Putative Mechanisms of the Relationship Between Obesity and Migraine Progression Marcelo E. Bigal, MD, PhD, and Richard B. Lipton, MD
Corresponding author Marcelo E. Bigal, MD, PhD Global Director for Scientific Affairs, Neuroscience, Merck Research Laboratories, One Merck Drive, PO Box 100, Whitehouse Station, NJ 08889, USA. E-mail:
[email protected] Current Pain and Headache Reports 2008, 12:207–212 Current Medicine Group LLC ISSN 1531-3433 Copyright © 2008 by Current Medicine Group LLC
Studies suggest that obesity is associated with migraine progression from an episodic into a chronic form. We discuss putative mechanisms to justify this relationship. Several of the inflammatory mediators that are increased in obese individuals are important in migraine pathophysiology, including interleukins and calcitonin gene–related peptide. Both migraine and obesity are prothrombotic states. Substances that are important in metabolic control are nociceptive at certain levels. Hypothalamic dysfunction in the orexin pathways seems to be a risk factor for both conditions. In addition, we discuss the importance of metabolic syndrome and autonomic dysfunction in modulating the obesity/ migraine progression relationship.
Introduction Some migraine sufferers have a clinically progressive disorder characterized by attacks of increasing frequency, at times leading to headaches 15 or more days per month. This state is often referred to as transformed or chronic migraine (CM), a subtype of the chronic daily headaches (CDHs) [1–4]. Migraine progression is supported by both clinical observation and epidemiologic research [5–7]. In a longitudinal epidemiologic study, the Frequent Headache Epidemiology Study, over the course of 1 year, 3% of individuals in the general population with infrequent episodic headache (2 to 104 headache days/year) progressed to CDH; an additional 6% progressed to high-frequency episodic headaches, characterized by 105 to 179 headache days/year [6]. Very similar rates were found as part of the American Migraine Prevalence and Prevention Study (Lipton et al., data in preparation).
Obesity, a highly prevalent disorder that severely affects health-related quality of life, is a risk factor for hypertension, metabolic syndrome, and diabetes, as well as myocardial infarction and stroke [8•]. It has reached epidemic proportions globally (in the United States, 64% of adults are either overweight or obese [9–11]). The economic impact on the health care system of obesity and its associated health problems is significant, accounting for 9.1% of total US medical expenditure in 1998 and reaching as high as $92.6 billion in 2002 [12]. The link between obesity and the frequency of primary headaches has been demonstrated in several population studies. In the Frequent Headache Epidemiology Study, the relative odds of CDH were five times higher in individuals with a body mass index (BMI) of 30 or more, compared with normal-weight individuals. Overweight individuals (BMI = 25–29) had a threefold increased risk of developing CDH, suggesting a dose-response relationship between BMI and CDH [6]. In a second population study, we assessed the influence of BMI on headaches in 30,215 individuals. Contrasted with normal-weight individuals, increased BMI was a risk factor for high-frequency episodic migraine (headaches on 10–14 days/month; obese: OR = 2.9, 95% CI = 1.9–4.4; severely obese: OR = 5.7, 95% CI = 3.6–8.8) [13••]. Additionally, obesity was associated with CM. The prevalence of CM ranged from 0.9% of the normal-weight (reference) group to 1.2% of the overweight group (OR = 1.4 [1.1–1.8]), 1.6% of the obese group (OR = 1.7 [1.2–2.43]), and 2.5% of the severely obese group (OR = 2.2 [1.5–3.2]) [14•]. The influence of obesity on headache severity was most striking for migraine and CM and marginal for chronic tensiontype headache [15]. In this article, we discuss putative mechanisms that link migraine and obesity. We start by providing a framework for understanding the linkages and then review overlapping neurochemical dysfunctions in both diseases. We stress that many of the putative mechanisms between frequent headaches and obesity are speculative or supported only by animal studies. For a thorough review of this topic, please see the study by Bigal et al. [16•].
208 Migraine Headache
study [6], obesity was a risk factor for incident CM. CM has not been studied as a risk factor for obesity. As detailed in the next section, unidirectional causal relationships may explain some of the relationship between both conditions (eg, inflammatory mediators that are elevated in obesity and may be of importance in migraine).
Shared environmental risk factors or comorbidities Comorbid relationships might be explained by shared environmental risks. A sedentary and stressful occupation might contribute to the co-occurrence of these disorders. There is no direct evidence to support this hypothesis. Depression has been suggested to mediate, at least partially, the relationship between migraine and obesity [18]. However, all population studies that assessed this topic at least partially adjusted for depression.
Shared genetic risk factors
Figure 1. Possible links between obesity and chronic migraine. CM—chronic migraine; TM—transformed migraine. (Adapted from Bigal et al. [16•], with permission.)
Migraine and obesity may share a common genetic underpinning. Shared genetic risk factors explain several of the comorbidities of migraine [19]. Some of the relationship between obesity and migraine may be explained by this model. As discussed in the following text, some neurochemicals, including orexins, are responsible for modulating a number of metabolic and nociceptive processes. Genetic risk factors that lead to dysmodulation in the orexin pathways could lead to both refractory pain and obesity.
Possible Links Between Migraine and Obesity Possible reasons for the association between obesity and migraine progression are summarized in Figure 1 [16•] and briefly discussed in the following text.
Spurious interaction It could be that obesity and frequent headaches appeared to be related as a consequence of biased ascertainment. If persons with obesity or migraine were more likely to be in the health care system, individuals with both disorders may be over-represented in clinic-based samples. Another potential source of spurious interaction is the fact that both migraine and obesity are common disorders, potentially leading to a statistically but not pathophysiologically significant association between the two. Because the association is supported by several large cross-sectional population studies [13••,14•,15,16•,17] and a longitudinal analysis adjusted by gender, age, and sociodemographic status [6], spurious interaction seems unlikely.
Unidirectional causal relationships Here, one disease would lead to the other. CM may be a risk factor for obesity, because individuals with daily pain may live more sedentary lives and may use preventive medications that increase weight. Obesity could increase the risk of CM if proinflammatory mediators contribute to headache progression. In the only available longitudinal
Putative Mechanisms Linking Migraine and Obesity Figure 2 summarizes some of the putative mechanisms that may link obesity and migraine progression. They are detailed in the following text.
Migraine and obesity as proinflammatory states Inflammation has been implicated in the mechanisms of migraine. The source of pain in migraine headache may involve neurogenic plasma extravasations and consequent vascular meningeal inflammation [20, 21]. Electrical stimulation of the trigeminal ganglion leads to increases in extracerebral blood flow and local release of calcitonin gene–related peptide (CGRP) and substance P, both of which are proinflammatory [22]. Trigeminal ganglion stimulation also causes release of a powerful vasodilator peptide, vasoactive intestinal polypeptide, through a reflex activation of the cranial parasympathetic outflow [23]. Other inflammatory promoters are also altered in migraineurs, including several cytokines, and some of these markers are normalized after treatment with sumatriptan [24]. Transient increase in soluble intracellular adhesion molecule, interleukin (IL)-6, and tumor necrosis factor (TNF)- α can be induced by sensory neuropeptides released from activated trigeminal endings and are seen during migraine attacks [24]. Studies also investigated the presence
Obesity and Migraine Progression Bigal and Lipton
209
Figure 2. Putative mechanisms of the obesity/migraine progression relationship. CRP—C-reactive protein; IL—interleukin; TNF—tumor necrosis factor.
of genetic abnormalities of the protein C system in subjects with migraine, contrasted with controls. C-reactive protein (CRP) was increased in individuals with migraine with aura in a clinic-based study [25]. Obesity is a proinflammatory state as well. Adipose tissue, previously considered a passive storage depot for fat, is now known to play an active role in metabolism [26]. Adipocytes produce and release inflammatory cytokines, including TNF- α and IL-6. The adipose tissue is estimated to produce about 25% of the systemic IL-6 in vivo [27]. Additionally, the adipose tissue is infiltrated by macrophages, which may also be a major source of locally produced proinflammatory cytokines [28]. Weight loss is associated with a reduction in the macrophage infiltration of adipose tissue [29]. Obesity is also associated with increased CGRP levels. Plasma levels of CGRP are elevated in obese individuals, and fat intake may also be associated with CGRP secretion [30]. In a clinic-based study, CGRP was significantly higher in obese subjects relative to controls. After fat intake, the CGRP levels further increased, and after weight loss, concentrations remained unchanged. It was suggested that CGRP levels may be genetically determined in obese individuals and that fat intake may be associated with increased CGRP secretion [30].
Migraine and obesity as prothrombotic states Migraine is also considered to be a prothrombotic state. Migraine with aura is a risk factor for stroke, angina, sudden death, and elevated cardiovascular risk factors [31]. It has been demonstrated that cortical spreading depression (CSD) alters blood–brain barrier (BBB) permeability by activating brain matrix metalloproteinases (MMPs), especially MMP-9 [32]. CSD induces upregulation of MMP-9, which, in turn, opens the BBB and
promotes sustained leakage of serum proteins. Barrier disruption may contribute to changes in brain permeability during migraine attacks, as well as neuronal death and an increase in infarct volume in the already compromised brain [32]. Additionally, migraineurs are more likely to have a mutation on the Arg506Gln gene related to the factor V, as well as protein S deficiency [33]. Obesity is a known and very important risk factor for cardiovascular diseases. In a population study, overweight and obese individuals were more likely to have increased CRP levels than were their normal-weight counterparts. After adjustment for potential confounders, the odds for elevated CRP were 2.1 for obese men and 6.2 for obese women. Obesity, as well as high levels of CRP, is an independent risk factor for leukocytosis [34]. Some of the potential drivers of the prothrombotic status in obesity are discussed in the following text.
The importance of substances that control the metabolism Secreted by the adipose tissue The adipose tissue plays an active role in metabolism [26]. The hormone adiponectin has endocrine effects in the liver, muscle, and vasculature. Adiponectin modulates a number of metabolic processes, important in the control of glycemia, as well as fatty acid catabolism. Levels of the hormone are inversely correlated with the BMI [35], which plays a key role in metabolic disorders such as type 2 diabetes, obesity, and atherosclerosis. Plasma concentrations are higher in females than in males [36]. At normal levels, adiponectin is anti-inflammatory. At lower levels, adiponectin induces a proinflammatory state [35, 36]. In addition, low levels of adiponectin have been recently reported to be associated with platelet aggregation [37 ].
210 Migraine Headache
Leptin and resistin are two other substances secreted by the adipocytes that may be of importance. Beyond their effects on central metabolic functions, leptin, resistin, and adiponectin have profound effects on a number of other physiologic processes, including inflammation [36 ]. It has been demonstrated that leptin and adiponectin activate proinflammatory cytokine release and phospholipid metabolism in the adipose tissue, and that anti-inflammatory agents counteract the induced inflammation [37 ]. The underlying mechanisms seem to involve a nitric oxide–dependent pathway [37 ]. Neurotransmitters Several peptides are involved in the modulation of appetite and energy homeostasis, including the orexins (orexin A and B). Orexins are implicated in a variety of functions, including feeding, sleep–wake cycle, cardiovascular function, hormone secretion [38], and more recently, the modulation of nociceptive processing [39]. The orexins are also of importance in weight control. In a clinic-based study, plasma orexin A concentrations were significantly lower in obese women, compared with controls [40]. The orexins have been linked with a possible role in migraine. In an animal model of trigeminovascular activation, activation of the orexin receptor 1 and 2 in the posterior hypothalamus differentially modulated nociceptive dural input [41]. This is of importance because regulation of autonomic and neuroendocrine functions as well as nociceptive processing is closely coupled in the hypothalamus, probably mediated by orexinergic mechanisms [17 ]. Thus, the orexinergic system could be a possible link between migraine pain and the possible hypothalamic dysfunction seen in migraineurs. In an animal model, orexin A, but not orexin B, was able to inhibit neurogenic dural vasodilation, resulting in inhibition of prejunctional release of CGRP from trigeminal neurons. The response was reversed by pretreatment with antagonists [42•].
Other putative mechanisms Metabolic syndrome and its components Metabolic syndrome (or the syndrome of insulin resistance) is directly related to obesity and other cardiovascular risk factors. Components of the metabolic syndrome include insulin resistance, visceral adiposity, dyslipidemia, hypertension, and elevated levels of inflammatory markers, as well as prothrombotic and proinflammatory peptides [43]. As defined by Adult Treatment Panel III, metabolic syndrome requires three of the following five characteristics: trunk obesity (waist circumference), increased fasting glucose, hypertension, low high-density lipoprotein (HDL), and increased triglycerides. Metabolic syndrome has been associated with chronic pain. In a recent study, women with fibromyalgia were five times more likely than healthy controls to have metabolic syndrome (95% CI, 1.25–24.74). Fibromyalgia was independently associated with larger waist circumfer-
ence (P = 0.04), higher levels of glycosylated hemoglobin (P = 0.01) and serum triglycerides (P < 0.001), as well as higher systolic (P = 0.003) and diastolic (P = 0.002) pressure. Total and low-density lipoprotein cholesterol were also significantly higher in women with fibromyalgia (P = 0.001 and 0.02, respectively) [44]. Hypertension and diabetes may be of importance for migraine progression. Compared with controls, persons with migraine were more likely to have increased blood pressure (BP; systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg [OR = 1.76; 1.04–3.0]) and increased Framingham scores after adjusting for covariates [45]. In the Frequent Headache Epidemiology Study, both hypertension and diabetes were associated with CDH (Scher, personal communication). Dyslipidemia is also associated with migraine. In the Genetic Epidemiology of Migraine study, 5755 individuals were screened to identify 620 current migraineurs. Compared with controls, migraineurs were more likely to report a parental history of early myocardial infarction. Migraineurs with aura were more likely to have an unfavorable cholesterol profile (total cholesterol [TC] ≥ 240 mg/dL [OR = 1.43; 0.97–2.1], TC:HDL ratio > 5.0 [OR = 1.64; 1.1–2.4]), increased BP (systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg [OR = 1.76; 1.04–3.0]), and report a history of early-onset coronary disease or stroke (OR = 3.96 [1.1–14.3]). The odds of having an increased Framingham risk score for cardiovascular disease were approximately doubled for the migraineurs with aura [45]. HDL cholesterol has anti-inflammatory properties that may diminish neurodegenerative processes and the perception of pain [46•]. The importance of the autonomic nervous system Obesity may be explained as a disturbance of energy balance, with energy intake exceeding energy expenditure. Because the autonomic nervous system has a role in the regulation of both of these variables, it has become a major focus of investigation in the fields of obesity pathogenesis [47 ]. A prospective study in 8000 obese and nonobese patients revealed a high relative risk to develop type 2 diabetes if autonomic dysfunction is present [48]. It may be suggested that an unbalanced autonomic output develops in obese individuals with increased parasympathetic dominance in the visceral compartment and increased sympathetic tone in the thoracic compartment and muscles. In addition, it is also speculated that the increase in the sympathetic tone, which occurs under fasting conditions in obesity, may be associated with high cardiovascular morbidity and mortality. At least partially, this dysmodulation is driven by leptin, a proinflammatory molecule. Autonomic dysfunction has been suggested in migraine [49]. It may be speculated that obesity leads to activation of the sympathetic nervous system (a “hypersympathetic state”) and changes in central serotonergic responsiveness (a reduction in central “serotonin tone”), which might increase the chance of migraine transformation.
Obesity and Migraine Progression Bigal and Lipton
Conclusions A better understanding of the determinants of the relationship between obesity and migraine progression is of great clinical importance and a crucial step toward public-health initiatives aimed at preventing migraine chronification. In this article we explored some of the possible clinical links between migraine progression and obesity. We hypothesize that remediable vascular risk factors (ie, metabolic syndrome, hyperlipidemia, and hypertension) may influence migraine progression mediating the effects of obesity. We also hypothesize that metabolic syndrome accounts for much of the relationship. We emphasize that some conditions common to both obesity and migraine (eg, allodynia, sleep apnea, and depression) may influence migraine progression, although they were not the focus of this article. On a longterm basis, a better comprehension of this relationship will define biologically vulnerable groups for intervention, clarify the mechanisms that link obesity and headache, and perhaps flag molecular targets for future drug development.
Disclosures Dr. Bigal is a full-time employee of Merck Research Laboratories. In the past, he has received grants from OMP, Merck, AstraZeneca, GlaxoSmithKline, and others. Dr. Lipton has participated in advisory boards, speakers’ bureaus, and received research or educational grants related to the following companies: Advanced Bionics, Allergan, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Cierra, Endo, GlaxoSmithKline, Minster, Merck, Neuralieve, Novartis, Ortho-McNeil, Pfi zer, Pozen, ProEthics, and St. Jude’s.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
Scher AI, Stewart WF, Lipton RB: Prevalence of frequent headache in a population sample. Headache 1998, 38:497–506. 2. Lipton RB, Bigal ME: Migraine: epidemiology, impact, and risk factors for progression. Headache 2005, 45(Suppl 1): S3– S13 3. Mathew NT, Reuveni U, Perez F: Transformed or evolutive migraine. Headache 1987, 27:102–106. 4. Silberstein SD, Lipton RB, Sliwinski M: Classification of daily and near-daily headaches: field trial of revised IHS criteria. Neurology 1996, 47:871– 875. 5. Saper JR: The mixed headache syndrome: a new perspective. Headache 1982, 22:284–286. 6. Scher AI, Stewart WF, Ricci JA, Lipton RB: Factors associated with the onset and remission of chronic daily headache in a population-based study. Pain 2003, 106:81– 89. 7. Katsarava Z, Muessig M, Dzagnidze A, et al.: Medication overuse headache: rates and predictors for relapse in a 4-year prospective study. Cephalalgia 2005, 25:12–15. 8.• National Center for Chronic Disease Prevention and Health Promotion: Overweight and obesity: obesity trends. Available at: http://www.cdc.gov/nccdphp/dnpa/obesity/ trend/maps/index.htm. Accessed June 18, 2006. Official report of obesity and overweight figures in the United States.
9.
211
Yan LL, Daviglus ML, Liu K, et al.: Midlife body mass index and hospitalization and mortality in older age. JAMA 2006, 295:190–198. 10. World Health Organization: Obesity and overweight. Global strategy on diet, physical activity, and health. Available at: http://www.who.int/dietphysicalactivity/publications/facts/obesity/en. Accessed August 19, 2006. 11. Wang Y, Mi J, Shan XY, et al.: Is China facing an obesity epidemic and the consequences? The trends in obesity and chronic disease in China. Int J Obes (Lond) 2007, 31:177–188. 12. Finkelstein EA, Fiebelkorn IC, Wang G: National medical spending attributable to overweight and obesity: how much, and who’s paying? Health Aff 2003, Suppl Web Exclusives:W3-219-226. 13.•• Bigal ME, Liberman JN, Lipton RB: Obesity and migraine: a population study. Neurology 2006, 66:545–550. Study showing that obesity is not a risk factor for migraine, but it is for frequent migraine attacks. 14.• Bigal ME, Lipton RB: Obesity is a risk factor for transformed migraine but not for chronic tension-type headache. Neurology 2006, 67: 252–257. Study suggesting that obesity is a risk factor for CM but not chronic tension-type headache. 15. Bigal ME, Tsang A, Loder E, et al.: Body mass index and primary headaches. The AMPP study. Arch Intern Med 2007, 167:1964–1970. 16.• Bigal ME, Lipton RB, Holland PR, Goadsby PJ: Obesity, migraine, and chronic migraine: possible mechanisms of interaction. Neurology 2007, 68:1851–1861. Study discussing the plausible mechanisms between obesity and migraine. 17. Peres MF, Lerário DD, Garrido AB, Zukerman E: Primary headaches in obese patients. Arq Neuropsiquiatr 2005, 63:931–933. 18. Tietjen GE, Peterlin BL, Brandes JL, et al.: Depression and anxiety: effect on the migraine-obesity relationship. Headache 2007, 47:866– 875. 19. Breslau N, Lipton RB, Stewart WF, et al.: Comorbidity of migraine and depression: investigating potential etiology and prognosis. Neurology 2003, 60:1308–1312. 20. Moskowitz MA, Macfarlane R: Neurovascular and molecular mechanisms in migraine headaches. Cerebrovasc Brain Metab Rev 1993, 5:159–177. 21. Moskowitz MA: Neurogenic inflammation in the pathophysiology and treatment of migraine. Neurology 1993, 43(Suppl 3): S16– S20. 22. Goadsby PJ, Edvinsson L: The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 1993, 33:48–56. 23. Goadsby PJ, Macdonald GJ: Extracranial vasodilatation mediated by VIP (vasoactive intestinal polypeptide). Brain Res 1985, 329: 285–288. 24. Sarchielli P, Alberti A, Baldi A, et al.: Proinflammatory cytokines, adhesion molecules, and lymphocyte integrin expression in the internal jugular blood of migraine patients without aura assessed ictally. Headache 2006, 46: 200–207. 25. Welch KM, Brandes AW, Salerno L, Brandes JL: C-reactive protein may be increased in migraine patients who present with complex clinical features. Headache 2006, 46:197–199. 26. Flier JS: The adipocyte: storage depot or node on the energy information superhighway? Cell 1995, 80:15–18. 27. Mohamed-Ali V, Pinkney JH, Coppack SW: Adipose tissue as an endocrine and paracrine organ. Int J Obes Relat Metab Disord 1998, 22:1145–1158. 28. Herishanu Y, Rogowski O, Polliack A, Marilus R: Leukocytosis in obese individuals: possible link in patients with unexplained persistent neutrophilia. Eur J Haematol 2006, 76:516–520.
212 Migraine Headache 29.
30.
31.
32.
33.
34.
35. 36.
37.
38. 39.
Curat CA, Wegner V, Sengenes C, et al.: Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin. Diabetologia 2006, 49:744–747. Gram DX, Hansen AJ, Wilken M, et al.: Plasma calcitonin gene-related peptide is increased prior to obesity, and sensory nerve desensitization by capsaicin improves oral glucose tolerance in obese Zucker rats. Eur J Endocrinol 2005, 153:963–969. Kurth T, Gaziano JM, Cook NR, et al.: Migraine and risk of cardiovascular disease in women. JAMA 2006, 296: 283–291. Gursoy-Ozdemir Y, Qiu J, Matsuoka N, et al.: Cortical spreading depression activates and upregulates MMP-9. J Clin Invest 2004, 113:1447–1455. D’Amico D, Moschiano F, Leone M, et al.: Genetic abnormalities of the protein C system: shared risk factors in young adults with migraine with aura and with ischemic stroke? Cephalalgia 1998, 18: 618– 621. Herishanu Y, Rogowski O, Polliack A, Marilus R: Leukocytosis in obese individuals: possible link in patients with unexplained persistent neutrophilia. Eur J Haematol 2006, 76:516–520. Matsuzawa Y: The metabolic syndrome and adipocytokines. FEBS Lett 2006, 580: 2917–2921. Ronti T, Lupattelli G, Mannarino E: The endocrine function of adipose tissue: an update. Clin Endocrinol 2006, 64:355–365. Shoji T, Koyama H, Fukumoto S, et al.: Platelet activation is associated with hypoadiponectinemia and carotid atherosclerosis. Atherosclerosis 2006, 188:190–195. Siegel JM: Hypocretin (orexin): role in normal behavior and neuropathology. Annu Rev Psychol 2004, 55: 25– 48. Kajiyama S, Kawamoto M, Shiraishi S: Spinal orexin-1 receptors mediate anti-hyperalgesic effects of intrathecally administered orexins in diabetic neuropathic pain model rats. Brain Res 2005, 1044:76– 86.
40.
Baranowska B, Wolinska-Witort E, Martynska M, et al.: Plasma orexin A, orexin B, leptin, neuropeptide Y (NPY) and insulin in obese women. Neuro Endocrinol Lett 2005, 26:714. 41. Bartsch T, Levy MJ, Knight YE, Goadsby PJ: Differential modulation of nociceptive dural input to [hypocretin] orexin A and B receptor activation in the posterior hypothalamic area. Pain 2004, 109:367– 378. 42.• Holland PR, Akerman S, Goadsby PJ: Orexin 1 receptor activation attenuates neurogenic dural vasodilation in an animal model of trigeminovascular nociception. J Pharmacol Exp Ther 2005, 315:1380–1385. Study demonstrating the importance of the orexins in trigeminal pain. 43. Haffner SM: Risk constellations in patients with the metabolic syndrome: epidemiology, diagnosis, and treatment patterns. Am J Med 2006, 119(Suppl 1): S3– S9. 44. Loevinger BL, Muller D, Alonso C, Coe CL: Metabolic syndrome in women with chronic pain. Metabolism 2007, 56:87–93. 45. Scher AI, Terwindt GM, Picavet HS, et al.: Cardiovascular risk factors and migraine: the GEM population-based study. Neurology 2005, 64: 614– 620. 46.• Chrysohoou C, Pitsavos C, Skoumas J, et al.: The emerging anti-inflammatory role of HDL-cholesterol, illustrated in cardiovascular disease free population; the ATTICA study. Int J Cardiol 2007, 122: 29– 33. Study suggesting an inverse relationship between HDL cholesterol levels and inflammatory markers in a sample population of cardiovascular disease–free adults. 47. Carnethon MR, Golden SH, Folsom AR, et al.: Prospective investigation of autonomic nervous system function and the development of type 2 diabetes: the Atherosclerosis Risk in Communities Study, 1987–1998. Circulation 2003, 107: 2190–2195. 48. Liatis S, Tentolouris N, Katsilambros N: Cardiac autonomic nervous system activity in obesity. Pediatr Endocrinol Rev 2004, 1(Suppl 3):476– 483. 49. Peroutka SJ: Migraine: a chronic sympathetic nervous system disorder. Headache 2004, 44:53– 64.
