Impotentie brengt een constant ongemak met zich mee, net als fysieke en psychologische problemen in uw leven cialis kopen terwijl generieke medicijnen al bewezen en geperfectioneerd zijn
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 Dis
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EULAR evidence-based recommendations for themanagement of fibromyalgia syndrome
S F Carville,1 S Arendt-Nielsen,2 H Bliddal,3 F Blotman,4 J C Branco,5 D Buskila,6J A P Da Silva,7 B Danneskiold-Samsøe,3 F Dincer,8 C Henriksson,9 K G Henriksson,10E Kosek,11 K Longley,12 G M McCarthy,13 S Perrot,14 M Puszczewicz,15 P Sarzi-Puttini,16A Silman,17 M Spa
commonly used in clinical and therapeutic research.
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.
collected any information on the cost-effectiveness of thesetreatments. Further analysis of disease duration and baselinevalues does not reveal any obvious pattern that would affect the
outcomes of this review. Review of the abstracts published
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