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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 Buskila, J AP Da Silva, B Danneskiold-Samsøe, F Dincer, C Henriksson, K G Henriksson, E Kosek, K Longley, G M McCarthy, S Perrot, M Puszczewicz, P Sarzi-Puttini, ASilman, M Späth and E H Choy 2008;67;536-541; originally published online 20 Jul 2007; Ann Rheum Disdoi:10.1136/ard.2007.071522 Updated information and services can be found at: References
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Objective: To develop evidence-based recommendations The healthcare utilisation by patients with FMS is for the management of fibromyalgia syndrome.
high averaging over $2000 per patient per year,10 butit has been shown that positive diagnosis and Methods: A multidisciplinary task force was formed representing 11 European countries. The design of the management can reduce healthcare utilisation.11 study, including search strategy, participants, interven- Although effective treatments are available12–14 no tions, outcome measures, data collection and analytical guidelines exist for the management of FMS. The King’s College London, WestonEducation Centre, Cutcombe method, was defined at the outset. A systematic review objectives were to ascertain the strength of the was undertaken with the keywords ‘‘fibromyalgia’’, research evidence on the effectiveness of treatment of ‘‘treatment or management’’ and ‘‘trial’’. Studies were FMS and develop recommendations for its manage- excluded if they did not utilise the American College of ment based on the best available evidence and expert Rheumatology classification criteria, were not clinical opinion to inform healthcare professionals.
trials, or included patients with chronic fatigue syndromeor myalgic encephalomyelitis. Primary outcome measures were change in pain assessed by visual analogue scale and fibromyalgia impact questionnaire. The quality of the A multidisciplinary taskforce was formed consist- studies was categorised based on randomisation, blinding ing of 19 experts in FMS representing 11 European and allocation concealment. Only the highest quality studies were used to base recommendations on. Whenthere was insufficient evidence from the literature, aDelphi process was used to provide basis for recom- A systematic search of Medline, PubMed, EmBASE, Results: 146 studies were eligible for the review. 39 PsycINFO, CINAHL, Web of Sciences, ScienceCitation Indices, Cochrane Central Register of pharmacological intervention studies and 59 non-phar- Controlled Trials and Cochrane Database of macological were included in the final recommendation Systematic Reviews using the keywords: ‘‘fibro- summary tables once those of a lower quality or with myalgia’’, ‘‘treatment or management’’ and ‘‘trial’’ insufficient data were separated. The categories of for all publications till the end of December 2005 treatment identified were antidepressants, analgesics, was carried out. A manual search of the biblio- and ‘‘other pharmacological’’ and exercise, cognitive graphies of trials was undertaken to verify that all behavioural therapy, education, dietary interventions and ‘‘other non-pharmacological’’. In many studies sample sizewas small and the quality of the study was insufficient forstrong recommendations to be made.
Conclusions: Nine recommendations for the manage- Included studies had to be clinical trials using the ment of fibromyalgia syndrome were developed using a ACR 1990 classification criteria for FMS9 to select systematic review and expert consensus.
patients. Studies, including patients with chronicfatigue syndrome or myalgic encephalomyelitis,were excluded unless they were divided into separate comparator groups for analysis.
rheumatological condition characterised by chronicwidespread pain and reduced pain threshold, with hyperalgesia and allodynia. Associated features A ‘‘checklist’’ method15 was used to assess quality of include fatigue, depression, anxiety, sleep distur- each study. Data were tabulated using a customised bance, headache, migraine, variable bowel habits, data extraction form. This included number of diffuse abdominal pain and urinary frequency.1 2 patients in each arm, randomisation and blinding status. Previous reviews have identified two main unknown, peripheral and central hyperexcitability outcome measures: pain assessed by the visual at spinal or brainstem level,3–5 altered pain percep- analogue scale (VAS) and function assessed by the tion6 and somatisation7 8 have been hypothesised fibromyalgia impact questionnaire (FIQ).16 17 The main measure of effect was the between-group The American College of Rheumatology (ACR) difference calculated from the mean change between classification criteria for FMS9 are the most the pre- and post-treatment values in these outcome Ann Rheum Dis 2008;67:536–541. doi:10.1136/ard.2007.071522 measures. Where possible, effect size for the ‘‘best’’ treatments in each category was calculated (averaged if there was more than one From tables 1–3 the following recommendations were made trial). Rosnow and Rosenthal’s modified version of the Cohen’s d calculation was used.18 The thresholds used for interpretationwere: values .0.2 = small, .0.5 = medium and .0.8 = large. The number needed to harm (NNH) was also calculated if possible, There was no weighting in terms of order of the recommenda- using withdrawal due to adverse event as the event. Additional tions. ! denotes recommendation derived from expert opinion.
information included: recruitment population; duration of disease, ! Full understanding of fibromyalgia requires comprehensive treatment and assessment; number of tender points; and myalgic assessment of pain, function and psychosocial context. Fibromyalgia score. Other outcome measures considered were also tabulated. If should be recognised as a complex and heterogeneous condition where required data were recorded, but not presented, or not presented in there is abnormal pain processing and other secondary features.
a suitable format, the author was contacted wherever possible. If This is based on expert opinion. It is important to recognise that data were only provided in graphical format, this was extracted FMS is a heterogeneous condition comprising a range of symptoms where possible. Data extraction was verified by a second and features, effective management must take all of these factors committee member to ensure accuracy. Any discrepancies were into account. The nociceptive system also has connections with the stress regulating, immune and the sleep system in the limbicbrain. It is these links that probably lead to the ‘‘syndrome’’ incorporating numerous symptoms and features.
Owing to the large variability in outcome measures and ! Optimal treatment requires a multidisciplinary approach with a assessments data could not be pooled to perform a formal combination of non-pharmacological and pharmacological treatment meta-analysis; therefore studies were classified according to modalities tailored according to pain intensity, function, associated their randomisation and blinding level. The highest quality features, such as depression, fatigue and sleep disturbance in study (randomised controlled trial) for each treatment class was used as a basis for the recommendations. The ranking was This is a logical progression from the first recommendation. It represents general practice, but is based solely on expert 1. Randomised controlled double-blind trials 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 4. Randomised open trials/non-randomised single blind to include self-management via patient education.47–49 Only two multidisciplinary trials were short-listed in the summary tables Evidence for each recommendation was categorised according for further analysis.50 51 Other reviews have supported the use of to study design and strength of each recommendation was multidisciplinary treatment,47 48 but highlighted the lack of 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. Delphiexercise was used to base recommendations on when limited Heated pool treatment with or without exercise is effective in evidence was found by systematic review. Agreement on the included recommendations was unanimous.
Heated pool treatment or balneotherapy was reported to beeffective in improving pain and function. Three of five trialsincluded exercise in the intervention34 35 38 (two positive for function and two for pain). Of those without exercise, two Abstracts published between 2002 and 2005 inclusive in Annals were positive for pain and function.34 36 In the third trial only of the Rheumatic Diseases, Pain, Arthritis & Rheumatism and the heated pool treatment group improved in pain, but no Journal of Musculoskeletal Pain were reviewed to guard against comparison was made with the control. Function was not non-inclusion of any negative studies that had not been fully assessed.37 Drop-out for adverse events was very low. Sample published. If available, data were extracted. Any contradictory sizes ranged from medium to large. Three of the studies data would be included when forming the recommendations.
restricted the use of medications (not stated in the remainingtwo). The fairly high quality of this small number of studies with positive results has led to this recommendation and there The committee proposed that these recommendations should be reviewed and updated in 4 years time, to see if (a) quality of trials ! Individually tailored exercise programmes, including aerobic and reporting in FMS had improved, and (b) if there was new exercise and strength training can be beneficial to some patients with evidence to suggest recommendation of new treatments, or to alter the recommendations of treatments already included.
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 (seven of 11). The best quality were a randomised, assessor blind 12-week study by Richards and Scott, with large sample size,53 and a In the preliminary search, 508 studies were identified. Tables 1 smaller randomised single blind study by Valim et al.42 Valim and 2 demonstrate how these were short-listed.
et al reported an improvement in VAS pain and FIQ comparedwith control. Richards and Scott did not report significant between-group improvements in either of our chosen outcome Effect size and NNH for the interventions recommended were measures although the FIQ score did improve more in the calculated where possible (table 3).
treatment group, and significant between-group improvements Ann Rheum Dis 2008;67:536–541. doi:10.1136/ard.2007.071522 Study breakdown from initial literature search Breakdown of the short-listed studies to base recommendations on, and those eliminated from further analysis Not American College of Rheumatology criteria Fibromyalgia syndrome combined for analysis Non-English language: translations reveal to be Non-English language: translations not available 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).
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 controls40 41 (with the exception of Valim et al who had a stretching control group42). The majority of exercise studies asked for participants not to change their medication intake while 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 recommended12 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 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. While 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 ! Other therapies such as relaxation, rehabilitation, physiotherapy CBT, cognitive behavioural therapy; FMS, fibromyalgia syndrome; MFP myofascial pain.
and psychological support may be used depending on the needs of theindividual patient.
Clinical trial evidence is lacking in these areas, although reviews This is based on expert opinion and some experimental evidence. Two studies of moderate quality were identified forphysiotherapy. An open study54 for connective tissue massage, Tramadol is recommended for the management of pain in which had larger subject numbers (25 control and 23 treated) and lasted 10 weeks, reported improvement in both pain and Simple analgesics such as paracetamol and other weak opioids function compared with control. Other relaxation and rehabi- can also be considered in the treatment of fibromyalgia.
litation techniques are recommended due to expert opinion.
Corticosteroids and strong opioids are not recommended.
Ann Rheum Dis 2008;67:536–541. doi:10.1136/ard.2007.071522 Effect size calculated using modified Cohen’s d method for recommended treatments where data MAOI, monoamine oxidase inhibitor; NNH, number needed to harm; SSRI, selective serotonin reuptake inhibitor.
Regarding tramadol, two randomised controlled trials were Russell et al disallowed sedative hypnotics only. Tramadol identified as eligible for the review.30 31 One was a high-quality should be used with some caution due to the possibility of study of large sample size and 13 weeks duration.31 The second typical opiate withdrawal symptoms with discontinuation and was preceded by an open label study and only included responders.30 Bennett et al reported positive effects for pain The recommendation for simple analgesics and other weak and function, and Russell et al reported improved pain levels but opioids is based mainly on expert opinion due to insufficient data.56 no change in function. There was no difference between placebo The negative recommendation for use of strong opioids and and treated group for adverse event withdrawals (high but non- corticosteroids is based on expert opinion. These medications have serious). Bennett et al restricted concomitant medications, but significant long-term side-effects and no clinical trials were iden-tified in FMS. Previous reviews support our recommendation.47 57 EULAR recommendations for the management of fibromyalgia Antidepressants: amitriptyline, fluoxetine, duloxetine, milnacipran, moclobemide and pirlindole, reduce pain and often improve functiontherefore they should be considered for the treatment of fibromyalgia Four of five trials of amitriptyline that assessed VAS pain had Full understanding of fibromyalgia requires comprehensive positive outcomes. Only two used the FIQ, one positive. However, assessment of pain, function and psychosocial context.
Fibromyalgia should be recognised as a complex and it is important to note, that as highlighted in previous reviews,14 heterogeneous condition where there is abnormal pain the only trial that lasted longer than 12 weeks did not show a significant improvement in pain compared with control.58 Two Optimal treatment requires a multidisciplinary approach trials assessing fluoxetine reported positive outcomes for both pain with a combination of non-pharmacological andpharmacological treatment modalities tailored according and function.22 28 These trials were of moderate to high quality, to pain intensity, function, associated features such as reasonable samples sizes and 6 and 12 weeks duration. Duloxetine depression, fatigue and sleep disturbance in discussion 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 Heated pool treatment with or without exercise is effective IIa pirlindole were assessed in one trial each, both of high quality and Individually tailored exercise programmes, including aerobic IIb with improvements in pain.21 23 FIQ was not assessed in either exercise and strength training can be beneficial to some trial. For all the trials withdrawals due to adverse events were Cognitive behavioural therapy may be of benefit to some In general these trials excluded other medications prescribed for FMS, with the exception of paracetamol. The only exception Other therapies such as relaxation, rehabilitation, physiotherapy and psychological support may be used was the Arnold et al trial that also allowed NSAIDs.28 Previous depending on the needs of the individual patient reviews have agreed with the recommendation of antidepres- sants with the strongest evidence for amitriptyline (or tricyclic 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 Tropisetron, pramipexole and pregabalin reduce pain and should be fibromyalgia. Corticosteroids and strong opioids are not considered for the treatment of fibromyalgia Two tropisetron clinical trials were eligible. One had positive Antidepressants: amitriptyline, fluoxetine, duloxetine, results for pain at a dose of 5 mg.59 Spa¨th et al did not report milnacipran, moclobemide and pirlindole, reduce pain andoften improve function, therefore they are recommended significantly positive results, but sample size was small and there was a positive trend in the treated group.32 FIQ was only Tropisetron, pramipexole and pregabalin reduce pain and assessed in the trial by Spa¨th et al with negative results; are recommended for the treatment of fibromyalgia therefore, no firm comment can be made on this outcome Ann Rheum Dis 2008;67:536–541. doi:10.1136/ard.2007.071522 measure. Fa¨ber et al made no comment on whether concomitant health benefits. These important factors were taken into medications had been controlled, but Spa¨th et al disallowed account in formulating these recommendations.
antidepressants, tranquillisers and sedatives. This treatmentappears well tolerated. These were short-term studies, so further research into longer-term effects is required.
These recommendations are the first to be commissioned for One trial for pramipexole was positive for both pain and FMS, although previous reviews have addressed the area.47 62 function.33 Frequency of mild/moderate adverse events was high The standard operating procedures published by EULAR63 were and this trial did not restrict concomitant medications, followed. They will be updated every 5 years and it is hoped although dosages were kept stable. A monotherapy trial isrequired for more conclusive assessment of effect.
that good quality clinical trials in this area will add to the One trial reported pregabalin 450 mg reduced pain, but FIQ was evidence currently available. These recommendations should not assessed.60 Drop-outs due to adverse events were largely classed assist healthcare providers, with a secondary intention to mild to moderate in severity. All medications for pain and sleep incorporate information into materials for patients.
disorders were restricted, with the exception of paracetamol.
The nine recommendations included eight management These are recent studies and suggest further research into the categories, three of which had strong evidence from the current use of these promising medications for FMS. Previous reviews literature, and three were based on expert opinion.
have also mentioned their potential benefit47 57 (neither include Author affiliations: 1Academic Rheumatology Unit, King’s College London, Weston the pramipexole study as this was not published).
Education Centre, Cutcombe Road, London SE5 9RJ, UK; 2Aalborg University, Centerfor Sensory-Motor Interaction, Department of Health Sciences and Technology,Denmark; 3The Parker Institute, Frederiksberg Hospital, Copenhagen, Denmark; 4Rheumatology Department, Hospital Lapyeronie, Montpellier, France; 5Servic¸o de These EULAR recommendations are based on expert opinion and Reumatologia, Hospital Egas Moniz, Centro Hospitalar Lisboa Ocidental, Lisbon, changes in pain assessed by VAS and function assessed by the FIQ Portugal; 6Department of Medicine, Soroka Medical Center, Beer Sheva, Israel;7 in clinical trials. Positive effects in other outcome measures were Reumatologia, Hopitais Da Universidade, Coimbra, Portugal; 8Department of Physical and Rehabilitation Medicine, Hacettepe Medical School, Ankara, Turkey; 9INR, Section not considered, neither were pain or function if assessed by of Occupational Therapy, Faculty of Health Sciences, Linko different instruments. Consequently some studies were excluded ¨ping, Sweden; 10Neuromuscular Unit, University Hospital, Linkoping; 11Department from our review due to not using these outcome measures, or not of Clinical Neuroscience, Karolinska Institute, Stockholm, and Stockholm Spine Center, presenting the data. Although other instruments might be more ¨sby, Sweden; 12FMA, Bath, UK; 13Rheumatology, sensitive in FMS it was decided that setting a standard for outcome Mater Misericordiae University Hospital, Dublin, Ireland; 14Pain Clinic, Hospital Cochin,Paris, France; 15Department of Rheumatology, Rehabilitation and Internal Medicine measures was vital so that comparisons could be made fairly University of Medical Sciences, Poznan, Poland; 16Rheumatology Unit, L. Sacco between trials and therefore using those most frequently reported University Hospital, Milan, Italy; 17Faculty of Medical and Human Sciences ARC allowed better analysis.47 61 Previous reviews have used different Epidemiology Unit, The University of Manchester, Manchester, UK; 18Bahnhofstr. 95 inclusion/exclusion criteria and/or assessed more or different outcome measures producing different evidence.16 47 48 Acknowledgements: We acknowledge EULAR for their financial support and the The high variability in outcome measures used, reporting of ESCISIT steering committee for their endorsement.
results, as well as the inadequacy of methodological quality were Competing interests: FB has been reimbursed by Laboratoires Procter and Gamble, barriers to conducting meta-analysis.12 14 16 17 57 62 This led to Sanofi-Aventis, Roche and Bristol Meyers Squibb for attending medical conferences difficulties in producing strict evidence-based recommendations.
and had honorarias for speaking for Laboratoires Pierre Fabre, Servier and Roche. JB In some areas evidence is lacking due to the poor quality of the has been paid by Pierre Fabre and Pfizer for running educational programmes and forspeaking at international conferences and reimbursed by Eli Lilly for attending studies, where expert opinion suggests otherwise, eg, exercise.
international conferences. DB has been reimbursed by Pierre Fabre Company, the Outcome measures may be decided according to desired manufacturer of Milnacipran, for attending several symposiums and by Pfizer for treatment effect. Non-pharmacological interventions have pre- consulting. EC has served on advisory panels of Pierre Fabre Medicament, Jazz viously been suggested to have a significantly better effect on Pharmaceutical, Allergan and Pfizer. EC has also lectured in meetings organised by function than medications,62 reflected by its wider assessment in Pierre Fabre Medicament, Eli Lilly and Pfizer. The Rheumatology Department received aresearch grant from Pierre Fabre Medicament. CH has participated in symposia these studies. However, if this outcome measure is not frequently organised by Laboratoires Pierre Fabre and received reimbursement for participation.
assessed in pharmacological trials, results could be biased.
She has also received fees for written material in proceedings from these symposia.
Guidance on how to conduct good randomised controlled KH has participated in symposia organised by Laboratoires Pierre Fabre and received trials in FMS, including standardised outcome measures and reimbursement for participation. He has also received fees for written material in validated, sensitive instruments is important for future research.
proceedings from these symposia. He has held a lecture on pain mechanisms andreceived a fee from Pfizer. EK has participated as a consultant in advisory board For the treatments that were recommended, effect sizes meetings (total of four) for the following pharmaceutical companies: Pfizer, Wyeth and generally range from medium to high. Although these results Pierre Fabre. She gave a speech on a satellite symposium organised by Pfizer. She has give an indication of the efficacy of each treatment, they should currently research collaboration with Pierre Fabre. SP has been paid by Pfizer, Eli Lilly, be interpreted with some caution as they were only calculated Grunenthal, Pierre Fabre and Sanofi Aventis for running educational programmes and where data were available and could be biased by factors such as participating in advisory boards. MS has served on advisory panels of Pierre FabreMedicament, Jazz Pharmaceuticals and Allergan. MS has also lectured in meetings whether or not the outcome measure was assessed. We have not organised by Novartis, Pierre Fabre Medicament and Lilly.
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