ar2455 ARJ Research article <p>A meta-analysis of the efficacy of fibromyalgia treatment according to level of care</p> Garcia-Campayo Javier jgarcamp@arrakis.es Magdalena Jesus jmagdalenab@gmail.com Magallón Rosa med000764@gmail.com Fernández-García Esther efergar@hotmail.com Salas Montserrat msalas@hotmail.com Andrés Eva eandres@unizar.com

Miguel Servet Hospital, University of Zaragoza, Zaragoza, Spain

Letux Health Centre, Letux, Zaragoza, Spain

Arrabal Health Centre, Zaragoza, Spain

Miguel Servet Hospital, University of Zaragoza, Zaragoza, Spain

Government of Aragon, Zaragoza, Spain

University of Zaragoza, Zaragoza, Spain

Grupo Aragonés de Investigación en Atención Primaria, Red de Actividades Preventivas y de Promoción de la Salud (REDIAPP) (G06/128), Instituto Aragonés de Ciencias de la Salud (IACS), Zaragoza, Spain

 Arthritis Research & Therapy 1478-6354 2008 10 4 R81 http://arthritis-research.com/content/10/4/R81 18627602 10.1186/ar2455 21 3 2008 30 4 2008 20 5 2008 15 7 2008 15 7 2008 2008 Garcia-Campayo et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Introduction

The aim of this paper was to compare the efficacy of the treatments for fibromyalgia currently available in both primary care and specialised settings.

Methods

Published reports of randomised controlled trials (RCTs) researching pharmacological and non-pharmacological treatments in patients with fibromyalgia were found in the MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and PsychInfo databases. The most recent electronic search was undertaken in June 2006.

Results

We identified a total of 594 articles. Based on titles and abstracts, 102 full articles were retrieved, 33 of which met the inclusion criteria. These RCTs assessed 120 treatment interventions in 7789 patients diagnosed with primary fibromyalgia. Of them, 4505 (57.8%) were included in the primary care group of our study and 3284 (42.2%) in the specialised intervention group. The sample was mostly made up of middle-aged women, who have had fibromyalgia for a mean period of 6 to 10 years. The mean effect size of the efficacy of the 120 treatment interventions in patients with fibromyalgia compared with controls was 0.49 (95% confidence interval [CI] = 0.39 to 0.58; p < 0.001). In the primary care group it was 0.46 (95% CI = 0.33 to 0.58) while in specialised care it was 0.53 (95% CI = 0.38 to 0.69), with no statistical significance in the differences. We analysed the efficacy of treatments by comparing primary and specialised care in the different fibromyalgia groups and there were no significant differences. The variables of the studies that affected the improvements in the efficacy of fibromyalgia treatment were low quality of the studies and a shorter duration of treatment. However, both factors were biased by the heterogeneity of the studies. Other variables that also improved outcome and were not biased by the heterogeneity of the studies, were younger age of the patients and shorter duration of the disorder. On the contrary, gender and type of treatment (pharmacological vs. psychological) did not affect outcome.

Conclusion

Based on this meta-analysis and despite the heterogeneity of specialised care studies and of the other limitations described in this article, treating fibromyalgia in specialised care offers no clear advantages.

Introduction

Fibromyalgia is a chronic musculoskeletal pain disorder of unknown aetiology, characterised by widespread pain and muscle tenderness and often accompanied by fatigue, sleep disturbance and depressed mood 12. With an estimated lifetime prevalence of approximately 2% in community samples 3, it accounts for 15% of outpatient rheumatology visits and 5% of primary care visits 4. The prognosis for symptomatic recovery is generally poor 5. A wide variety of interventions are used in the management of this disorder, although there is no clear consensus on the treatment of choice and fibromyalgia remains relatively refractory to treatment.

A number of meta-analyses and reviews have been conducted on the pharmacological 678 and non-pharmacological 910 treatments available for fibromyalgia. The studies main objectives are to guide clinicians in their everyday practice using evidence-based decisions. However, the aim of our current study is rather different. The high prevalence and clinical impact of fibromyalgia makes it a significant public health problem given its high cost. In Spain and other public health systems, a difficult cost-benefit decision must be taken as to which level of the health care system these patients should be treated in: either in specialised settings, which many patients prefer, or in primary care, which is usually more cost-effective. To our knowledge, there is no published meta-analysis on this subject.

We carried out a systematic review and meta-analysis of all randomised controlled trials (RCTs) of pharmacological and non-pharmacological treatments that are available in standard primary care settings and those that are administered in standard secondary care settings of public health care systems in developed countries for the treatment of fibromyalgia. The aim of this paper is to compare the efficacy of the treatments for fibromyalgia available in both settings using the most important outcomes assessed in this disorder, such as pain, quality of life, depression, etc.

Materials and methods

We followed the QUOROM guidelines for reporting meta-analyses 11.

Database search

Published reports of RCTs researching pharmacological or non-pharmacological treatments in patients with fibromyalgia were found in the following databases: MEDLINE (1966–2006), EMBASE (1988–2006), The Cochrane Central Register of Controlled Trials (the Cochrane Library Issue 2006) and Psychinfo (1987–2006). Search strategy is summarised in the additional data file. The search was performed without language restrictions but was limited to RCTs in humans. The last electronic search was undertaken in June 2006. All primary and review articles, as well as their references, were reviewed independently in duplicate. The authors of the original reports were contacted for additional information where needed.

Selection criteria

Studies were screened for inclusion, by reviewing the title and published abstract, based on the following criteria:

Type of participants

The studies evaluated the treatment or management of fibromyalgia as indicated by the use of recognised diagnostic criteria, such as American College of Rheumatology (ACR) 1. Despite the concept of primary fibromyalgia (patients in which fibromyalgia can not be explained by other medical disorders) not being accepted by the ACR, most studies on fibromyalgia, and many of the papers included in the meta-analysis, do accept this distinction. Therefore, it has been maintained to increase comparability.

Types of studies

The papers described a randomisation of treatment, placebo control and at least one group receiving an active (pharmacological or non-pharmacological) treatment.

Types of interventions

Treatment can be defined as pharmacological or non-pharmacological, and can be allocated to primary or specialised care. The duration of treatment was at least eight weeks.

Types of outcomes

Outcomes had to be measurable. One of the major problems in fibromyalgia is the wide variety of outcomes. Seven types of outcomes were included: pain, fatigue, quality of life, global function, anxiety/depression, insomnia and tender points. Each of them were assessed with several questionnaires.

Each study was reviewed in duplicate (by EF and JGC) for inclusion with substantial inter-rater agreement (kappa = 0.7). Disagreements were resolved by a consensus agreement. Reviews and abstracts were not considered. The study selection process flowchart is summarised in Figure 1.

<p>Figure 1</p>

Flowchart showing the process of study selection

Flowchart showing the process of study selection.

Allocation

All studies included were allocated to a level of health care (primary care or specialised care) and category of treatment (pharmacological or non-pharmacological) by a consensus with substantial inter-rater agreement (kappa = 0.91) from a panel of two general practitioners (RM and JM), a psychiatrist (JGC) and a psychologist (EF). A treatment was considered to be available at the primary care level when most general practitioners from most Western national health services were able to provide that treatment without any specific training. Tables 1 and 2 summarise which treatments were allocated to the primary and specialised care groups and to the pharmacological and non-pharmacological treatment groups. We have not included RCTs on acupuncture because of the recent meta-analyses showing that this treatment is not effective 10.

<p>Table 1</p>

Allocation of treatments according to level of care

Primary care

Secondary care

Amitriptyline

Pirlindole

Tramadol

Tropisetron

Milnacipran

Dehydroepiandrosterone (DHEA)

Moclobemide

Pramipexole

Fluoxetine

Malic acid

Cyclobenzaprine

Rehabilitation

Nortriptyline

Laser treatment

Duloxetine

Hyperbaric oxygen therapy

Pregabaline

Bright light treatment

Zolpidem

Aerobic exercise

Exercise

Stress-reduction treatment

Chiropractic management

Cognitive behavioural therapy

Cognitive educational therapy

Education training

Behavioural insomnia therapy

Music vibration

<p>Table 2</p>

Pharmacological and non-pharmacological treatments

Pharmacological treatments

Non-pharmacological treatments

Amitriptyline

Hyperbaric oxygen therapy

Cyclobenzaprine

Bright light treatment

Dehydroepiandrosterone (DHEA)

Aerobic exercise

Duloxetine

Education training

Fluoxetine

Behavioural therapy

Malic acid

Cognitive behavioural therapy

Milnacipran

Cognitive educational therapy

Moclobemide

Exercise

Nortriptyline

Rehabilitation

Pirlindole

Music vibration

Pramipexole

Chiropractic management

Pregabaline

Stress-reduction treatment

Tramadol

Behavioural insomnia therapy

Tropisetron

Laser

Zolpidem

Validity assessment

All included reports were then independently read by two reviewers (EF and JGC) who assessed the validity of the studies using the modified Oxford Scale (Table 3) 1213. The minimum score of an included trial was one and the maximum was six. Discrepancies were resolved by discussion or by consulting a third reviewer (RM).

<p>Table 3</p>

Modified Oxford Scale. Validity score (0 to 7)

Randomisation

0 None

1 Mentioned

2 Described and adequate

Concealment of allocation

0 None

1 Yes

Double blinding

0 None

1 Mentioned

2 Described and adequate

Flow of patients

0 None

1 Described but incomplete

2 Described and adequate

Data abstraction

A data abstraction form was created and the following data were included: number of patients and controls, gender (percentage of women), age (median), diagnosis, time of evolution of the disorder (years), severity of the disorder, level of health care (primary care or specialised), kind of treatment (pharmacological or non pharmacological), duration of treatment, modified Oxford Scale ratings and outcomes (ratings in different used scales of quality of life, pain, depression, anxiety, etc).

Meta-analyses

Both dichotomous and continuous data were extracted. Continuous data were analysed as standardised differences in the means (SDM) with 95% confidence intervals (CI). Where mean values and standard deviations were not reported, the authors of the studies were contacted. If they did not reply and the data were presented graphically, data were extracted from the graphs. If this was not possible, the data were not considered. A random effects model was used by default. Analyses were performed using Comprehensive Meta-analysis, version 2 (Biostat, Englewood, NJ, USA). Data were graphically plotted using forest plots to evaluate treatment effects. Clinical heterogeneity was minimised using stringent diagnostic criteria for fibromyalgia and homogeneous criteria for the treatments and outcomes of the studies included in the meta-analysis.

Results

Literature search and study selection

We first performed our literature search in MEDLINE (374 hits), followed by EMBASE (133 hits), and subsequently in the Cochrane Library (41 hits) and in Psychinfo (34 hits). By checking references, we identified an additional 12 hits, resulting in a total of 594 articles (Figure 1). Based on titles and abstracts, 102 full articles were retrieved, 33 of which met the inclusion criteria 141516171819202122232425262728293031323334353637383940414243444546. These 33 studies are summarised in Table 4.

<p>Table 4</p>

Characteristics of the 33 selected randomised controlled trials and the patients studied in them

N

Randomized controlled trial

Year

Country

Treatment

Level of care

% of women

Mean age

Length of treatment (years)

Simple size

Oxford scoring (quality)

Duration of disease at baseline (years)

Instruments used (outcome assessed)

1

Carette

94

Canada

Amitryptiline Cyclobenzaprine

Primary care

93.8

44.4

24

208

3

7.7

Mc Gill-BPI (p) SIP (gf)

2

Russell

94

USA

Malic acid

Specialised care

90

49.5

8

24

3

VAS (p) TPI (tp)

3

Wolfe

94

USA

Fluoxetine

Primary care

100

50.4

3

42

5

13

TPI (tp) BDI (ad)

4

Carette

95

Canada

Amitryptiline

Primary care

95.5

43.8

8

22

2

6.9

VAS (p) VAS (i) VAS (gf)

5

Chesky

95

USA

Music vibration

Specialised care

92.6

48.8

30 minutes

26

3

11

VAS (p) TPI (tp)

6

Goldenberg

96

USA

Fluoxetine Amitryptiline

Primary care

90.3

43

6

31

5

5.7

VAS (p) FIQ (GF) BDI (ad) VAS (i) VAS (gf) VAS (f) TPI (tp)

7

Ginsberg

96

Belgium

Amitryptiline

Primary care

82.5

46

8

46

2

32

VAS (p) VAS (i) TPI (tp) VAS (f) VAS (gf) NTP (tp)

8

Moldofsky

96

Canada

Zolpidem

Primary care

95

42

2.5

19

4

NTP (tp) PGI (i)

9

Vlayen

96

Holland

Cognitive behavioural therapy Education training

Specialised care

87

44

6

131

5

10

BDI (ad)

10

Wigers

96

Norway

Aerobic exercise Stress-reduction treatment

Specialised care

92

44

14

48

3

10

VAS (p) VAS (i) VAS (f)

11

Pearl

96

Canada

Bright light treatment

Specialised care

100

38

10

14

2

5

VAS (p) VAS (f) VAS (i)

12

Kelli

97

Canada

Chiropractic treatment

Specialised care

-

49

4

19

4

8

VAS (p) NTP (tp)

13

Hannonen

98

Finland

Moclobemide Amitryptiline

Primary care

100

49

12

130

5

11.2

NTP (tp) VAS (p) VAS (f) VAS (i)

14

Yavuzer

98

Turkey

Moclobemide

Primary care

58

33

6

60

1

TPI (tp)

15

Ginsberg

98

Belgium

Pirlindole

Specialised care

85

40

4

61

4

2.9

VAS (p) TPI (tp) VAS (gf)

16

Russell

00

USA

Tramadol

Primary care

94

49

6

69

4

4.7

VAS (p) FIQ (gf) NTP (tp)

17

Heymann

01

Brazil

Amitryptiline Nortryptiline

Primary care

100

50

8

118

4

FIQ (gf) NTP (tp)

18

Färber

01

Germany

Tropisetron

Specialised care

92

48

1.5

403

3

11

Vas (p) NTP (tp)

19

Gowans

01

Canada

Exercise

Specialised care

88

47

23

50

3

9

FIQ (gf) BDI (ad) STAI (ad) NTP (tp)

20

Mannerkorpi

01

Sweden

Education training

Specialised care

100

46

24

58

4

8.7

FIQ (gf) QOLS (ql)

21

Gür

02

Turkey

Laser Amitryptiline

Primary care (Amytriptiline) – Specialised care (laser)

80

30

8

75

3

4.6

HADS (ad) FIQ (gf)

22

Joaquim

02

Sweden

Education training Behavioural therapy

Specialised care

100

45

12

53

6

3.6 pain

FIQ (gf) Mc Gill (p)

23

King

02

Canada

Exercise Education training

Specialised care

100

46

12

152

4

FIQ (gf) NTP (tp)

24

Lemstra

05

Canada

Rehabilitation

Specialised care

84.5

49.5

6

79

3

10

VAS (p) BDI (ad)

25

Schachter

03

Canada

Aerobic exercise (long-term and short-term)

Specialised care

100

42

16

143

4

3.5

VAS (p) FIQ (gf)

26

Arnold

04

USA

Duloxetine

Primary care

88

49

12

207

6

8.9

BDI (ad) BPI (ad) NTP (tp) CGI (gf) FIQ (gf)

27

Yildiz

04

Turkey

Hyperbaric oxigen therapy

Specialised care

70

40

2.5

50

2

4.5

VAS (p) NTP (tp)

28

Crofford

05

USA

Pregabaline

Primary care

92

48.5

8

529

5

9

VAS (p) MAF (f)

29

Arnold

05

USA

Duloxetine

Primary care

100

50

12

354

5

BPI (ad)

30

Gendreau

05

USA

Milnacipran

Primary care

98

47

12

125

6

4.1

FIQ (gf)

31

Finckh

05

Switzerland

Dehydroepiandrosterone (DHA)

Specialised care

100

59

12

52

6

13

HADS (ad) VAS (f)

32

Holman

05

USA

Pramipexole

Specialised care

94.4

48.5

14

60

6

8.4

BDI (ad) HAMD (ad) TPI (tp) FIQ (gf)

33

Edinger

05

USA

Cognitive behavioural therapy Sleep hygiene

Specialised care

100

49

6

47

3

Mc Gill (p) BPI (ad) SF-36 (ql)

Outcome types: P, Pain; QL, Quality of life; AD, Anxiety-depression; I, Insomnia; TP, Tender points; F, Fatigue; GF, Global Function.

Questionnaires: Mc Gill PQ, Mc Gill Pain Questionnaire; BPI, Brief Pain Inventory; VAS, Visual Analogue Scale; QOLS, Quality of Life Scale; BDI, Beck Depression Inventory; HADS, Hospital Anxiety and Depression Scale; HDS, Hamilton Depression Scale; STAI, State-trait Anxiety Inventory; PGI, Patient Global Impression; TPI, Tender Points Index; MAF, Multi-dimensional Assessment of Fatigue; FIQ, Fibromyalgia Impact Questionnaire; CGIS, Clinical Global Impression of Severity; SIP, Sickness Impact Profile.

Of the 69 studies that were excluded 23 were not an RCT; the patient population of 28 were not primary fibromyalgia (but secondary fibromyalgia or allied conditions) or the fibromyalgia criteria used were not ACR criteria 1; in 16 studies the intervention had a duration shorter than eight weeks or it was so specific that it was not available in standard Western health care systems 47; and two studies did not use comparable outcome measures. There was seven types of outcomes used in the studies selected from 16 questionnaires or tests summarised in Table 5.

<p>Table 5</p>

Questionnaires and outcome types used in the studies selected

    Type of outcome

    Questionnaires

Pain (p)

McGill Pain Questionnaire 48

Brief Pain Inventory 49

Visual Analogue Scale 50

Quality of life (ql)

SF-36 51

Quality of Life Scale (QOLS) 52

Anxiety and depression (ad)

Beck Depression Inventory 53

Hospital Anxiety and Depression Scale 54

Hamilton Depression Scale 55

State-trait Anxiety Inventory 56

Insomnia (i)

Visual Analog Scale 50

Patient Global Impression 57

Tender points (tp)

Tender Points Index 58

Number of Tender Points according to American College of Rheumatology criteria 1

Fatigue (f)

Visual Analog Scale 50

Multi-dimensional Assessment of Fatigue 59

Global Function (gf)

Visual Analog Scale 50

Fibromyalgia Impact Questionnaire 60

Clinical Global Impression of Severity 57

Sickness Impact Profile (SIP) 61

Methodological quality of the included studies

Only 11 of the 33 included studies (33.3%) showed a rating of 5+ on the modified Oxford Scale, that is, a score of high methodological quality. Most of them (nine of 11) were pharmacological studies and the remaining two studies were psychological interventions. Many of them were recent studies, carried out in 2004 and 2005 (six of 11), as can be seen in Tables 4 and 6. The most commonly absent items were an adequate description of the flow of patients and adequate description of double blinding.

<p>Table 6</p>

Characteristics of the patients included in the meta-analysis

Total

%

Control group

%

Intervention group

%

Level of care

Primary care

4505

57.8

2127

57.6

2378

58.1

Specialised care

3284

42.2

1567

42.4

1717

41.9

Overall

7789

100.0

3694

100.0

4095

100.0

Kind of treatment

Pharmacological

5706

73.3

2684

72.7

3022

73.8

Non-pharmacological

2083

26.7

1010

27.3

1073

26.2

Overall

7789

100.0

3694

100.0

4095

100.0

Outcome assessed

Anxiety/depression

1195

15.3

570

15.4

625

15.3

Quality of life

115

1.5

51

1.4

64

1.6

Pain

2074

26.6

980

26.5

1094

26.7

Fatigue

650

8.3

320

8.7

330

8.1

Tender points

1533

19.7

738

20.0

795

19.4

Insomnia

397

5.1

196

5.3

201

4.9

Global function

1825

23.4

839

22.7

986

24.1

Overall

7789

100.0

3694

100.0

4095

100.0

Methodological quality

1 to 2

595

7.6

289

7.8

306

7.5

3 to 4

3396

43.6

1577

42.7

1819

44.4

5 to 6

3798

48.8

1828

49.5

1970

48.1

Overall

7789

100.0

3694

100.0

4095

100.0

Length of treatment (weeks)

0 to 8

3644

46.8

1750

47.4

1894

46.3

09 to 16

3467

44.5

1678

45.4

1789

43.7

17 to 24

678

8.7

266

7.2

412

10.1

Overall

7789

100.0

3694

100.0

4095

100.0

Age

30 to 39

253

3.2

125

3.4

128

3.1

40 to 49

6662

85.5

3140

85.0

3522

86.0

50 to 59

874

11.2

429

11.6

445

10.9

Overall

7789

100.0

3694

100.0

4095

100.0

Percentage of women

< 80

151

1.9

73

2.0

78

1.9

80 to 89

2258

29.0

1111

30.1

1147

28.0

90 to 99

2874

36.9

1297

35.1

1577

38.5

100

2506

32.2

1213

32.8

1293

31.6

Overall

7789

100.0

3694

100.0

4095

100.0

Duration of the disorder (years)

0 to 5

1459

25.3

710

26.3

749

24.5

6 to 10

2987

51.9

1344

49.7

1643

53.8

11 to 15

1310

22.8

649

24.0

661

21.7

Overall

5756

100.0

2703

100.0

3053

100.0

Country