1

1

Chronic fatigue syndrome versus chronic pain syndrome: A comparative study.

Summary (Norwegian):

Kronisk utmattelse og kronisk smerte er begge veldig vanlige plager i befolkningen med en

forekomst på omtrent 25 %. Undergruppene kronisk utmattelsessyndrom (CFS/ME) og

fibromyalgi syndrom (CWP) har en prevalens på henholdsvis 0.5- 1 % og 4 - 18 % . De er

medisinsk uforklarte og ofte årsaker til langtidssykemelding og uføretrygd (ref), og få studier

konkluderer med gode evidensbaserte behandlingsstrategier. Både på folkemunne og til dels

fra vitenskaplig hold har det vært hevdet at de griper over i hverandre med felles etiologi,

patogenese og overlappende symptomer som smerter, fatigue, dysautonomi, nevroendokrin

dysfunksjon, psykososiale belastninger og nevrogene inflammasjons-symptomer. De er

vanligst hos kvinner, har en familiær/genetisk assosiasjon og er ofte utløst av indifferente

stressorer. De fleste CFS/ME pasienter har problemer med økt smertesensitivitet på samme

vis som CWP pasientene, mens de fleste CWP pasientene har utmattelsessymptomer som er

assosiert med CFS/ME. Syndromene overlapper altså mye. Det er likevel ingen enighet om at

man skal se på dem som ett eller flere syndrom. Vår intensjon er å undersøke om CFS/ME og

CWP skiller seg fra hverandre i forhold til livskvalitet (QoL), depresjon og angst (HADS),

fysisk funksjon(SF36), fysisk kapasitet (indirekte VO2 max), smertesensitivisering (antall

tenderpoints), immunologisk funksjon (cytokiner) og nevropsykologi. Sekundært er det også

interessant å sammenligne andre somatiske og mentale parametere samt studere prediktorer

for hovedutfallsmålene. Våre hovedhypoteser er at (i) CFS/ME overlapper med CWP i

forhold til QOL, fysisk funksjon og kapasitet, angst, depresjon, og nevropspykologi. (ii)

CFS/ME overlapper ikke med CWP i forhold til smerte og fatigue.

Background.

1.1 Introduction:

Chronic fatigue syndrome (CFS /ME) is a condition characterized by disabling fatigue lasting

over 6 months that inhibit the individual in relation to daily life functions. The CFS / ME

should be medically unexplained fatigue, onset and with little effect of the rest. Additional

symptoms may be memory and concentration difficulties, prolonged fatigue over 24 hours

2

2

after effort, muscle and joint pain, headache onset, non-restorative sleep, sore throat and

tender lymph nodes (11). Epidemiological studies are difficult due to different diagnostic

criteria, but the Fukuda criterias are validated for research and will be used in this study (12).

Chronic widespread pain (CWP) is an important measure of pain in the general population

[16] . Wolfe et al. (46) have defined CWP as pain in the left and right sides of the body, above

and below the waist, plus pain in the axial skeleton. CWP, in which females are often

overrepresented, seems to remain constant across the lifespan, is associated with several

complex medical conditions (49) CWP often co-occur and overlap with other medical states

and psychological complaints, e.g. depression, anxiety, poor sleep, appetite disturbances, and

fatigue and may inhibit the individual in relation to daily life functions, and is a heterogenic

syndrome with varying function and comorbidity from clinical to non-clinical populations

(15). Fibromyalgia (FM) is a subtype of chronic widespread pain and a condition defined by

the American College of Rheumatology (13) which is characterized by an increased

mechanical pressure pain sensitivity (from at least 4.2 kg/cm2) in more than 10 defined

tenderpoints, often allodynia (painful response to a normally stimulus) and hyperalgesia

(extreme reaction to an usually painful stimulus), lasting over 6 months (14) in addition to

chronic widespread pain,

Chronic fatigue syndrome (CFS / ME) (1) and chronic widespread pain (CWP) (46) have

many factors in common (50) A recent review-article of Abbi et al. 2013 summarizes these

(45). Both are medically unexplained, they have comorbid health complaints and illnesses, are

controversial with frequent causes of long-term sickness-absenteeism and vocational

disability (3). Few studies have been done with quality of life and function measures, and

there are few good evidence-based treatment strategies. It has been claimed that they overlap

to a great extent with symptoms such as fatigue, pain (5,6), in addition to cognitive

dysfunctions (44, 51) and that they appear in epidemic waves (7). Both syndromes are most

prevalent in women, they have a familiy association and often triggered by indifferent

stressors (8). Are they one or more different syndromes? We hypothesise that both CFS/ME

and CWP have symptoms which are distinguishable from both each other and healthy controls

(1, 9), but that they ovelap to a large extent in clinical symptoms sharing commom etiology

and pathogeniesis (10).More research is needed to understand this, in order to implement

adequate treatment (4).

3

3

1.2 Previous research about similarities and differences between Chronic Fatigue Syndrome

and Chronic Widespread Pain:

Sociodemographics: CFS/ME has a prevalence of about 0.5- 1 % while CWP has 4-18%

48.49), age varies from 40-60 years for both syndromes, gender 3:1 versus 9:1, respectively

(14,18,46). Similar symptoms between CFS/ME and fibromyalgia includes e.g. pain, fatigue,

sleeping problems, cognitive impairment (7,8,19). Population-Based Studies show that 94 %

of persons with CFS report muscle aches and pains, and 84% of persons with CFS report joint

pain (20). In clinic-based studies 35 %-70 % of patients with CFS meet criteria for CWP,

20%-70% of patients with CWP also meet criteria for CFS (21).

Quality of life (QOL)and mood: Only a few studies have specifically investigated the impact

of CFS on patients’ quality of life (QOL) (22). QOL seem lower in CFS patients than in

healthy subjects (23), particularly low with life as a whole, leisure activities and financial

situation. The data also suggest that treatment of depression associated with CFS, regardless

of causation could help to improve QOL in CFS patients. CWP also is associated with

impairments on quality of life (QoL) and function. Between-groups comparisons have

revealed that CWP patients have significantly lower mental health scores than RA patients

(24). There are no known studies which compare these two syndroms for QoL, but we

hypothesize that physical function SF36 are lower in CFS/ME, with behaviour (sedate

lifestyle measured byVO2max) and cognitive parameters as predictors (17).

Pain/neurosensitisation: There are differences for abnormal pain sensitivity between persons

with CFS/ME and fibromyalgia in the numbers of significant tenderpoints (TP), but not for

CWP without fibromyalgia. While CFS ME has a mean of 4.4 significant TPs, fibromyalgia

has12.4 and mixed CFS/ME & fibromyalgia has 13.1 TP (25), and quantitative tender point

measures show that CWP/fibromyalgia are much more sensitive to mechanical pressure

measured by a dolorimeter (15). In several controlled studies, spinal fluid levels of substance

P have been elevated as an indication of central neurosensitisation (26), while spinal fluid

levels of serotonin products were lowered in patients with CWP (27), but opposite features for

CFS/ME (15). Thus, we hypothesize that the tender point count s are lower in CFS/ME than

in CWP.

4

4

Neuropsychology: Impaired basic cognitive functions are an aspect of both CFS/ME and

CWP, in particular with respect to information processing speed, attention and working

memory (44; 51). Learning and recall as well as executive functions are also impaired in a

proportion of patients. However, no previous studies have compared patients with CFS/ME

and CWP with respect to cognitive functioning. Similarites and differences along these

dimensions might contribute to a better undertstanding of causation and might also have

implications for rehabilitation/treatment.

2. Aims and research questions

2.1 Aims:

The main aim of the project is to compare CFS/ME and CWP in order to increase the

knowledge of both syndromes and improve the treatment of them. Are subtypes of CFS/ME

and CWP with little pain and fatigue, respectively, distinguishable in Qol and allodynia

(neurosensitisation) while other subsets overlap?

2.2 Primary research questions:

1) Is CFS/ME significantly different from CWP and healthy controls by (i) Physical function ,

SF36) and (ii) somatic symptoms (pain NRS, tender points counts and fatigue (Chalder

Fatigue Scale)

2.3 Secondary research questions:

1) Are there differences between the groups for fitness (VO2max), muscular tension (GFM-

52), mood (HADS & SCL-90) and subjective health compliants (SHC) and

neuropsychological functioning, and are these factors associated with physical function

(SF36), pain and fatigue?

3. Methods:

3.1 Patient samples:

Patients with CFS/ME and CWP are referred from primary care to special care services at St.

Olavs Hospital, approximately 100-350 for both CFS/ME and CWP per year, and thus eligible

to be included in the study. The CFS/ME patients are alrady included. Patients were recruited

from two clinics at the Department of Pain and complex disorders (ASSL). CFS/ME patients

were part of another ongoing study, and the CWP/ pain patients were selected based on an

examination of tender points in any of the referred pain patients at the pain clinic. Patients

5

5

with CWP will be asked to join the study, based on the same procedures as the CFS/ME

patients with informed consent.

Inclusion/exclusion: Those who meet the criteria for diagnosis of CFS / ME after Fukuda

CDC 1994 (2) and CWP according to Wolfe et al. i.d. pain both sides, and above and below

the waist in addition to axial skeletal pain. Age >18 years and < 62 years. Exclusion: Serious

somatic or psychiatric disorders. Pregnancy. Problematic drug consumption.Patients was

recruited from two clinics at the Department of Pain and complex disorders (ASSL).

3.2 Procedure:

The clinical examination involves a medical-, a physiotherapist-, and a psychologist

examination. The medical examination will include common history and blood pressure, heart

rate and general status. Physiotherapist will conduct a clinical study on strength, fitness (VO2

max), relaxation ability and motor flexibility (modified Global Physiotherapy Method

"GCWP-52" on the basis of psychomotor physiotherapy (43). Tender points will be counted,,

and a preliminary neurological and rheumatology joint screening. Clinical psychologist will

rule out serious psychiatric disorders, while neuropsychologist will examine cognitive

function. Patients will answer questions after examination at St.Olavs Hospital. Amd pain,

fatigue and psychometric data will be collected. The assessment includes several validated

research forms that cover a wide range of parameters. A multidisciplinary evaluation will

identify CFS/ME (12) or CWP (13, 46). Appoximately 200 CFS / ME have already been

included, and 200 consecutive CWP patients will be included in the study.

3.3 Inclusion/exclusion:

Those who meet the criteria for diagnosis of CFS / ME after Fukuda CDC 1994 (2) and CWP

according Wolfe et al. definition (46) Age >18 years and < 62 years. Exclusion: Serious

somatic or psychiatric disorders. Pregnancy. Problematic drug consumption.

3.4 Design:

The present study has a comparative cross-sectional design to study differences between

CFS/ME, CWP and will be conducted at the Department of Pain and Complex dosorders, St

Olavs hospital (ASSL) with consecutive enrolement procedures. .

3.5 Main outcomes:

6

6

Physical function (SF36): Group differences will be measured with the primary outcome

measure "physical function" operationalized by the physical function dimension of the SF-36.

Cutoff for reduced function = 56, but our cutoff will be 50, according to the requirement of a

50% disability of CFS / ME. SF-36 "(26). This is a 36-item questionnaire that produces scales

for mental, physical and total QoL. It is a generic measure, and the questionnaire was

designed for self-reporting. Higher scores represent higher functional levels.The review

shows that SF-36 is used to measure quality of life in CFS studies. Reliability and validity

studies of the SF-36 has shown adequate internal consistency, discriminant validity among

subscales, and large differences between patient and non-patient populations in the pattern of

scores (27). When the SF-36 is used by CFS it has shown adequate psychometric properties as

a measure of functional status (28). Reeves et al (29) has recommended use of the SF-36 at

the CFS / ME (after the Fukuda criteria), and describes it as "a well-validated instrument that

measures the effect of the disease (ie, fatigue and associated symptoms). In summary, SF-36

provides a reliable, validated measure of functional status and quality of life in CFS / ME.

Pain: Pain will med masured by selfreport in pain intensity and localization and number

tenderpoints (TP)., .

"Fatigue" with Chalders Fatigue Scale (scoring 0-3 with 11 items, max fatigue = 44) (16),

quality of life QoL (SF-36 total) and mental function in SF-36 (000-100). Outcome success

criteria will be> 10 point improvement in physical and / or physical function in SF-36 as

analyzed by a 0-100 scale where 100 is best and 0 is the worst (5), or 50% improvement or

achievement of a score of 75 (30).

3.6 Secondary outcomes:

Fitness (VO2 max)(31), mood (HADS), number of comorbide health copmplaints (SCL-90,

SHC) in addition to psychometry with behaviour and cognition aspects, included

metacogntions (MCQ) and catastrophic thoughts (PCS).

3.7 Statistical power:

Assuming mean group differences in SF36 score of 10, 5 and 0 respectively for the CFS/ME,

CWP and Healthy controls and a within cell SD of 15, we will need 40 cases in each group

(120 in total) to achieve a power of 80 % at a significance level of 5%. The analysis of

variance is non-directional (i.e. two-tailed) which means that a difference in either direction

7

7

will be interpreted. Assuming a maximum drop-out of 25 % we would need an additional 18

subjects in each group, i.e. n = 58. Assuming a mean group difference in SF36 score of 10, 10

and 0 for theCFS/ME, CWP and Health controls respectively, would increase the power to

90%. Statistical analyses: Ancova and mixed random effects regression will be used to

compare the physical function/quality of life (SF36) scores across the three groups. The three

groups will be compared at one time-point with a cross-sectional comparative design. Results

will be presented as least-squares means with standard errors (SEs). Differences between the

groups will be reported with 95% confidence intervals (CIs).

4. Perspectives and strategic focus:

4.1 Strategic foundation:

The project is important to gain more knowledge about both fibromyalgia (CWP) and CFS /

ME by looking at similarities and differences between them. It will be relevant according to

the strategic plans, because it is patient related, with impact on clinical practice within a small

research field (mental and psychosomatic health). It is positively translational,

multidisciplinary research to a certain degree, and the projct will also use data from HUNT

for comparisons. In addition, this is a joint project with the expertise regionally, nationally

and internationally.

4.2 Scientific importance and societal relevance

The study is aimed to identify the variables that differentiate individuals with CWP or

CFS/ME from those who meet criteria for both disorders. This may identify vulnerability

factors, e.g. physiologic, and psychosocial variables, that predict the onset of CWP and

CFS/ME, and links to other similar syndromes like irritable bowel syndrome (IBS),

temporomandibular joint disorder (TMJD), vulvodynia, pain bladder syndrome etc., which

also are called “functional somatic syndromes” (10). In addition, the study prove the potential

predictors and prognostic factors for disease and function, and lead to better information to

patients, with advice on prophylaxis and other procedures in addition to treatment. One aim is

also to examine the influence of environmental and psychosocial variables on behavioral and

physiologic responses to noxious stimulation in CWP and CFS (e.g., effects of stress on pain

and immune system function).

4.3 Ethical aspects

8

8

Recruitment procedures are equal, patients are well informed and have the opportunity to ask

questions before signing the written consent.

4.4 Feasibility

Regarding the feasibility of the project in general, we o01.01.2011 start to include all

fibromyalgia patients (CWP) and CFS / ME patients in a consecutive self-developed online

questionnaire and registration system, approved by the Regional ethical committee. This

system is already piloted by NKSL so we know that the logistics will work. The accsess of

these patient groups are very good and they will all meet at NKSLs outpatient clinic.

5. Dissemination of information to users:

The project will, in addition to publishing articles in scientific articles in international

journals, also aim to write informative articles in Norwegian journals.

The intention is that the project will generate at least 4 articles, but he potential is much

greater.

Articles:

[Paper 1): Quality of life in chronic fatigue syndrome (CFS/ME) and chronic

widespread pain: A comparative study].

Primary outcomes: Physical and mental functioning (SF-36). . Predictors: Demographics, >

physical fitness (VO2max) anxiety and depression (HADS), tension/flexibility (GFM-52) and

number of health complaints > (SHC). CFS/ME will be scored by Fukuda criterias and CWP

by > Wolfe et al . definition.

Paper 2: [Fatigue and pain in CFS/ME and CWP. Do they have different profiles?]

Outcomes: Chalder Fatigue Scale, pain (BPI) + tenderpoints. Predictors: Demographics,

psychometrics (HADS), tension/flexibility (GCWP-52) and physical fitness (VO2max)

Paper 3 : [Anxiety and depression in CFS/ME and CWP. Do they have different

profiles?] Outcomes: Anxiety and depression (HADS). Predictors: Demographics,

psychometrics, tension/flexibility (GCWP-52) and physical fitness (VO2max)

9

9

Paper 4 : [Does neuopsychological functioning differ in CFS/ME and CWP?] Outcomes:

Neuropsychology. Predictors: Chalder Fatigue Scale, pain (BPI and tender ponts) and mood

(HADS).

Paper 5: [Does physical capacity, muscle tension and flexibility differ in CFS/ME and

fchronic widespread pain?] Outcomes: Indirect VO2 max (Åstrands test), GCWP-52.

Predictors: Chalder Fatigue Scale, pain (BPI and tender ponts) and mood (HADS).

6. Project group and supervisors:

All patients are enrolled in the study from the clinical practise at the Department of pain and

complex disorders at St.Olavs Hospital. This hospital department is directly linked with a

group of researchers at the National competency center for complex disorders, at Institute of

Sirculation and Imaging, NTNU. This involves a group of competent researchers involved in

both national and international research. The project group also involves researchers from

other national and international institutes. The interdisciplinary team consists of associate

professor Egil A Fors, psychiatrist and specialist in general medicine, professor in psychology

Tore Stiles, professor Nils Inge Landrø (neuropsychologist),, , department of Psychology,

University of Oslo, Norway who along with professor Petter C Borchgrevink , a professor of

anesthesiology and pain management, will safeguard guide the clinical research. Consultative

group . professor Dan Clauw, Director of the Chronic Pain and Fatigue Research Center,

University of Michigan Medical Center, Ann Arbor, Michigan, USA, and specialist in

anesthesia, rheumatologu and psychiatry; professor; Pål Romundstad, (statistician), DMF /

ISM / NTNU.

References 45) Abbi B, Natelson BH Is chronic fatigue syndrome the same illness as fibromyalgia: evaluating the 'single syndrome' hypothesis. QJM. 2013 Jan;106(1):3-9. doi: 10.1093/qjmed/hcs156. Epub 2012 Aug 26. 28) Anisman H, Merali Z, Poulter MO, Hayley S. Cytokines as a precipitant of depressive illness: animal and human studies. Curr Pharm Des. 2005;11(8):963-72. 21) Aaron LA, Burke MM, Buchwald D. Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Arch Intern Med. 2000 Jan 24;160(2):221-7.

10

10

24) Birtane M, Uzunca K, Taştekin N, Tuna H. The evaluation of quality of life in fibromyalgia syndrome: a comparison with rheumatoid arthritis by using SF-36 Health Survey. Clin Rheumatol. 2007 May;26(5):679-84. 14) Branco JC. State-of-the-art on fibromyalgia mechanism. Acta Reumatol Port. 2010 Jan-Mar;35(1):10-5. 15) Bradley LA, McKendree-Smith NL. Central nervous system mechanisms of pain in fibromyalgia and other musculoskeletal disorders: behavioral and psychologic treatment approaches. Curr Opin Rheumatol. 2002 Jan;14(1):45-51. 4) Bruusgaard D, Natvig B. Unclear conditions--common mechanisms? Tidsskr Nor Laegeforen. 2009 Aug 13;129(15):1481-3. 25) Buchwald D. Fibromyalgia and chronic fatigue syndrome: similarities and differences. Rheum Dis Clin North Am. 1996 May;22(2):219-43. 6) Croft P, Blyth FM, van der Windt D. Chronic Pain Epidemiology. From Aetiology to Public Health. Oxford New York: Oxford University Press, 2010. 17) Clauw DJ, Chrousos GP. Chronic pain and fatigue syndromes: overlapping clinical and neuroendocrine features and potential pathogenic mechanisms. Neuroimmunomodulation. 1997 May-Jun;4(3):134-53. 19) Clauw DJ. Perspectives on fatigue from the study of chronic fatigue syndrome and related conditions. PMR. 2010 May;2(5):414-30. 50) Clauw DJ, Crofford LJ. Chronic widespread pain and fibromyalgia: what we know, and what we need to know. Best practice & research Clinical rheumatology 2003;17(4):685-701. 10) Clauw DJ. Fibromyalgia: Update on mechanisms and management. The ACR criteria for fibromyalgia: The good and the bad. J Clin Rheumatol 2007;13:102–9. 36) Cleare AJ, Messa C, Rabiner EA, Grasby PM.Brain 5-HT1A receptor binding in chronic fatigue syndrome measured using positron emission tomography and [11C]WAY-100635. Biol Psychiatry. 2005 Feb 1;57(3):239-46. 44) Cockshell SJ, Mathias JL. Cognitive functioning in chronic fatigue syndrome: a meta-analysis. Psychol Med. 2010 Jan; 5:1-15. 11) Dinos S, Khoshaba B, Ashby D, White PD, Nazroo J, Wessely S, Bhui KS. A systematic review of chronic fatigue, its syndromes and ethnicity: prevalence, severity, co-morbidity and coping. Int J Epidemiol. 2009 Dec;38(6):1554-70. 18) Dinos S, Khoshaba B, Ashby D, White PD, Nazroo J, Wessely S, Bhui KS. A systematic review of chronic fatigue, its syndromes and ethnicity: prevalence, severity, co-morbidity and coping. Int J Epidemiol. 2009 Dec;38(6):1554-70

11

11

32) Gür A, Karakoc M, Erdogan S, Nas K, Cevik R, Sarac AJ. Cytokines and depression in cases with fibromyalgia. J Rheumatol 2002;29:358-61 12. Fukuda K, Strauss SE, Hickie I et al. The chronic fatigue syndrome, a comprehensive approach to its definition and study. Ann Intern Med 1994;121:953-9. 1) Fukuda K, Strauss SE, Hickie I et al. The chronic fatigue syndrome, a comprehensive approach to its definition and study. Ann Intern Med 1994;121:953-9. 35) Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PP. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev. 1994 Jun;46(2):157-203. 9) Jason LA, Corradi K, Torres-Harding S et al. Chronic fatigue syndrome: the need for subtypes. Neuropsychol Rev 2005;15: 29–58; 20) Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huang CF, Plioplys S. A community-based study of chronic fatigue syndrome. Arch Intern Med. 1999 Oct 11;159(18):2129-37. 42) Katafuchi T, Kondo T, Take S, Yoshimura M. Brain cytokines and the 5-HT system during poly I:C-induced fatigue. Ann N Y Acad Sci. 2006 Nov;1088:230-7. 51) Landrø NI, Fors EA, Våpenstad LL, Holthe O, Stiles TC, Borchgrevink PC. The extent of neurocognitive dysfunction in a multidisciplinary pain centre population. Is there a relation between reported and tested neuropsychological functioning? Pain. 2013 Jul;154(7):972-7. doi: 10.1016/j.pain.2013.01.013. Epub 2013 Feb 8. 37) Lesch KP, Balling U, Gross J, Strauss K, Wolozin BL, Murphy DL, Riederer P. Organization of the human serotonin transporter gene. J Neural Transm Gen Sect. 1994;95(2):157-62 47) Lindell L, Bergman S, Petersson IF, Jacobsson LT, Herrstrom P. Prevalence of fibromyalgia and chronic widespread pain. Scand J Prim Health Care 2000;18(3):149-153. 40) Lonsdorf TB, Rück C, Bergström J, Andersson G, Ohman A, Schalling M, Lindefors N. The symptomatic profile of panic disorder is shaped by the 5-HTTLPR polymorphism. Prog Neuropsychopharmacol Biol Psychiatry. 2009 Nov 13;33(8):1479-83. 3) Malterud, Nr. 11 – 30. april 2002, Tidsskr Nor Lægeforen 2002;122:1092. 48) McBeth J, Nicholl BI, Cordingley L, Davies KA, Macfarlane GJ. Chronic widespread pain predicts physical inactivity: results from the prospective EPIFUND study. European journal of pain (London, England) 2010;14(9):972-979. 39) Menza MA, Palermo B, DiPaola R, Sage JI, Ricketts MH. Depression and anxiety in Parkinson's disease: possible effect of genetic variation in the serotonin transporter. J Geriatr Psychiatry Neurol. 1999 Summer;12(2):49-52 26) Millan MJ. The induction of pain: an integrative review. Prog Neurobiol 1999;57:1-164.

12

12

41) Mössner R, Henneberg A, Schmitt A, Syagailo YV, Grässle M, Hennig T, Simantov R, Gerlach M, Riederer P, Lesch KP. Allelic variation of serotonin transporter expression is associated with depression in Parkinson's disease. Mol Psychiatry. 2001 May;6(3):350-2. 38) Narita M, Nishigami N, Narita N, Yamaguti K, Okado N, Watanabe Y, Kuratsune H. Association between serotonin transporter gene polymorphism and chronic fatigue syndrome. Biochem Biophys Res Commun. 2003 Nov 14;311(2):264-6. 23) Rakib A, White PD, Pinching AJ, Hedge B, Newbery N, Fakhoury WK, Priebe S. Subjective quality of life in patients with chronic fatigue syndrome. Qual Life Res. 2005 Feb;14(1):11-9 27) Russell IJ, Vaeroy H, Javors M, Nyberg F. Cerebrospinal fluid biogenic amine metabolites in fibromyalgia/fibrositis syndrome and rheumatoid arthritis. Arthritis Rheum 1992;35:550-6. 7) Showalter E. Hystories: Hysterical Epidemics and Modern Culture. New York: Columbia Univ Pr; 1997 22) Schweitzer R, Kelly B, Foran A, Terry D, Whitting J. Quality of life in chronic fatigue syndrome. Social Sci Med 1995; 41: 1367–1372; Anderson JS, Ferrans CE. The quality of life of persons with chronic fatigue syndrome. JNMD 1997;185(6): 359 – 367. 43) Sundsvold, MØ: (Norwegian): Global Fysioterapeutisk Muskelundersøkelse. Til bruk I klinisk arbeid og forskning. (Manual). 1997. Utgitt av forfatter. 49) Thomas E, Peat G, Harris L, Wilkie R, Croft PR. The prevalence of pain and pain interference in a general population of older adults: cross-sectional findings from the North Staffordshire Osteoarthritis Project (NorStOP). Pain 2004;110(1-2):361-368. 6) Van Houdenhove B, Kempke S, Luyten P. Psychiatric aspects of chronic fatigue syndrome and fibromyalgia. Curr Psychiatry Rep. 2010 Jun;12(3):208-14. 29) Vgontzas AN, Zoumakis M, Papanicolaou DA, Bixler EO, Prolo P, Lin HM, Vela-Bueno A, Kales A, Chrousos GP. Chronic insomnia is associated with a shift of interleukin-6 and tumor necrosis factor secretion from nighttime to daytime. Metabolism. 2002 Jul;51(7):887-92. 30) Wallace DJ, Margolin K, Waller P. Fibromyalgia and interleukin-2 therapy for malignancy. Ann Intern Med 1988;108:909 31) Wallace DJ. Is there a role for cytokine based therapies in fibromyalgia? Curr Pharm Des 2006;12:17-22 46) Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 1990;33(2):160-172.

13

13

5) Wessley, S, White, PD. There is only one functional somatic syndrome. Debate. British Journal of Psychiatry 2004;185: 95-96. 2) Wolfe F. Fibromyalgia. Rheum Dis Clin North Am.1990 Aug;16(3):681-98. 13. Wolfe F. Fibromyalgia. Rheum Dis Clin North Am.1990 Aug;16(3):681-98 34) Yamamoto S, Ouchi Y, Onoe H, Yoshikawa E, Tsukada H, Takahashi H, Iwase M, Yamaguti K, Kuratsune H, Watanabe YReduction of serotonin transporters of patients with chronic fatigue syndrome. Neuroreport. 2004 Dec 3;15(17):2571-4. 8) Yunus, MB. Central sensitivity syndromes: a new paradigm and group nosology for fibromyalgia and overlapping conditions, and the related issue of disease versus illness, Semin Arthritis Rheum 2008;, 37:339–352. 33) Üceyler N, Valenza R, Stock M, Schedel R, Sprotte G, Sommer C. Reduced levels of anti-inflammatory cytokines in patients with chronic widespread pain. Arthritis Rheum 2006;54:2656-64