samples can be auto collected at different time points with great precision ...... within one week; otherwise an automatic email reminder would appear in-.
To Elisabeth and Hans
“ ...you can say to this mountain, ‘Move from here to there’ and it will move. Nothing will be impossible for you.” Matthew 17:20
List of Papers
This thesis is based on the following papers, which will be referred to in the text by their Roman numerals. I.
Hedborg, K., Anderberg, U M., Muhr, C. Stress in Migraine: Personality-Dependent Vulnerability, Life Events and Gender are of Significance. Ups J Med Sci 116(3): 187-199.
II.
Hedborg, K., Muhr, C. Multimodal Behavioral Treatment of Migraine: An Internet-administered, randomized, controlled trial. Ups J Med Sci 116(3): 169-186.
III. Hedborg, K., Muhr, C. Complete Drug Use in Migraine and Changes in Use during Multimodal Behavioral Treatment. (submitted) IV. Hedborg, K., Muhr, C. E Evaluation of Salivary Cortisol in Adult Migraineurs Participating in an Internet-Administered Multimodal Behavioral Treatment Program. (manuscript) Reprints were made with the permission of the publishers.
Contents
INTRODUCTION ........................................................................................ 11 Migraine symptoms .................................................................................. 11 Pathophysiology ....................................................................................... 13 The burden of migraine ............................................................................ 14 Stress – general aspects ............................................................................ 15 Stress and migraine .................................................................................. 16 Cortisol as a biological stress marker ....................................................... 16 Personality ................................................................................................ 17 Life events ................................................................................................ 18 Migraine and depression .......................................................................... 19 Pharmacological treatment ....................................................................... 19 Behavioral treatment ................................................................................ 20 GENERAL AIM ........................................................................................... 22 SPECIFIC AIMS .......................................................................................... 23 METHODS ................................................................................................... 24 Recruitment of participants and initial data collection ............................. 24 Ethical approval........................................................................................ 24 Design ...................................................................................................... 24 Questionnaires .......................................................................................... 26 Personality traits (SSP) ........................................................................ 26 Current stress (CEOS inventory) ......................................................... 27 Life events ........................................................................................... 30 Quality of life (PQ23) .......................................................................... 30 Depressive mood (MADRS-S) ............................................................ 30 MBT program........................................................................................... 35 Web tool for the MBT program and for a migraine diary ........................ 39 Hand massage ........................................................................................... 39 Self-evaluation of the MBT program and the hand massage ................... 40 Collection and analyses of blood and saliva samples ............................... 41 Statistical methods.................................................................................... 41 RESULTS ..................................................................................................... 43 DISCUSSION ............................................................................................... 49
Methodological considerations................................................................. 53 Representativeness of the material ...................................................... 53 Questionnaires ..................................................................................... 53 Internet as a tool for communication ................................................... 54 Strengths and limitations ..................................................................... 54 CONCLUSIONS .......................................................................................... 56 FUTURE RESEARCH ................................................................................. 58 SWEDISH SUMMARY ............................................................................... 59 ACKNOWLEDGEMENTS .......................................................................... 61 REFERENCES ............................................................................................. 64
LIST OF ABBREVIATIONS
ACR ACTH BMI CEOS CGRP CI DHEA-S HPA IHS MA MADRS-S MBT MO NSAID PDF PQ 23 SAM SBU SPSS SSP VAS
Awakening Cortisol Response AdrenoCorticoTropic Hormone Body Mass Index The Center for Environment-Related Disorders and Stress questionnaire Calcitonine Gene-Related Peptide Confidence Interval Dehydroepiandrosterone Sulphate Hypothalamic-Pituitary-Adrenal International Headache Society Migraine with Aura Montgomery-Asberg Depression Scale Multimodal Behavioral Treatment Migraine without aura Non-Steroidal Anti-Inflammatory Drugs Portable Document Format PQ 23 quality of life questionnaire Sympathetic-Adrenal-Medullary Scientific Assessment of Health Care Statistical Package for Social Sciences 18.0 Swedish universities Scales of Personality Visual Analogue Scale
INTRODUCTION
Migraine symptoms Migraine is a common, hereditary, chronic and disabling neurological disorder. According to the International Classification of Headache Disorders, it is characterized by recurrent attacks of pulsating unilateral headache of moderate to severe intensity with duration of 4-72 hours, in connection with one or several of the following symptoms: nausea, photophobia, osmophobia and phonophobia; and with complete resolution of symptoms inbetween attacks (Campbell 1990; IHS 2004). The headache is aggravated by physical activity – e.g. when bending down, walking or climbing stairs. Migraine is divided into two major sub-groups: migraine without aura (MO) and migraine with aura (MA), of which MO is more prevalent (Table 1). Migraine aura is characterized by reversible episodes of neurological symptoms with a duration of twenty to sixty minutes, which have a clear onset and end, and usually precede the headache phase (IHS 2004). The most common form of aura is visual, consisting of spreading scintillations and scotoma (Pietrobon 2005). More rarely, sensory forms of aura are experienced with symptoms of unilateral numbness or parasthesia of the arm or face. Even more infrequently, loss of motor function may occur, causing difficulties in speech or signs of hemiplegia (Pietrobon 2005), which in extreme cases can lead to manifest stroke in the presence of certain risk factors (Lampl and Marecek 2006). Approximately 30 percent (Stewart, Linet et al. 1991; Rasmussen and Olesen 1992) of individuals with migraine have MA, defined as repeated aura symptoms, among which only a small minority experience aura as a constant phenomenon in association with their headache attacks. Aura without ensuing headache may occur, but is rare (Cutrer and Huerter 2007). Prodromal symptoms – e.g. tiredness, yawning, difficulty concentrating, cravings for food, thirst, and increased micturition – that precede the attack by hours or even days are commonly experienced (Santoro, Bernasconi et al. 1990; Giffin, Ruggiero et al. 2003; Kelman 2004; Quintela, Castillo et al. 2006; Schoonman, Evers et al. 2006).
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Table I. Criteria for migraine without and with aura according to the 2004 International Classification of Headache Disorders 2nd Edition. 1. 1.1 1.2
1.3
1.4 1.5
1.6
Migraine Migraine without aura Migraine with aura 1.2.1 Typical aura with migraine headache 1.2.2 Typical aura with non-migraine headache 1.2.3 Typical aura without headache 1.2.4 Familial hemiplegic migraine 1.2.5 Sporadic hemiplegic migraine 1.2.6 Basilar-type migraine Childhood periodic syndromes that are commonly precursors of migraine 1.3.1 Cyclical vomiting 1.3.2 Abdominal migraine 1.3.3 Benign paroxysmal vertigo of childhood Retinal migraine Complications of migraine 1.5.1 Chronic migraine 1.5.2 Status migrainosus 1.5.3 Persistent aura without infarction 1.5.4 Migrainous infarction 1.5.5 Migraine-triggered seizures Probable migraine 1.6.1 Probable migraine without aura 1.6.2 Probable migraine with aura 1.6.3 Probable chronic migraine
1.1 Migraine without aura (MO) Diagnostic criteria: A At least five attacks criteria fulfilling B-D B Headache lasting 4-72 hours (untreated or unsuccessfully treated) C Headache has at least two of the following characteristics: 1 unilateral location pulsating quality 2 3 moderate or severe pain intensity 4 aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing stairs) D During headache at least one of the following: 1 nausea and/or vomiting photophobia and phonophobia 2 E Not attributed to another disorder
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1.2.1. Typical aura with migraine headache Diagnostic criteria: A. At least 2 attacks fulfilling B-D. B. Aura consisting of at least one of the following, but no motor weakness: 1. fully reversible visual symptoms including positive features (e.g., flickering lights, spots or lines) and/or negative features (i.e., loss of vision) 2. fully reversible sensory symptoms including positive features (i.e., pins and needles) and/or negative features (i.e., numbness) 3. fully reversible dysphasic speech disturbance. C. At least two of the following: 1. homonymous visual symptoms and/or unilateral sensory symptoms. 2. at least one aura symptom develops gradually over 5 minutes and/or different aura symptoms occur in succession over 5 minutes 3. each symptom lasts 5 and 60 minutes D. Headache fulfilling criteria B D for 1.1 Migraine without aura begins during the aura or follows aura within 60 minutes. E. Not attributed to another disorder
Pathophysiology The fundamental cause of migraine is still not established. Historically, two main theories have competed. One early theory proposed by Thomas Willis, a renowned 17th century researcher on vascular physiology, postulated that migraine is caused by distension of the cerebral blood vessels. In the late 19th century, Willis’ theory was challenged by Edward Liveing, who theorized that migraine is neurological in origin and analogous to epilepsy (Eadie 2009). With the advent of neurosurgery, the vascular theory regained popularity, in large part due to the experiments performed by Wolff in the 1930s, showing that vascular structures were the source of headache and that migraine symptoms were affected by vaso-constrictive drugs (Ray and Wolff 1940). The current up-to-date theory, supported by empirical data (Moskowitz 2007), builds on an eclectic view that postulates a combination of disturbances of both these systems: It is believed that the migraine attack starts in the central nervous system and, secondarily, affects the blood vessels to become abnormally pain sensitive. The trigeminal nerve plays a crucial role in transmitting this chain of events as it supplies the face and inside of the head with sensory fibers. The initial events of an attack affect many parts of the brain, as evidenced by the array of prodromal and aura phenomena previously described (Blau 1992; Cutrer and Huerter 2007). The prevailing theory on the origin of aura is that it is caused by a slow neuronal discharge – e.g. over the visual cortex – called “cortical spreading depression” (Bolay, Reuter et al. 2002; Moskowitz 2007). Secondarily, an increased activity of the nerve cells of the trigeminal ganglion is elicited and several neuropeptides are released that affect the blood vessels supplied by the nerve and cause a sterile inflammation which sensitizes the vascular pain receptors 13
– thus causing pain. These neuropeptide-mediated events of the trigeminal ganglion are the targets of current treatment (Ferrari, Roon et al. 2001; Ferrari, Goadsby et al. 2002; Khoury and Couch 2010) as well as of the ongoing development of new drugs such as calcitonin gene-related peptide (CGRP) receptor antagonists (Edvinsson 2008; Edvinsson and Ho 2010).
The burden of migraine The prevalence of migraine is high, with figures for women twice that of those for men (Lipton, Stewart et al. 2001; Rasmussen 2001; Bigal, Lipton et al. 2004; Lipton and Bigal 2005; Stovner, Hagen et al. 2007; Cooke and Becker 2010; Stovner and Andree 2010). A Swedish epidemiological study (Dahlof and Linde 2001) showed a one-year prevalence of 13. 2 percent for the general population and, when separated by gender, 16.7 percent of the women and 9.5 percent of the men were affected. The average frequency of migraine in the mentioned study by Dahlof and Linde was 1.3 attacks a month. However, it has been estimated that approximately one-third of all individuals with migraine generate two-thirds of all attacks (Dahlof and Solomon 1998), thus reflecting the wide individual variations in disease burden. The impact of migraine on the individual and society has been studied extensively (Rasmussen, Jensen et al. 1992; Dahlof and Solomon 1998; Lipton, Stewart et al. 2001; Lipton, Stewart et al. 2001; Lipton, Bigal et al. 2003; Steiner, Scher et al. 2003; Linde and Dahlof 2004; Berg and Stovner 2005; Hazard, Munakata et al. 2009; Leonardi, Raggi et al. 2010). The World Health Organization classifies migraine as a global public health problem and migraine is ranked number nineteen among the twenty most disabling diseases world-wide (Leonardi, Steiner et al. 2005). In a Swedish study by Dahlöf et al. (Dahlof and Solomon 1998) 709 individuals with migraine answered questions from a postal survey about how they were affected by their migraine. The three most affected areas in their lives were: work, family situation and leisure time. It is not unusual for individuals with migraine to refrain from social contacts and from planning leisure activities out of fear of a migraine attack. Such avoidance behavior may also have negative effects on relatives, friends and workmates. Women generally assume greater responsibility for children and the household, indicating that migraine might place a greater burden on women and, secondarily, on their families as well (Stroud, Salovey et al. 2002; Diamond 2007; Boye 2008). The direct costs of migraine for society include sick leave and medical treatment expenditures (Stovner and Andree 2008). Decreased social capacity and society’s expenses for comorbidity, such as depression and anxiety, may lead to indirect costs. Although these costs are significant, the personal costs for those affected would seem to be even higher, when considering the number of “lost days” in a lifetime perspective (Lipton, Bigal et al. 2003; Dueland, Leira et al. 2004). 14
Stress – general aspects The concept of stress emerged from studies conducted by French physiologist Claude Bernard (1813-78) and American physiologist Walter Cannon (1871-1945), who described the mechanisms through which the body maintains a stable internal environment “milieu interieur” and the concept of homeostasis (“stability through constancy”) (Cannon 1932). The term stress was originally suggested by Hans Selye (1907-1982) an endocrinologist of Austrian-Hungarian origin, active in Canada in the 1930s, who defined stress as “a nonspecific response of the body to any demand made upon it” (Selye 1973). Selye later modified the stress concept by dividing it into: ”eustress”, which is healthy stress and gives a feeling of fulfillment or other positive feelings, and “distress”, which is an aversive state that may lead to maladaptive behavior such as aggression, passivity and withdrawal (Selye 1976). The concept of homeostasis was further developed by Sterling and Eyer (Sterling 2004). They believed that homeostasis – described as internal fluctuations within close normal values, e.g., to maintain stability in body temperature and access to energy (blood glucose levels) – was too narrow when used to describe the stress reaction. They instead used the term allostasis – “to reestablish stability through change” – to describe situations with over- and under-production of central mediators when the limits for homeostasis were exceeded. The term explained the difference between the system that sustains life (homeostasis) and the system that keeps these life-sustaining physiological functions in balance (allostasis). Bruce McEwen introduced the concept of allostatic load as a long-term state of bodily overstimulation and abnormal performing to keep up the physiological balance, causing wear and tear on the regulatory systems of the body which eventually may lead to disease (McEwen 2004). Two main systems are involved in the stress reaction: the sympatheticadrenal-medullar system (SAM) and the hypothalamic-pituitary-adrenal (HPA) axis. Both these systems are governed by the brain, target the adrenal gland and are regulated via feed-back systems. The SAM system is responsible for the immediate stress reaction leading to a rapid release of catecholamines from the adrenal medulla and from other parts of the sympathetic nervous system. The HPA axis is responsible for a relatively slower stress reaction consisting of release of cortisol from the adrenal cortex which is elicited via release of corticotropin-releasing hormone (CRH) from the hypothalamus stimulating the pituitary gland to release adrenocorticotropic hormone (ACTH), which is then transported via the blood to stimulate the adrenal cortex. The two systems cooperate, and their primary influence is on energy metabolism. It has been claimed that chronic stress leads to dysregulation of the HPA axis (Kirschbaum and Hellhammer 1994; Kudielka, Hellhammer et al. 2009; Vreeburg, Hoogendijk et al. 2009). For example depression is associated with raised cortisol levels (van Eck, Berkhof et al. 15
1996; Theorell 2007), whereas chronic fatigue syndromes and fibromyalgia, are claimed to be associated with low values and poor diurnal variations (Demitrack and Crofford 1998; Strickland, Morriss et al. 1998; Theorell 2007).
Stress and migraine It is well known that stress plays a major role as a triggering factor for acute migraine attacks (Ehde and Holm 1992; Rasmussen 1992; Rasmussen and Olesen 1992; Holm, Lamberty et al. 1997; Fanciullacci, Alessandri et al. 1998; Wacogne, Lacoste et al. 2003; Nash and Thebarge 2006; Kelman 2007; Hashizume, Yamada et al. 2008; Maki, Vahtera et al. 2008; Radat, Mekies et al. 2008; Sauro and Becker 2009; Andress-Rothrock, King et al. 2010). The physiological stress response via the SAM system and the HPA axis is generally associated with a subjective feeling of external or internal threat or demand (Selye 1976). The intensity of this reaction is dependent on the duration, frequency, and severity of the stressors as well as on the current health condition of the affected individual. Some stressors such as low blood glucose or oxygen levels are genuine parts of human physiology, but many are largely contextually defined and dependent on culture, life situation, previous experiences, and personality factors (Paykel 2001; Dedovic, Wadiwalla et al. 2009; Peterlin, Katsnelson et al. 2009; Peterlin, Tietjen et al. 2009). However, it has been shown that psychological stress plays an important role not only before the onset of migraine (Wober and WoberBingol 2010; Yadav, Kalita et al. 2010), but also in the maintenance of the disorder, for the frequency of attacks (Dodick 2009; Aguggia and Saracco 2010) as well as in the change from episodic to chronic migraine (defined as attacks more than 15 days a month (Bigal and Lipton 2009)). In view of these effects of stress in migraine, it is interesting that experimental data have shown that a migraine attack is preceded by increased neurophysiological reactivity to stress 1-3 days before the actual attack (Siniatchkin, Averkina et al. 2006).
Cortisol as a biological stress marker The glucocorticoids are hormones that serve important functions in physiological adaptation to diurnal rhythm, physical and psychological demands, and disease. Cortisol, the most important glucocorticoid, is frequently used in evaluation of the HPA axis function (Wust, Wolf et al. 2000; Clow, Thorn et al. 2004; Patacchioli, Monnazzi et al. 2006). Methods have been developed to evaluate changes in cortisol secretion via measurement of sputum levels as sputum levels are shown to be parallel to serum levels (Wust, Wolf 16
et al. 2000). This has greatly facilitated the sampling procedures as multiple samples can be auto collected at different time points with great precision and minimal discomfort. Measurement of salivary cortisol has been used as a complement to questionnaires and interviews in the evaluation of acute and chronic stress, as salivary cortisol levels reflect the physiological processes underlying the stress response (Åkerstedt and Theorell 2001). Aberrant awakening cortisol response (ACR), low daytime and overall low cortisol levels and high evening values are examples of cortisol parameters used in stress research as evidence of a disturbed HPA axis (Wust, Wolf et al. 2000; Clow, Thorn et al. 2004; Theorell 2007; Hansen, Garde et al. 2008; Kudielka, Hellhammer et al. 2009). Dehydroepiandrosterone sulphate (DHEA-S) is another steroid hormone produced by the adrenal glands that is also believed to be secreted in response to stress. It is a pro-hormone for sex steroids and a cortisol antagonist (Hechter, Grossman et al. 1997) and is claimed to have anabolic and neuroprotective effects (Arnetz, Theorell et al. 1983; Romanowska, Larsson et al. 2011). Reduced ability to cope with stress is claimed to be reflected by high cortisol levels and low levels of DHEA-S (Patacchioli, Monnazzi et al. 2006). Therefore, the cortisol/DHEA-S ratio has been used as an inverse marker for wellbeing, e.g. the cortisol/DHEA-S ratio in women with chronic migraine was found to be raised, which hence was interpreted as a sign of decreased wellbeing (Patacchioli, Monnazzi et al. 2006).
Personality Personality may be defined as the deeply ingrained and enduring patterns of thoughts, feelings and behavior that characterize the unique lifestyle and adaptation of an individual. These patterns may be described as combinations of personality traits – e.g. dependence, suspiciousness and impulsiveness – that vary across individuals (Ekselius 2006). Personality traits are largely constitutionally determined, but may also depend on developmental events and social experience. There are several perspectives on personality, depending on which psychological theory is used. Examples of the most influential perspectives are: the psychodynamic perspective, which focuses on how our subconscious and our early relationships influence our personality; the cognitive perspective, which concentrates on the individual’s management of information; and the trait perspective, which, as mentioned above, advocates that personality traits are mainly genetically determined and for which the use of tests to assess these traits is fundamental. Several such instruments exist for assessment of personality traits. In the AngloSaxon world, the Minnesota Multiphasic Personality Inventory (MMPI) is frequently used (Luconi, Bartolini et al. 2007). Another internationally used instrument is the Temperament and Character Inventory (TCI), which has 17
been normalized to Swedish conditions (Brandstrom, Schlette et al. 1998). In Sweden, the Karolinska Scales of Personality was developed in the 1960s to identify stable personality traits of importance for psychiatric vulnerability – and is still in use (Schalling, Asberg et al. 1987). A revised version of this inventory, the Swedish University Scales of Personality (SSP), was published in 2000 (Gustavsson, Bergman et al. 2000). Other commonly used personality inventories are the five-factor model of personality (McCrae and Costa 1987) and Eysenck’s personality questionnaires (EPQ) (Breslau, Chilcoat et al. 1996). The number of traits in these different instruments is relatively high. Also, they are dependent on each other to different degrees. Therefore, using factor analysis, personality traits can be merged into a higher order of more fundamental personality characteristics usually called personality factors. One such set of factors commonly referred to is “the big five”, in which the five factors are: extraversion, agreeableness, conscientiousness, neuroticism, and openness. Neuroticism may be described as a tendency for negative emotional states such as anxiety, anger, guilt, and depression. Such individuals respond more poorly to stress, and are more likely to interpret situations as threatening or hopelessly difficult. They are often self-conscious and shy. Neuroticism is associated with anxiety disorders such as phobia, depression, and panic disorders. Claims have been made that individuals with migraine display increased neuroticism and anxiety and are anti-aggressive (Wolff and HG 1937; Schmidt, Carney et al. 1986; Silberstein, Lipton et al. 1995).
Life events There is evidence to indicate that life events can be important for the onset or the aggravation of migraine (Sauro and Becker 2009). Tietjen et al. claimed that emotional abuse during childhood is a risk factor for chronic headache (Tietjen, Brandes et al. 2010) and, likewise, Peterlin et al. suggested that severe life events during adulthood causing post-traumatic stress are more frequently found among individuals with chronic migraine (Peterlin, Tietjen et al. 2008). Furthermore, it has been claimed that individuals with migraine are less capable of coping with their life stressors than the general population and therefore appraise their stressors as more stressful and threatening (Breslau and Andreski 1995; Holm, Lamberty et al. 1997; Holm, Lokken et al. 1997; Hassinger, Semenchuk et al. 1999; Sauro and Becker 2009).
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Migraine and depression A positive association between migraine and depression is well established (Breslau, Schultz et al. 2000; Lanteri-Minet, Radat et al. 2005; Frediani and Villani 2007; Radat, Mekies et al. 2008). The prevalence of major depression has been reported to be 1.7- to 2.7-fold higher among individuals with migraine compared to non-migraineurs (Rorsman, Grasbeck et al. 1990; Lipton, Hamelsky et al. 2000; Lanteri-Minet, Radat et al. 2005) and in a Swedish study a 1-year prevalence of 17.8% and a life-time prevalence of 31.3% depression were reported for women with migraine aged 40-74 years (Mattsson and Ekselius 2002). A causative relationship between migraine and major depression has been suggested and there is evidence to support the notion that the causality may be bidirectional (Breslau, Schultz et al. 2000; Breslau, Schultz et al. 2001).
Pharmacological treatment Pharmacological treatment of migraine may be separated into preventive or acute forms. Preventive medication for migraine is usually taken continuously, independent of whether or not headache is present (Silberstein and Goadsby 2002). The primary goals for migraine preventive therapy were presented in Guidelines for Migraine Headache in the Primary Care Setting (Ramadan, Silberstein et al. 2000): (i)to reduce attack frequency, severity, and duration; (ii)to improve responsiveness to treatment of acute attacks; and (iii) to improve function and reduce disability. The majority of preventive drugs were not primarily developed for anti-migraine use, and their usefulness was therefore discovered on the basis of empirical clinical observations. Beta blockers are the most common preventive prescription drugs (Bigal and Lipton 2006). Other preventive drugs are calcium channel blockers (flunarizin), 5-HT2-antagonists (pizotifen and cyproheptadin), 5-HT1-agonist/2antagonists (methysergide), non-steroidal anti-inflammatory drugs (NSAID; e.g. naproxen and diclofenac), antiepileptic drugs (valproate, gabapentine and topiramat), angiotensin II-receptorantagonists (kandesartan) and antidepressants (e.g., amitriptylin) (Fumal and Schoenen 2008). The use of migraine preventive drugs is relatively uncommon. Four studies (Lucas, Chaffaut et al. 2005; Morillo, Alarcon et al. 2005; Diamond, Bigal et al. 2007; Lafata, Tunceli et al. 2009) showed 13, 12, 6 and 2 percent users of preventive drugs, respectively. Adherence to preventive drugs may also be low (Linde, Jonsson et al. 2008; Lafata, Tunceli et al. 2009). Drugs for acute treatment of migraine can be separated into non-specific and specific. Examples of non-specific drugs are acetylsalicylic acid, acetaminophen, non-steroidal anti-inflammatory drugs (NSAID), morphine analogues and combinations of analgesics. Migraine-specific drugs are triptans 19
(serotonin 5–HT1B/1D receptor agonists) and, more recently, CGRP receptor antagonists (Edvinsson 2008; Edvinsson and Ho 2010; Monteith and Goadsby 2011). Several generations of triptans have been tested, with minor differences in efficacy (Ferrari, Goadsby et al. 2002; Hedberg and Ramsberg 2004). Triptans act as serotonin agonists by binding to specific 5–HT1B/1D receptors that are expressed in several regions of the brain and in the trigeminal nerve. Triptans are therefore believed to exert their effects on several anatomical and physiological levels involved in the migraine process. When introduced in the early 1990s triptans offered tremendous advantages compared to previous migraine medication owing to their superior efficacy and their rapid effects on an ongoing attack (Bigal, Lipton et al. 2004; Sheftell, Bigal et al. 2004). However, triptans are far from optimal, because they are sometimes ineffective, may have unpleasant side effects and the effect is often of limited duration, necessitating repeated administrations at 6- to 12hour intervals (Bigal, Rapoport et al. 2007). Furthermore, the initially high prices for these drugs have restricted their use in several countries (Lipton, Scher et al. 2002; Dueland, Leira et al. 2004; Morillo, Alarcon et al. 2005; Cevoli, D'Amico et al. 2009). In view of the suboptimal efficacy of current migraine drugs there is still a demand for improved forms of treatment (Malik, Hopkins et al. 2006; Bigal, Rapoport et al. 2007), including alternative non-pharmacological methods (Sandor and Afra 2005; Holroyd and Drew 2006; Linde 2006).
Behavioral treatment Because migraine drugs still have drawbacks (Bigal, Rapoport et al. 2007; Buse and Andrasik 2009) and because migraine is highly conditional on stress it is important to explore forms of migraine treatment that are focused on psycho-social factors. Furthermore, behavioral therapies are in line with current thinking in health care, which increasingly focuses on self-care and patient empowerment (Marlowe 1998; Merelle, Sorbi et al. 2010). Combining pharmacological and behavioral treatments also has the advantage of additive effects in the treatment of migraine (Holroyd, Cordingley et al. 1989; Ehde and Holm 1992; Rains, Penzien et al. 2005; Holroyd and Drew 2006; Buse and Andrasik 2009). Behavioral therapies are therefore of clear and increasing interest in migraine treatment. A variety of behavior therapies for migraine have been tested, alone or combined, such as cognitive therapies, lifestyle modifications, bio-feedback training, and relaxation training – all of which have shown efficacy (Goslin, Gray et al. 1999; Lemstra, Stewart et al. 2002; Nicholson, Nash et al. 2005; Campbell, Penzien et al. April 25, 2000). The interest in a multimodal approach to behavioral treatment has increased during recent years (SBU 2010). This approach utilizes a holistic 20
perspective and aims at achieving broad cognitive and lifestyle changes. It has demonstrated efficacy in the treatment of pain disorders (Haldorsen, Kronholm et al. 1998; Becker, Sjogren et al. 2000), including headache in general (Magnusson, Riess et al. 2004; Zeeberg, Olesen et al. 2005; Gunreben-Stempfle, Griessinger et al. 2009) and migraine in particular (Lemstra, Stewart et al. 2002; Nicholson, Nash et al. 2005). Massage has also been tested as a treatment modality for pain (Goslin, Gray et al. 1999; Furlan, Brosseau et al. 2002; Ezzo, Haraldsson et al. 2007; SBU 2010). With regard to headache disorders, decreased headache frequency and improved sleep quality in response to massage have been shown (Hernandez-Reif, Dieter et al. 1998; Lawler and Cameron 2006), presumably through increased muscular relaxation and decreased bodily symptoms of stress (Hanley, Stirling et al. 2003). However, the benefits of massage are controversial, and in a meta-analysis from The Swedish Council on Technology Assessment in Health Care (SBU) evidence for a beneficial analgesic effect of massage in pain disorders was rated as “insufficient” (SBU 2010) . The Internet offers possibilities to increase the availability of different kinds of behavioral treatment programs at a low cost, and the efficacy of such web-based health care programs has been demonstrated for a variety of conditions such as headache, depression, chronic pain and tinnitus (Andersson, Bergstrom et al. 2005; Cuijpers, van Straten et al. 2008). The high availability of Internet-based programs is particularly valuable in relation to migraine, as many individuals with migraine have poor access to specialized health care (Lipton, Stewart et al. 1992; Linde and Dahlof 2004; Cevoli, D'Amico et al. 2009). However, many Internet-administered treatment programs have shown high attrition rates, making them difficult to evaluate (Cuijpers, van Straten et al. 2008).
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GENERAL AIM
The overall objective of the present thesis was to study the role of stress in migraine. The intention was to develop and evaluate an Internetadministered multimodal behavioral treatment (MBT) program addressing stress, specifically designed for migraine, and in conjunction with this to also evaluate salivary cortisol as a biological stress marker, and study the complete use of migraine drugs and how it was affected by the MBT program. A further intent was to characterize the relationships between personality traits, current stress, life events, and gender in this disease.
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SPECIFIC AIMS
To describe personality traits, current stress, life events and comorbidity in a migraine population and to investigate gender differences in relation to these aspects (Paper I). To assess the effects of an MBT program on migraine frequency, physical activity, depressive mood and well-being and the participants own evaluation of the feasibility and value of different parts of the program (Paper II). To assess the effects on migraine frequency of the hand massage element of the MBT program and the participants’ own evaluation of the feasibility and value of hand massage (Paper II). To characterize the complete migraine drug use among women and men participating in the MBT study, including any changes in drug use and efficacies of the respective drugs throughout the course of the MBT study (Paper III). To assess salivary cortisol and serum-DHEA-S levels as biological stress markers in migraine and relate them to stress burden, depressive mood and gender, and to evaluate changes in these hormone levels during the course of the MBT program (Paper IV).
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METHODS
Recruitment of participants and initial data collection One-hundred and fifty individuals with migraine, 106 women and 44 men, were recruited via advertisements in the local daily newspaper. Seven advertisements were published from March 2004 through January 2005, of which the last three addressed men exclusively. All participants underwent an interview regarding demographic data and their medical history including: headache characteristics, stress as a trigger for migraine, concomitant illnesses, and general wellbeing. A neurological examination was also performed by one of the researchers (CM) who is a specialist in neurology. In connection with the interview, participants also answered questionnaires on a computer. Complete responses were obtained from all participants. Inclusion criteria were: a confirmed migraine diagnosis according to the International Classification of Headache Disorders (IHS 2004), and a current migraine intensity of two or more attacks monthly. The study population of Paper I was comprised of these 150 individuals with migraine. The study population of the multimodal behavior treatment (MBT) of Paper II was recruited from these one-hundred fifty migraineurs, yielding 83 participants, 58 women and 25 men. Paper III and Paper IV were based on the same study population as that described in Paper II, but six women and one man were not included due to the fact that they had dropped out of the MBT study.
Ethical approval All studies were approved by the Regional Board for Ethics Review, Uppsala, Sweden, and informed consent was obtained from all participants prior to inclusion.
Design The following designs were used for the four empirical studies (I-IV). The study of Paper I was a descriptive, cross-sectional study describing relationships between personality traits, current stress, life events, co-morbidity and 24
gender. The study of Paper II was a prospective randomized controlled intervention (two intervention groups; Fig. 1). The studies of Paper III and Paper IV were based on Paper II, evaluating overall migraine drug use and its efficacy throughout the MBT study and salivary cortisol levels, respectively. Hence, the basic designs were identical to that of Paper II, with the exception that the two intervention groups of Paper II were merged. A general overview of the respective designs, sample sizes, methods of data collection and questionnaires used in Studies I-IV are presented in Table II.
Figure 1. Flow chart of the design of Study II with group sizes and dropouts. Abbreviations: MBT: multimodal behavior treatment; Q: questionnaires; R: randomization; CD: compact disc
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Table II. General overview of study designs, sample sizes and methods of data collection Paper
Design
Paper I (Personality and stress) Paper II (MBT)
Descriptive (crosssectional) Intervention (prospective, randomized, controlled) Two intervention groups Intervention (prospective, randomized, controlled) Single intervention group Intervention (prospective, randomized, controlled) Single intervention group
Paper III (Drug use)
Paper IV (Salivary cortisol)
Sample size
Methods of data collection 150; 106 women and Questionnaires 44 men
Questionnaires SSP, CEOS inventory, life events
83; 58 women and 25 Migraine diary/ men (part of Paper I) questionnaires
PQ23, MADRS-S, self-evaluation of MBT and hand massage
76; 52 women and 24 Migraine diary men. Same population as in Paper II, with exclusion of drop-outs
-
Same study population as in Paper III
SSP, PQ23, Salivary cortisol and serum DHEA-S MADRS-S, life levels/migraine events diary/ questionnaires
Questionnaires Personality traits (SSP) The Swedish Universities Scales of Personality was used to assess personality traits (Gustavsson, Bergman et al. 2000). This instrument is a revised version of the Karolinska Scales of Personality Inventory, which was developed to identify stable personality traits of importance for psychological vulnerability (Schalling, Asberg et al. 1987). The purpose of revising the instrument was to enhance its psychometric properties, to shorten it to prevent exhaustion effects, and to secure its validity for: psychiatric patients as well as healthy subjects, different age groups, and the instrument as a whole as well as extracted single scales used for research purposes. The SSP inventory comprises 91 items divided into 13 traits. The SSP inventory results were standardized to normative data included in the instrument. The normative data were drawn from a random sample of the Swedish population, with the normative average for each trait defined as 50 and with a standard deviation of 10. The original factor analysis for the instrument (Gustavsson, Bergman et al. 2000) showed three factors consisting of neuroticism, aggressiveness and an extroversion factor, as shown in Table III. 26
Table III. Personality traits (“scales”) underlying the Swedish University Scales of Personality (SSP) questionnaire. Personality trait Neuroticism-related scales* Somatic trait anxiety
Abbreviation
Description
STA
Autonomic disturbances, restlessness, tension
Psychic trait anxiety
PsTA
Worry, anticipation, lack of selfconfidence
Stress susceptibility
SS
Easily fatigued, feeling of unease when urged to speed up
Lack of assertiveness
LA
Lack of ability to speak up and to be self-assertive in social situations
Embitterment
E
Unsatisfied, blaming and envying others
SD
Socially conforming, friendly, helpful
Trait irritability
TI
Irritability, lack of patience
Mistrust
M
Suspiciousness, distrust of people’s motives
Verbal trait aggression
VTA
Getting into arguments, berating people when annoyed
Physical trait aggression
PhTA
Getting into fights, starting fights, hitting back
I
Acting on the spur of the moment, nonplanning, impulsive
Adventure seeking
AS
Avoiding routine, need for change and action
Detachment
D
Aggressiveness-related scales* Social desirability
Extroversion-related scales* Impulsiveness
Avoiding involvement in others, withdrawn, schizoid *According to a three-factor solution of factor analysis of normative data (Gustavsson, Bergman et al. 2000)
Current stress (CEOS inventory) The Department of Environmental Stress Disorders Questionnaire on Current Stress was used for evaluation of current stress. The questionnaire contains 75 questions, developed for clinical research at the Department of Environmental Stress Disorders (CEOS), Uppsala University, Sweden (Arnetz 2002; CEOS 2006; Hansson, Arnetz et al. 2006). Forty-three items regarding 27
stress-related psychosocial factors, stress coping, general health, and sleep were measured on a visual analogue scale (VAS) graded from 0 – 100 (0 = low/no stress; 100 = maximal stress). Thirty-eight of these 43 items refer to experiences of stress during the past month and 5 refer to such experiences during the past year or expectations thereof for the coming year (1 question). The remaining 32 items concerned demographic data and concomitant illnesses and were answered by choosing different response options. To identify groups of related items, a factor analysis with Varimax rotation (Field 2005) was conducted for Paper I, based on the current responses to the 43 items answered on a VAS scale. The eight factors with the highest eigenvalues were chosen to represent measurement of current stress, all of which had eigenvalues above 1.0. These factors covered 29 of the 43 stress-related items (Table IV). Our designations of these factors were as follows and are listed in the order of magnitude of their eigenvalues: Factor 1: Feeling of meaningfulness regarding your home situation and your social situation; Factor 2: Mental symptom; Factor 3: Subjective level of stress; Factor 4: Quality of sleep; Factor 5: General health; Factor 6: Difficulties with concentration and memory; Factor 7: Ability to prioritize recovery from stress; Factor 8: Ability to cope with stress. The reliability of these eight factors was tested using the Cronbach method, which yielded alpha values between 0.730 and 0.897 (Table IV).
Table IV. The CEOS inventory developed at the Department of Environmental Stress Disorders, Uppsala University, Uppsala, Sweden It consists of the following 43 items
Response options were given on a VAS scale for each item graded from 0 - 100
For each of these statements make a mark on the VAS scale. Choose a point on the scale that best applies to your situation. 1. Describe your health status during the past year. 5 2. What is your health status right now? 5 3. What do you think your health status will be next year? 5 4. I have felt great strain during the past year. 3 5. I feel great strain right now. 3 6. Your quality of sleep during the past year? 4 7. What is your quality of sleep right now? 4 8. My life has felt meaningful during the past year. 1 9. My life feels meaningful right now. 1 10. I have felt very stressed during the past year. 3 11. I feel very stressed right now. 3
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0 excellent excellent excellent do not agree do not agree excellent excellent agree totally agree totally do not agree not stressed
100 poor poor poor agree totally agree totally poor poor do not agree do not agree agree totally very stressed
The following questions concern your situation during the past month 12. Do you feel fully recovered upon awakening? * daily 13. Do you have difficulties falling asleep in the evening? 4 never 14. Do you have periods of awakening with difficulties falling never asleep again at nights? 4 15. Do you feel physically exhausted? * never 16. What is your energy level? * very high satisfied 17. How is your overall satisfaction with your social life? 1 18. How is your overall satisfaction with your home conditions? 1 satisfied 19. How is your overall satisfaction with your working conditions? *satisfied Have you had any trouble during the past month with: 20. Headache * never 21. Anxiety/restlessness * never never 22. Depression 2 never 23. Restlessness 2 never 24. Irritability 2 never 25. Zest for life 2 26. Concentration difficulties. 6 never never 27. Abnormal forgetfulness. 6 28. Heart symptoms (palpitations, irregular heartbeats, presnever sure/pain in the chest). * 29. Dizziness * never 30. Loss of appetite. * never 31. Gastrointestinal problems (nausea, flatulence, acid regurgita- never tion, pain/burn in the pit of the stomach). * 32. Neck, shoulder and/or back pain. * never 33. Diffuse muscle pain. * never 34. Problems with learning. 6 never never 35. Memory difficulties. 6 36. I concentrate and take one step at a time when I handle strain. 8 agree totally 37. There is one or several persons who support me. * agree totally 38. I give more support to others than I get myself.* do not agree at all agree totally 39. I give myself the time I need for rest and relaxation. 7 40. I give myself the time I need for stimulating leisure activities. 7 agree totally 41. I prioritize recovery in my daily life. 7 agree totally agree totally 42. I can easily ”charge my batteries”. 8 43. I can easily mobilize extra energy when needed. 8 agree totally 1- 8 refer to factor analysis grouping, see material and methods; 1. Feeling of meaningfulness with your home situation and social situation 2. Mental symptoms 3. Subjective level of stress 4. Quality of sleep 5. General health 6. Difficulties with concentration and memory 7. Ability to prioritize recovery from stress 8. Ability to cope with stress * Not part of any of the factors above.
never daily daily daily very low dissatisfied dissatisfied dissatisfied daily daily daily daily daily daily daily daily daily daily daily daily daily daily daily daily do not agree at all do not agree at all agree totally do not agree at all do not agree at all do not agree at all do not agree at all do not agree at all
Cronbach’s alpha 0.897 0.868 0.896 0.872 0.897 0.884 0.812 0.730
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Life events As a measure of cumulated long-term stress, life events during childhoodadolescence and adulthood were evaluated (Anderberg, Marteinsdottir et al. 2000; Marteinsdottir, Svensson et al. 2007). These age groups were defined by an age limit of 18 years. The instrument used consisted of 11 childhoodadolescence life event categories and 21 adulthood categories, listed in Table V. The participants rated the effect of the event(s) in the respective categories into three grades: “strongly negative”, “notably negative”, and “hardly negative at all”. For the last seven adulthood life event categories (Table V), a “positive” response alternative was also provided. In the further analyses, the data were grouped into either: event categories in which the participants had had experiences they rated as “strongly negative”, or into: “any” type of negative event, including all categories in which the rating was any of the following: “strongly negative”, “notably negative” and “hardly negative at all”.
Quality of life (PQ23) The PQ 23 questionnaire (Andersson, Johnsson et al. 2009) (Table VI) is composed of 23 questions, all of which refer to the current situation (“right now”) and are answered on a visual analogue scale (VAS) graded 0 – 100. We sought a way to group these questions, so as to reduce the number of variables. Therefore, a factor analysis was also performed on the PQ23 instrument. Because the instrument had not been previously validated for migraine, we applied the analysis to the present study, based on answers given at study onset. It yielded a four-factor solution with an eigenvalue of >1. One question, concerning physical activity, was excluded, as it was the only question not included in any of these four factors. The factors were designated as follows: Factor 1: Well-being; Factor 2: Occupational satisfaction; Factor 3: Home situation/mood; Factor 4: Perceived work performance. The internal consistency of scales was tested according to Cronbach alpha, which yielded values between 0.745 and 0.903. PQ 23 was used for Paper II and Paper IV.
Depressive mood (MADRS-S) The Montgomery-Åsberg Depression Rating Scale instrument was used for evaluation of depressive symptoms (Montgomery and Asberg 1979; Svanborg and Asberg 2001) (TableVII). It is a self-estimating scale, based on evaluations of the past three days regarding the following nine issues: mood, feeling of unease, sleep, appetite, ability to concentrate, initiative, emotional involvement, pessimism, and zest for life. Seven response options were given for each issue, with ratings running from zero to six. A total score above 12 was defined as a depressive state, with the limits of 20 and 35 defining those with moderate and severe depression, respectively (Montgomery and Asberg 1979). MADRS-S was used for Paper II and Paper IV. 30
Table V. Life events categories during childhood – adolescence and adulthood “hardly negative at all”
“notably negative”
“strongly negative”
“hardly negative at all”
“notably negative”
“strongly negative”,
Childhood - adolescence Conflict with parents Conflict with close relative or friend Support for close relative (e.g. due to drug abuse, old age, disability) Physical or psychological abuse Neglect Sexual assault Own disease or accident Disease or accident in close relative Death of parent Death of close relative or friend Bullying Adulthood Conflict with partner Conflict with children, close relative or close friend Support for close relative or friend (e.g. due to drug abuse, old age, disability) Physical or psychological abuse Sexual assault Own disease or accident Disease, accident in close relative Death of partner Death of close relative or friend Bullying Financial problems Conflicts at work Lack of control of work situation “Other” important negative events “positive” Marital separation Marriage Move to a new home Birth of child or adoption New job Decreased responsibility at work Increased responsibility at work
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Table VI. The PQ23 questionnaire: Questions are presented according to categories as a result of factor analysis. Reliability values according to Cronbach alpha, and response options are shown Question
Well-being Health status right now? Feeling of great strain right now? Daytime physical exhaustion? Daytime mental tiredness? Fatigue right now? General feeling right now? Quality of sleep right now? Ability to concentrate right now? Stress level right now? Energy level right now?
*
Cronbach alpha
Response options were given on a VAS scale for each item graded from 0-100 0 100
0.903 excellent do not agree rarely rarely never excellent excellent excellent not stressed excellent
poor agree totally very often very often daily poor poor poor very stressed poor
Occupational satisfaction 0.856 Satisfaction with working conditions? Own influence on working conditions. Stimulation at work? Positive feedback for good performance at work?
excellent agree totally excellent often
poor do not agree at all poor never
Home situation/mood 0.790 Depression/sadness right now? Restlessness right now? Life control right now? Satisfaction with social life right now? Satisfaction with home conditions right now?
never never agree totally satisfied satisfied
daily daily do not agree at all dissatisfied dissatisfied
Perceived work performance 0.745 Intensity of work right now? Efficacy in work performance right now? Degree of overexcitement?
low excellent low
Frequency of physical exercise? * often not included in any of the factor-analysis-based categories
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high poor high never
Table VII. Montgomery and Åsberg Depression Rating Scale (MADRS) 1. Mood. Representing reports of depressed mood, regardless of whether it is reflected in appearance or not. Includes low spirits, despondency or the feeling of being beyond help and without hope. Rate according to intensity, duration and the extent to which the mood is reported to be influenced by events. 0. Occasional sadness in keeping with the circumstances. 1. 2. Sad or low but brightens up without difficulty. 3. 4. Pervasive feelings of sadness or gloominess. The mood is still influenced by external circumstances. 5. 6. Continuous or unvarying sadness, misery or despondency 2. Feeling of unease Representing feelings of ill-defined discomfort, edginess, inner turmoil, mental tension mounting to intensity, frequency, duration and the extent of reassurance called for. 0. Placid. Only fleeting inner tension. 1. 2. Occasional feelings of edginess and ill-defined discomfort 3. 4. Continuous feelings of inner tension or intermittent panic which the patient can only master with some difficulty. 5. 6. Unrelenting dread or anguish. Overwhelming panic. 3. Sleep Representing the experience of reduced duration or depth of sleep compared to the subject´s own normal pattern when well. 0. Sleeps as usual. 1. 2. Slight difficulty dropping off to sleep or slightly reduced, light or fitful sleep. 3. 4. Sleep reduced or broken by at least two hours. 5. 6. Less than two or three hours sleep. 4. Appetite Representing the feeling of a loss of appetite compared with when well. Rate by loss of desire for food or the need to force oneself to eat. 0. Normal or increased appetite. 1. 2. Slightly reduced appetite. 3. 4. No appetite. Food is tasteless. 5. 6. Needs persuasion to eat at all.
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5. Ability to concentrate Representing difficulties in collecting one’s thoughts mounting to incapacitating lack of concentration. Rate according to intensity, frequency, and degree of incapacity produced. 0. No difficulties in concentrating. 1. 2. Occasional difficulties in collecting one’s thoughts. 3. 4. Difficulties in concentrating and sustaining thought which reduces ability to read or hold a conversation. 5. 6. Unable to read or converse without great difficulty. 6. Initiative Representing a difficulty getting started or slowness initiating and performing everyday activities. 0. Hardly any difficulty in getting started. No sluggishness. 1. 2. Difficulties in starting activities. 3. 4. Difficulties in starting simple routine activities which are carried out with effort. 5. 6. Complete lassitude. Unable to do anything without help. 7. Emotional involvement Representing the subjective experience of reduced interest in the surroundings, or activities that normally give pleasure. The ability to react with adequate emotion to circumstances or people is reduced. 0. Normal interests in the surroundings and in other people. 1. 2. Reduced ability to enjoy usual interests. 3. 4. Loss of interests in the surroundings. Loss of feelings for friends and acquaintances. 5. 6. The experience of being emotionally paralyzed, inability to feel anger, grief or pleasure and a complete or even painful failure to feel for close relatives and friends. 8. Pessimism Representing thoughts of guilt, inferiority, self-reproach, sinfulness, remorse and ruin. 0. No pessimistic thoughts. 1. 2. Fluctuating ideas of failure, self-reproach or self-depreciation. 3. 4. Persistent self-accusations, or definite but still rational ideas of guilt or sin. Increasingly pessimistic about the future. 5. 6. Delusions of ruin, remorse or unredeemable sin. Self-accusations which are absurd and unshakable.
34
9. Zest for life Representing the feeling that life is not worth living, that a natural death would be welcome, suicidal thoughts, and preparations for suicide. Suicidal attempts should not in themselves influence the rating. 0. Enjoys life or takes it as it comes. 1. 2. Weary of life. Only fleeting suicidal thoughts. 3. 4. Probably better off dead. Suicidal thoughts are common, and suicide is considered as a possible solution, but without specific plans or intention. 5. 6. Explicit plans for suicide when there is an opportunity. Active preparations for suicide. Reference: Montgomery SA and Åsberg M. A new depression scale designed to be sensitive to change. British Journal of Psychiatry, 1979; 134:382-389.
MBT program A program for multimodal behavioral treatment, tailored specifically for migraine and using a holistic perspective, was designed during a one-year development phase. A professional advisor in stress management and psychologists with knowledge of the different cognitive parts of the program were consulted during the course of these preparations. This resulted in a 53page training program divided into the following topics: stress physiology, issues of lifestyle (physical activity, diet), and cognitive aspects related to stress (thought patterns, handling of emotions, and attitudes toward oneself and others). Parts of these elements were derived from a stress coping program that had previously been tested face-to-face on conditions such as pain, burn-out syndrome, and fibromyalgia and gave satisfactory results (unpublished data). A summary of the content of these topics and associated recommendations for behavioral change are shown in Table VIII. The sources of inspiration for this holistic MBT approach were referenced in the program and are listed in Table IX. The participants were asked to continue medication as usual, and they could also change it if needed. A videotape demonstrating the elements of hand massage and photographic illustrations of the short work-out program that is part of the MBT program were also produced during this period of preparation.
35
Table VIII. Summary of content of the Multimodal Behavior Treatment program Topic Background information Recommended behavioral change Stress Concept of stress as a spe- (i) Identify own symptoms of stress and own physiology cific syndrome of bodily and protective ”peace-and-rest” reactions against mental reactions to unspecifstress. ic strain; importance of (ii) Identify personal stressors in daily life and cognitive processes for analyze how they can be diminished. perceived stress; difference between acute and chronic (iii) Practice a muscular relaxation program via a provided CD. stress; role of stress in migraine; importance of relaxation and sleep habits to mitigate stress reactions. Physical Description of potential (i) Perform some form of daily conditionenhancing exercise with a minimal duration activity benefits of physical activity of 30 minutes. and examples of different forms of physical activity. (ii) Perform a provided 5- to 10-minute exercise program for improved strength, posture and balance. Diet Physiology of metabolism; (i) Increase awareness of personal dietary habits types of foodstuffs; body by answering a set of questions. mass index and abdominal (ii) circumference as measures Avoid sugar and other simple carbohydrates. of metabolic health. Have meals at regular intervals. (iii) Avoid over-eating. Thought Effects of positive and (i) Identify personal strengths. patterns negative thoughts, respec(ii) Focus on possibilities rather than on difficultively; how to identify perties. sonal strengths; how to (iii) Sustainably change habits of thought from accomplish and maintain negative to positive thinking. changes in thought patterns.
Handling of emotions
Attitudes
36
(iv) Improve awareness of realistic limits in daily life and how to implement them. (i) Identify which types of feelings you easily come in contact with and those that are difficult to become aware of.
How feelings of sadness, anger, envy and happiness affect thinking and wellbeing; the roles of feelings (ii) Identify how you react to and are affected by and empathy in communicayour feelings. tion; the concept of emo(iii) Apply various strategies for coping with tional intelligence (EQ). negative feelings: analyze their causes, verbalize them for those concerned, improve emotional balance via improved relaxation and sleep habits, and avoid unproductive thoughts, e.g., of revenge. How individuals differ in (i) Achieve increased awareness of attitudes of degree of trust in themselves trust/mistrust (one’s own and others’). and in others; how trust (ii) Improve self-reliance and trust in others. affects thinking and attitudes.
Table IX. References that inspired the multimodal behavioral treatment program Topic Stress
1.
physiology
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
Physical activity
1. 2. 3. 4.
Reference Angelöw, B. (1999). Konsten att hantera stress och möta förändringar. Falun, Natur och Kultur. Antonovsky, A. (1979). Health, Stress and Coping,. San Francisco, Jos sey-Bass Publishers. Csikszentmihalyi, M. (1996). Flow den optimala upplevelsens psykologi. Stockholm, Natur och Kultur. Dahlöf, C., M. Linde, et al. (2003). Migrän - kliniska aspekter. Lund, Studentlitteratur. Dryden, G. and J. Vos (2001). Inlärningsrevolutionen. Finland, WS Bookwell. Ekman, R. and B. Arnetz (2002). Stress. Molekylerna - individen organisationen - samhället. Falköping, Författarna och Liber AB. Guyton, A. C. (1991). Textbook of Medical Physiology, Eighth Edition. Philadelphia, W.B. Saunders Company. Jeding et al. (1999). Ett friskt arbetsliv - fysiska och psykosociala orsakssamband samt möjligheter till tidig rehabilitering. Arbetslivsinstitutet, Institutet för Psykosocial Medicin. Johnson, J., A. Lugn, et al. (2003). Långtidsfrisk. Stockholm, Ekerlids förlag. Lännergren, J. et al. (2000). Fysiologi. Lund, Studentlitteratur. McGraw, P. C. (2003). Angelägenheter. Stockholm/Stehag, Östlings Bokförlag Symposion. Ornstein, R. and D. Sobel (2001). Sunda synder. Njut av livet för hälsans skull. Danmark, Nörhaven A/S Viborg. Pollak, K. (2001). Att välja Glädje. Finland, Gummerus Printing, Jyväskylä. Sapolsky, R. M. (2003). Varför zebror inte får magsår. Selye, H. (1958). Stress. Stockholm, Rydahls Boktryckeri AB. Selye, H. (1978). The stress of Life. New York, McGraw-Hill Paper backs. Stenström, Å. (2002). Mindre migrän mera liv. Kappelshamn, Stenströms Information & Marknadsföring. Titmuss, C. (1999). Meditationens kraft. Malmö, Egmont Richter AB. Uneståhl, L. -E. (2001). Den nya livsstilen, Mentala träningsråd för stresshantering och ett bättre liv. Örebro, Veje International AB. Währborg, P. (2002). Stress och den nya ohälsan. Smedjebacken, Natu r och Kultur. Ehdin, S. (1999). Den självläkande människan. Falun, Forum. Guyton, A. C. (1991). Textbook of Medical Physiology, Eighth Edition. Philadelphia, W.B. Saunders Company. Henriksson, J. (2004). Fyss för alla. En bok om att röra på sig för att må bättre. Stockholm, Apoteket AB. Zubay, G. (1993). Biochemistry - Energy, Cells and Catalysis. IA USA, Wm. C. Brown Publishers
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Diet
Thought patterns
Handling of emotions
Attitudes
1.
Abrahamsson, L. et al. (1999). Näringslära för högskolan. Stockholm, Liber AB. 2. Chopra, D. (1991). Perfekt hälsa - Det helande sambandet mellan kropp och själ. Stockholm, Norstedts. 3. Ehdin, S. (1999). Den självläkande människan. Falun, Forum. 4. Paulun, F. (2002). Allt om fettförbränning. Finland, Fitnessförlaget, Arkmedia. 5. Zubay, G. (1993). Biochemistry - Energy, Cells and Catalysis. IA USA, Wm. C. Brown Publishers 1. Dryden, G. and J. Vos (2001). Inlärningsrevolutionen. Finland, WS Bookwell. 2. Ehdin, S. (1999). Den självläkande människan. Falun, Forum. 3. Thomas, K. W. and W. G. Tymon (1992). Stresstoleransprofilen. New York, Xicom Incorpoated. 4. Uneståhl, L.-E. (2001). Den nya livsstilen, Mentala träningsråd för stresshantering och ett bättre liv. Örebro, Veje International AB. 1. Ehdin, S. (1999). Den självläkande människan. Falun, Forum. 2. Goleman, D. (1999). Känslans intelligens och arbetet. Smedjebacken, Wahlström&Widstrand. 3. Kast, V. (2002). Avund och svartsjuka. Falun, Natur och Kultur. 4. McGraw, P. C. (2003). Angelägenheter. Stockholm/Stehag, Östlings Bokförlag Symposion. 5. Ornstein, R. and D. Sobel (2001). Sunda synder. Njut av livet för hälsans skull. Danmark, Nörhaven A/S Viborg. 6. Pert, C. (1997). Molecules of Emotion - Why You Feel the Way You Feel. New York, Scribner. 7. Pollak, K. (2001). Att välja Glädje. Finland, Gummerus Printing Jyväskylä. 8. Uneståhl, L.-E. (1999). Skratta dig friskare. Örebro, Veje International AB. 9. Uneståhl, L.-E. (2001). Den nya livsstilen, Mentala träningsråd för stresshantering och ett bättre liv. Örebro, Veje International AB. 10. Uvnäs Moberg, K. (2000). Lugn och beröring. Borås, Natur och Kultur. 1. Berne, E. (1997). Så bär vi oss åt. Studier i mänskliga attityder. Stockholm, Norstedts Förlag AB. 2. Bylund, P. and K. Bylund (2004). Samspel. Stockholm, Natur och Kultur AB. 3. Pollak, K. (2001). Att välja Glädje. Finland, Gummerus Printing Jyväskylä.
In an introductory part, participants were informed that migraine can be aggravated by stress and that the purpose of the program was to create an increased awareness of the individual’s life conditions in order to identify avoidable stress. Participants were told that the overriding goal of the program was to achieve “lifestyle competence”, by which was meant increased individual responsibility for finding a strategy for improved wellbeing. The means for this was improved understanding of bodily reactions to stress and how this interacts with mental and emotional capacities. Also, to achieve this “lifestyle competence”, the program aimed at improving the participant’s knowledge and understanding of how she/he interacts with other people. Participants were also informed that the six parts of the program had a uniform structure including: specific information on the respective topic, followed by a self-evaluation of the participant’s situation in this respect during 38
the past six months. Thereafter, the respective topic was exemplified by two fictive cases – one for each sex – which the participant was told to reflect upon on her/his own. Finally, recommendations for behavioral changes were given, as listed in Table VII, and a self-estimation of the current situation was to be performed. Participants were instructed to follow these recommendations throughout the rest of the program, including making repeated evaluations of the current situation.
Web tool for the MBT program and for a migraine diary With support from web designers who were associated with the Department of Environmental Stress Disorders, Uppsala University (CEOS), and who had experience of designing web tools for this kind of research, a web tool was developed containing the treatment program and a diary. Participants accessed the tool via a personal login. The diary was filled in day-by-day. In order to register on the next day, the program required that data for the previous day first be completed. Via the web tool, participants were also asked to answer the Quality of life (PQ23) (Andersson, Johnsson et al. 2009) and Montgomery-Asberg Depression Rating Scale (MADRS-S) (Montgomery and Asberg 1979; Svanborg and Asberg 2001) questionnaires, repeated at three- to five-month intervals. A paper version of the diary could be used instead if participants did not have immediate access to the Internet. They were asked to transfer the data from the paper version to the web-based diary within one week; otherwise an automatic email reminder would appear informing them that the missing data were necessary for continued diary recording. The items recorded in the diary were: time point for start of migraine headache or time point for waking up with migraine, time point for intake of medication and type(s) of drug(s) used – including preventive migraine medication, and time point for attaining freedom from headache pain. Four-point scales were used for recording headache intensity (0 = no pain, 1 = mild pain, 2 = moderate pain, and 3 = severe pain) and effect of medication (1 = excellent, 2 = good, 3 = moderate, and 4 = poor). Physical activity – defined as sessions of physical activity exceeding 30 minutes – was also recorded in the diary. Printouts of the MBT program were made possible through attached PDF files. The Swedish language was used throughout in the web tool.
Hand massage Massage was chosen as a possible complementary means of achieving stress reduction along with the MBT program. Hand massage was chosen as an easy variant of massage that was minimally intrusive on the participants’ 39
privacy. The massage was not intended as a measure for acute alleviation of migraine attacks. The massage time was fifteen minutes per session. The massage was of “Swedish” type, consisting of: effleurage (stroking from the wrist down to the fingers, simultaneously on the palm and on the back of the hand, using soft circular stretching strokes), petrissage (kneading of the palm) and friction (strokes in circles on the fingers) (manual in Swedish provided on request). A collaborator, chosen by the participant, performed the massage. One of the researchers (K.H.), trained by a professional massage therapist, provided a one-hour face-to-face training on the massage technique to each participant-collaborator pair, ending with a practical examination. Each pair also received an instructional videotape on how to perform the massage. The participants were asked to perform hand massage at least twice a week during the first four weeks of the study period and then at least once a week during the remaining 32 weeks.
Self-evaluation of the MBT program and the hand massage The participants’ opinions about the MBT program were obtained by posing four questions after completion of the program. Question 1: “How would you rate the clarity of the program?” Question 2: “How would you rate the feasibility of the program?” Answers were given for each part of the program as a score on a VAS scale graded from 0 – 10 (0 = poor; 10 = good). The remaining questions were in an open format: Question 3: “Which element(s) of the entire MBT program do you personally consider the most valuable?” Answers were evaluated using a qualitative analysis inspired by the method of manifest content analysis (Graneheim and Lundman 2004). Question 4: “Do you have any general suggestions that could improve the program?” The hand massage was also evaluated using four questions. Answers were given as a VAS score on a scale from 0 – 10: Question 1: “How clear was the information given at the training session on how to perform the hand massage?” (0 = poor; 10 = good). Question 2: “How clear were the instructions given on the videotape on how to perform the hand massage?” (0 = poor; 10 = good). Question 3: “What were your emotional impressions of the hand massage?” (0 = negative; 10 = positive). Question 4: “Did the hand massage have a positive effect on your migraine?” (0 = negative; 10 = positive).
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Collection and analyses of blood and saliva samples Salivary cortisol was sampled at inclusion, at mid-treatment and at treatment conclusion. The participants were given detailed oral and written instructions for collection of saliva samples: They were instructed not to brush their teeth or eat and/or drink 30 minutes in advance of sample collection and they had to be free from migraine headache and migraine medication during the 24 hours prior to collection. Date and time for specimen collection were registered in a protocol by the participants. Saliva samples were collected in Salivette® (Sarstedt, Nümbrecht, Germany) tubes four times during the day: at awakening, 30´ after awakening, at 5 p.m. and at 10 p.m. or bed time. These salivary cortisol values were evaluated according to ”Awakening Cortisol Response (ACR)”, yielding both an ACR % and an actual ACR in nmol/L, high bedtime and low daytime values, and ”low flat” profile. For reference values concerning ACR, we used previously suggested criteria, defining normal ACR as an increment equal to or more than 50%, but equal or less than 160% or an absolute increment of at least 2.5 nmol/L (Wust, Wolf et al. 2000; Clow, Thorn et al. 2004; Hansen, Garde et al. 2008). A high bedtime value was defined as a 10 p.m. value exceeding 6.0 nmol/L (Grossi, Perski et al. 2001). A low daytime value was defined as any of the three daytime values (excluding the bedtime value) below 2.5 nmol/L and a ”low flat” profile was defined as all four values equal to or below 13 nmol/L (Alderling, Theorell et al. 2006; Theorell 2007). We also combined these four ways of evaluating cortisol into a so-called ”index” ranging from 0 to 4, referring to how many of these four parameters were outside the defined normal values. Saliva samples were analyzed by the accredited Clinical Chemistry and Pharmacology Department, University Hospital, Uppsala, Sweden. Serum DHEA-S was sampled at 7 to 9 a.m. the day after sampling for salivary cortisol. Participants had been fasting from midnight and had been free from migraine headache and medication for at least 24 hours prior to sampling. Samples were analyzed by the accredited clinical laboratory at Uppsala University Hospital, Uppsala.
Statistical methods SPSS’s generalized linear model with a binary response variable and a logit link was used for multivariate analyses in Paper II. In Paper IV, a multivariate model was built using the generalized linear models tool (PASW Genlin) with use of Generalized Estimating Equations (GEE; (Fitzmaurice, Laird et al. 2004). Differences in proportions were analyzed using the Chi-Square test. Mean differences were examined using either the t-test or the MannWhitney test, depending on the distribution and sample size of the variables. Group differences regarding continuous parameters were examined using 41
one-way ANOVA with Tukey post hoc test. Differences in proportions of subcategories between groups were analyzed using the Kruskal-Wallis test. Two-way analysis of variance (ANOVA), including interaction effect analysis, was used for evaluation of the repeated measures of the questionnaires. Initial values from these questionnaires, obtained at study onset, were used as the reference for all comparisons. Co-variation was analyzed using correlation analyses, and the result was expressed as the Spearman’s rho coefficient. Factor analysis was performed by means of principal components analysis with Varimax rotation. The number of latent variables was determined using eigenvalues above 1.0 and scree plot analysis. Cronbach’s alpha was used as a measure of the reliability of each component. All analyses were performed with SPSS 18.0 software. The significance level was uniformly set at 0.05, two-tailed test. A qualitative analysis, inspired by the method of manifest content analysis (Graneheim and Lundman 2004), was performed on answers to the openended question regarding participants’ opinions as to which topic(s) of the behavioral treatment program had been most valuable.
42
RESULTS
Paper I: The personality trait inventory showed high mean scores for stress susceptibility and low mean scores for aggressiveness and adventure-seeking both for women and men as well as high mean scores for psychic and somatic anxiety in women. Stress susceptibility, the overall most deviant trait, correlated strikingly with current level of stress in both sexes. In women, stress susceptibility also correlated strongly with experiences of negative life events, and women reported considerably more strongly negative life events. Tension type headache, anxiety and depression were approximately twice as prevalent in women compared to men. All mentioned differences were statistically significant. Paper II: All 150 participants in the study for Paper I were asked whether they would like to participate in Paper II; 83 accepted. Comparing these participants to the 67 non-participants revealed that these two groups were very similar in terms of demographics, migraine characteristics, and stress susceptibility (Table X). A 50 percent, or greater, reduction in migraine frequency was found in 40 and 42 percent of participants in the two groups receiving MBT (with and without hand massage, respectively), which meant statistically significantly more improved participants than in the control group (Fig. 2). Gender and baseline migraine frequency did not show any independent contribution to the effect in a multivariate analysis. No effect of hand massage on migraine frequency was detected despite the feasibility of the method chosen and its positive emotional impact. The point prevalence of depressivity was higher than in the general population, but unaltered throughout the study. No major differences in quality of life could be detected throughout the study. Qualitative analysis of participants’ impressions of the MBT program showed that 95 percent of participants rated the cognitive aspects of the program (emotions, thoughts and attitudes) as the most rewarding (exemplified in Table XI). The attrition rate was low at 8.4 percent.
43
Table X. Demographic profiles, migraine characteristics and stress susceptibility of participants participating in the Intervention study (n = 83) compared to non-participants (n = 67). Chi-2 (a), t-test (b) were used for statistical comparisons.
Gender (%)* Age (years) Body Mass Index
Women/ Men Mean (SD) Mean (SD)
2 Participants Non particiP value /CI n = 83 pants n = 67 69.9/30.1 71.6/28.4 Chi-2; 0.056 0.814 (a) 47.2 (10.9) 46.5 (13.1) CI; - 3.2 – 4.6 0.718 (b) 25.0 (3.8) 24.9(4.3) CI; - 1.2 – 1.4 0.846 (b)
Income per year (%)* > 40 000 € 25 000-40 000 € 10 000-25 000 € < 10 000 €
6.0 51.8 31.3 10.8
6.0 61.2 23.9 9.0
Education (%)*
College/University/ Postgraduate studies Upper secondary school Nine-year compulsory school/elementary school
57.8
50.7
31.3 10.8
35.8 13.4
Full-time Part-time Pension/unemployed
67.5 20.5 12.0
53.7 23.9 22.4
Married/partner Single
73.5 26.5
Married/partner and children living at home Single parent with children living at home
Employment (%)*
Marital status and children (%)*
Migraine frequency Mean (SD) self-reported at inclusion. Tension type headache (%)* Aura§ (%)* Years of migraine Mean (SD) Stress as a trigger for Mean (SD) migraine (VAS 0-100)
Chi-2; 1.450
0.694 (a)
Chi-2; 0.772
0.680 (a)
Chi-2; 3.71
0.156(a)
79.1 20.9
Chi-2; 0.640
0.424(a)
38.6
47.8
Chi-2; 1.29
0.257(a)
8.4
4.5
Chi-2; 0.933
0.334 (a)
4.3 (3.1)
5.0 (4.4)
36.1
41.8
CI; - 1.9 – 0.59 0.293 (b)
Chi-2; 0.50
0.480 (a)
30.1 47.8 Chi-2; 4.90 0.027 (a) 22.8 (11.9) 27.1(16.3) CI; - 9.0 – 0.46 0.076(b) 70.8 (26.5) 70.3 (27.6) CI; - 8.3 – 9.3 0.909(b)
Stress susceptibility Mean (SD) 54.2 (10.2) 55.5 (10.6) CI; - 4.7 – 2.1 0.444(b) trait *: percent of participants in the group, SD: Standard Deviation, CI: Confidence Interval for mean, §: scintillation, numbness, and difficulties in speaking
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Figure 2. Relative change in migraine frequency between baseline and end period registrations. Individual changes, measured as the percentage decrease or increase of migraine frequency during end period registration compared to the base-line period, are shown in order of magnitude for the respective study groups. Horizontal lines define our main outcome measure: 50%, or more, decreased migraine frequency.
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Table XI. Selected quotations of answers to the question “Which element(s) of the entire MBT program do you personally consider the most valuable?” grouped according to the result of a content analysis. Perspectives on my life situation “Increased awareness of what causes negative stress in life” “Better understanding of the connection between a stressful period and a migraine attack” ”To understand that my own thoughts and emotions are just as important as those of other people” “Knowledge about patterns of thought was the most fruitful part of the program and I increased my self-awareness, allowing me to understand myself more easily” “I have learned to put into words what I feel – you can’t blame others for the feelings they arouse in you, but you can make clear to the person what you feel” “I have realized and accepted that emotions are an important part of life, which I previously had rejected. I have opened up a bit and learned how quickly feelings of happiness or discomfort come to you. This insight into how feelings come to you has been rewarding, and increased awareness of my own feelings has sometimes been helpful in deciding how to react in a specific situation” Increased knowledge ”Knowledge of brain functions has been valuable – it has deepened my understanding of personal experiences” “The CD on muscular relaxation was valuable. It gave an opportunity to experience the difference between being tense and being relaxed” “Increased awareness of the importance of a balanced diet” “Increased awareness of the importance of food habits for migraine” “Interesting that thoughts lead to physical and emotional experiences” “I have come to understand a little more about my own thought patterns and how they can influence my health – I knew this already but it was good to get it in writing” “A great awakening regarding the importance of my way of thinking and its impact on my mode of life”
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Possibilities for change “To realize the importance of planning your time in order to avoid stress” “I have started to practice physical exercise and I have found that it diverts my mind from thinking about problems” “I have radically changed my eating habits” “I really appreciated reading about the different intelligences. I have started focusing more on possibilities and I am trying to abandon bad thoughts about myself” “I realized that I was focusing on my own imperfections more than I thought – Now I say no to things and avoid just struggling on without first reflecting” “I have difficulties with changing my thought patterns – I have to work a lot on this” “I have allowed myself to have positive feelings even though this has resulted in occasional backlashes” ”To learn how to change my thoughts in order to feel less tense when experiencing unpleasant situations” ”You can’t change other people - first you must change yourself”
Paper III: During the 4256 days of baseline registration, participants experienced migraine headache on 20.1 percent of the days. 859 drug doses were taken on 655 of the 856 days with migraine headache. Participants reported use of a single dose on 75.3 percent of the days with medication. The two most frequently used drug groups were triptans and analgesics, representing 56.7 and 38.3 percent of all doses, and these drugs were chosen on 52.5 and 28.9 percent of the days with migraine, with efficacy ratios of 0.41 and 0.20, respectively. Men displayed significantly lower drug efficacy and used triptans significantly less and analgesics significantly more than women did. At the end of multimodal behavioral treatment, total drug consumption decreased by 22 percent, corresponding to 27 percent fewer days with migraine headache. Drug efficacy increased significantly during multimodal behavioral treatment from 0.30 to 0.52, mainly explained by a decreased proportion of severe attacks and an increased proportion of mild attacks, which was also the attack category that displayed the largest increase in drug efficacy. No similar differences were seen in the control group. The number of drug doses per migraine day and the types of drugs used were stable throughout the MBT study and among controls. Notably, the efficacy of analgesics was significantly lower in men, despite the fact that analgesics were their drugs of choice and triptan efficacy was considerably higher. The most interesting findings in Paper IV were that stress susceptibility correlated with “low flat” cortisol profiles, and that strongly negative life events during childhood and adolescence showed a correlation with low daytime cortisol values and with a high cortisol index – i.e. many different 47
aberrations in cortisol levels. As many as 53 to 83 percent of participants in the MBT study showed aberrant ACR. No significant differences in cortisol were seen as a function of gender, body mass index, MBT participation, or headache improvement during the course of the study. The overall result was difficult to interpret and partly ambiguous.
48
DISCUSSION
Paper I confirms previous data (Wolff and HG 1937; Schmidt, Carney et al. 1986; Silberstein, Lipton et al. 1995) showing that the average migraineur deviates from normative data with regards to personality traits. High stress susceptibility was the most characteristic feature in this respect, and low aggressiveness and lack of adventure seeking as well were prominent traits of the migraine population studied, independent of gender. Furthermore, the study showed that the individual’s current stress level was strongly correlated with her/his degree of stress susceptibility. The obvious interpretation of this correlation is that susceptibility to stress amplifies the perception and impact of various stressors. There is experimental neurophysiological evidence for such increased sensitivity to stimuli in migraine, indicating a brainstem-related dysfunction in information processing characterized by cortical hypersensitivity and reduced habituation to external stimuli (Wang, Wang et al. 1999; Sand and Vingen 2000; Huber and Henrich 2003; Siniatchkin, Averkina et al. 2006). The alternative interpretation that individuals with migraine who are stress sensitive are more exposed to stress, in an objective sense, has been refuted by some investigators (Henryk-Gutt and Rees 1973; Abramson, Hopp et al. 1980). Several gender differences that relate to stress were identified in this study. Apart from scoring higher on anxiety traits, women also scored strikingly higher for negative life events and displayed a higher comorbidity in disorders associated with neuroticism (anxiety, depression) and in tension type headache. It has been shown that women and men respond to different kinds of stressors: Whereas women are more inclined to react to social rejection challenges men react more to achievement challenges (Stroud, Salovey et al. 2002). The mentioned gender differences found in Paper I may reflect such a general difference in stress responses between the sexes. However, it may be debated whether such differential stress reactions are genuinely constitutional or whether they also depend on the different demands put on women and men due to current gender roles (Stroud, Salovey et al. 2002; Dedovic, Wadiwalla et al. 2009). To summarize, Paper I demonstrates that stress susceptibility, life events and concomitant disorders, especially those of a psychiatric nature, ought to be considered when investigating and treating individuals with migraine. The data indicates that stress susceptibility and parameters of stress can be used interchangeably in the individual characterization of migraine patients. 49
At present, Paper II seems to be the only PubMed indexed study using an Internet-administered MBT program specifically for migraine. It showed efficacy both in terms of number of participants who decreased their migraine by 50 percent or more, and in terms of reduced migraine days. Another relatively unique quality was the low headache frequency limit used for inclusion (at least two attacks a month) and, linked to this, the long study period (11 months), which was believed to be important for obtaining sufficient power in studying effects on participants with migraine frequencies in the lower range. Three additional Internet-based studies on behavioral treatment of mixed headache in adults were identified, all of which showed high attrition with a range of 38-56 percent (Strom, Pettersson et al. 2000; Andersson, Lundstrom et al. 2003; Devineni and Blanchard 2005). All three had in common that no face-to-face contacts were included in the study design. One further study on mixed headache, which addressed children and adolescents (Trautmann and Kroner-Herwig 2010), showed the same low attrition (8 %) as in Paper II. This study used active monitoring via email of the participants by several specially trained therapists. The most important conclusions from Paper II were that it showed feasibility and efficacy with a low attrition rate (8.4 percent), despite the program’s relatively long treatment period and many components. These conclusions are of potential health economics interest considering the great prevalence of migraine and the Internet format of our program, with its high accessibility. When comparing Paper II with the other Internet-administered headache studies, the addition of personal contacts in some form seems to have been important for achieving low attrition. The impression was that the thorough initial face-to-face contact employed in the study for Paper II was of crucial importance in this respect. This is important, because low attrition is a prerequisite for valid evaluation of the efficacy of Internet-administered studies. Out of the different parts of the MBT program, participants evaluated the cognitive aspects as the most rewarding. This finding confirms that cognitive control is an important aspect of migraine treatment (Marlowe 1998; Merelle, Sorbi et al. 2010) and is in line with current thinking that behavioral treatment and cognitive empowerment are essential in migraine treatment (Rains, Penzien et al. 2005). In this perspective the present MBT program appears to be timely and promising. However, the transformation of the present MBT program into a program for public use would require additional validation and testing. For instance, it would be interesting to collect data on its longer term efficacy. Also, modern information technology opens new perspectives on how to further improve the communication and interaction for treatment programs such as this. Regarding hand massage, our results show that the format used was feasible and that the massage was appreciated by the participants, but without 50
demonstrable effect. We believe therefore that massage, or at least hand massage in the present format, is of limited value for obtaining decreased migraine symptoms. In Paper III, the spontaneous use of migraine drugs in a current Swedish setting is comprehensively described. Single-use of triptans displayed an efficacy twice that of analgesics and together these two drug groups were, by far, the most frequently used. Men displayed significantly lower efficacy for analgesics than the studied women did, whereas no gender difference in the efficacy of triptans was found. Therefore, it was a paradox that men chose analgesics significantly more often than women did. Conversely, men made use of triptans significantly less often than women, and because it is well documented that women are more active in taking responsibility for their medical care (Verbrugge 1985; Eggen 1994; Unden and Elofsson 2006) this may indicate that men are not taking full advantage of the benefits of triptans. Therefore, one question raised by Paper III is whether there is a potential for increased male use of triptans in migraine. Interestingly, when studying changes in drug use and in drug efficacy during MBT, both a significant decrease in drug use and a significant increase in drug efficacy were seen at termination of the behavioral treatment program. Seemingly, the MBT-induced change in drug efficacy was explained mainly by decreased proportion of attacks with severe headache and an increased proportion of mild attacks at study completion, in combination with the fact that it was the mild attacks that showed the largest increase in drug efficacy. A synergistic effect of behavioral and pharmacological treatment of migraine has been claimed also by others (Rains, Penzien et al. 2005; Holroyd and Drew 2006; Buse and Andrasik 2009). Paper IV constitutes a survey on how different measures of HPA axis function, as reflected by day profiles of salivary cortisol, correlate with other stress-related parameters during the course of a stress intervention (described in Paper II). Clearly, cortisol is one of the major effectors of the physiological stress response and therefore of interest as a biomarker for stress. However, the data on how cortisol levels fluctuate in disease contain a number of confounding factors and there is still a lack of consensus on how to utilize this information (Hellhammer, Wust et al. 2009; Kudielka, Hellhammer et al. 2009). A Swedish network of scientists has recently been formed, the purpose of which is to establish useful guidelines for cortisol measurements (ScanCort); this work is still in progress. Claims have been made that major depression and traumatic experiences lead to raised levels – particularly applying to ACR but also to bedtime values (Vreeburg, Hoogendijk et al. 2009), whereas in long-term stress conditions (e.g. chronic fatigue syndrome and post-traumatic stress syndrome), cortisol values are claimed to be low 51
(Demitrack and Crofford 1998; Strickland, Morriss et al. 1998; Rasmusson, Vythilingam et al. 2003), possibly due to secondary enhancement of cortisol sensitivity at the receptor level (Theorell 2007). Furthermore, a heightened rise in morning cortisol values has been shown to correlate to work-related stress (Schlotz, Hellhammer et al. 2004). In Paper IV, the majority of the comparisons made between the different cortisol parameters and other stress-related parameters did not show statistical significance. This included the parameters: gender, MBT participation, and headache improvement. Of those correlations that did show significance, two findings were of particular interest because they seemed to accord with previous observations regarding stress-related cortisol profiles: degree of stress susceptibility correlated positively with “low flat” profiles, and number of strongly negative life events experienced during childhood and adolescence correlated positively with low daytime values. This is in good accordance with reported findings showing that early traumatic life events can cause long-lasting disturbances of the HPA axis function (van Eck, Berkhof et al. 1996; Cirulli, Berry et al. 2003). Low daytime values are also in accord with what has been found in persons suffering from post-traumatic stress disorder (Rasmusson, Vythilingam et al. 2003). Other researchers have also described how such serious traumas can cause long-term disturbances of the HPA axis, especially in women (Heim, Ehlert et al. 2000; Heim and Nemeroff 2001). However, because adulthood experiences of strongly negative life events were correlated with few low daytime values these opposite correlations between life events and cortisol levels, depending on life period, are not easy to interpret. Also, an astounding 59 to 83 percent of the ACR values were outside the reference values, which would seem to reflect methodological problems rather than evidence of stress-induced HPA axis activity. An alternative interpretation could be that these aberrant ACRs reflect a specific migraine constitution, analogous to what has been suggested for the high ACR values seen in individuals with a history of major depression (Vreeburg, Hoogendijk et al. 2009). In summary, it seems that the interpretation of data of Paper IV ought to be made with great caution. However, the correlations between aberrant cortisol levels and stress susceptibility and life events, respectively, were of particular interest. Further studies are definitely needed to validate these findings as well as reference values, before establishing the role of salivary cortisol in the evaluation of stress in migraine.
52
Methodological considerations Representativeness of the material The method of recruiting the original study population for the thesis via advertisements may have introduced factors of selection, compared with a random selection from the general population or compared with selecting individuals with migraine in clinical settings, such as migraine clinics or general or neurological out-patient clinics. Moreover, the fact that the study was carried out in Uppsala, an old university town, should perhaps be taken into consideration when generalizing the study results. It is our understanding that both the advertisement procedure and the university town setting could favor the inclusion of individuals with an academic background and/or particular ability to deal with written information. In view of the potential for such biases, it was interesting to observe that the 150 advertisement responders did not differ when comparing their educational background with that of the general population of Uppsala (SCB), thus arguing that the material is representative. Furthermore, when comparing the demographic data of the 83 MBT participants with the 67 non-participants no significant differences were found, arguing against a strong selection bias at recruitment for the MBT study. These two groups also did not differ in stress susceptibility, the most deviant personality trait (Paper I), which argues in the same direction. For these reasons it may be claimed that the present MBT results are valid for individuals with migraine living in regions with similar socioeconomic conditions as that of the present study.
Questionnaires The SSP is a questionnaire for evaluation of personality traits underlying psychological vulnerability. It has been developed in a Swedish context and evaluated for validity and reliability (Gustavsson, Bergman et al. 2000). Furthermore, SSP has been used in the study of a number of conditions, e.g. migraine (Mattsson and Ekselius 2002), depressive mood and anxiety disorders (Volgsten, Ekselius et al. 2010), pain (Kalliomaki, Sandblom et al. 2009), alcoholism (Birath, DeMarinis et al. 2010), and burn injuries (Willebrand, Wikehult et al. 2005). MADRS-S is a validated and reliable instrument for measurement of current level of depression and has been widely used (Montgomery and Asberg 1979; Svanborg and Asberg 2001; McIntyre, Konarski et al. 2006; Fantino and Moore 2009). The Life Event instrument used was developed at Uppsala University and had previously been used in the study of fibromyalgia (Anderberg, Marteinsdottir et al. 2000) and social phobia (Marteinsdottir, Svensson et al. 2007). It was designed to measure the full range of important life experiences for the individual, as opposed to only more extreme events, such as those studied in the 53
context of post-traumatic stress disorders (Peterlin, Tietjen et al. 2008). The CEOS inventory for current stress has been developed at Uppsala University (Arnetz 2002; Hansson, Arnetz et al. 2006) and the PQ23 quality of life instrument was developed and validated at the same department as the mentioned CEOS inventory (Andersson, Johnsson et al. 2009).
Internet as a tool for communication In the present thesis we made multiple use of the Internet for communicating with study participants and for data collection: It was used for transmitting the MBT program via a specially designed web tool which also provided pdf files to enable printouts. An electronic migraine diary was also kept and reported back via the web tool and was used for keeping track of migraine symptoms, medication and physical activity. Direct contacts were also made via email for automatic reminders to keep up the diary if more than one week had passed without diary registration, and participants were allowed to make email contact when in need of advice. Given that all participants were met face-to-face on three to four occasions and in view of participants’ constant access to study leaders via email or phone, when in need, the conclusion is that there were few technical problems with this medium. Examples of problems that did occur were: server malfunction, forgotten passwords, and difficulties in correcting diary errors.
Strengths and limitations The methodological strengths of the cross-sectional design of Paper I were its relatively large size (n = 150) and the complete response rate for the questionnaires used. Lack of a concomitant control group for this study, for normalization of values, was a limitation and the uneven gender distribution was also a weakness. The strengths of intervention Paper II were: its proven efficacy despite including participants with moderate symptoms (at least two attacks a month) and using a relatively strict standard for efficacy (50 % or more reduction in headache frequency), a low attrition rate, and the completeness of diary data. Limitations were the size of the study and lack of follow-up data on its efficacy. A potential weakness of the study design was the numerous components of the MBT program, the sum of which may have been too demanding for some participants. In view of the fact that many of the constituents of the program had been practiced face-to-face previously to a considerable extent, feasibility pretesting was believed to be unnecessary (Campbell, Murray et al. 2007). A considerable weakness of the hand massage part of this study was its low power in terms of massage frequency. 54
The major strengths of Paper III were: the complete characterization of migraine drug use – including over-the-counter drugs, and the prospective design both for the observational part of the study during a baseline period and for the MBT intervention part. The high compliance of the diary registration was another strength of the study, whereas the skewed gender distribution was a limitation. The principal weakness of Paper IV alludes to the difficulties in defining aberrant cortisol values. Also the array of tested measurements entails a considerable risk for type 2 statistical errors.
55
CONCLUSIONS
The presently developed MBT program was feasible, had a low attrition rate and yielded high-quality diary data The MBT program was efficient in terms of decreasing migraine headache Participants evaluated the cognitive part of the MBT program as the most rewarding treatment modality The program for hand massage was feasible and appreciated in the short term by the participants, but no long-term effects were seen on migraine headache. The overall drug use was significantly decreased at the end of MBT, with an unaltered pattern of use of the different drug groups Drug efficacies were significantly improved at completion of MBT Triptans displayed significantly better efficacy than analgesics Women displayed significantly higher usage of triptans Despite its low efficacy, men used analgesics significantly more than women On one quarter of the recorded days with migraine headache, no migraine drugs were used Stress susceptibility was the personality trait that deviated most from the norm among the studied individuals with migraine. Current stress displayed a strong positive correlation with degree of stress susceptibility for the studied group of individuals with migraine Individuals with migraine of both sexes reported high numbers of negative life events – women strikingly more than men. Among the studied individuals with migraine, past and ongoing comorbidity in depression, anxiety, and tension type headache was significantly more common in women. The present data support the notion that individuals with migraine score high on the neuroticism factor. ACR values were mostly aberrant among the studied individuals with migraine Stress susceptibility was associated with low flat cortisol profiles Severely negative life events during childhood were associated with low daytime cortisol values 56
Determining the optimal use of salivary cortisol measurements to characterize biological evidence of stress in migraine requires further exploration
57
FUTURE RESEARCH
The need for improved treatment of migraine in the general population is high, and the potential for beneficial effects of behavioral change also seems high for this stress-dependent disease. Therefore, the present program is promising as it is effective and has potential to reach out on a large scale. With a web interface adjusted for evaluation in a larger format a study on its efficacy as a purely Internet-administered treatment could be performed. Furthermore, gender differences in migraine drug use seem of further interest.
58
SWEDISH SUMMARY
Migrän är en vanlig kronisk neurologisk sjukdom med viss ärftlighet som orsakar avsevärt lidande för den drabbade i form av kraftig ensidig huvudvärk, ljus- och ljudkänslighet och illamående/kräkningar. Det är välkänt att stress spelar en viktig roll vid migrän och stress är den vanligaste utlösande orsaken till anfall. Den aktuella synen på de grundläggande mekanismerna bakom en migränattack är att det föreligger en ökad känslighet för inkommande signaler på hjärnstamsnivå som gör att impulserna fortleds till blodkärl och känselnerver med abnorm smärtkänslighet som följd. Den femte hjärnnerven, trigeminusnerven, som försörjer känseln i hjärnhinnorna och ansiktet spelar en viktig roll för detta. Migrän är dubbelt så vanligt bland kvinnor som hos män. Förekomsten av migrän är cirka 13 procent hos den vuxna befolkningen i Sverige, med konsekvenser för arbete, familjeliv och fritidsaktiviteter. Med tanke på sjukdomens kroniska natur och betydelsen av livsstilsfaktorer krävs en bredare syn på behandlingen än den rent farmakologiska. Läkemedel har dessutom biverkningar och är bara effektiva cirka hälften av gångerna de används. Huvudsyftet med denna avhandling har varit att utveckla ett beteendeterapeutiskt program specialdesignat för migrän som fokuserar på stressens betydelse och utvärdera dess genomförbarhet och effektivitet. En multimodal design har använts och programmet, inklusive en migrändagbok, har anpassats för Internetanvändning i en strävan att finna former som ökar åtkomligheten av beteendeterapi vid migrän. Deltagarna, som hade minst två huvudvärksattacker per månad, fick stegvis ta del av information och råd avseende stressfysiologi, kost, fysisk aktivitet, sömn, och kognitiva aspekter rörande betydelsen av tankemönster, känsloliv och relationer till sig själv och andra, relaterat till stress. Hälften av deltagarna randomiserades till att även få handmassageterapi. Studien visar att efter 6 månaders praktiserande av programmet hade deltagarna en statistiskt säkerställd lägre migränfrekvens. Drygt 40 procent av deltagarna minskade sin huvudvärk med minst 50 procent jämfört med endast 15 procent i en kontrollgrupp. Deltagarna uppgav att det var de kognitiva delarna i programmet som hade upplevts som mest värdefulla. 59
Programmet var väl genomförbart: Endast sju av 83 personer avbröt studien och rapporteringen i migrändagboken var mycket god. Förutom migränsymptom rapporterades även medicinintag i dagboken. Analys av läkemedelsanvändningen visade att deltagande i programmet medförde en minskad läkemedelsanvändning som stod i ungefär proportion till den minskade huvudvärken. Däremot ökade läkemedlens effektivitet efter genomgången beteendeterapi. Den främsta anledningen till detta syntes vara att anfallen var mindre svåra efter beteendeterapi och att deltagarna i högre grad medicinerade även de lätta anfallen efter beteendeterapin. Ett intressant fynd var att män använde mer smärtstillande läkemedel av typen acetylsalicylsyra, paracetamol eller så kallade NSAID-preparat än kvinnorna trots att de tycktes ha sämre effekt av dessa läkemedel än kvinnorna och framförallt sämre effekt än av triptaner. Detta har väckt frågan om männen varit optimalt medicinerade. Trots att de deltagare som randomiserats till handmassage både lyckades genomföra massagen i relativt hög grad och uppskattade dess momentana effekter kunde ingen minskning av migränen uppmätas. I samband med studien mättes även nivåerna av stresshormonet cortisol, vilka inte visade sig påverkas under beteendeterapin. Personlighetsdrag, aktuell stressnivå och negativa livshändelser analyserades hos 150 personer med migrän. Resultaten visade att det personlighetsdrag som avvek mest från normalvärdena var stresskänslighet. Graden av stresskänslighet visade sig vara korrelerad till antalet negativa livshändelser, aktuell stressnivå och förekomst av en låg dygnscortisolprofil. En sammanfattande beskrivning av de undersöktas personlighetsdrag är att de som grupp skattade högt för personlighetsfaktorn ”neuroticism”. Materialet har även analyserats med avseende på genderskillnader, vilket visade att kvinnorna med migrän uppvisade ökad förekomst av ångestbenägenhet, negativa livshändelser, depressiv sinnesstämning, ångest, och spänningshuvudvärk. Vidare sågs högre triptananvändning och bättre effekt av analgetika än hos män, samtidigt som männen med migrän uppvisade en högre användning av analgetika. Sammanfattningsvis visade sig det Internetadministrerade MBT-programmet för migrän vara effektivt och genomförbart, vilket talar för att det skulle kunna vidareutvecklas till en användbar och lättillgänglig behandling i större skala. Stresskänslighet visade sig vara ett utmärkande drag hos individer med migrän vilket är väl förenligt med sjukdomens grundläggande problematik, och kan vara viktigt att ta hänsyn till vid omhändertagande av personer med migrän.
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ACKNOWLEDGEMENTS
Det är många som under mina doktorandstudier bidragit med värdefulla kunskaper, givit praktiskt och ekonomiskt stöd och, inte minst, uppmuntran och moralisk support, vilket varit en förutsättning för genomförandet av denna avhandling. Jag vill härmed tacka var och en av er för era bidrag. Särskilt tack till: Alla forskningspersoner som gjort det möjligt att genomföra studierna i avhandlingen. Ni har alla bidragit med era upplevelser av att ha migrän och många av er har också lagt ner ett stort arbete på att under en längre tid föra dagbok, svara på frågeformulär och komma för provtagningar. Utan er hade denna avhandling inte varit möjligt. Min huvudhandledare Carin Muhr, docent i neurologi vid Uppsala universitet. Dina genuina kunskaper om migrän och dina värdefulla tankar och idéer under arbetets gång har varit avgörande. Särskilt stort tack för samarbetet kring planeringen av studierna, mottagandet av forskningspersonerna och utformningen av behandlingsprogrammet. Tack även för att du alltid har varit tillgänglig oavsett var i världen du har befunnit dig och att du alltid är vänlig, positiv och mycket uppmuntrande. Min biträdande handledare Ulla Maria Anderberg, docent i psykiatri vid Uppsala universitet, med din mångåriga erfarenhet av stressrelaterade sjukdomstillstånd och utformning av interventionsstudier. Tack för alla kloka råd och bra kontakter som du har bidragit med. Numera avlidne överläkaren i neurologi Carl-Einar Westerberg, Akademiska sjukhuset Uppsala, för att du tog dig tid att ge synpunkter på planeringen av studierna och din stora vänlighet och goda pedagogiska förmåga att förmedla dina idéer.
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Harriet Marnell, leg. sjuksköterska, medicinsk magister vid Uppsala universitet, för din kompetens inom stressområdet och dina professionella kunskaper och erfarenheter av att ha arbetat med stresshantering och massageterapi. Tack för att du med stor generositet delade med dig av dina kunskaper. It-teknikerna och webbdesignerna Jens Pettersson och Mattias Sjöberg, CEOS, Uppsala universitet, för ert fina jobb med att utforma dagbok och webb-plattform på ett ändamålsenligt sätt och för ständigt snabb support. Ett speciellt tack till dig Jens för att du under din ledighet flyttade mina data till en säkrare server. Hans Arinell, statistiker vid Institutionen för neurovetenskap, psykiatri, Uppsala universitet, för alla timmar med planering och statistikgenomgång av de olika studierna och att du alltid är vänlig och tillgänglig. Karl-Erik Westergren, Tech. Lic., tidigare utbildningschef på Högskolan i Gävle, för att du bidragit med statistikhjälp. Tack för din hjälpsamhet och skarpa analytiska förmåga. Lars-Olof Nordesjö, docent och min tidigare chef på avdelningen för klinisk fysiologi i Gävle, som inspirerat mig till forskning och tålmodigt bistått mig när jag behövt diskutera forskningsfrågor och statistiska spörsmål. Gun Schönnings, institutionsadministratör på Institutionen för Neurovetenskap, neurologi, Uppsala universitet, för all administrativ hjälp och vänligt bemötande under min doktorandtid. Maj-Britt Brolin, tidigare institutionssekreterare vid Sveriges lantbruksuniversitet, Uppsala, för trägen och noggrann hjälp med databearbetning. Lena Frenzel, tidigare avdelningschef på CEOS, för gott samarbete i samband med lån av lokaler för mottagande av forskningspersoner till studierna samt att jag kunde beredas datorplats vid behov. Tack för att du alltid varit så hjälpsam och tillgänglig. Olav Mäepea, forskningsingenjör vid Institutionen för Neurovetenskap, Uppsala universitet, för hjälp med datorprogram. Tack för din energi, entusiasm och alla roliga samtal under min doktorandtid. 62
Eva Heldesjö Blom, ansvarig för forskningsprover och Inga-Lena Sporrong och Gunhild Öst, kem. lab., provmottagningen Akademiska sjukhuset i Uppsala, samt Marianne Johansson, sektionsledare på kem. lab. i Gävle, för all hjälp i samband med att jag tog prover på forskningspersonerna i studien. Alla kollegor på Akademin för hälsa och arbetsliv, avdelningen för hälso- och vårdvetenskap, Högskolan i Gävle, för ert alltid positiva bemötande och visade intresse för min forskning. Särskilt tack till alla som bidrog aktivt vid mitt forskningsseminarium inför halvtidsprövningen. Speciellt tack till mina närmaste medarbetare i ämnesgruppen medicinsk vetenskap, Högskolan i Gävle: Ola Dahlberg, Jenny Larsson, Britt-Marie Wågström, Annsofie Wigert, Ewa Westergren, Sarah Karlsson, Jenny Riddarström, Anna Hofsten inklusive mina doktorandkollegor, Kerstin Stake-Nilsson och Lena Thunander Sundberg. Tack för att ni alla är så positiva, uppmuntrande och roliga! Tänk vad mycket kul vi har haft och vad mycket som finns kvar att göra! Högskolan i Gävle, Erik, Karin och Gösta Selanders Stiftelse samt fonden för anslag till vårdforskning, medicinska och farmaceutiska fakulteten, Uppsala universitet, för ekonomiskt stöd. Alla mina vänner som gör att livet känns roligt och meningsfullt. Mina barn Elisabeth och Hans för att ni är självständiga och alltid ger energi och livsglädje och generöst delar med er av era liv och vänner. Min livskamrat och make Fredrik för att du alltid är stöttande, glad, reflekterande och rolig och för våra ständiga samtal om allt mellan himmel och jord, inklusive en hel del forskningsfrågor. Tack för ditt stora engagemang!
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