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EULAR evidence based recommendations for the
management of fibromyalgia syndrome
S F Carville, S Arendt-Nielsen, H Bliddal, F Blotman, J C Branco, D Buskilla, J AP DaSilva, B Danneskiold-Samsøe, F Dincer, C Henriksson, K Henriksson, K Kosek, K Longley, G M McCarthy, S Perrot, M J Puszczewicz, P Sarzi-Puttini, A Silman, MSpäth and E H Choy Ann Rheum Disdoi:10.1136/ard.2007.071522 Updated information and services can be found at: Rapid responses
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EULAR evidence based recommendations for the
management of fibromyalgia syndrome
S. F. Carville1, L. Arendt-Nielsen2, H. Bliddal3, F. Blotman4, J. C. Branco5, D. Buskila6, J. A. P. Da Silva7, B. Danneskiold-Samsøe3, F. Dincer8, C. Henriksson9, K. G. Henriksson10, E. Kosek11, K. Longley12, G. M. McCarthy13, S. Perrot14, M. Puszczewicz15, P. Sarzi-Puttini16, A. Silman17, M. Späth18, E. H. Choy1 Corresponding address: Dr Serena Carville, 1Sir Alfred Baring Garrod Clinical Trials Unit, Academic Rheumatology Unit, King's College London, Weston Education Centre, Cutcombe Road, London, SE5 9RJ, United Kingdom., email: serena.carville@kcl.ac.uk 2 Aalborg University, Center for Sensory-Motor Interaction, Department of Health Sciences and Technology, Denmark. 3The Parker Institute, Frederiksberg Hospital, Copenhagen, Denmark. 4Rheumatology Department, Hospital Lapyeronie, Montpellier, France. 5Serviço de Reumatologia, Hospital Egas Moniz, Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal. 6Department of Medicine, Soroka Medical Center, Beer Sheva, Israel. 7Reumatologia, Hopitais Da Universidade, Coimbra, Portugal. 8Department of Physical and Rehabilitation Medicine, Hacettepe Medical School, Ankara, Turkey. 9INR, Section of Occupational Therapy, Faculty of health sciences, Linköping University, S-581 85 Linköping, Sweden 10Neuromuscular Unit, University Hospital, Linkoping. 11Department of Clinical Neuroscience, Karolinska Institute, Stockholm, and Stockholm Spine Center, Löwenströmska Hospital, Upplans Väsby, Sweden. 12Bath, United Kingdom. 13Rheumatology, Mater Misericordiae University Hospital, Dublin, Ireland. 14Pain Clinic, Hospital Cochin, Paris, France. 15Department of Rheumatology, Rehabilitation and Internal Medicine University of Medical Sciences, Poznan, Poland 16Rheumatology Unit, L. Sacco University Hospital, Milan, Italy, 17Faculty of Medical and Human Sciences ARC Epidemiology Unit, The University of Manchester, Manchester, United Kingdom, 18Bahnhofstr. 95 82166 Graefelfing, Germany The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd to permit this article (if accepted) to be published in ARD and any other BMJPGL products and sublicences such use and exploit all subsidiary rights, as set out in our licence (http://ARD.bmjjournals.com/ifora/licence.pdf)." Keywords: EULAR, fibromyalgia, management, systematic review Word count: 3012 Copyright Article author (or their employer) 2007. Produced by BMJ Publishing Group Ltd (& EULAR) under licence.
ABSTRACT

Objective: To develop evidence based recommendations for the management of
fibromyalgia syndrome (FMS).
Methods: A multidisciplinary task force was formed representing eleven European
Countries. The design of the study including search strategy, participants,
interventions, outcome measures, data collection and analytical method was defined at
the outset. A systematic review was undertaken with the keywords ‘fibromyalgia’,
‘treatment or management’ and ‘trial’. Studies were excluded if they did not utilise
the ACR classification criteria, were not clinical trials, or included patients with
chronic fatigue syndrome or myalgic encephalomyelitis. Primary outcome measures
were change in pain assessed by visual analogue scale (VAS) and fibromyalgia
impact questionnaire (FIQ). The quality of the studies was categorised based on
randomisation, blinding and allocation concealment. Only the highest quality studies
were used to base recommendations on. When there was insufficient evidence from
the literature, a Delphi process was used to provide basis for recommendation.
Results: One hundred and forty six studies were eligible for the review. Thirty nine
pharmacologic intervention studies and 59 non-pharmacologic were included in the
final recommendation summary tables once those of a lower quality or with
insufficient data were separated. The categories of treatment identified were
antidepressants, analgesics, and ‘other pharmacological’ and exercise, cognitive
behavioural therapy, education, dietary interventions and ‘other non-
pharmacological’. In many studies sample size was small and the quality of the study
was insufficient for strong recommendations to be made.
Conclusion: Nine recommendations for the management of FMS were developed
using a systematic review and expert consensus.
INTRODUCTION

Fibromyalgia syndrome (FMS) is a common rheumatologic condition characterised
by chronic widespread pain and reduced pain threshold, with hyperalgesia and
allodynia. Associated features include fatigue, depression, anxiety, sleep disturbance,
headache, migraine, variable bowel habits, diffuse abdominal pain and urinary
frequency [1][2]. Although the precise pathogenesis remains unknown, peripheral
and central hyperexcitability at spinal or brainstem level [3][4][5], altered pain
perception [6] and somatisation [7][8] have been hypothesised and demonstrated in
some patients.
The American College of Rheumatology (ACR) classification criteria for FMS [9] are
the most commonly used in clinical and therapeutic research. The healthcare
utilisation by patients with FMS is high averaging over $2000 per patient per year
[10], but it has been shown that positive diagnosis and management can reduce
healthcare utilisation [11].
Although effective treatments are available [12][13][14] no guidelines exist for
management of FMS. The objectives were to ascertain the strength of the research
evidence on effectiveness of treatment of FMS and develop recommendations for its
management based on the best available evidence and expert opinion to inform
healthcare professionals.
Participants
A multidisciplinary taskforce was formed consisting of 19 experts in FMS representing eleven European Countries. Search strategy
A systematic search of Medline, PubMed, EmBASE, PsycINFO, CINAHL, Web of
Sciences, Science Citation Indices, Cochrane Central Register of Controlled Trials
and Cochrane Database of Systematic Reviews using the key words: “fibromyalgia”,
“treatment or management” and “trial” for all publications till the end of December
2005 was carried out. A manual search of the bibliographies of trials was undertaken
to verify that all published trials were identified.
Inclusion criteria
Included studies had to be clinical trials using the American College of Rheumatology
1990 classification criteria for FMS [9] to select patients. Studies including patients
with Chronic Fatigue Syndrome or Myalgic Encephalomyelitis, were excluded unless
they were divided into separate comparator groups for analysis.
Assessment of literature
A ‘checklist’ method [15] was used to assess quality of each study. Data was tabulated using a customised data-extraction form. This included number of patients in each arm, randomisation and blinding status. Previous reviews have identified two main outcome measures: pain assessed by visual analogue scale (VAS) and function assessed by the Fibromyalgia Impact Questionnaire (FIQ) [16][17]. The main measure of effect was the between group difference calculated from the mean change between the pre- and post- treatment values in these outcome measures. Where possible, effect size for the ‘best’ treatments in each category was calculated (averaged if there was more than one trial). Rosnow and Rosenthal’s modified version of the Cohen’s d calculation was used [18]. The thresholds used for interpretation were: values >0.2 = small, >0.5 = medium and >0.8 = large. The number needed to harm (NNH) was also calculated if possible, using withdrawal due to adverse event as the event. Additional information included; recruitment population; duration of disease, treatment and assessment; number of tender points; and myalgic score. Other outcome measures considered were also tabulated. If required data were recorded, but not presented, or not presented in a suitable format, the author was contacted wherever possible. If data was only provided in graphical format, this was extracted where possible. Data extraction was verified by a second committee member to ensure accuracy. Any discrepancies were re-evaluated. Categorising evidence Due to the large variability in outcome measures and assessments data could not be pooled to perform a formal meta-analysis. Therefore studies were classified according to their randomisation and blinding level. The highest quality study (randomized controlled trial) for each treatment class was used as a basis for the recommendations. The ranking was graded as (with 1 being highest): Randomised controlled double-blind trials Randomised open trials / Non-randomised single blind Evidence for each recommendation was categorised according to study design and strength of each recommendation was classified according to the criteria previously published [19]. The recommendations were discussed at a final committee meeting and via email for a consensus to be reached. Delphi exercise was used to base recommendations on when limited evidence was found by systematic review. Agreement on the included recommendations was unanimous. Publication Bias Analysis
Abstracts published between 2002 and 2005 inclusive in Annals of Rheumatic Disease, Pain, Arthritis & Rheumatism and Journal of Musculoskeletal Pain were reviewed to guard against non-inclusion of any negative studies that had not been fully published. If available, data was extracted. Any contradictory data would be included when forming the recommendations. Future research plan
The committee proposed that these recommendations should be reviewed and updated in 4 years time, to see if a) quality of trials and reporting in FMS had improved and b) if there was new evidence to suggest recommendation of new treatments, or to alter the recommendations of treatments already included.
Research evidence identified
In the preliminary search, 508 studies were identified. Table 1 demonstrates how these were shortlisted. rejected
180
Eligible clinical trials
Non-English language – translations not Table 1. Study breakdown from initial literature search. The 146 eligible clinical trials included 59 pharmacological and 87 non-pharmacological (including multidisciplinary). Studies were further subdivided into treatment interventions and the highest quality studies from each intervention were selected to be the basis for recommendations, (table 2). Quality of
Reasons for
Intervention
Total no.
included
excluding
included
Analgesics
Antidepressants
Exercise
Education / CBT
Table 2. Breakdown of the short listed studies to base recommendations on, and those eliminated from further analysis. Sensitivity Analysis
Effect size and NNH for the interventions recommended were calculated where possible (table 3). Pharmacological
Intervention
Effect size (95% confidence interval)
Pain Function
1.033 (-0.393,
Amitriptyline
Dual re-uptake
Tramadol
Tropisetron
Pramipexole
Non-pharmacological
Pool based
Exercise
Balneotherapy
Aerobic Exercise
Strength training
Table 3. Effect size calculated using modified Cohen’s d method for recommended treatments where data available. EULAR Recommendations

From these tables the following recommendations were made (table 4).
Full understanding of fibromyalgia requires comprehensive assessment of pain, function, and psychosocial context. Fibromyalgia should be recognised as a complex and heterogeneous condition where there is abnormal pain processing and other secondary features. Optimal treatment requires a multidisciplinary approach with a combination of non-pharmacological and pharmacological treatment modalities tailored according to pain intensity, function, associated features such as
depression, fatigue and sleep disturbance in discussion
with the patient.
Non-Pharmacological Management
Heated pool treatment with or without exercise is effective in fibromyalgia. Individually tailored exercise programmes including aerobic exercise and strength training can be beneficial to some patients with fibromyalgia. Cognitive behavioural therapy may be of benefit to some patients with fibromyalgia. Other therapies such as relaxation, rehabilitation, physiotherapy and psychological support may be used depending on the needs of the individual patient.
Pharmacological Management
Tramadol is recommended for the management of pain in Simple analgesics such as paracetamol and other weak opioids can also be considered in the treatment of fibromyalgia. Corticosteroids and strong opioids are not recommended. Antidepressants: amitriptyline, fluoxetine, duloxetine, milnacipran, moclobemide and pirlindole, reduce pain and often improve function, therefore they are recommended for the treatment of fibromyalgia. Tropisetron, pramipexole and pregabalin reduce pain and are recommended for the treatment of fibromyalgia. Table 4. EULAR Recommendations for the management of fibromyalgia.
Assessment of Recommendations

There was no weighting in terms of order of the recommendations. √ denotes
recommendation derived from expert opinion.
√ Full understanding of fibromyalgia requires comprehensive assessment of pain,
function, and psychosocial context. Fibromyalgia should be recognised as a
complex and heterogeneous condition where there is abnormal pain processing and
other secondary features.

This is based on expert opinion. It is important to recognise that FMS is a
heterogenous condition comprising a range of symptoms and features, effective
management must take all of these factors into account. The nociceptive system also
has connections with the stress regulating, immune, and the sleep system in the limbic
brain. It is these links that probably lead to the ‘syndrome’ incorporating numerous
symptoms and features.
√ Optimal treatment requires a multidisciplinary approach with a combination of
non-pharmacological and pharmacological treatment modalities tailored according
to pain intensity, function, associated features such as depression, fatigue and sleep
disturbance in discussion with the patient.

This is a logical progression from the first recommendation. It represents general
practice, but is based solely on expert opinion. As FMS is polysymptomatic, lacking
one treatment that acts on all symptoms, a multidisciplinary approach tailored to the
needs of the individual is often required. This may need to include self-management
via patient education [47][48] [49]. Only two multidisciplinary trials were short-
listed in the summary tables for further analysis [50][51]. Other reviews have
supported the use of multidisciplinary treatment [47][48], but highlighted the lack of
high quality trials in this area [48] [52].
Heated pool treatment with or without exercise is effective in fibromyalgia.

Heated pool treatment or balneotherapy was reported to be effective in improving
pain and function. Three of 5 trials included exercise in the intervention [34][35] [38]
(two positive for function and two for pain). Of those without exercise, two were
positive for pain and function [34] [36]. In the third trial only the heated pool
treatment group improved in pain, but no comparison was made to the control.
Function was not assessed [37]. Drop out for adverse events was very low. Sample
sizes ranged from medium to large. Three of the studies restricted the use of
medications, (not stated in the remaining two). The fairly high quality of this small
number of studies with positive results has lead to this recommendation and there is
agreement with previous reviews [47][48].
√ Individually tailored exercise programmes including aerobic exercise and
strength training can be beneficial to some patients with fibromyalgia.

This is based largely on expert opinion with a combination of some experimental
evidence and previous reports.

For aerobic exercise the majority of trials were open (7/11). The best quality were a
randomized, assessor blind 12 week study by Richards et al. 2002, with large sample
size [53], and a smaller randomised single blind study by Valim et al 2003 [42].
Valim et al. reported an improvement in VAS pain and FIQ compared to control.
Richards et al. did not report significant between group improvements in either of our
chosen outcome measures although the FIQ score did improve more in the treatment
group, and significant between group improvements were seen at 12 months follow-
up. All three strength training studies were randomised but only one single blind.
This had no significant between group differences in pain or function, although both
improved in the exercise group only [44].
In general the quality of studies among exercise trials was considerably variable.
Blinding and/or control was frequently inadequate. Those that did show some
differences in favour of exercise used usual activity and care for their controls [40]
[41] (with the exception of Valim et al. who had a stretching control group [42]). The
majority of exercise studies asked for participants not to change their medication
intake whilst on the trial (9),
Although evidence in the literature was poor, the committee felt that given the safety
and benefit of exercise to general health exercise should be included as a
recommendation. The poor quality of the trials and our predetermined outcome
measures were likely precluding positive outcomes from being shown. In previous
reviews, exercise has been recommended [12] [16][17] [47][48] with aerobic exercise
gaining the most support. It is likely that different forms of exercise would suit
different subgroups of patients, hence these programmes should be tailored to the
individual.
√ Cognitive behavioural therapy may be of benefit to some patients with
fibromyalgia.

This is based on expert opinion. The only two studies identified for our review with
pure cognitive behavioural therapy (CBT) were of poor quality; neither had a control
group, both allowed patients to remain on their usual medication and only one used
either of our predetermined outcome measures.
This is another area in which the poor quality of trials has masked what experts
believe to be a realistic reflection of possible benefits. Whilst previous review work
has also been hampered by the inadequacy of research in this field, strong evidence
has been reported for CBT with positive results for pain & function [47].
√ Other therapies such as relaxation, rehabilitation, physiotherapy and
psychological support may be used depending on the needs of the individual patient.

This is based on expert opinion and some experimental evidence. Two studies of
moderate quality were identified for physiotherapy. An open study [54] for
connective tissue massage which had larger subject numbers (25 control and 23
treated) and lasted 10 weeks, reported improvement in both pain and function
compared to control. Other relaxation and rehabilitation techniques are recommended
due to expert opinion. Clinical trial evidence is lacking in these areas although
reviews report some benefits [47].
Tramadol is recommended for the management of pain in fibromyalgia.
Simple analgesics such as paracetamol and other weak opioids can also be
considered in the treatment of fibromyalgia. Corticosteroids and strong opioids are
not recommended.
Regarding tramadol, two randomised controlled trials were identified as eligible for
the review [30][31]. One was a high quality study of large sample size and 13 weeks
duration [31]. The second was preceded by an open label study and only included
responders [30]. Bennett et al. reported positive effects for pain and function, and
Russell et al. reported improved pain levels but no change in function. There was no
difference between placebo and treated group for adverse event withdrawals (high but
non-serious). Bennett et al. restricted concomitant medications, but Russell et al.
disallowed sedative hypnotics only. Tramadol should be used with some caution due
to the possibility of typical opiate withdrawal symptoms with discontinuation and the
risk of abuse and dependence [55].
The recommendation for simple analgesics and other weak opioids is based mainly on
expert opinion due to insufficient data [56].
The negative recommendation for use of strong opioids and corticosteroids is based
on expert opinion. These medications have significant long-term side effects and no
clinical trials were identified in FMS. Previous reviews support our recommendation
[47] [57].

Antidepressants: amitriptyline, fluoxetine, duloxetine, milnacipran, moclobemide
and pirlindole, reduce pain and often improve function therefore they should be
considered for the treatment of fibromyalgia.

Four out of 5 trials of amitriptyline that assessed VAS pain had positive outcomes.
Only two used the FIQ, one positive. However, it is important to note, that as
highlighted in previous reviews [14], the only trial that lasted longer than 12 weeks
did not show a significant improvement in pain compared to control [58]. Two trials
assessing fluoxetine reported positive outcomes for both pain and function [22] [28].
These trials were of moderate to high quality, reasonable samples sizes and 6 and 12
weeks duration. Duloxetine improved function in two trials and pain in one [25] [27].
The milnacipran trial reported an improvement in pain [26]. These were all large,
high quality trials of 12 weeks duration. Moclobemid and pirlindole were assessed in
one trial each, both of high quality and with improvements in pain [21] [23]. FIQ was
not assessed in either trial. For all the trials withdrawals due to adverse events were
generally low and non-serious.
In general these trials excluded other medications prescribed for FMS, with the
exception of paracetamol. The only exception was the Arnold et al. 2002 trial which
also allowed NSAIDs [28]. Previous reviews have agreed with the recommendation
of antidepressants with the strongest evidence for amitriptyline (or tricyclic
antidepressants) [12] [14] [47] [57].
Tropisetron, pramipexole and pregabalin reduce pain and should be considered for
the treatment of fibromyalgia.

Two tropisetron clinical trials were eligible. One had positive results for pain at a
dose of 5mg [59]. Späth et al. 2004 did not report significantly positive results, but
sample size was small and there was a positive trend in the treated group [32]. FIQ
was only assessed in the trial by Späth et al. 2004 with negative results therefore no
firm comment can be made on this outcome measure. Fäber et al. 2000 made no
comment on whether concomitant medications had been controlled, but Späth et al.
disallowed antidepressants, tranquilizers and sedatives. This treatment appears well
tolerated. These were short term studies, so further research into longer term effects
is required.
One trial for pramipexole was positive for both pain and function [33]. Frequency of
mild/moderate adverse events was high and this trial did not restrict concomitant
medications, although dosages were kept stable. A monotherapy trial is required for
more conclusive assessment of effect.
One trial reported pregabalin 450mg reduced pain, but FIQ was not assessed [60].
Dropouts due to adverse events were largely classed mild to moderate in severity. All
medications for pain and sleep disorders were restricted, with the exception of
paracetamol.
These are recent studies and suggest further research into the use of these promising
medications for FMS. Previous reviews have also mentioned their potential benefit
[47] [57] (neither include the pramipexole study as this was not published).
DISCUSSION These EULAR recommendations are based on expert opinion and changes in pain assessed by VAS and function assessed by the FIQ in clinical trials. Positive effects in other outcome measures were not considered, neither were pain or function if assessed by different instruments. Consequently some studies were excluded from our review due to not using these outcome measures, or not presenting the data. Although other instruments might be more sensitive in FMS it was decided that setting a standard for outcome measures was vital so that comparisons could be made fairly between trials and therefore using those most frequently reported allowed better analysis [47] [61] Previous reviews have used different inclusion/exclusion criteria and/or assessed more or different outcome measures producing different evidence e.g. [16] [47][48]. The high variability in outcome measures used, reporting of results, as well as the inadequacy of methodological quality were barriers to conducting meta-analysis [12] [14] [16][17] [57] [62]. This led to difficulties in producing strict evidence based recommendations. In some areas evidence is lacking due to the poor quality of the studies, where expert opinion suggests otherwise, e.g.exercise. Outcome measures may be decided according to desired treatment effect. Non-pharmacological interventions have previously been suggested to have a significantly better effect on function than medications [62], reflected by its wider assessment in these studies. However, if this outcome measure is not frequently assessed in pharmacological trials,results could be biased. Guidance on how to conduct good RCTs in FMS, including standardised outcome measures and validated, sensitive instruments is important for future research. For the treatments that were recommended, effect sizes generally range from medium to high. Although these results give an indication of the efficacy of each treatment, they should be interpreted with some caution as they were only calculated where data was available and could be biased by factors such as whether or not the outcome measure was assessed. We have not collected any information on the cost effectiveness of these treatments. Further analysis of disease duration and baseline values does not reveal any obvious pattern that would affect the outcomes of this review. Review of the abstracts published between 2002 and 2005 revealed no conflicting evidence to that derived from the published articles identified. The assessment of strength of evidence tends to favour pharmacological studies as double blinding and placebo controls are impossible in many non-pharmacological studies. However, most non-pharmacological interventions are safe and have other health benefits. These important factors were taken into account in formulating these recommendations. These recommendations are the first to be commissioned for FMS, although previous reviews have addressed the area [47] [62]. The standard operating procedures published by EULAR [63] were followed. They will be updated every 5 years and it is hoped that good quality clinical trials in this area will add to the evidence currently available. These recommendations should assist health care providers, with a secondary intention to incorporate information into materials for patients. The 9 recommendations included 8 management categories, 3 of which had strong evidence from the current literature, and 3 were based on expert opinion. Acknowledgements / funding
We acknowledge EULAR for their financial support and the ESCISIT steering
committee for their endorsement.
Competing Interests
The following authors have no competing interests to declare: L. Arent-Nielsen, H. Bliddal, S.F. Carville, J. da Silva, B. Danneskiold-Samsøe, F Dincer, K. Longley, G. McCarthy, M. Puszczewicz, P. Sarzi Puttini and A Silman. Declarations: Francis Blotman has been reimbursed by Laboratoires Procter and Gamble, Sanofi-Aventis, Roche and Bristol Meyers Squibb for attending medical conferences and had honorarias for speaking for Laboratoires Pierre Fabre, Servier and Roche. Jaime Branco has been paid by Pierre Fabre and Pfizer for running educational programmes and for speaking at international conferences and reimbursed by Eli Lilly for attending international conferences. Dan Buskila has been reimbursed by Pierre Fabre Company, the manufacturer of Milnacipran, for attending several symposiums and by Pfizer for consulting. Ernest Choy has served on advisory panels of Pierre Fabre Medicament, Jazz Pharmaceutical, Allergan and Pfizer. Ernest Choy has also lectured in meetings organized by Pierre Fabre Medicament, Eli Lilly and Pfizer. The Rheumatology Department received a research grant from Pierre Fabre Medicament. Chris Henriksson has participated in symposia organized by Laboratoires Pierre Fabre and received reimbursement for participation. She has also received fees for written material in proceedings from these symposia. Karl Henriksson has participated in symposia organized by Laboratoires Pierre Fabre and received reimbursement for participation. He has also received fees for written material in proceedings from these symposia. He has held a lecture on pain mechanisms and received a fee from Pfizer. Dr Kosek has participated as a consultant in advisory board meetings (total of 4) for the following pharmaceutical companies; Pfizer, Wyeth and Pierre Fabre. She gave a speech on a satellite symposium organized by Pfizer. She has currently research collaboration with Pierre Fabre. Serge Perrot has been paid by Pfizer, Eli Lilly, Grunenthal, Pierre Fabre and Sanofi Aventis for running educational programmes and participating in advisory boards. Michael Spaeth has served on advisory panels of Pierre Fabre Medicament, Jazz Pharmaceuticals and Allergan. Michael Spaeth has also lectured in meetings organized by Novartis, Pierre Fabre Medicament and Lilly. References
1. Hudson JI, Goldenberg DL, Pope HG, Jr., Keck PE, Jr., Schlesinger L. Comorbidity of fibromyalgia with medical and psychiatric disorders. American 2. Mease P. Fibromyalgia syndrome: review of clinical presentation, pathogenesis, outcome measures, and treatment. Journal of Rheumatology 2005;6-21. 3. Henriksson KG. Fibromyalgia - From syndrome to disease. Overview of pathogenetic mechanisms. Journal of Rehabilitation Medicine, Supplement 4. Desmeules JA, Cedraschi C, Rapiti E, Baumgartner E, Finckh A, Cohen P et al. Neurophysiologic evidence for a central sensitization in patients with fibromyalgia. Arthritis & Rheumatism 2003;1420-1429. 5. Staud R, Cannon RC, Mauderli AP, Robinson ME, Price DD, Vierck Jr CJ. Temporal summation of pain from mechanical stimulation of muscle tissue in normal controls and subjects with fibromyalgia syndrome. Pain 2003;102:87-95. 6. Kosek E, Ekholm J, Hansson P. Sensory dysfunction in fibromyalgia patients with implications for pathogenic mechanisms. Pain 1996;68:375-383. 7. McBeth J, Macfarlane GJ, Benjamin S, Silman AJ. Features of somatization predict the onset of chronic widespread pain: Results of a large population-based study. Arthritis & Rheumatism 2001;44:940-946. 8. Geisser ME, Casey KL, Brucksch CB, Ribbens CM, Appleton BB, Crofford LJ. Perception of noxious and innocuous heat stimulation among healthy women and women with fibromyalgia: Association with mood, somatic focus, and 9. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL et al. The American college of rheumatology 1990 criteria for the classification of fibromyalgia. Arthritis & Rheumatism 1990;33:160-172. 10. Wolfe F, Anderson J, Harkness D, Bennett RM, Caro XJ, Goldenberg DL et al. A prospective, longitudinal, multicentre study of service utilization and costs in fibromyalgia. Arthritis & Rheumatism 1997;40:1560-1570. 11. Hughes G, Martinez C, Myon E, Taieb C, Wessely S. The impact of a diagnosis of fibromyalgia on health care resource use by primary care patients in the UK: An observational study based on clinical practice. Arthritis & Rheumatism 12. Crofford LJ, Appleton BE. The treatment of fibromyalgia: a review of clinical trials. Current Rheumatology Reports 2000;2:101-103. 13. Crofford LJ. Meta-analysis of antidepressants in fibromyalgia. Current 14. Arnold LM, Keck PE, Jr., Welge JA. Antidepressant treatment of fibromyalgia. A meta-analysis and review. Psychosomatics 2000;4:104-113. 15. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. Journal of Epidemiology & Community Health 16. Busch A, Schachter CL, Peloso PM, Bombardier C. Exercise for treating fibromyalgia syndrome. [Systematic Review]. Cochrane Database of Systematic 17. Sim J, Adams N. Systematic review of randomized controlled trials of nonpharmacological interventions for fibromyalgia. Clinical Journal of Pain 18. Rosnow RL, Rosenthal R. Computing contrasts, effect sizes, and counternulls on other people's published data: General procedures for research consumers. 19. Shekelle PG, Woolf SH, Eccles M, Grimshaw J. Clinical guidelines; Developing guidelines. British Medical Journal 1999;318:593-596. 20. Carette S, Oakson G, Guimont C, Steriade M. Sleep electroencephalography and the clinical response to amitriptyline in patients with fibromyalgia. Arthritis & 21. Ginsberg F, Mancaux A, Joos E, Vanhove P, Famaey J-P. A randomized placebo-controlled trial of sustained-release amitriptyline in primary fibromyalgia. Journal of Musculoskeletal Pain 1996;4:37-47. 22. Goldenberg D, Mayskiy M, Mossey C, Ruthazer R, Schmid C. A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis & Rheumatism 1996;39:1852-1859. 23. Hannonen P, Malminiemi K, Yli-Kerttula U, Isomeri R, Roponen P. A randomized, double-blind, placebo-controlled study of moclobemide and amitriptyline in the treatment of fibromyalgia in females without psychiatric disorder. British Journal of Rheumatology 1998;37:1279-1286. 24. Heymann RE, Quaresma M, Helfenstein M, Feldman D. A double-blinded, randomized, controlled study between amitrptyline and placebo in patients with fibromyalgia: Analysis of the outcome measures. Revista Brasileria De Reumatologia 25. Arnold LM, Lu Y, Crofford LJ, Wohlreich M, Detke MJ, Iyengar S et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis & 26. Vitton O, Gendreau M, Gendreau J, Kranzler J, Rao SG. A double-blind placebo-controlled trial of milnacipran in the treatment of fibromyalgia. Human 27. Arnold LM, Rosen A, Pritchett YL, D'Souza DN, Goldstein DJ, Iyengar Set al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. 28. Arnold LM, Hess EV, Hudson JI, Welge JA, Berno SE, Keck PE, Jr. A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia. American Journal of Medicine 2002;112:191- 29. Norregaard J, Volkmann H, Danneskiold-Samsoe B. A randomized controlled trial of citalopram in the treatment of fibromyalgia. Pain 1995;61:445-449. 30. Russell J, Kamin M, Bennett RM, Schnitzer TJ, Green JA, Katz WA. Efficacy of tramadol in treatment of pain in fibromyalgia. JCR: Journal of Clinical 31. Bennett RM, Kamin M, Karim R, Rosenthal N. Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind, randomized, placebo-controlled study. American Journal of Medicine 2003;114:537- 32. Spath M, Stratz T, Neeck G, Kotter I, Hammel B, Amberger CC et al. Efficacy and tolerability of intravenous tropisetron in the treatment of fibromyalgia. Scandinavian Journal of Rheumatology 2004;33:267-270. 33. Holman AJ, Myers RR. A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications. Arthritis & Rheumatism 2005;52:2495-2505. 34. Altan L, Bingol U, Aykac M, Koc Z, Yurtkuran M. Investigation of the effects of pool-based exercise on fibromyalgia syndrome. Rheumatology International 35. Jentoft ES, Kvalvik AG, Mengshoel M. Effects of pool-based and land-based aerobic exercise on women with fibromyalgia/chronic widespread muscle pain. Arthritis & Rheumatism-Arthritis Care & Research 2001;45:42-47. 36. Evcik D, Kizilay B, Gokcen E. The effects of balneotherapy on fibromyalgia patients. Rheumatology International 2002;22:56-59. 37. Yurkuran M, Celiktas M. A randomized, controlled trial of balneotherapy in the treatment of patients with primary fibromyalgia syndrome. Physikalische Medizin Rehabilitationsmedizin Kurortmedizin 1996;6:109-112. 38. Zijlstra TR, van de Laar MAFJ, Bernelot Moens HJ, Taal E, Zakraoui L, Rasker JJ. Spa treatment for primary fibromyalgia syndrome: A combination of thalassotherapy, exercise and patient education improves symptoms and quality of 39. Norregaard J, Lykkegaard JJ, Mehlsen J, Danneskiold-Samsoe B. Exercise training in treatment of fibromyalgia. Journal of Musculoskeletal Pain 1997;5:71-79. 40. Schachter CL, Busch AJ, Peloso PM, Sheppard MS. Effects of short versus long bouts of aerobic exercise in sedentary women with fibromyalgia: a randomized controlled trial. Physical Therapy 2003;83:340-358. 41. Gowans SE, deHueck A, Voss S, Silaj A, Abbey SE, Reynolds WJ. Effect of a randomized, controlled trial of exercise on mood and physical function in individuals with fibromyalgia. Arthritis & Rheumatism 2001;45:519-529. 42. Valim V, Oliveria L, Suda A, Silva L, De Assis M, Neto TB et al. Aerobic fitness effects in fibromyalgia. Journal of Rheumatology 2003;30:1060-1069. 43. Da Costa D, Abrahamowicz M, Lowensteyn I, Bernatsky S, Dritsa M, Fitzcharles M-A et al. A randomized clinical trial of an individualized home-based exercise programme for women with fibromyalgia. Rheumatology 2005;44:1422- 44. Jones KD, Burckhardt CS, Clark SR, Bennett RM, Potempa KM. A randomized controlled trial of muscle strengthening versus flexibility training in fibromyalgia. Journal of Rheumatology 2002;29:1041-1048. 45. Hakkinen A, Hakkinen K, Hannonen P, Alen M. Strength training induced adaptations in neuromuscular function of premenopausal women with fibromyalgia: Comparison with healthy women. Annals of the Rheumatic Diseases 2001;60:21-26. 46. Kingsley JD, Panton LB, Toole T, Sirithienthad P, Mathis R, McMillan V. The effects of a 12-week strength-training program on strength and functionality in women with fibromyalgia. Archives of Physical Medicine & Rehabilitation 47. Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia syndrome. Journal of the American Medical Association 2004;292:2388-2395. 48. Adams N, Sim J. Rehabilitation approaches in fibromyalgia. Disability & 49. Burckhardt CS, Mannerkorpi K, Hedenberg L, Bjelle A. A randomized, controlled clinical trial of education and physical training for women with fibromyalgia. Journal of Rheumatology 1994;21:714-720. 50. Alamo MM, Moral RR, Perula de Torres LA. Evaluation of a patient-centred approach in generalized musculoskeletal chronic pain/fibromyalgia patients in primary care. Patient Education & Counseling 2002;48:23-31. 51. Mason LW, Goolkasian P, McCain GA. Evaluation of multimodal treatment program for fibromyalgia. Journal of Behavioral Medicine 1998;21:163-178. 52. Karjalainen KA, Hurri H, Jauhiainen M, Koes BW, Malmivaara A, Roine R et al. Multidisciplinary rehabilitation for fibromyalgia and musculoskeletal pain in working age adults. [Systematic Review]. Cochrane Database of Systematic Reviews 53. Richards SC, Scott DL. Prescribed exercise in people with fibromyalgia: parallel group randomised controlled trial. British Medical Journal 2002;325:185-188 54. Brattberg G. Connective tissue massage in the treatment of fibromyalgia. European Journal of Pain 1999;3:235-244. 55. Senay EC, Adams EH, Geller A, Inciardi JA, Mur~oz A, Schnoll SH et al. Physical dependence of Ultram (tramadol hydrochloride): Both opioid-like and atypical withdrawal symptoms occurr. Drug & Alcohol Dependence 2003;69:233- 56. McCleane G. Does intravenous lidocaine reduce fibromyalgia pain?: A randomized, double-blind, placebo controlled cross-over study. Pain Clinic 57. Baker K, Barkhuizen A. Pharmacologic treatment of fibromyalgia. Current Pain & Headache Reports 2005;9:301-306. 58. Carette S, Bell MJ, Reynolds WJ, Haraoui B, McCain GA, Bykerk VP et al. Comparison of amitriptyline, cyclobenzaprine, and placebo in the treatment of fibromyalgia. A randomized, double-blind clinical trial. Arthritis Rheum 1994;37:32- 59. Farber L, Stratz T, Bruckle W, Spath M, Pongratz D, Lautenschlager J et al. Efficacy and tolerability of tropisetron in primary fibromyalgia - A highly selective and competitive 5-HT3 receptor antagonist. Scandinavian Journal of Rheumatology - 60. Crofford LJ, Rowbotham MC, Mease PJ, Russell IJ, Dworkin RH, Corbin AE et al. Pregabalin for the treatment of Fibromyalgia syndrome: Results of a randomized, double-blind, placebo-controlled trial. Arthritis & Rheumatism 61. Sim J, Adams N. Therapeutic approaches to fibromyalgia syndrome in the United Kingdom: A survey of occupational therapists and physical therapists. European Journal of Pain 2003;7:173-180. 62. Rossy LA, Buckelew SP, Dorr N, Hagglund KJ, Thayer JF, McIntosh MJ et al. A meta-analysis of fibromyalgia treatment interventions. Annals of Behavioral 63. Dougados M, Betteridge N, Burmester GR, Euller-Ziegler L, Guillemin F, Hirvonen J et al. EULAR standardised operating procedures for the elaboration, evaluation, dissemination, and implementation of recommendations endorsed by the EULAR standing committees. Annals of the rheumatic diseases 2004;63:1172-1176.

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