKGROUND: Major depressive

disorder (MDD) is a common disorder during adolescence and it is associated with an increased risk of suicide, poor school performance, impaired social skills, social withdrawal and substance abuse. Further, as many depressive episode in adolescents do not reach the diagnostic threshold for MDD, the disorder remains undetected. AIM: This review aims to provide an update of clinical features of adolescent MDD and to focus on the most appropriate therapeutic strategies to adopt in clinical practice. MATERIALS AND METHODS: We reviewed the international literature to identify studies focusing on clinical features and therapeutic options in adolescents affected by MDD. PubMed,

Medline and Cochrane Library databases were searched for English language papers. RESULTS: The clinical picture of depression is variable with sex and age. Somatic complaints, particularly headache and fatigue, are a common presentation in adolescent MDD. Irritability is present most frequently in female and it is related to the severity of MDD. Adolescent MDD is also characterized by a high rates of suicides. The therapeutic strategy in adolescent depression includes psychotropic medications, psychotherapy or a combination of both treatments, with selection of the most appropriate strategy depending on symptom severity. As first-line treatment the traditional cognitive behavioural therapy (CBT), as well as the cognitive Post-Rationalist (PR) approach, are so far considered the goal standard. CONCLUSIONS: The therapeutic approach to the adolescent affected by MMD should respect the person in his/her psycho-physical entirety. The intervention may help the subject in seeking a more stable and adaptable identity. It is relevant to have a good knowledge of the peculiar clinical picture of adolescent MDD in order to make an early identification of the disorder and to define an appropriate personalized therapeutic program. Key Words: Adolescent, Major depressive disorder (MDD), Psychopatology, Psychotherapy, Antidepressants, Selective serotonin reuptake inhibitors (SSRIs).

Adolescent depression: clinical features and therapeutic strategies

B. NARDI, G. FRANCESCONI, M. CATENA-DELLOSSO, C. BELLANTUONO
Psychiatric Unit, Section of Clinical Neuroscience, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy Corresponding Author: Bernardo Nardi, MD; e-mail: b.nardi@univpm.it

Introduction
Major depressive disorder (MDD) is a complex disabling condition which affects all aspects of life and impairs individuals family and personal relationships, work adjustment and general health. This disorder represents a major cause of morbidity and disability worldwide and is currently considered the fourth-leading cause of disease burden1-3. MDD is common also during childhood and adolescence and it is associated with an increased risk of suicide, poor school performance, impaired social skills, social withdrawal,

and substance abuse4. In particular, the physiological, psychological and social changes that characterize adolescence can increase the risk for MDD and other related depressive disorders 5. The incidence of depression in preadolescence is between 0.5% and 2.5% and from 2.5% to 8% during adolescence, while the prevalence is estimated to be between 4% to 8%6. Further, as many depressed adolescents do not reach the diagnostic threshold for MDD, the disorder is often not identified. Even though the depressive episode may not meet the criteria for MDD, the symptoms may still have long-term clinical and social implications and can predispose to later development of a full blown disorder 7. The clinical picture of MDD in adolescents is quite different from the adult, in fact it is characterized by heterogeneous and changing symptoms, sometime hidden from somatic complaints and complicated by the high comorbidity rates with anxiety disorders, substance abuse, disruptive behavior disorders, personality disorders, and medical illnesses8-11. In detail, in adolescents as well as in adults, although suicide has many causes, 85% to 95% of those dying by suicide have psychiatric illness (especially MDD)12. Further, there are significant psychosocial and educational consequences if such an episode remains undetected13. It should be noted that parents can both minimize or overestimate symptoms, espe2013; 17: 1546-1551 cially if they are emotionally distressed as often it happens when an adolescent requires psychiatric interventions. Therefore, in these subjects it is difficult to recognize depressive symptoms and make a correct diagnosis, as well as to establish an adequate therapeutic strategy. The aims of this review are a) to provide a comprehensive update of the clinical features of MDD in adolescents, and b) to indicate, on the basis of evidences so far available, the most appropriate therapeutic interventions to adopt in adolescent MMD.

Materials and Methods

We reviewed the international literature to identify studies focusing on adolescent MDD. PubMed, Medline and Cochrane Library databases were searched for English language papers by using the following key words: adolescent, major depressive disorder (MDD), clinical manifestations, psychopharmacology, antidepressants, psychotherapy.

Results and Discussion

Clinical Features During adolescence, medically unexplained symptoms, such as headache and abdominal pain, fatigue or loss of energy, and irritability are particularly common in subjects with MDD14,15. In fact, a common early presentation of depression in primary care is characterized by somatic complaints in the absence of an organic disease 6. Somatic complaints are the most frequent symptoms in both gender and are strictly related to the presence of depressive symptoms. 4 In a populationbased study, it was demonstrated that duration and severity of depression were related to the number of somatic symptoms16. Further, a strong correlation between the presence of somatic symptoms and suicidal ideation, suicidal attempts, disruptive behavior and stressful relationships has been reported17,18. Irritability is another common symptom of adolescent MDD. In fact, the Diagnostic and Statistical Manual for Mental Disorders IV-Text Revised19s pecifies that depression in children and adolescents may be characterized as an irritable mood. Irritability is more common in female and it appears to be age related, becoming more frequent during mid-adolescence (13-15 years) with a rate of 75.5% while decrease in adulthood (1921 years) till to 51.5%20. The presence of irritability is also strongly related to severity of MDD21. Concerning gender differences, it has been reported that in female feelings of sadness, lonely, irritability, pessimism, hating themselves, crying, and eating disorders are more frequent; in male are more present somatic complaints, reduced ability to think or concentrate, decision making, feelings restless and anhedonia. In addition, irritability in males is very often associated to the presence of conduct disorders and substance use15,20-22. Furthermore, in female, negative body image is frequently present. In fact, because appearance is a relevant concern for girls in western culture, feelings of displeasure with their body may have a consequent impact on their mood 23. Negative body image becomes less likely as symptom of depression as subjects were reaching young adulthood with a rate of 23.5% versus 45.4% in mid-adolescence20. In particular, 20%-24% of MDD adolescents

attempt suicide, while 25%-66% show suicidal ideation, especially from 16 to 19 years and in presence of irritability20,24-28. The clinical picture of depression is extremely variable with age. Overall, while children and younger adolescents have more symptoms of somatic complaints, anxiety and irritability, older adolescents and youth adults have more affective and cognitive symptoms, closely resembling those of adults20. Treatment Options The treatment strategy for adolescent MDD includes psychotropic medications, psychotherapy or a combination of both treatments, with selection of the most appropriate strategy depending on symptom severity29,30. The guidelines of the National Institute for Health and Clinical Excellence (NICE)31 recommend that ...when assessing a young person with MDD, healthcare professionals should routinely consider, and record in the patients notes, potential comorbidities, and the social, educational and family context for the patient and family members, including the quality of interpersonal relationships.... As firstline treatment, the NICE guidelines suggest a specific psychological therapy cognitive behavoiural therapy: CBT, interpersonal psychotherapy (IPT) or shorter-term family therapy for at least 3 months. If there is no response to a specific psychotherapy within four to six ses1547

Adolescent depression: clinical features and therapeutic strategies sions, it is suggested to review and consider alternative or additional psychological therapies. According to the NICE guidelines, antidepressants should not be used except that in combination with a concurrent psychological therapy. In fact, in adolescents all antidepressants were found to significantly increase the risk of suicide 32-34. Fluoxetine (FLX) is the most studied Selective Serotonin Reuptake Inhibitor (SSRI) and recent reviews indicated that FLX should be considered the first-line drug treatment of adolescent MDD35-37. If treatment with FLX is unsuccessful or is not tolerated because of side effects, consideration should be given to the use of another antidepressant 31. In this case sertraline or citalopram are the recommended second-line treatments. The Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) as well as old generation antidepressants

should not be used for the treatment of young people with MDD31,38,39. In fact, the evidence that antidepressants may induce a worsening of depressive symptoms and increase the risk of suicide led the Food and Drug Administration (FDA) to publish a warning regarding such a risk in patients up to age 2440,41. In the recent years, the use of antidepressants in adolescence has decreased as a result of the above-mentioned concerns regarding the suicide during antidepressant treatment. On the contrary, according to other Authors, the use of SSRIs in adolescent MDD is not related to any increase of the risk of suicide 36,42,43. In any case, a close drug monitoring of antidepressant drugs should be considered if such drugs must be utilized in the treatment of adolescents with moderate to severe MDD. According to the Treatment for Adolescents with Depression Study (TADS)44,45 an appropriate treatment for moderately to severely depressed adolescents has been established. The combination of FLX and CBT was significantly superior to CBT or FLX alone as allowed to minimize the risk of suicidality that could be related to the use of FLX alone46. A recent meta-analysis on combined treatment with newer-generation antidepressants and CBT confirmed an advantage (even if limited) for the treatment of an episode of depression in adolescents47. However, patients and providers may wish to begin treatment with CBT alone in order to avoid the risk of antidepressantinduced suicidality. Moreover, as recently demonstrated in the naturalistic 1-year follow-up phase of the TADS, patients treated with the combination of FLX and CBT maintain the improvement in both depressive and suicidality scores. The CBT is the most effective psychotherapeutic intervention, besides to the interpersonal psychotherapy for depressed adolescents (IPTA) 28,48,49. In particular, although CBT has been mainly studied in adults, there is a growing evidence that it can be useful both in children and adolescents50-52. Further, adding continuation CBT sessions after acute improvement may decrease the risk of relapse53-56. Among cognitive psychotherapies, the Post-Rationalist (PR) approach constitutes one of the most innovative strategy, proposing a useful epistemological theory of mental functioning with successful application in clinical practice 57-60.

According to the PR theory, different significant factors are involved in the development of a Personal Meaning Organization (PMO), such as constitutional factors, attachment relationships, and a subjective manner of managing life experiences. Knowledge of the self system is central, as it deeply influences the attitude of the therapist, the assessment procedures and the dynamics of the therapeutic change. Furthermore, the PR approach allows a subject-centred reconstruction of immediate experiencing, thus modifying dysfunctional patterns of self-perception and achieving more adaptive and lasting changes 61. Using this approach, feelings of self-negativity, perceived as objective and unchanging aspects of the self, are focused as subjective patterns in organizing experience, giving them a new significant. A specific early intervention on adolescent turmoil, which causes a negative view of the self and the world, can be useful to cope such problems and to prevent chronicity62.

Conclusions

MDD is common during childhood and adolescence and it is characterized by a high incidence of somatic complaints, loss of energy, irritability, and by disruptive consequences, including increased risk of suicide and behavior disorders, poor school performance, impaired social skills, and substance abuse. The lack of recognition and appropriate treatment of depressive symptoms can be consequently at risk of serious long-term psychological and educational consequences. The treatment options of MDD during adolescence, however, is still controversial. A warning on the possible negative consequences of the use of antidepressants, in particular the increased risk B. Nardi, G. Francesconi, M. Catena-DellOsso, C. Bellantuono
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Adolescent depression: clinical features and therapeutic strategies 1549

8) RENOUF AG, KOVACS M, MUKERJI P. Relationship of depressive, conduct, and comorbid disorders and social functioning in childhood. J Am Acad Child Adolesc Psychiatr 1997; 36: 998-1004. 9) ANGOLD A, COSTELLO EJ, ERKANLI A. Comorbidity. J Child Psychol Psychiatr 1999; 40: 57-87. 10) ANGOLD A, ERKANLI A, FARMER EM, FAIRBANK JA, BURNS BJ, KEELER G, COSTELLO EJ. Psychiatric disorder, impairment, and service use in rural African American and white youth. Arch Gen Psychiatr 2002; 59: 893-901.

11) PARIS J. Recent research in personality disorders. Preface. Psychiatr Clin North Am 2008; 31: 21-22. 12) OQUENDO MA, MANN JJ. Suicidal behavior: a developmental perspective. Psychiatr Clin North Am 2008; 31: 23-26. 13) SEPEDE G, GAMBI F, DE BERARDIS D, BROCCO C, NACCI M, CAMPANELLA D, ET AL. Somatic complaints and depressive symptoms in adolescence. Ital J Psychopathol 2004; 10: 343-348. 14) CARLSON G-A, KASHANI J-H. Phenomenology of major depression from childhood through adulthood: Analysis of three studies. Am J Psychiatr 1988; 145: 1222-1225. 15) TOROS F, GAMSIZ BILGIN N, BUGDAYCI R, SASMAZ T, KURT O, CAMDEVIREN H. Prevalence of depression as measured by the CBDI in a predominantly adolescent school population in Turkey. Eur Psychiatr 2004; 19: 264-271. 16) PATTON G-C, COFFEY C, POSTERINO M, CARLIN J-B, WOLFE R. Adolescent depressive disorder: A population based study of ICD-10 symptoms. Aust N Z J Psychiatr 2000; 34: 741-747. 17) BUCKNER JD, JOINER TEJ, PETTIT JW, LEWINSOHN PM, SCHMIDT NB. Implications of the DSM's emphasis on sadness and anhedonia in major depressive disorder. J Psychiatr Res 2008; 159: 25-30. 18) BOHMAN H, JONSSON U, VON KNORRING AL, VON KNORRING L, PAAREN A, OL S SON G. Somatic symptoms as a marker for severity in adolescent depression. Acta Paediatr 2010; 99: 17241730. 19) DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL DISORDERS, Fourth edition, Text Revision. Washington, DC, American Psychiatric Association; 2000. 20) KOVACS M, OBROSKY DS, SHERRILL J. Developmental changes in the phenomenology of depression in girls compared to boys from childhood onward. J Affect Disord 2003; 74: 33-48. 21) CROWE M, WARD N, DUNNACHIE B, ROBERTS M. Characteristics of adolescent depression. Int J Ment Health Nurs 2006; 15: 10-18. 22) BENNETT DS, AMBROSINI P-J, KUDES D, METZ C, RABINOVICH H. Gender differences in adolescent depression: Do symptoms differ for boys and girls? J Affect Disord 2005; 89: 35-44. 23) BEARMAN SK, STICE E. Testing a gender additive model: The role of body image in adolescent depression. J Abnorm Child Psychol 2008; 36: 1251-1263.

of suicide, has been indicated by the FDA, while a CBT approach is considered the first line treatment. On the contrary, there is a numbers of clinical evidences suggesting the efficacy of CBT in combination with antidepressants. In any case, it is clear that the best therapeutic intervention in the adolescent with MDD should be always personalized.

The intervention may help the subject in seeking a more stable and adaptable identity. Helping the adolescent to cope the turmoil related to growth can give to the subject adequate tools to become a well-balanced adult.

Conclusions

It is relevant to have a good knowledge of the clinical features of adolescent MDD in order to make an early diagnosis and to define an appropriate personalized therapeutic program.
Conflict of Interest
None to declare.

References
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24) KOVACS M, GOLDSTON D, GATSONIS C. Suicidal behaviors and childhood-onset depressive disorders: A longitudinal investigation. J Am Acad Child Adolesc Psychiatr 1993; 32: 8-20. 25) PELKONEN M, MARTTUNEN M, PULKKINEN E, LAIPPALA P, ARO H. Characteristics of out-patients adolescents with suicidal tendencies. Acta Psychiatr Scand 1997; 95: 100-107. 26) ESSAU CA, CONRADT J, PETERMANN F. Frequency, comorbidity and psychosocial impairment of depressive disorders in adolescents. J Adolesc Res 2000; 15: 470-481. 27) PANTUSA MF, BERARDI M, PAPARO S, SCORNAIENCHI C. Differenze di genere e sintomatologia depressiva

in adolescenza. Relazioni tra autostima, sintomi depressivi e ideazione suicidarla. It J Psychopatol 2006; 12: 407-414. 28) TUISKU V, PELKONEN M, KARLSSON L, KIVIRUUSU O, HOLI M, RUUTTU T, PUNAMKI RL, MARTTUNEN M. Suicidal ideation, deliberate self-harm behaviour and suicide attempts among adolescent outpatients with depressive mood disorders and comorbid axis I disorders. Eur Child Adolesc Psychiatr 2006; 15: 199-206. 29) VITIELLO B. Prevention and treatment of child and adolescent depression: Challenges and opportunities. EPS 2011; 20: 37-43. 30) HENDREN R, MCCARTHLY M. Child and adolescent psychiatry for the general psychiatrist. Psychiatr Clin North Am 2009; 32: 13-15. 31) NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE, NICE (2005). Depression in children and young people: Identification and management in primary, community and secondary care. Clin Guidel 28. http://guidance.nice.org.uk/CG28/niceguidance/ pdf/English 32) EMISLIE G, KRATOCHVIL C, VITIELLO B, SILVA S, MAYES T, MCNULTY S, WELLER E, WASLICK B, CASAT C, WALKUP J, PATHAK S, ROHDE P, POSNER K, MARCH J. Treatment for adolescent with depression study (TADS): safety results. J Am Acad Child Adolesc Psychiatr 2006; 45: 1440-1455. 33) BARBUI C, ESPOSITO E, CIPRIANI A. Selective serotonin reuptake inhibitors and risk of suicide: A systematic review of observational studies. CMAJ 2009; 180: 291-297. 34) AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY. Practice parameter on the use of psychotropic medication in children and adolescents. J Am Acad Child Adolesc Psychiatr 2009; 8: 961-973. 35) GOODYER I, DUBICKA B, WILKINSON P KELVIN R, ROBERTS C, BYFORD S, BREEN S, FORD C, BARRETT B, LEECH A, ROTHWELL J, WHITE L, HARRINGTON R. Selective serotonin reuptake inhibitors (SSRIs) and routine specialist care with and without cognitive behavior therapy in adolescents with major depression: Randomized controlled trial. Br Med J 2007; 335: 142. 36) GENTILE S. Antidepressant use in children and adolescents diagnosed with major depressive disorder: What can we learn from published data? Rev Recent Clin Trials 2010; 5: 63-75. 37) MASI G, LIBONI F, BROVEDANI P. Pharmacotherapy of major depressive disorder in adolescents. Expert Opin Pharmacother 2010; 11: 375-386. 38) BERARD R, FONG R, CARPENTER DJ, THOMASON C, WILKINSON C. An international, multicenter, placebocontrolled trial of paroxetine treatment in adolescents with major depressive disorder. J Child Adolesc Psychopharmacol 2006; 16: 59-75. 39) EMSLIE GJ, FINDLING RL, YEUNG PP, KUNZ NR, LI Y.

Venlafaxine ER for treatment of pediatric subjects with depression: Results of two placebo-controlled trials. J Am Acad Child Adolesc Psychiatr 2007; 46: 479-488. 40) REEVES RR, LADNER ME. Antidepressant-induced suicidality: An update. CNS Neurosci Ther 2010; 16: 227-234. 41) SCNEEWEISS S, PATRICK AR, SOLOMON DH, DORMUTH CR, MILLER M, METHA J, LEE JC, WANG PS. Comparative safety of antidepressant agents for children and adolescents regarding suicidal acts. Pediatrics 2010; 125: 876-888. 42) DUDLEY M, GOLDNEY R, HADZI-PAVLOVIC D. Are adolescents dying by suicide taking SSRI antidepressants? A review of observational studies. Austral Psychiatr 2010; 18: 242-245. 43) KUBA T, YAKUSHI T, FUKUHARA H, NAKAMOTO Y, SINGEO STJ, TANAKA O, KONDO T. Suicide-related events among child and adolescent patients during short-term antidepressant therapy. Psychiatr Clin Neurosci 2011; 65: 239-245. 44) MARCH J, SILVA S, PETRYCKI S, CURRY J, WELLS K, FAIRBANK J, BURNS B, DOMINO M, MCNULTY S, VITIELLO B, SEVERE J. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents with Depression Study (TADS) randomized controlled trial. JAMA 2004; 292: 807-820. 45) TREATMENT FOR ADOLESCENTS WITH DEPRESSION STUDY TEAM. Treatment for Adolescents with Depression Study (TADS): rationale, design, and methods. J Am Acad Child Adolesc Psychiatr 2003; 42: 531-542. 46) MARCH JS, VITIELLO B. Clinical messages from the treatment for adolescents with depression study (TADS). Am J Psychiatr 2009; 166: 1118-1123. 47) DUBICKA B, ELVINS R, ROBERTS C, CHICK G, WILKINSON P, GOODYER I-M. Combined treatment with cognitivebehavioural therapy in adolescent depression: meta analysis. B J Psychiatr 2010; 197: 433440. 48) BRUNSTEIN-KLOMEK A, ZALSMAN G, MUFSON L. Interpersonal Psychotherapy for Depressed Adolescents (IPT-A). Isr J Psychiatr Relat Sci 2007; 44: 40-46. 49) GUNLICKS-STOESSEL M, MUFSON L, JEKAL A, TURNER JB. The impact of perceived interpersonal functioning on treatment for adolescent depression: IPT-A versus treatment as usual in schoolbased health clinics. J Consult Clin Psychol 2010; 78: 260-267.

B. Nardi, G. Francesconi, M. Catena-DellOsso, C. Bellantuono

50) KLEIN JB, JACOBS RH, REINECKE MA. Cognitive-behavioural therapy for adolescent depression: a meta-analytic investigation of changes in effectsize estimates J Am Acad Child Adolesc Psychiatr 2007; 46: 1403-1413. 51) SCOTT A. Cognitive behavioural therapy and young people: An introduction. J Fam Health Care 2009;

19: 80-82. 52) MUOZ RF, CUIJPERS P, SMIT F, BARRERA AZ, LEYKIN Y. Prevention of major depression. Annu Rev Clin Psychol 2010; 27: 181-212. 53) HARRINGTON R, CAMPBELL F, SHOEBRIDGE P, WHITTAKER J. Meta-analysis of CBT for depression in adolescents. J Am Acad Child Adolesc Psychiatr 1998; 37: 1005-1007. 54) CHEUNG AH, ZUCKERBROT RA, JENSEN PS, GHALIB K, LARAQUE D, STEIN RE. GLAD-PC Steering Group. Guidelines for Adolescent Depression in Primary Care (GLAD-PC): II. Treatment and ongoing management. Pediatrics 2008; 121: 227. 55) DERUBES RJ, SIEGLE GJ, HOLLON SD. Cognitive therapy versus medication for depression: Treatment outcomes and neural mechanisms. Nat Rev Neurosci 2008; 9: 788-796. 56) KENNARD B, EMSLIE GJ, MAYES TL, NIGHTINGALE-TERESI J, NAKONEZNY PA, HUGHES JL, JONES JM, TAO R, STEWART SM, JARRETT RB. Cognitive-behavioral therapy to prevent relapse in pediatric responders to pharmacotherapy for major depressive disorder. J Am Acad Child Adolesc Psychiatr 2008; 47: 13951404. 57) GUIDANO VF, LIOTTI G. Cognitive Processes and Emotional Disorders. New York: Guilford; 1983. 58) GUIDANO VF. Complexity of the Self. New York: Guilford; 1987. 59) GUIDANO VF. The Self in Progress. New York: Guilford; 1991. 60) NARDI B, PANNELLI G. Adolescent depression: How to cope with turmoil and development of self negativity. Med Mind Adol 1998; 13: 65-78. 61) NARDI B, BELLANTUONO C. A new adaptive and evolutionary conceptualization of the Personal Meaning Organization (P.M.O.) framework. Eur Psychother 2008; 8: 5-16. 62) NARDI B. Guidelines on the construction of a postrationalist therapeutic approach. Eur Psychother 2010; 9: 57-67.

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10
974 Annals Academy of Medicine Risk Adjustment for Comparing Health OutcomesYew Yoong Ding Antidepressants in the Treatment of Chronic PainHerng Nieng Chan et al

Review Article
Abstract
There is a high prevalence of chronic pain disorders in the population and the individual and societal costs are large. Antidepressants have been used in the treatment of chronic pain and the pain-relieving effects are independent of the mood-elevating properties. We reviewed randomisedcontrolled trials, systematic reviews and meta-analyses of antidepressants in the treatment of chronic pain disorders which were identifi ed through searches of MEDLINE and EMBASE. Antidepressants have proved to be effective in the treatment of fi bromyalgia, chronic low back pain, diabetic neuropathy, postherpetic neuralgia and chronic headache, in particular tricyclic antidepressants (TCAs). There is emerging evidence that newer dual-action antidepressants are

equally effi cacious. Antidepressants provide a viable option in the management of chronic pain disorders. Further research into novel antidepressants will aid the pain clinician in optimising treatment for patients. Ann Acad Med Singapore 2009;38:974-9 Key words: Fibromyalgia, Headache, Neuralgia, Neuropathy

Use of Antidepressants in the Treatment of Chronic Pain

Herng Nieng Chan,1MBBS, MMed (Psychiatry), Johnson Fam,1MBB S, MMed (Psychiatry), Beng-Yeong Ng,1MBBS, MMed (Psychiatry),
FAMS

Department of Psychiatry, Singapore General Hospital, Singapore Address for Correspondence: Dr Chan Herng Nieng, Department of Psychiatry, Singapore General Hospital, Outram Road, Singapore 169608. Email: chan.herng.nieng@sgh.com.sg
1

Introduction Pain, as defi ned by the International Association for the Study of Pain, is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.1 Chronic pain is widely defi ned as pain that lasts longer than 3 months.2 Chronic pain affects almost 20% of the adult population in the United Kingdom,3 while up to 66.4% of adults in the United States suffer from it.4 In Singapore, the prevalence of chronic pain in the population had been estimated to be 9%.5 The prevalence of chronic pain varies greatly in different studies due to inconsistencies and differences in defi nitions of chronic pain.6 Chronic pain impacts greatly on the individual and society at large. It reportedly costs society $43 billion per year in terms of lost productivity, substance abuse and/or suicide.7 There is also a high correlation with depression, perhaps more so than with other chronic illnesses. The treatment modalities for chronic pain are varied and include both non-invasive and invasive interventions. Non-invasive interventions include drug treatments using analgesics, anticonvulsants and antidepressants. Invasive interventions involve facet joint injections and various nerve blocks.8 Methodology In our review, English-language articles of randomisedcontrolled trials, systematic reviews and meta-analyses of antidepressants in the treatment of chronic pain disorders were identified through searches of MEDLINE and EMBASE, from 1966 to March 2009. The search terms included serotonin selective reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, venlafaxine, duloxetine, trazodone, nefazadone, mirtazapine, bupropion, reboxetine, moclobemide, chronic pain, fi bromyalgia, back pain, neuropathy, neuralgia, headache, and migraine. Antidepressants and Pain Despite the close association between chronic pain and depression, we now know that the pain-relieving effect of antidepressants is independent of their mood-elevating properties.9,10 In a meta-analysis of 39 placebo-controlled studies, antidepressants were shown to effectively reduce chronic pain.11 Antidepressants thus provide clinicians an

effective option in the treatment of chronic pain conditions. Antidepressants have been postulated to modulate pain through the central and peripheral nervous system. The mechanisms involve noradrenaline and serotonin
November 2009, Vol. 38 No. 11 Antidepressants in the Treatment of Chronic PainHerng Nieng Chan et al 975

(5-HT) neurotransmission, actions on opioid, adrenergic, 5-HT, GABA and N-methyl-D-aspartate receptors, ion channel activations, and possible effects on infl ammatory cytokines.12 Effects on peripheral nociceptors, descending inhibitory pain pathways, central sensitization and brain areas involved in pain and emotional processing have been described.13 Types of Antidepressants (Table 1) Tricyclic Antidepressants (TCAs) TCAs are widely used in the treatment of pain disorders. Their therapeutic effects are attributed to inhibition of norepinephrine and serotonin reuptake at synapses. However, their use can be limited by intolerable side effects. Anticholinergic side effects such as blurring of vision in glaucoma patients, urinary retention, constipation and dry mouth are common. Anti-histaminergic side effects such as oversedation and weight gain can preclude its use. TCAs can also prolong QT intervals and induce orthostatic hypotension and should be used with caution in patients with underlying cardiac diseases. They are lethal if accidentally or intentionally overdosed. Monoamine Oxidase Inhibitors (MAOIs) Classical MAOIs inhibit monoamine oxidases type A and B irreversibly, with antidepressant effects attributed to MAO-A inhibition of the breakdown of serotonin, epinephrine, and norepinephrine. However, MAOIs are infrequently used due to their extensive adverse effects, need for dietary restrictions and varied drug interactions, as a result of their mechanism of action. Adverse effects range from headaches, dizziness and blurred vision to weight gain, weakness and sexual dysfunction. Patients on MAOIs need to avoid food with tyramine, common in cheese and wine, to prevent hypertensive crises. TCAs and serotonin selective reuptake inhibitors (SSRIs) should be used cautiously in combination with MAOIs due to the risk of precipitating serotonin syndrome. Over-thecounter medications containing sympathomimetics, such as cold and weight loss products, can potentially interact with MAOIs to cause adverse reactions. Moclobemide is a reversible inhibitor of monoamine oxidase (RIMA) and is a safer alternative but its use in treating chronic pain remains limited. Serotonin Selective Reuptake Inhibitors SSRIs exert their therapeutic effects by selectively inhibiting the reuptake of serotonin. They have a milder side effect profi le and are safer in overdoses, compared with TCAs and MAOIs. Gastrointestinal side effects like nausea, vomiting, diarrhoea are common but transient.

Sexual dysfunctions have been reported but are reversible. SSRIs inhibit cytochrome P450 isoenzymes leading to drug interactions. SSRIs can potentially elevate TCAs, which are widely used in chronic pain disorders, to toxic levels in serum by inhibiting their metabolism. The use of MAOIs and SSRIs in combination should be avoided due to the risk of serotonin syndrome. Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) SNRIs inhibit the reuptake of both serotonin and norepinephrine at synapses. Venlafaxine blocks the reuptake of serotonin at lower doses; at higher doses it predominantly blocks the reuptake of norepinephrine. There is some concern of increased blood pressure when higher doses of venlafaxine are used. Duloxetine does not have these effects. Both drugs have similar side effect profi les of dry mouth, dizziness, headaches and sexual dysfunction. Drug interactions are reportedly minimal but they should not be used in combination with MAOIs due to the risk of serotonin syndrome. Serotonin-2 Antagonist and Reuptake Inhibitors (SARIs) SARIs antagonise the post-synaptic 5-HT2 receptors and inhibit the reuptake of serotonin, leading to a net increase in serotonin neurotransmission. It is widely used in the US and the UK as a hypnotic agent. Common side effects of trazodone include nausea, headache, dry mouth and orthostasis. It should be prescribed with caution in patients with underlying cardiac disease due to the risk of cardiac rhythm abnormalities and hypotension. Rare cases of priapism have been reported. Nefazadone is similar to
Table 1. Types of Antidepressants14 1. Tricyclic and tetracyclic antidepressants: Imipramine. amitriptyline, clomipramine, desipramine, nortriptyline, amoxapine, doxepin, protriptyline, trimipramine, maprotiline 2. Enzyme inhibition a) Irreversible and nonselective classical MAO inhibitor Isocarboxazid, phenelzine, tranylcypromine b) Reversible inhibitor of MAO-A (RIMA) Moclobemide 3. Serotonin selective reuptake inhibitors (SSRIs) Citalopram, escitalopram, fl uvoxamine, fl uoxetine, paroxetine, sertraline 4. Dual serotonin and norepinephrine reuptake inhibitors (SNRIs) Duloxetine, venlafaxine 5. Serotonin-2 antagonist and reuptake inhibitors (SARIs) Nefazodone, trazodone 6. Noradrenergic and specifi c serotonergic antidepressant (NaSSA) Mirtazapine 7. Norepinephrine and dopamine reuptake inhibitor (NDRI) Bupropion 8. Noradrenaline reuptake inhibitors Reboxetine 976 Annals Academy of Medicine Antidepressants in the Treatment of Chronic PainHerng Nieng Chan et al

trazodone but was suspected to be associated with 56 cases of liver failure worldwide since its introduction in 1994. The drug has been voluntarily withdrawn from sale in Singapore since 2004 due to low usage here. In the US, the FDA has

added a Black Box Warning since 2002. Noradrenergic and Specifi c Serotonergic Antidepressant (NaSSA) Mirtazapine blocks presynaptic alpha-2 adrenergic receptors, leading to higher levels of norepinephrine and serotonin in synapses. Its blockade of 5HT2 receptor reduces anxiety and enhances sleep while 5HT3 receptor antagonism reduces incidence of nausea. Common side effects are oversedation and increased appetite with weight gain, a result of its anti-histaminergic effect. It is generally safe in overdose and has minimal drug interaction. Norepinephrine and Dopamine Reuptake Inhibitor (NDRI) Bupropion predominantly blocks the reuptake of dopamine and is a weak norepinephrine and serotonin reuptake inhibitor. Due to its minimal effects on the serotonin system, it does not cause sexual side effects common to other antidepressants, in particular SSRIs. Cardiac and anticholinergic effects are absent. There is a risk of seizures with high doses, which should not exceed 450 mg per day. Bupropion is also used in smoking cessation therapy. Noradrenaline Reuptake Inhibitors Reboxetine selectively inhibits the reuptake of noradrenaline with little effect on other neurotransmitters. Common side effects include dry mouth, constipation, headache, drowsiness, dizziness and excessive sweating but it is generally well tolerated. It is not available in Singapore. Chronic Pain Conditions Fibromyalgia Fibromyalgia presents with a variety of signs and symptoms which includes fatigue and sleep disturbance and is defi ned as a syndrome of chronic widespread pain and tenderness at a minimum of 11 to 18 defi ned tender points by the American College of Rheumatology (ACR).15 There have been reviews on the use of antidepressants in the treatment of fi bromyalgia. In the latest metaanalysis, 16 which included 18 randomised controlled trials involving 1427 patients, antidepressants improved pain, depression, sleep disturbances and health-related quality of life. The effect size was the largest for TCAs, in particular amitriptyline, with smaller effect sizes for SSRIs (fluoxetine), SNRIs (duloxetine) and MAOIs (moclobemide). The fi ndings are consistent with previously reported meta-analyses.17,18 It was shown that the effective doses for pain relief by TCAs were between 12.5 and 50 mg per day, less than that required for antidepressant action. It was also demonstrated that duloxetine exhibited effi cacy regardless of whether patients were depressed or not. This further strengthens the observation that antidepressants are analgesics independent of their mood-elevating effects. Duloxetine has emerged in recent years as a credible alternative to TCAs from the results of well designed, randomised controlled trials.19-21 TCAs are now

recommended22 and duloxetine has been approved by the US FDA for the treatment of fi bromyalgia. There is a lack of placebo-controlled studies investigating the use of venlafaxine in fi bromyalgia. Chronic Low Back Pain Low back pain is often a benign and self-limiting condition but up to 45% of patients experience persistent symptoms.23 Low back pain is defi ned as chronic in nature when it lasts for more than 3 months.24 Pain intensity in low back pain predicts disability.25 Because of the debilitating nature of the persistent symptoms, it is a major reason for medical consultations and leads to reduced productivity, work absence and early retirement, contributing to large economic losses. In a recent review,26 10 trials involving patients with chronic low back pain were included for analysis. The antidepressants investigated included TCAs and SSRIs. The authors concluded that there was no clear evidence that antidepressants reduce pain, depression or functional status in patients with chronic low back pain. This is in contrast to previous fi ndings. In 1 meta-analysis 27 and 2 systematic reviews28,29 reported earlier, antidepressants were found to be effective, with the analgesic effect mainly provided for by TCAs and independent of a patients depression status. SSRIs unfortunately do not seem to alleviate chronic back pain. The 3 reviews cautioned that the analgesic effect of antidepressants must be weighed against their adverse effects, which affected up to 14% of patients and was more common with TCAs than SSRIs. The American College of Physicians and the American Pain Society30 had jointly issued a guideline which recommended the use of TCAs, but not SSRIs, as an option for pain relief in chronic back pain. Clinicians were reminded to assess and treat depression, which is a common comorbid condition. Diabetic Neuropathy Painful diabetic neuropathy affects up to 3.6 million people in the US, representing up to 21% of patients with type 2
November 2009, Vol. 38 No. 11 Antidepressants in the Treatment of Chronic PainHerng Nieng Chan et al 977

diabetes mellitus of more than 10 years duration.31Like most chronic pain conditions, it is closely associated with depression, disruptions in activities of daily living and lowered quality of life.32 TCAs (amitriptyline, clomipramine, imipramine) and SSRIs (fl uoxetine, citalopram, paroxetine) were shown to be effective analgesic agents in a r ecent systematic review,33 with an overall effectiveness of 1.3 in terms of NNT. The results of some studies have suggested that TCAs are more effective than SSRIs. In a randomised, doubleblind, cross-over trial,34 paroxetine was found to be less effective than imipramine. In another study,35 patients in both desipramine and amitriptyline groups improved

signifi cantly but not in the fl uoxetine group. SNRIs are increasingly being considered as alternatives to TCAs and SSRIs. Three large double-blind, placebo controlled trials36-38 investigated the effi cacy of duloxetine in reducing diabetic neuropathy pain and found that duloxetine at 60mg/day was the best effective dose. Duloxetine has been approved by the FDA for the treatment of diabetic neuropathic pain. Venlafaxine in the extended release form and at doses of 150 to 225 mg/day was found to be effective in reducing pain in one randomised, double-blind, placebo-controlled study.39 A more recent study of similar design also reported similar fi ndings.40 Postherpetic Neuralgia Postherpetic neuralgia results from herpes zoster infection and often manifests itself years after the initial infection. It is common in the elderly population and causes persistent and distressing pain that defi es easy treatment.41 Antidepressants were able to provide pain relief in postherpetic neuralgia as reported in a systematic review.33 The antidepressants that were effective included TCAs (amitriptyline, desipramine and nortriptyline) and SSRI (fl uoxetine). Other Neuropathic Pain Conditions Central neuropathic pain occurs due to lesions in the central nervous system, leading to spinal cord injury pain or brain-related central pain. The former commonly occur secondary to traumatic spinal cord injury while the latter, cerebral vascular accidents.42 Antidepressants have shown mixed results. A small study43 reported that amitriptyline was superior to placebo in relieving post-stroke pain but in another study of 84 spinal cord injury patients,44 it was of no effect. Clomipramine and nortriptyline was found to be superior to placebo in providing pain relief to a group of 39 patients with central pain of various causes.45 Two studies investigating amtriptyline in the treatment of HIV-related neuropathy did not show that it was effective.46,47 Chronic Headache Chronic headache is common and includes migraine and chronic tension type headache. Chronic tension type headache occurs for at least 15 days per month and lasts for at least six months.48 In Singapore, migraines affect up to 9.3% of the population, while 2.4% suffer from chronic tension type headache.49 A meta-analysis50 reported that antidepressants were effective, with the evidence for amitriptyline the strongest on subgroup analysis. The authors of a systematic review51 concluded that SSRIs are not better than placebos in patients with migraine. In patients with chronic tension type headaches, SSRIs are less effi cacious than tricyclic antidepressants. Newer dual action antidepressants have been investigated. Venlafaxine is effective in treating migraines and tensiontype

headaches.52-54 In a trial involving patients who suffered from treatment resistant chronic tension-type headache, mirtazapine was found to be effective and comparable to that of amitriptyline.55 The Singapore Ministry of Health clinical practice guidelines56 recommend amitriptyline, clomipramine, maprotiline and mirtazapine to treat chronic tensiontype headaches. For the treatment of migraines, the antidepressants recommended include amitriptyline, fl uoxetine and venlafaxine. Treatment Considerations in the Use of Antidepressants Drug Tolerability The use of TCAs is often limited by their intolerable side effects, which are dose-dependent. Anti-cholinergic side effects are often most uncomfortable. Orthostatic hypotension, oversedation and cognitive impairment are not well tolerated by elderly patients. SSRIs are generally better tolerated compared to TCAs but gastrointestinal and sexual side effects are common. To minimise the occurrence of adverse effects, it is advisable to start at low dosages and titrate over time. Patients should be informed of the potential side effects, which are frequently transient, so that they are not alarmed by them. The pain-relieving effects of antidepressants generally appear from 1 to 3 weeks after initiation of treatment and this should be conveyed to patients to help them better manage expectations. The newer antidepressants are well-tolerated and are appropriate options should patients not tolerate TCAs and SSRIs, or fail to experience improvement with them. Drug Interactions Most antidepressants are metabolised in the liver via isoenzyme CYP2D6 in the cytochrome P450 system. Many of them also inhibit this isoenzyme. The use of
978 Annals Academy of Medicine Antidepressants in the Treatment of Chronic PainHerng Nieng Chan et al

SSRIs (except escitalopram/citalopram), in combination with TCAs, is cautioned due to the inhibitory effect of SSRIs on the metabolism of TCAs by CYP2D6. This can lead to dangerously elevated levels of TCAs, which can be life-threatening. Drug interactions can result between antidepressants and analgesic agents. The analgesic property of tramadol and codeine is reduced by medications inhibiting CYP2D6, including antidepressants like fl uoxetine.57,58 It has also been reported that more patients request for peptic ulcer drugs when taking a combination of SSRI and NSAID than those taking TCA with NSAID.59 The use of tramadol in combination with bupropion could potentially induce seizures in vulnerable patients.60 Serotonin Syndrome It is a rare condition associated with high levels of circulating serotonin and can be fatal. It is characterised by psychiatric, neuromuscular and autonomic features. These

include confusion, agitation, tremors, myoclonus, rigidity, hyperrefl exia, ataxia, hyperthermia, tachycardia, diarrhoea, hyper/hypotension.61 It usually occurs in the context of initiation or dose increase of serotonergic agents the maxim of start low and go slow would be most appropriate here. In addition the combination of MAOIs with SSRIs, and to a lesser extent MAOIs with TCAs and SSRIs with TCAs, is avoided to prevent rapid escalation of serotonin levels which may lead to serotonin syndrome Presence of Depression Psychiatric comorbidities are common in patients suffering from chronic pain, especially depression. Up to 85% of such patients suffer from depression but unfortunately, the presence of pain often obscures its diagnosis and treatment. Chronic pain patients with depression report greater severity of pain symptoms, experience more functional impairments and had greater likelihood for non-recovery.62 There is a close biological link between depression and pain. Serotonin and norepinephrine descending pathways in the spinal cord from the brain stem suppresses pain.63 In depression, there is dysfunction in the serotonin and norepinephrine neurotransmitter systems, which could account for the greater intensity of pain experienced. Recent evidence of a central hyperexcitability state with changes in pain thresholds among depressed patients further reinforces the close relationship between pain and depression. 64 Optimisation of depression treatment would seem to improve pain symptoms. TCAs, duloxetine and venlafaxine have shown effi cacy in relieving pain and improving mood when prescribed to chronic pain patients with comorbid depression.65 SSRIs are not able to sustain the analgesic effect but their mood elevating properties prove to be longer lasting. In addition to pharmacological treatment, social interventions and established psychotherapeutic treatments like cognitive behavioural therapy should be utilised to address the psychosocial factors in the depressed patient experiencing pain. Conclusion Antidepressants are effective in the treatment of chronic pain disorders. The safe use of antidepressants requires the clinician to consider drug tolerability and interactions and to counsel patients appropriately. Psychiatric comorbidities, if present, need to be treated to provide patients with the best chance of recovery. There are established recommendations and guidelines for the use of antidepressants in the treatment of fi bromyalgia, chronic low back pain, chronic headache and diabetic neuropathy. Good scientifi c evidence supports treating postherpetic neuralgia with antidepressants. TCAs remain the most-studied and consistently provide better analgesia than SSRIs in a broad range of pain conditions. SNRIs have emerged as viable alternatives, especially with their better safety and side effect profi les

and reduced risk of drug interactions. In addition, TCAs and SNRIs are able to treat comorbid depression and pain with good results. Further research into the use of other novel antidepressants will increase the therapeutic options available to the pain clinician.
REFERENCES 1. Merskey H, Bogduk N. International Association for the Study of Pain (IASP). Task force on taxonomy: classifi cation of chronic pain. Seattle (WA): IASP Press, 1994. 2. Bouckoms AJ, Hackett TP. Pain patients. Massachusetts General Hospital Handbook of General Hospital Psychiatry. 4th ed. St. Louis: Mosby Yearbook,1997. 3. Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain 2006;10:287-333. 4. Watkins EA, Wollan PC, Melton III LJ, Yawn BP. A population in pain: report from the Olmsted County health survey. Pain Med 2008;9:166-74. 5. Yeo SN. State-of-the-art pain management in Singapore. Singapore Medical Association News 2007;39(6):24-6. 6. Sjgren P, Ekholm O, Peuckmann V, Grnbk M. Epidemiology of chronic pain in Denmark: an update. Eur J Pain 2009;13:287-92. 7. Jackson KC, St Onge EL. Antidepressant Pharmacotherapy: Considerations for the Pain Clinician. Pain Pract 2003;3:135-43. 8. Nocom G, Ho KY, Perumal M. Interventional management of chronic pain. Ann Acad Med Singapore 2009;38:150-5. 9. Woodforde JM, Dwyer B, McEwen BW, De Wilde FW, Bleasel K, Connelley TJ, et al. Treatment of post-herpetic neuralgia. Med J Aust 1965; 2:869-72. 10. Max MB, Culnane M, Schafer SC, Gracely RH, Walther DJ, Smoller B, et al. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology 1987;37:589-96 11. Onghena P, Van Houdenhove B. Antidepressant-induced analgesia in chronic non-malignant pain: a meta- analysis of 39 placebo-controlled studies. Pain 1992;49:205-19. 12. Verdu B, Decosterd I, Buclin T, Stiefel F, Berney A. Antidepressants for the treatment of chronic pain. Drugs 2008;68:2611-32. 13. Clark MR. Psychopharmacology of chronic pain. Prim psychiatry 2007;14:70-9. 14. Mahendran R, Yap HL. Clinical practice guidelines for depression. Singapore Med J 2005;46:610-5. November 2009, Vol. 38 No. 11 Antidepressants in the Treatment of Chronic PainHerng Nieng Chan et al 979 15. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, et al. Report of the Multicenter Criteria Committee. The American College of Rheumatology 1990 Criteria for the Classifi cation of Fibromyalgia. Arthritis Rheum 1990;33:160-72. 16. Huser W, Bernady K, eyler N, Sommer C. Treatment of fi bromyalgia syndrome with antidepessants. JAMA 2009;301:198-209. 17. Arnold LM, Keck Jr PE. Welge JA. Antidepressant treatment of fi bromyalgia: a meta-analysis and review. Psychosomatics 2000;41:104-113. 18. OMalley PG, Balden E, Tomkins G, Santoro J, Kroenke K, Jackson JL. Treatment of fi bromyalgia with antidepressants: a meta-analysis. J Gen Intern Med 2000;15:659-66. 19. Arnold LM, Lu Y, Crofford LJ, Wohlreich M, Detke MJ, Iyengar S, et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fi bromyalgia patients with and without major depressive disorder. Arthritis Rheum 2004;50:2974-84. 20. Arnold LM, Rosen A, Pritchett YL, D'Souza DN, Goldstein DJ, Iyengar S, et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of women with fi bromyalgia with or without major depressive disorder. Pain 2005;119:5-15. 21. Russell IJ, Mease PJ, Smith TR, Kajdasz DK, Wohlreich MM, Detke MJ, et al. Effi cacy and safety of duloxetine for treatment of fi bromyalgia in patients with or without major depressive disorder: results from a 6-month, randomised, double-blind, placebo-controlled, fi xed dose trial. Pain 2008;136:432-44. 22. Goldenberg DL, Burckhardt C, Crofford L. Management of fi bromyalgia syndrome. JAMA 2004;292:2388-95.

23. Andersson GBJ. The epidemiology of spinal disorders. In: Frymoyer JW, editor. The Adult Spine: Principles and Practice. 2nd ed. Philadelphia, PA: Lippincott-Raven, 1997. 24. Frank A. Low back pain. BMJ 1993;306:901-9. 25. Cai CC, Pua YH, Lim KC. Correlates of self-reported disability in patients with low back pain: the role of fear-avoidance beliefs. Ann Acad Med Singapore 2007;36:1013-20. 26. Urquhart D, Hoving JL, Assendelft WJJ, Roland M, van Tulder MW. Antidepressants for non-specifi c low back pain. Cochrane Database Syst Rev 2008;l:CD001703. 27. Salerno SM, Browning R, Jackson JL. The effect of antidepressant treatment on chronic back pain: a meta-analysis. Arch Intern Med 2002;162:19-24. 28. Schnitzer TJ, Ferraro A, Hunsche E, Kong SX. A comprehensive review of clinical trials on the effi cacy and safety of drugs for the treatment of low back pain. J Pain Symptom Manage 2004;28:72-95. 29. Staiger TO, Gaster B, Sullivan MD, Deyo RA. Systematic review of antidepressants in the treatment of chronic low back pain. Spine 2003;28:2540-5. 30. Chou R, Qaseem A, Snow V, Casey D, Gross Jr TC, et al for the Clinical Effi cacy Assessment Subcommittee of the American College of Physicians and the American College of Physicians/ American Pain Society Low Back Pain Guidelines Panel. 31. Argoff CE, Cole BE, Fishbain DA, Irving GA. Diabetic peripheral neuropathic pain: clinical and quality of life issues. Mayo Clin Proc 2006;81(4suppl):S3-11. 32. Benbow SJ, Wallymahmed ME, MacFarlane IA. Diabetic peripheral neuropathy and quality of life. QJM 1998;91:733-7. 33. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database of Syst Rev 2007;4:CD005454. 34. Sindrup SH, Gram LF, Brosen K, Eshoj O, Mogensen EF. The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain 1990;42:135-44. 35. Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B. Effects of desipramine, amitriptyline, and fl uoxetine on pain in diabetic neuropathy. N Engl J Med 1992;326:1250-6. 36. Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S. Duloxetine vs placebo in patients with painful diabetic neuropathy. Pain 2005;116:109-18. 37. Raskin J, Pritchett YL, Bailey RK, et al. Duloxetine in the treatment of diabetic peripheral neuropathic pain results from 3 clinical trials. Presented at the American Academy of Nurse Practitioners, Fort Lauderdale, FL, June 14-17,2005. 38. Raskin J, Pritchett YL, Wang F, DSouza DN, Waninger AL, Iyengar S, et al. A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med 2005;6:346-56. 39. Rowbatham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebocontrolled study. Pain 2004;110:697-706. 40. Kadiroglu AK, Sit D, Kayabasi H, Tuzcu AK, Tasdemir N, Yilmaz ME. The effect of venlafaxine HCl on painful peripheral diabetic neuropathy in patients with type 2 diabetes mellitus. J Diabetes Complications 2008;22:241-5. 41. Raja SN, Haythornwaite JA, Pappagallo M, Clark MR, Travison TG, Sabeen S, et al. Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo controlled trial. Neurology 2002;59:1015-21. 42. Nicholson BD. Evaluation and treatment of central pain syndromes. Neurology 2004;62(5 Suppl 2):S30-6 43. Leijon G, Boivie J. Central post-stroke pain: a controlled trial of amitriptyline and carbamazapine. Pain 1989;36:27-36. 44. Cardenas DD, Warms CA, Turner JA, Marshall H, Brooke MM, Loeser JD. Effi cacy of amitriptyline for relief of pain in spinal cord injury: results of a randomized controlled trial. Pain 2002;96:365-73. 45. Panerai AE, Monza G, Movilia P, Bianchi M, Francucci BM et al. A randomized, within patient, cross over, placebo-controlled trial on the effi cacy and tolerability of the tricyclic antidepressants clomipramine and nortriptyline in central pain. Acta Neurol Scand 1990;82:34-8. 46. Kieburtz K, Simpson D, Yiannoutsos C, Max MB, Hall CD, Ellis RJ, et al. A randomised trial of amitriptyline amd mexiletine for painful neuropathy in HIV infection. Neurology 1998;51:1682-8.

47. Shlay J, Chaloner K, Max M, Flaws B, Reichelderfer P, Wentworth D, et al. Acupuncture and amitriptyline for pain due to HIV-related peripheral neuropathy. JAMA 1998;280:1590-5. 48. Kakuyama M, Fukuda K. The role of antidepressants in the treatment of chronic pain. Pain Reviews 2000;7:119-28. 49. Ho KH, Ong BK. A community-based study of headache diagnosis and prevalence in Singapore. Cephalalgia 2003;23:6-13. 50. Tomkins GE, Jackson JL, OMalley PG, Balden E, Santoro JE. Treatment of chronic headache with antidepressants: a meta-analysis. Am J Med 2001;111:54-63. 51. Moja L, Cusi C, Sterzi R, Canepari C. Selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension type headaches. The Cochrane database of systematic reviews 2005;3:CD002919. 52. Bulut S, Berilgen MS, Baran A, Tekatas A, Atmaca M, Mungen B. Venlafaxine versus amitriptyline in the prophylactic treatment of migraine: randomized, double-blind, crossover study. Clin Neurol Neurosurg 2004;107:44-48. 53. Ozyalcin SN, Talu GK, Kiziltan E, Yucel B, Ertas M. The effi cacy and safety of venlafaxine in the prophylaxis of migraine. Headache 2005;45:144-52. 54. Zissis NP, Harmoussi S, Vlaikidis N, Mitsikostas D, Thomaidis T. A randomized, double-blind, placebo-controlled study of venlafaxine XR in outpatients with tension-type headache. Cephalalgia 2007;27:315-24. 55. Bendtsen L, Jensen R. Mirtazapine is effective in the prophylactic treatment of chronic tension-type headache. Neurology 2004;62:1706-11. 56. Ministry of Health Clinical Practice Guidelines. Diagnosis and management of headache. Singapore: Ministry of Health, Sept 2007. 57. Otton SV, Wu D, Joffe RT, Cheung SW, Sellers EM. Inhibition by fl uoxetine of cytochrome P450 2D6 activity. Clin Pharmacol Ther 1993;53:401-9. 58. Laugesen S, Enggaard TP, Pedersen RS, Sindrup SH, Brsen K. Paroxetine, a cytochrome P450 2D6 inhibitor, diminishes the stereoselective O-demethylation and reduces the hypoalgesic effect of tramadol. Clin Pharmacol Ther 2005;77:312-23. 59. de Jong CF, van den Berg PB, Tobi H, de Jong-van den Berg LTW. Combined use of SSRIs and NSAIDs increases the risk of gastrointestinal adverse effects. Br J Clin Pharmacol 2003;55:5915. 60. Horst WD, Preskorn SH. Mechanisms of action and clinical characteristics of three atypical antidepressants: venlafaxine, nefazodone, bupropion. J Affect Disord 1998;51:237-54. 61. Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148:705-13. 62. Bair MJ, Robinson RL, Katon W, Kroenke K. Depression and pain comorbidity. A literature review. Arch Intern Med 2003;163:2433-45. 63. Stahl SM. The psychopharmacology of painful physical symptoms in depression. J Clin Psychiatry 2002;63:382-3. 64. Klauenberg S, Maier C, Assion H-J, Hoffmann A, Krumova EK, Magrel W, et al. Depression and changed pain perception: hints for a central disinhibition mechanism. Pain 2008;140:332-43. 65. Jann MW, Slade JH. Antidepressant agents for the treatment of chronic pain and depression. Pharmacotherapy 2007;27:1571-87.

Cara Mengatasi Sakit Kepala

Sakit kepala memang sangat menyebalkan, bahkan dapat mengganggu aktivitas dan pekerjaan anda. Berikut adalah tips mengatasi sakit kepala: 1. Stretching : Sakit kepala dapat timbul akibat otot yang tegang. Menarik nafas yang dalam dan meregangkan otot-otot leher dan pundak dapat membantu merelaksasi otot-otot tegang yang dapat menyebabkan sakit kepala. Jika anda ada waktu, senam yoga juga dapat merelaksasi otot-otot tubuh anda dan membantu mengatasi stres yang dapat memicu nyeri kepala. 2. Kompres dingin/ panas : Kompres dingin dapat mengurangi peredaran darah dan peradangan, sedangkan kompres darah dapat meningkatkan peredaran darah. Namun menurut ahli, kedua jenis kompres ini dapat membantu meringankan nyeri kepala. 3. Kafein : Kafein terbukti dapat mengurangi gejala sakit kepala dengan cara menghambat reseptor adenosin yang ada di otak. Adenosin adalah neurotransmitter yang berfungsi untuk pelebaran pembuluh darah, sehingga nantinya akan menekan otak dan menyebabkan nyeri kepala. Dengan menghambat produksi adenosin, maka pembuluh darah akan berkonstriksi dan meringankan gejala sakit kepala. 4. Teh peppermint : Terkadang nyeri kepala dapat pula disertai dengan sakit perut atau mual. Menurut penelitian, teh peppermint dapat meringkankan sakit perut dan mual. 5. Obat-obatan : Obat seperti parasetamol dan aspirin dapat meringankan peradangan dan menghambat zat-zat kimia di otak yang menyebabkan rasa sakit. Obat-obat tersebut terkadang ditambahkan dengan kafein yang dapat meningkatkan penyerapan di usus, sehingga lebih efektif jika dipakai pada nyeri kepala yang lebih berat.

Tips di atas hanya ditujukan untuk mengurangi nyeri kepala yang ringan. Jika anda mengalami snyeri kepala yang hebat dan/atau menetap, segeralah periksa ke dokter terdekat.

12. Jangan

Sepelekan Nyeri Kepala!

Nyeri kepala dapat merupakan salah satu gejala dari penyakit saraf yang serius, seperti stroke, tumor otak, kelainan pembuluh darah otak, dan infeksi otak. Secara umum nyeri kepala dapat dikelompokkan menjadi dua, yaitu nyeri kepala primer dan nyeri kepala sekunder. Nyeri kepala primer adalah nyeri kepala yang muncul akibat respons terhadap stres (baik fisik maupun psikis). Nyeri kepala primer sendiri dapat dibagi menjadi tiga jenis, yaitu Tension Headache, Migrain, dan Cluster Headache. Tension Headache merupakan jenis nyeri kepala yang paling banyak dikeluhkan pasien dengan gejala rasa sakit pada kedua sisi kepala seperti terikat kencang dan terkadang rasa sakitnya sampai ke leher. Biasanya nyeri kepala jenis ini disebabkan oleh stress, kelelahan, kurang tidur, atau otot tegang. Sedangkan migraine merupakan nyeri kepala berdenyut di salah satu sisi kepala, yang biasanya berlangsung selama beberapa jam. Penderita migraine juga biasanya menjadi sensitif terhadap cahaya, suara, dan bau. Nyeri kepala primer Cluster Headache adalah nyeri kepala pada daerah sekitar mata atau di belakang mata. Rasanya seperti tertusuk-tusuk dan biasanya disertai dengan gejala lain, seperti hidung tersumbat, mata merah dan berair di salah satu mata yang sakit. Umumnya Cluster Headache lebih banyak diderita oleh pria. Nyeri kepala sekunder adalah nyeri kepala dengan disertai gejala gangguan saraf seperti kejang-kejang, mata juling, penglihatan ganda, dan kelemahan di salah satu alat gerak. Nyeri kepala sekunder dapat disebabkan oleh adanya kelainan patologis pada otak. Kelainan ini dapat berupa tumor otak, stroke, thrombosis (sumbatan pada arteri), hipertensi berat (maligna), infeksi otak (meningitis, encephalitis, abses), atau kelainan pembuluh darah otak, seperti aneurisma dan AVM (artiriovenous malformation). Nyeri kepala ini yang harus diwaspadai dan harus mendapatkan penanganan medis dengan segera. Segera berkonsultasi kepada dokter bila sakit kepala didukung dengan beberapa kondisi, misalnya memiliki riwayat penyakit kronis lain seperti tekanan darah tinggi, jantung, stroke, dan diabetes; terjadi nyeri kepala yang sangat hebat; keluhan nyeri kepala tidak hilang dengan obat-obatan yang biasa diminum, dan nyeri terjadi pada daerah wajah atau di sekitar mata.

Selain itu, waspadalah dan segera ke UGD rumah sakit terpercaya, bila mengalami gejala-gejala berikut:

Nyeri kepala yang luar biasa hebatnya dan mendadak Nyeri kepala bertambah berat secara cepat Nyeri kepala disertai penurunan kemampuan konsentrasi dan berpikir Terjadi penurunan kesadaran Terjadi perubahan dalam kemampuan berbicara Mengalami kelemahan, rasa baal, atau kesulitan berjalan, disertai gangguan penglihatan Leher atau tengkuk terasa kaku atau nyeri Nyeri disertai keluhan pusing berputar, seperti ruangan terbalik, atau rasa akan jatuh ke satu sisi Nyeri kepala terjadi setelah benturan kepala Nyeri kepala disertai demam (suhu lebih dari 38C)

Tindakan untuk mengatasi nyeri kepala adalah dengan pain management yaitu dengan farmakoterapi (menggunakan obat-obatan), fisioterapi, dan psikoterapi. Namun apabila dari gejala yang muncul menunjukkan kemungkinan terjadinya nyeri kepala sekunder, maka sebaiknya dilakukan proses screening dengan MRI atau CT Scan untuk melihat kemungkinan adanya kelainan pada daerah otak.

13.
last update : 26 June 2013 NYERI KEPALA PADA LANSIA Medikaholistik.com
Nyeri kepala atau sefalgia adalah suatu kondisi terdapatnya rasa nyeri di kepala, kadang nyeri pada leher bagian belakang atau punggung bagian atas. Kebanyakan nyeri kepala disebabkan oleh kontraksi otot, kelainan pembuluh darah atau keduanya. Secara garis besar klasifikasi nyeri kepala dibagi menjadi 2, yaitu : Nyeri kepala primer a. Migren. Migren merupakan nyeri kepala berulang dengan serangan nyeri yang berlangsung 4 - 72 jam. Nyeri biasanya unilateral, sifatnya berdenyut, dapat diperberat oleh aktivitas, dan dapat disertai oleh muak dan muntah. Migren terjadi lebih sering pada wanita. Penatalaksanaan migren khususnya pada lansia dapat dilakukan dengan mengonsumsi obat tertentu sesuai anjuran dokter karena ada jenis obat, seperti triptan yang umum dikonsumsi sebagai obat sakit kepala, tetapi tidak boleh sembarangan dikonsumsi oleh lansia. b. Tension type headache adalah suatu keadaan yang melibatkan sensasi nyeri atau rasa tidak nyaman di daerah kepala, kulit kepala, atau leher yang biasanya berhubungan dengan ketegangan otot di daerah ini. Lebih sering terjadi pada lansia dari pada populasi yang lebih muda. Menurut data yang ada, prevalensi menderita sakit kepala jenis ini pada laki-laki sebesar 69%, sedangkan pada wanita sebesar

88%. Peranan faktor emosional / psikologis diketahui dapat berpengaruh terhadap nyeri kepala pada seseorang. Untuk pengobatan tension type headache dapat dilakukan dengan mengonsumsi obat analgesik (penahan rasa sakit) biasa. Akan tetapi untuk mengurangi kekambuhan harus disertai dengan cara lain, seperti relaksasi, terapi biofeedback, dan kadang-kadang menggunakan obat antidepresan. Terapi fisik, seperti biofeedback, fisioterapi terapi relaksasi dapat membantu pada kasus pasien yang tidak dapat merelaksasikan otot-ototnya. c. Nyeri kepala klaster adalah jenis nyeri kepala yang berat, unilateral yang timbul dalam serangan-serangan mendadak, sering disertai dengan rasa hidung tersumbat, keluar ingus (rinore), keluar air mata dalam jumlah banyak (lakrimasi), dan injeksi konjungtiva (mata merah) disisi nyeri. Nyeri kepala ini ditandai dengan rasa nyeri luar biasa yang ditimbulkan sehingga sering disebut "sakit kepala bunuh diri". Jarang terjadi pada orang tua, tetapi 4% lansia tercatat mengunjungi klinik karena menderita nyeri kepala klaster. Pengobatan dapat dilakukan dengan mengonsumsi obat tertentu sesuai anjuran dokter karena obat tersebut memiliki efek samping yang cukup berbahaya sehingga tidak boleh dikonsumsi oleh orang yang mengidap gangguan vaskuler (peredaran darah), jantung, serebral (otak), menderita penyakit ginjal atau hati, pada wanita hamil, orang yang infeksi dan masa pasca bedah. Nyeri kepala sekunder a. Obat berlebihan (drug overuse). Pasien lansia diketahui dapat mengonsumsi sepertiga dari semua resep obat sehingga dikhawatirkan dapat menderita rebound headache. Seperti pasien yang lebih muda, obat yang umum diberikan untuk lansia adalah over-the-counter analgesik, obat kombinasi senyawa yang mengandung ergotamine, triptans, dan narkotika. Penggunaan obat tersebut penting untuk ditapering dan dihentikan penggunaannya jika tidak mutlak dibutuhkan.

b.

Temporal (giant cell) artritis. Nyeri kepala adalah gejala yang paling umum dan alasan utama pasien dengan GCA datang ke ahli saraf. Karena gejala yang paling umum adalah nyeri kepala, GCA harus dipertimbangkan pada setiap lansia dengan nyeri kepala onset baru atau perubahan pada nyeri kepala yang sebelumnya dalam bentuk stabil, adanya klaudikasi rahang, penurunan berat badan, penurunan fungsi pengkihatan, demam atau anemia (kekurang darah) yang berkepanjangan, atau laju sedimentasi (pengendapan) sel darah merah/eritrosit yang tinggi. Gejala lain GCA adalah hilangnya penglihatan pasien. Jika terdapat dua gejala tersebut, yaitu nyeri kepala dan hilangnya penglihatan, maka dapat dilakukan pemeriksaan tingkat sedimentasi eritrosit untuk mengetahui apakah pasien tersebut menderita GCA. c. Exploding Head Syndrome. Tipe ini biasanya jarang terjadi, tetapi lebih sering terjadi pada wanita dibandingkan pria. Umumnya terjadi pada orang yang berusia lebih dari 50 tahun. Saat pasien tertidur, mereka bisa terbangun karena sensasi suara keras atau ledakan di kepala mereka. Sensasi ini dapat terjadi beberapa kali per malam dan dapat bertahan selama beberapa bulan. Mekanisme penyakit ini tidak diketahui secara jelas, tetapi mungkin berhubungan dengan gangguan tidur yang terjadi pada seseorang. Pengobatan yang disarankan adalah pasien menenangkan dirinya.

d. Lesi nyeri kepala (Lesional Headache). Kejadian meningkat seiring dengan bertambahnya usia sebagai akibat penyakit intrakranial. Lansia lebih rentan terhadap berkembangnya sub-dural hematoma (penimbunan darah dalam rongga sub-dural) atau tumor otak. Nyeri kepala akibat tumor otak tidak mudah diidentifikasi dengan gejala, seperti nyeri kepala parah yang lebih buruk terjadi di pagi hari disertai muntah. Bahkan sakit kepala jenis ini banyak disalah-artikan dengan tension-type headache. Untuk mengetahui apakah nyeri kepala tersebut merupakan lesi dari tumor otak, dapat dilakukan pemeriksaan MRI dengan gadolinium

14. Home Penyakit Jenis-jenis Sakit Kepala dan Gejalanya

Jenis-jenis Sakit Kepala dan Gejalanya

Diulas oleh dokterLisin on Sunday, June 9th, 2013, Rating: 4.5

Setiap orang pasti pernah mengalami sakit kepala termasuk Anda sendiri, sakit kepala yang anda alami atau orang lain alami banyak sekali penyebabnya dan sangat bervariasi, atas dasar inilah sakit kepala juga bermacam-macam jenisnya yang memiliki gejalagejala masing-masing yang berbeda pula. Berikut akan kita ulas Jenis-jenis sakit kepala dan Gejalanya, Karena dengan mengetahui jenis-jenis sakit kepala akan sangat bermanfaat bagi kita untuk bisa mengatasi atau mengobati sakit kepala dengan tepat sesuai degan jenis sakit kepala yang sedang diderita. Pada tahun 2007, International Headache Society menyepakati sistem klasifikasi atau jenis-jenis sakit kepala. Karena begitu banyak orang yang menderita sakit kepala dan karena juga pengobatan sakit kepala yang terkadang sulit, diharapkan dengan sistem klasifikasi yang baru ini akan membuat para dokter menegakkan diagnosis spesifik untuk jenis sakit kepala dan untuk menyediakan pengobatan yang lebih baik dan lebih efektif.

ilustrasi sakit kepala Ada tiga kategori utama untuk jenis-jenis sakit kepala:

1. Sakit kepala primer 2. Sakit kepala sekunder 3. Nyeri saraf kranial (cranial neuralgia), nyeri wajah, dan sakit kepala lainnya.

1. Sakit Kepala Primer Yang termasuk dalam jenis sakit kepala primer diantaranya : sakit kepala migrain, tension dan cluster. Sakit kepala jenis tension Sakit kepala tension ditandai dengan kepala terasa tegang dan berat, jenis sakit kepala ini merupakan jenis sakit kepala primer yang paling umum. sampai dengan 90% orang dewasa mengalami atau akan mengalami jenis sakit kepala ini. Sakit kepala tension lebih sering diderita oleh wanita dibanding pria. Gejala sakit kepala tension : 1. Rasa sakit dimulai di belakang kepala dan leher atas dan digambarkan seperti mendesak atau tertekan. 2. Sering digambarkan sebagai tekanan melingkari kepala dengan tekanan paling kuat di atas alis. 3. Nyeri biasanya ringan (tidak melumpuhkan) dan bilateral (mempengaruhi kedua sisi kepala). 4. Rasa sakit ini tidak terkait dengan aura, mual, muntah, atau sensitivitas terhadap cahaya dan suara. 5. Rasa sakit terjadi secara sporadis (jarang dan tanpa pola) namun dapat terjadi sering dan bahkan setiap hari pada beberapa orang. 6. Rasa sakit memungkinkan kebanyakan orang untuk berfungsi secara normal, meskipun sakit kepala sedang ia derita. Sakit kepala migrain Urutan nomor dua untuk jenis sakit kepala primer yang paling umum adalah migrain. Diperkirakan 28 juta orang di Amerika Serikat (sekitar 12% dari populasi) akan mengalami sakit kepala migrain. Migrain mempengaruhi anak maupun orang dewasa. Sebelum pubertas, anak laki-laki dan perempuan dipengaruhi sama oleh sakit kepala migrain, tapi setelah pubertas, perempuan lebih sering dari laki-laki. Diperkirakan bahwa 6% dari laki-laki dan sampai 18% wanita akan mengalami sakit kepala migrain dalam hidup mereka. Sakit kepala migrain ditandai dengan sakit kepala berdenyut hebat atau sensasi berdenyut di satu daerah kepala (sakit kepala sebelah) dan umumnya disertai mual, muntah, dan kepekaan yang ekstrim terhadap cahaya dan suara.

Serangan migrain dapat menyebabkan rasa sakit yang signifikan selama berjam-jam samapi sehari dan penderita akan lebih nyaman berada di tempat gelap, tempat yang tenang untuk berbaring. Beberapa migrain didahului atau disertai dengan gejala peringatan sensorik (aura) pada penglihatannya, seperti kilatan cahaya, bintik-bintik buta, atau kesemutan di lengan atau kaki. Sakit kepala cluster Sakit kepala cluster adalah jenis sakit kepala primer yang jarang yang mempengaruhi 0,1% dari populasi (1 dalam 1.000 orang). Lebih sering mempengaruhi pria berusia dua puluhan, perempuan dan anak-anak juga dapat menderita jenis sakit kepala ini. Gejala Sakit kepala Cluster : Sakit kepala Cluster merupakan sakit kepala yang datang dalam kelompok (cluster) berdasarkan waktu yang berlangsung minggu atau bulan, dipisahkan oleh periode bebas nyeri-bulan atau tahun. 1. Selama periode di mana sakit kepala cluster terjadi, nyeri kepala biasanya terjadi sekali atau dua kali sehari, tetapi beberapa pasien mungkin mengalami sakit kepala lebih dari dua kali sehari. 2. Setiap episode nyeri kepala berlangsung dari 30 sampai 90 menit. 3. Serangan nyeri kepala cenderung terjadi pada waktu yang sama setiap hari dan sering terbangun pada malam hari ketika pasien tidur nyenyak. 4. Rasa sakit kepala biasanya menyiksa dan terletak di sekitar atau di belakang salah satu mata. 5. Beberapa pasien menggambarkan rasa sakit sebagai perasaan seperti ada benda panas di mata. Mata yang terkena bisa menjadi merah, meradang, dan berair. 6. Hidung pada sisi yang terkena dapat menjadi tersumbat atau terasa sesak dan meler. Sakit kepala primer ini dapat mempengaruhi kualitas hidup seseorang. Beberapa orang yang sakit kepala jenis ini mudah sembuh sementara yang lain sulit sekali sembuh. Sakit kepala jenis ini tidak mengancam nyawa, namun bisa juga berhubungan dengan gejala yang dapat menyerupai stroke atau perdarahan otak (intraserebral). 2. Sakit kepala skunder Sakit kepala sekunder merupakan jenis sakit kepala yang disebabkan oleh masalah struktural di kepala atau leher. Ada banyak penyebab dari jenis sakit kepala ini mulai dari perdarahan di otak, tumor, atau meningitis dan ensefalitis. Gejala Sakit Kepala Sekunder :

Sakit kepala jenis ini merupakan gejala yang terkait dengan banyak penyakit. Sakit kepala sekunder disebabkan oleh penyakit yang mendasari atau cedera yang perlu didiagnosa dan diobati. Mengontrol atau mengobati gejala sakit kepala sangat diperlukan sambil menunggu tes diagnostik untuk mengetahui penyakit yang mendasarinya. Beberapa penyebab sakit kepala sekunder dapat berpotensi mengancam nyawa dan mematikan. Diagnosis dini dan pengobatan sangatlah penting. International Headache Society menyatakan ada delapan kategori sakit kepala sekunder. Beberapa contoh dalam setiap kategori dicatat. (Ini bukan daftar lengkap). : 1. Trauma kepala dan leher 2. Gangguan pembuluh darah pada kepala dan leher, seperti stroke, TIA, AVM. 3. Gangguan pada otak selain pembuluh darah seperti tumor dan kanker. 4. Akibat obat-obatan 5. Infeksi seperti meningitis, ensefalitis, HIV/AIDS, pneumonia, flu,dan lain-lain 6. Perubahan Lingkungan fisik 7. Masalah dengan mata, telinga, tenggorokan hidung, gigi dan leher 8. Masalah psikiatri

3. Neuralgia Neuralgia berarti nyeri saraf (neur = saraf + algia = nyeri). Neuralgia kranial menggambarkan jenis sakit kepala yang terjadi karena saraf di leher, kepala dan bagian atas menjadi meradang dan menjadi sumber rasa sakit di kepala. Nyeri wajah dan berbagai penyebab lain untuk sakit kepala termasuk dalam kategori ini. Itulah ringkasan mengenai Jenis-jenis Sakit Kepala dan Gejalanya semoga menjadi referensi yang bermanfaat untuk Anda.

Melalui artikel ini, saya harap Anda sudah mengerti tentang : sakit kepala, jenis sakit kepala, macam macam sakit kepala, gejala sakit kepala, jenis jenis sakit kepala, Penyakit apa yang gejalanya sakit kepala tidak sembuh-sembuh, Penyakit apa yang di derita jika kepala sering sakit Sumber : http://mediskus.com/penyakit/jenis-jenis-sakit-kepala-dangejalanya.html#ixzz2f8x2UbWT

15.

Sakit Kepala Migraine

Definisi Sakit Kepala Migraine

Sakit kepala migraine adalah bentuk dari sakit kepala vascular. Sakit kepala migraine disebabkan oleh vasodilasi (pembesaran dari pembuluh-pembuluh darah) yang menyebabkan pelepasan dari kimia-kimia dari serat-serat syaraf yang melingkar (menggulung) sekeliling arteri-arteri besar dari otak. Pembesaran dari pembuluhpembuluh darah ini meregangkan syaraf-syaraf yang melingkar sekeliling mereka dan menyebabkan syaraf-syaraf melepaskan kimia-kimia. Kimia-kimia ini menyebabkan peradangan, nyeri, dan pembesaran yang lebih jauh dari arteri. Pembesaran yang meningkat dari arteri-arteri memperbesar nyeri. Serangan-serangan migraine umumnya mengaktifkan sistim syaraf sympathetic dalam tubuh. Sistim syaraf sympathetic seringkali dipikirkan sebagai bagian dari sistim syaraf yang mengontrol respon-respon yang primitif pada stres dan nyeri, yang disebut respon "lawan atau lari", dan pengaktifan ini menyebabkan banyak gejala-gejala yang berhubungan dengan serangan-serangan migraine; contohnya, aktivitas syaraf sympathetic yang meningkat pada usus menyebabkan mual, muntah, dan diare.

Aktivitas sympathetic juga menunda pengosongan lambung kedalam usus kecil dan dengan demikian mencegah obat-obat oral memasuki usus dan diserap. Penyerapan yang terganggu dari obat-obat oral adalah sebab yang umum untuk ketidakefektifan dari obat-obat yang diminum untuk merawat sakit-sakit kepala migraine. Aktivitas sympathetic yang meningkat juga mengurangi sirkulasi darah, dan ini menjurus pada kepucatan kulit serta tangan-tangan dan kaki-kaki yang dingin. Aktivitas sympathetic yang meningkat juga berkontribusi pada kepekaan pada kepekaan cahaya dan suara serta penglihatan yang kabur.

Migraine merundung (menimpa) 28 juta orang-orang Amerika, dengan wanita-wanita menderita lebih sering (17%) daripada pria-pria (6%). Pekerjaan yang hilang dan kehilangan produktivitas dari migraine menciptakan beban publik yang signifikan. Meskipun demikian, migraine masih tetap sebagian besar kurang terdiagnosa dan terawat. Kurang dari setengah dari individu-individu dengan migraine didiagnosa oleh dokterdokter mereka.