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Clinical Review | Clinician's Corner

Treatment of Fibromyalgia Syndrome With Antidepressants:  A Meta-analysis FREE

Winfried Häuser, MD; Kathrin Bernardy, PhD; Nurcan Üçeyler, MD; Claudia Sommer, MD
[+] Author Affiliations

Author Affiliations: Department of Internal Medicine, Klinikum Saarbrücken, Saarbrücken, Germany (Dr Häuser); Department of Anesthesiology, Emergency Medicine and Pain Therapy, University of Saarland, Saarbrücken (Dr Bernardy); Department of Psychosomatic Medicine, MediClin Bliestal Clinics, Blieskastel, Germany (Dr Bernardy); and Department of Neurology, University of Würzburg, Würzburg, Germany (Drs Üçeyler and Sommer).


JAMA. 2009;301(2):198-209. doi:10.1001/jama.2008.944.
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Context Fibromyalgia syndrome (FMS) is a chronic pain disorder associated with multiple debilitating symptoms and high disease-related costs. Effective treatment options are needed.

Objectives To determine the efficacy of antidepressants in the treatment of FMS by performing a meta-analysis of randomized controlled clinical trials.

Data Sources MEDLINE, PsycINFO, Scopus, and the Cochrane Library databases were searched through August 2008. Reference sections of original studies, meta-analyses, and reviews on antidepressants in FMS were reviewed.

Study Selection Randomized placebo-controlled trials with tricyclic and tetracyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) were analyzed.

Data Extraction and Data Synthesis Two authors independently extracted data. Effects were summarized using standardized mean differences (SMDs) by a random-effects model.

Results Eighteen randomized controlled trials (median duration, 8 weeks; range, 4-28 weeks) involving 1427 participants were included. Overall, there was strong evidence for an association of antidepressants with reduction in pain (SMD, −0.43; 95% confidence interval [CI], −0.55 to −0.30), fatigue (SMD, −0.13; 95% CI, −0.26 to −0.01), depressed mood (SMD, −0.26; 95% CI, −0.39 to −0.12), and sleep disturbances (SMD, −0.32; 95% CI, −0.46 to −0.18). There was strong evidence for an association of antidepressants with improved health-related quality of life (SMD, −0.31; 95% CI, −0.42 to −0.20). Effect sizes for pain reduction were large for TCAs (SMD, −1.64; 95% CI, −2.57 to −0.71), medium for MAOIs (SMD, −0.54; 95% CI, −1.02 to −0.07), and small for SSRIs (SMD, −0.39; 95% CI, −0.77 to −0.01) and SNRIs (SMD, −0.36; 95% CI, −0.46 to −0.25).

Conclusion Antidepressant medications are associated with improvements in pain, depression, fatigue, sleep disturbances, and health-related quality of life in patients with FMS.

Figures in this Article

Fibromyalgia syndrome (FMS) has an estimated prevalence in North America and Europe of 0.5% to 5.8%.1Quiz Ref IDAccording to the criteria of the American College of Rheumatology (ACR), FMS is defined as chronic widespread pain and tenderness at a minimum of 11 of 18 defined tender points.2 Other symptoms of FMS are fatigue and nonrestorative sleep. Most patients report additional somatic and psychological symptoms.3,4 Patients with FMS experience disability and reduced health-related quality of life (HRQOL).5 Fibromyalgia syndrome is also associated with high direct6,7 and indirect disease-related costs.8 Effective treatment of FMS is therefore necessary for medical and economic reasons.9

Whether FMS is a distinct disorder or a manifestation of another underlying disorder is controversial. The spectrum of possible underlying disorders ranges from inflammatory arthritic diseases to depression. Others classify FMS as a functional somatic syndrome.10

Evidence-based guidelines on the management of FMS from the American Pain Society11 and the European League Against Rheumatism12 included published literature through 2004 and 2005, respectively. Antidepressants are the drugs most often studied for treatment of FMS. However, no meta-analyses on antidepressant therapy for FMS have been published since 2000.13,14

We therefore performed a meta-analysis with 3 goals: to evaluate the effects of treatment with antidepressants on FMS-related symptoms; to examine possible differences in the efficacy of distinct antidepressant classes in therapy for FMS; and to determine the internal validity (methodological quality) and external validity (generalizability) of randomized controlled trials (RCTs) with antidepressants in FMS.

The meta-analysis was performed according to the QUORUM guidelines (Quality of Reporting of Meta-analyses)15 and the recommendations of the Cochrane Collaboration.16

Data Sources and Searches

The electronic databases screened were MEDLINE (1966 through August 2008), PsycINFO (1966 through August 2008), Scopus (1980 through August 2008), and the Cochrane Library (1993 through August 2008). Using Medical Subject Headings terms, searches were limited to human and performed for all languages. The keyword fibromyalgia was used in combination with tricyclic antidepressant or serotonin reuptake inhibitors or monoamine oxidase inhibitors or antidepressant or antidepressive agents and randomized controlled trial or controlled clinical trial or review. After consulting with the German center of the Cochrane Collaboration, we did not use a filter such as the highly sensitive search strategy17 because limiting the number of reports with a filter did not seem reasonable considering the potential number of studies. Reference sections of relevant original articles, reviews, meta-analyses,13,14 and evidence-based guidelines11,12 were screened manually and independently by 2 of us (K.B., W.H.).

Study Selection

Study inclusion criteria were as follows: use of recognized criteria to define FMS (ACR,2 Smythe and Moldofsky,18 or Yunus19); RCT design with a control group receiving pharmacological placebo; and treatment with antidepressants (tricyclic and tetracyclic antidepressants [TCAs], selective serotonin reuptake inhibitors [SSRIs], serotonin and noradrenaline reuptake inhibitors [SNRIs], or monoamine oxidase inhibitors [MAOIs]).

We did not include studies assessing cyclobenzaprine, S-adenosylmethionine, or combinations of antidepressants. Cyclobenzaprine combines characteristics of an antidepressant and a muscle relaxant. S-adenosylmethionine is a dietary supplement. We contacted corresponding authors of RCTs with incomplete data presentation (eg, missing means, standard deviations of pretest and posttest data, or standard deviations of change scores). Studies in which only categorical data were provided and those for which we were not able to obtain missing data were excluded.

Data Extraction

Two of us (K.B., W.H.) independently screened the titles and abstracts of potentially eligible studies identified. The full text articles were examined independently by 2 of us (C.S., W.H.) to determine whether they met the inclusion criteria. Two of us (N.U., W.H.) independently extracted data (study characteristics and results) using data extraction forms. Point estimates for selected variables were extracted and checked by the other 2 reviewers. We used κ statistics to assess agreement between reviewers. All discrepancies were rechecked and consensus was achieved by discussion.

We selected the following outcome measures, which are features of FMS20: pain, fatigue, sleep, and depressed mood. Health-related quality of life was an additional outcome. When researchers reported more than 1 measure for an outcome, we used the following priority for inclusion in the meta-analysis:

  1. Pain: visual analog scale (VAS), VAS Fibromyalgia Impact Questionnaire (FIQ), Numeric Rating Scale (NRS), other pain questionnaire

  2. Fatigue: VAS, VAS FIQ, other questionnaire

  3. Sleep: VAS, VAS FIQ, NRS, other questionnaire

  4. Depressed mood: VAS, VAS FIQ, other questionnaire

  5. HRQOL: FIQ total score, other HRQOL scale.

The van Tulder test (11 items)21 and the Jadad test (5 items)22 were applied for assessing methodological quality. The van Tulder items were used to arbitrarily classify quality as high (scores 8-11), moderate (scores 5-7), or low (scores 1-4). The Jadad score was used to classify quality as high (score 5), moderate (score 4), or low (scores 1-3).

Data Synthesis and Analysis

We analyzed intention-to-treat data whenever available. For the comparison of proportions, the χ2 test was applied. Nonparametric tests (Mann-Whitney test, Kruskal-Wallis test) were used for comparing continuous variables. A 2-sided P value of .05 or lower was considered significant. Meta-analyses were conducted using RevMan analyses software (RevMan 4.2.10).23

Because most outcomes were presented as continuous data (mean value or mean changes), we used either the weighted mean differences (WMDs) or the standardized mean difference (SMDs) as effect measures. Weighted mean differences were calculated when the outcome measure in all trials was determined on the same scale, SMDs when outcomes were measured using different scales. To calculate WMDs or SMDs, we used means and change scores and their standard deviations. When only the standard error was reported, it was converted into standard deviation.24

I2 statistics were used to measure heterogeneity of the RCTs. If the I2 value was less than 50%, a fixed-effects meta-analysis was applied. If the I2 value was 50% or more, the random-effects meta-analysis was used.23 We used Cohen categories25 to evaluate the magnitude of the effect size, calculated by WMD or SMD, and designated a D greater than 0.2 through 0.5 as a small effect size, a D greater than 0.5 up to 0.8 as a medium effect size, and a D greater than 0.8 as a large effect size. We used the following descriptors to classify meta-analysis results21: “strong” indicated consistent findings in multiple (at least 2) high- or moderate-quality RCTs; “moderate” indicated consistent findings in multiple low-quality RCTs or 1 high- or moderate-quality RCT; “limited” indicated 1 low-quality RCT; and “conflicting” indicated inconsistent findings among multiple RCTs.

A sensitivity analysis was conducted to determine whether different classes of antidepressants (TCA, SSRI, SNRI, MAOI) influenced the results by calculating the effect sizes of the outcomes assessed of each class of antidepressants.

Potential publication bias (ie, the association of publication probability with the statistical significance of study results) was investigated using visual assessment of the funnel plot (plots of effect estimates against sample size) calculated by RevMan Analyses software. Publication bias may lead to asymmetrical funnel plots.26 Furthermore, we tested the sensitivity of our results to potential unpublished studies using a file-drawer test for meta-analysis. This test determines how many negative studies with an effect size of D = 0.01 would be needed to negate our findings (fail-safe number). If the fail-safe number exceeds the file-drawer number, the results of the meta-analysis can be regarded as robust against potential reporting bias.2729 The file-drawer number is calculated as 5k + 10; where k is the number of study groups in the meta-analysis.

Study Selection

The literature search yielded 337 citations. Initially, 34 studies met our inclusion criteria. The excluded 303 studies contained duplicate publications, review articles, uncontrolled studies, and studies without an antidepressant group. On more detailed review, an additional 16 papers were excluded for the following reasons: no recognized criteria for FMS,30 duplicate publication,31 report of N-of-1 trials,32 lack of an antidepressant-only group,3335 lack of a pharmacological placebo group,3639 outcome measures not suitable for meta-analysis,40 or means or standard deviations of pretest and posttest data or standard deviations of change scores were not included in the publication and were not provided by the authors on request.4146 The remaining 18 studies met our selection criteria and were included in the meta-analysis (Figure 1).4764 The interrater reliability for this assessment was κ = 0.92.

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Figure 1. Study Selection
Graphic Jump Location

FMS indicates fibromyalgia syndrome.

Meta-analyses

The effect sizes for all antidepressants are shown in Figures 2, 3, 4, 5, and 6. Quiz Ref IDThere was strong evidence for a reduction of pain (SMD, −0.43; 95% confidence interval [CI], −0.55 to −0.30; P < .001), fatigue (SMD, −0.13; 95% CI, −0.26 to −0.01; P = .04), and depressed mood (SMD, −0.26; 95% CI, −0.39 to −0.12; P < .001) and improved sleep (SMD, −0.32; 95% CI, −0.46 to −0.18; P < .001) and HRQOL (SMD, −0.31; 95% CI, −0.42 to −0.20; P < .001). Based on Cohen categories for evaluating the magnitude of effect sizes, the effect of antidepressant therapy was negligible for fatigue and small for remaining outcomes.

Place holder to copy figure label and caption
Figure 2. Effectiveness of Antidepressants in Fibromyalgia for the Outcome Pain
Graphic Jump Location

CI indicates confidence interval; SMD, standardized mean difference.

Place holder to copy figure label and caption
Figure 3. Effectiveness of Antidepressants in Fibromyalgia for the Outcome Fatigue
Graphic Jump Location

CI indicates confidence interval; SMD, standardized mean difference.

Place holder to copy figure label and caption
Figure 4. Effectiveness of Antidepressants in Fibromyalgia for the Outcome Sleep
Graphic Jump Location

CI indicates confidence interval; SMD, standardized mean difference.

Place holder to copy figure label and caption
Figure 5. Effectiveness of Antidepressants in Fibromyalgia for the Outcome Depressed Mood
Graphic Jump Location

CI indicates confidence interval; SMD, standardized mean difference.

Place holder to copy figure label and caption
Figure 6. Effectiveness of Antidepressants in Fibromyalgia for the Outcome Health-Related Quality of Life
Graphic Jump Location

CI indicates confidence interval; SMD, standardized mean difference.

Table 1 gives a comparison of the effect sizes of each antidepressant class. There was strong evidence for the efficacy of the TCA amitriptyline in reducing pain (SMD, −1.64; 95% CI, −2.57 to −0.71; P < .001), fatigue (SMD, −1.12; 95% CI, −1.87 to −0.38; P = .003), and sleep disturbances (WMD, −1.84; 95% CI −2.62 to −1.06; P < .001). Based on Cohen categories, these effect sizes were large. The effect size on depressed mood (WMD, −0.60; 95% CI, −4.53 to 3.33; P = .76) was not significant. The effect on HRQOL was small (WMD, −0.31; 95% CI, −0.60 to −0.01; P = .04).

Table Graphic Jump LocationTable 1. Effect Sizes of the Different Classes of Antidepressants on Selected Outcome Variables

There was strong evidence for the efficacy of the SSRIs fluoxetine and paroxetine in reducing pain (SMD, −0.39; 95% CI, −0.77 to −0.01; P = .04). The effects were small on depressed mood (WMD, −0.37; 95% CI, −0.66 to −0.07, P = .02) and HRQOL (WMD, −0.41; 95% CI, −0.78 to −0.05, P = .03). There were no effects on fatigue (WMD, −0.17; 95% CI, −0.47 to 0.12, P = .25) or sleep (SMD, −0.23; 95% CI, −0.56 to 0.10, P = .18).

There was strong evidence for the efficacy of the SNRIs duloxetine and milnacipran in reducing pain (SMD, −0.36; 95% CI, −0.46 to −0.25; P < .001) and sleep disturbances (SMD, −0.31; 95% CI, −0.47 to −0.14; P < .001). There was strong evidence for the efficacy of duloxetine in improving depressed mood (SMD, −0.26; 95% CI, −0.42 to −0.10; P = .001) and HRQOL (SMD, −0.31; 95% CI, −0.44 to −0.17; P < .001). Based on Cohen categories for the magnitude of effect size, these effect sizes were small. There was no effect of duloxetine on fatigue (WMD, −0.08; 95% CI, −0.20 to 0.05; P = .23).

There was strong evidence for the efficacy of the MAOIs moclobemide and pirlindole in reducing pain (SMD, −0.54; 95% CI, −1.02 to −0.07; P = .03). There was no evidence of efficacy for moclobemide on fatigue (WMD, 0.30; 95% CI, −1.04 to 1.64; P = .66) or sleep disturbances (WMD, 1.00; 95% CI, −0.49 to 2.49; P = .19). There was no effect of pirlindole on depressed mood (WMD, 0.18; 95% CI, −2.16 to 2.52; P = .88).

Median rates of reported adverse effects (antidepressants, 75.5%, vs placebo, 62.5%; P = .49) and dropout due to adverse effects (antidepressants, 15.7%; placebo, 8.1%; P = .18) did not differ between treatment and placebo groups. Only 3 studies differentiated the degree of adverse effects (slight, moderate, severe).50,59,64 The median frequency of severe adverse effects was not different between treatment and placebo (2.30% vs 2.95%; P  = .60).

Validity Analysis

Characteristics of included studies are presented in Table 2. Interrater reliability for characteristics shown in Table 2 was κ = 0.89.

Seven studies had a multicenter design. Eleven had a single-center design. Sixteen studies used a parallel design and 2 used a crossover design. Tricyclic or tetracyclic antidepressants were investigated in 7 studies (amitriptyline in 7, nortriptyline in 1), and MAOIs in 3 (moclobemide in 2, pirlindole in 1). Selective serotonin reuptake inhibitors were investigated in 6 studies (fluoxetine in 3, citalopram in 2, paroxetine in 1). Four RCTs studied SNRIs (duloxetine in 3, milnacipran in 1). Five studies had multiple groups: Arnold et al50 compared duloxetine (60 and 120 mg/d) with placebo. Russell et al64 compared duloxetine (20-60 mg/d, 60 mg/d, and 120 mg/d) with placebo. Goldenberg et al55 compared fluoxetine, amitriptyline, and the combination of both drugs with placebo. Hannonen et al56 compared moclobemide and amitriptyline with placebo. Heymann et al57 compared amitriptyline and nortriptyline with placebo.

The median duration of the RCTs was 8 weeks (range, 4-28 weeks). Outcomes were assessed at the end of the treatment. No study measured outcomes at an additional follow-up visit after treatment cessation.

Serum antidepressant levels were not measured in any RCTs to assess patients' adherence. All RCTs allowed additional therapy with paracetamol or acetaminophen. Eight allowed therapy with paracetamol or acetaminophen in combination with acetylsalicylic acid or nonsteroidal anti-inflammatory drugs or codeine. Seven studies reported a defined dosage of the allowed comedication. No study controlled for additional therapy with comedication. No study provided detailed information about nonpharmacological therapies or controlled for nonpharmacological therapies.

Ten studies performed a power analysis to ensure an adequate sample size. Five studies had a Jadad score of 5, 8 had a Jadad score of 4, and 5 had a Jadad score less than 4. Eleven studies had a van Tulder score of 5 to 7, and 7 studies had scores of 8 to 11. Only 4 studies were high on both measures.49,56,57,59 Interrater reliability for this assessment was κ = 0.89.

There was significant heterogeneity between the analyzed RCTs in most outcome measures. The large ranges of the 95% CIs are also indicative of marked variations between the studies.

Eleven studies were performed in North America or Puerto Rico, 1 was performed in Brazil, 5 were performed in western Europe (Scandinavia, Belgium), and 1 was performed in Turkey. All studies were outpatient-based. Patients were recruited from rheumatology departments in 11 studies, from research centers in 3 studies, and from a psychiatric department in 1 study. Three publications did not report the recruitment setting.

All studies excluded patients with severe somatic diseases. Eleven excluded patients with severe mental disorders. Ten excluded specific age categories (<18 or >60 years). Four excluded patients with pending applications for disability. A total of 1427 individuals completed treatment. Of these, 916 were receiving antidepressants. The median percentages of patients completing the trials were 71.0% for participants randomized to antidepressants and 78.0% for participants randomized to placebo (P = .78). The median age of study participants was 47.0 years. Seven studies included only women; 10 included both men and women, and 1 study did not specify participant sex. The median percentage of women in all studies was 98%. Ten studies reported the participants' race. Among these, the median percentage of white participants was 89.5%. Fibromyalgia syndrome was defined in 16 studies according to the ACR criteria.2 One study defined FMS according to Yunus,19 and 1 study defined FMS according to Smythe and Moldofsky.18 No study provided data on nonpsychiatric comorbidities. Five studies provided data on the prevalence of major depressive disorder (up to 35%). Three studies provided information on working status (working, sick leave, or disability). Potential participants considered treatment refractory were excluded in 2 studies.

Publication Bias

Visual scanning of forest plots for subgroup analysis suggested a random distribution with results in the same direction for most outcomes, indicating that although study effect sizes differed, results were mostly consistent (data not shown). The fail-safe number with a D = 0.01 as the selected criterion value to “nullify” the average effect on pain was n = 924; on fatigue, n = 168; on sleep, n = 403; on depressed mood, n = 250; and on HRQOL, n = 360. Thus the fail-safe numbers were larger than Rosenthal rule of thumb28 of n = 120 for pain, n = 80 for fatigue, n = 75 for sleep, n = 60 for depressed mood, and n = 70 for HRQOL. These results indicate that a publication bias is unlikely to change the overall results of this meta-analysis.

The primary aim of this meta-analysis was to determine the efficacy of antidepressants for treatment of FMS. We found strong evidence for the efficacy of antidepressants in reducing pain, sleep disturbances, and depressed mood and for improving HRQOL. All effect sizes were small. We found strong evidence against a favorable effect of antidepressants on fatigue.

Quiz Ref IDWe found large effect sizes of TCAs for reducing pain, fatigue, and sleep disturbances; small effect sizes of SSRIs for reducing pain; small effect sizes of SNRIs for reducing pain, sleep disturbances, and depressed mood; and small effect sizes of MAOIs for reducing pain. Conclusions regarding the efficacy of single drugs on outcomes were limited because of small sample sizes. Of the antidepressants studied, duloxetine is the only one that has been approved by the Food and Drug Administration for treating FMS.65

Three studies that did not meet inclusion criteria for this meta-analysis were head-to-head comparisons of antidepressant drugs. Of these, 1 study found that paroxetine was superior to amitriptyline in reducing pain,41 while another study found that amitriptyline was superior to paroxetine in reducing pain and sleep disturbances.42 A third study found no difference between amitriptyline and fluoxetine in reducing sleepiness.40 Overall, none of these head-to-head comparisons of different antidepressant classes nor this meta-analysis allows a definitive conclusion regarding superiority of one class of antidepressants over another.

Doses of TCAs used in the studies, between 12.5 and 50 mg per day, were typical for pain treatment but far below the doses of TCAs necessary for an antidepressant benefit. This likely explains the positive association of TCAs for reducing pain in the absence of a benefit for depressive symptoms. In contrast, doses of SSRIs and SNRIs were equal to those used for treating affective disorders. However, we could only find an effect of SNRIs on depressed mood.

Quiz Ref IDThe internal validity of the RCTs analyzed was limited for the following reasons. First, serum antidepressant levels were not measured in any RCTs to assess patients' adherence. Second, no study controlled for consumption, dose, or adverse effects of concomitant analgesic medications. The influence of this comedication on study outcomes is unclear. Third, 3 studies of duloxetine used a 1-week, single-blind, placebo-lead-in phase. Medication adverse effects indicating the presence of active drug may have biased the duloxetine trials more than other studies. Finally, some studies did not report the results of all outcomes assessed.

The external validity of the RCTs analyzed was limited by the following. Quiz Ref IDFirst, the short duration of most studies and the lack of follow-up after treatment cessation leave unanswered whether antidepressants have long-term beneficial effects on FMS symptoms and the optimal treatment duration. One excluded RCT failed to demonstrate an advantage of amitriptyline over placebo regarding pain, sleep disturbances, and fatigue after 26 weeks.43 Second, despite evidence of higher prevalences of mental disorders in FMS,10 only 6 studies performed a standardized psychiatric interview. Only 3 studies performed subgroup analyses among participants with vs without major depressive disorder. The effects of duloxetine on pain did not differ between FMS patients with vs without major depressive disorder.49,50,64 Therefore, only duloxetine has demonstrated efficacy in FMS patients both with and without major depressive disorder. Third, no definitive statements are possible on the efficacy of antidepressants in men, nonwhite individuals, patients older than 65 years, children, and adolescents because these subgroups were not analyzed, with the exception of 2 studies with duloxetine: 1 study found no significant response in primary and secondary outcomes in male patients.49 Another study reported similar significant pain reduction between women and men.64 One study reported similar results among racial groups and patients aged 65 years and younger.64 Fourth, since most studies excluded patients with severe somatic diseases, including inflammatory arthritic diseases, it is unknown whether antidepressants are effective in these patients with FMS. Finally, 2 duloxetine studies excluded patients who were judged by the investigator to be treatment refractory.50,64 This procedure could have favored the outcomes of the treatment group.

Our findings are mainly consistent with published literature. The meta-analysis of O’Malley et al13 included 9 studies with TCAs, 3 studies with SSRIs, and 2 studies with S-adenosylmethionine. Medium effect sizes were reported for improving pain, sleep, and fatigue. Sensitivity analysis by way of meta-regression revealed no effect of drug class.13 Differences between results of the meta-analysis of O’Malley et al and our review regarding class effects are due to the fact that we analyzed more studies with TCAs and SSRIs and included RCTs of MAOIs and SNRIs. In addition, the studies failing to demonstrate an advantage of citalopram over placebo47,58 were published after the meta-analysis by O’Malley et al. Arnold et al14 included 9 studies (6 with TCAs and 3 with cyclobenzaprine) into a meta-analysis and found a global effect size of 0.44 for pain, sleep, tenderness, fatigue, and sleep.

This review has limitations. First, since demographics and comorbidities of study participants and the amount of comedication were not reported, these possible sources of heterogeneity could not be examined. Second, we did not seek to identify unpublished studies. Third, 6 RCTs were excluded because the published data were not suitable for meta-analysis, and necessary data were not provided by the authors on request. With the exception of 1 study, which failed to demonstrate an advantage of amitriptyline over placebo regarding pain, sleep disturbances, and fatigue after 26 weeks,43 the other 5 studies excluded from the meta-analysis reported an advantage of amitriptyline41,42,45,46 or paroxetine41,42,44 over placebo regarding pain and sleep disturbances that was consistent with our results. Fourth, there are limitations of some methods used in this article, such as using I2 for assessing the amount of heterogeneity in random-effects meta-analysis66,67 and fail-safe numbers68 for excluding a publication bias.

Short-term usage of amitriptyline and duloxetine can be considered for the treatment of pain and sleep disturbances in FMS. This recommendation is based on the number of patients studied (duloxetine) and on the effect sizes (amitriptyline). Before treatment is initiated, concomitant diseases related to potential adverse effects of the drugs and patients' preferences should be considered. Goals of pharmacological therapy should be defined (no cure, but possible symptom reduction). Since evidence for a long-term effect of antidepressants in FMS is still lacking, their effects should be reevaluated at regular intervals to determine whether benefits outweigh adverse effects.

Studies of longer duration than those currently available are needed to investigate the long-term efficacy of antidepressant therapy for FMS. It is currently unknown whether benefits of antidepressants for treatment of FMS persist after cessation of therapy. It is also unknown whether antidepressants reduce FMS-related costs.9 The identification of patient characteristics associated with positive and negative therapeutic outcomes are needed to better target antidepressant therapy for FMS. Future studies of the effects of antidepressants on FMS should include patients with somatic and mental comorbidities and fully report all patient characteristics and outcomes assessed.69

Corresponding Author: Winfried Häuser, MD, Klinikum Saarbrücken, Winterberg 1, D-66119 Saarbrücken, Germany (whaeuser@klinikum-saarbruecken.de).

Author Contributions: Dr Häuser had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Häuser, Üçeyler, Sommer.

Acquisition of data: Häuser, Bernardy, Üçeyler, Sommer.

Analysis and interpretation of data: Häuser, Bernardy, Üçeyler, Sommer.

Drafting of the manuscript: Häuser, Bernardy.

Critical revision of the manuscript for important intellectual content: Häuser, Bernardy, Üçeyler, Sommer.

Statistical analysis: Häuser, Bernardy.

Obtained funding: Häuser, Bernardy, Üçeyler.

Administrative, technical, or material support: Sommer.

Study supervision: Häuser, Sommer.

Financial Disclosures: The authors reported that none has been employed by pharmaceutical companies and that none has stock, options, grants, patents, or pending royalties. Dr Häuser reported receiving honoraria for educational talks from Lilly, Mundipharma, Pfizer, and Janssen-Cilag. Dr Häuser reported that he will receive consulting honoraria from Lilly and Pfizer. Dr Bernardy and Dr Häuser reported receiving travel grants for scientific conferences by Lilly and Pfizer. Dr Sommer reported receiving honoraria for educational talks from Boehringer Ingelheim, Genzyme, Pfizer, and Schwarz-Pharma.

Funding/Support: The study was supported by grants from the German Rheumatology League and German Fibromyalgia Association, German Ministry of Education and Research (Bundesministerium für Bildung und Forschung), German Research Network on Neuropathic Pain, and intramural funds of the University of Würzburg (Germany).

Role of the Sponsor: The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

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Henriksson CM, Liedberg GM, Gerdle B. Women with fibromyalgia: work and rehabilitation.  Disabil Rehabil. 2005;27(12):685-694
PubMed   |  Link to Article
Robinson RL, Jones ML. In search of pharmacoeconomic evaluations for fibromyalgia treatments: a review.  Expert Opin Pharmacother. 2006;7(8):1027-1039
PubMed   |  Link to Article
Henningsen P, Zipfel S, Herzog W. Management of functional somatic syndromes.  Lancet. 2007;369(9565):946-955
PubMed   |  Link to Article
Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia syndrome.  JAMA. 2004;292(19):2388-2395
PubMed   |  Link to Article
Carville SF, Arendt-Nielsen S, Bliddal H,  et al; EULAR.  EULAR evidence-based recommendations for the management of fibromyalgia syndrome.  Ann Rheum Dis. 2008;67(4):536-541
PubMed   |  Link to Article
O’Malley PG, Balden E, Tomkins G, Santoro J, Kroenke K, Jackson JL. Treatment of fibromyalgia with antidepressants: a meta-analysis.  J Gen Intern Med. 2000;15(9):659-666
PubMed   |  Link to Article
Arnold LM, Keck PE Jr, Welge JA. Antidepressant treatment of fibromyalgia: a meta-analysis and review.  Psychosomatics. 2000;41(2):104-113
PubMed   |  Link to Article
Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement: Quality of Reporting of Meta-analyses.  Lancet. 1999;354(9193):1896-1900
PubMed   |  Link to Article
Bero L, Rennie D. The Cochrane Collaboration: preparing, maintaining, and disseminating systematic reviews of the effects of health care.  JAMA. 1995;274(24):1935-1938
PubMed   |  Link to Article
Robinson KA, Dickersin K. Development of a highly sensitive search strategy for the retrieval of reports of controlled trials using PubMed.  Int J Epidemiol. 2002;31(1):150-153
PubMed   |  Link to Article
Smythe HA, Moldofsky H. Two contributions to understanding of the ‘fibrositis’ syndrome.  Bull Rheum Dis. 1977;28(1):928-931
PubMed
Yunus MB. Primary fibromyalgia syndrome: a critical evaluation of recent criteria developments.  Z Rheumatol. 1989;48(5):217-222
PubMed
Mease PJ, Arnold LM, Crofford LJ,  et al.  Identifying the clinical domains of fibromyalgia: contributions from clinician and patient Delphi exercises.  Arthritis Rheum. 2008;59(7):952-960
PubMed   |  Link to Article
van Tulder M, Furlan A, Bombardier C, Bouter L.Editorial Board of the Cochrane Collaboration Back Review Group.  Updated method guidelines for systematic reviews in the Cochrane Collaboration Back Review Group.  Spine. 2003;28(12):1290-1299
PubMed
Jadad AR, Moore RA, Carroll D,  et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary?  Control Clin Trials. 1996;17(1):1-12
PubMed   |  Link to Article
 Review Manager (RevMan) version 4.2.10 [computer program]. The Nordic Cochrane Centre, The Cochrane Collaboration; 2003
Altman DG, Bland JM. Standard deviations and standard errors.  BMJ. 2005;331(7521):903
PubMed   |  Link to Article
Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, OK: Lawrence Erlbaum Assoc; 1988
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test.  BMJ. 1997;315(7109):629-634
PubMed   |  Link to Article
Orwin RG. A fail-safe N for effect size in meta-analysis.  J Stat Educat. 1983;8:157-159
Link to Article
Rosenthal R. The “file drawer problem” and tolerance for null results.  Psychol Bull. 1979;86:638-641
Link to Article
Hayashino Y, Noguchi Y, Fukui T. Systematic evaluation and comparison of statistical tests for publication bias.  J Epidemiol. 2005;15(6):235-243
PubMed   |  Link to Article
Bibolotti E, Borghi C, Pasculli E. The management of fibrositis: a double-blind comparison of maprotiline (Ludiomil) and placebo.  Clin Trials J. 1986;23:269-280
Gendreau RM, Thorn MD, Gendreau JF,  et al.  Efficacy of milnacipran in patients with fibromyalgia.  J Rheumatol. 2005;32(10):1975-1985
PubMed
Jaeschke R, Adachi J, Guyatt G, Keller J, Wong B. Clinical usefulness of amitriptyline in fibromyalgia: the results of 23 N-of-1 randomized controlled trials.  J Rheumatol. 1991;18(3):447-451
PubMed
Cantini F, Bellandi F, Niccoli L, Di Munno O. Fluoxetin combined with cyclobenzaprine in the treatment of fibromyalgia [in Italian].  Minerva Med. 1994;85(3):97-100
PubMed
Isomeri R, Mikkelsson M, Latikka P, Kammonen K. Effects of amitriptyline and cardiovascular fitness training on pain in patients with primary fibromyalgia.  J Musculoskel Pain. 1993;1:253-260
Link to Article
Fors EA, Sexton H, Gotestam KG. The effect of guided imagery and amitriptyline on daily fibromyalgia pain: a prospective, randomized, controlled trial.  J Psychiatr Res. 2002;36(3):179-187
PubMed   |  Link to Article
Gonzalez-Viejo MA, Avellanet M, Hernandez-Morcuende MI. A comparative study of fibromyalgia treatment: ultrasonography and physiotherapy versus sertraline treatment [in French].  Ann Readapt Med Phys. 2005;48(8):610-615
PubMed   |  Link to Article
Gür A, Karakoç M, Nas K, Çevik R, Saraç J, Ataoğlu S. Effects of low power laser and low dose amitriptyline therapy on clinical symptoms and quality of life in fibromyalgia: a single-blind, placebo-controlled trial.  Rheumatol Int. 2002;22(5):188-193
PubMed   |  Link to Article
Sencan S, Aki S, Karan A, Müslümanoglu L, Ozcan E, Berker E. A study to compare the therapeutic efficacy of aerobic exercise and paroxetine in fibromyalgia syndrome.  Back Musculoskeletal Rehabil. 2004;17(2):57-61
Targino RA, Imamura M, Kaziyama HH,  et al.  A randomized controlled trial of acupuncture added to usual treatment for fibromyalgia.  J Rehabil Med. 2008;40(7):582-588
PubMed   |  Link to Article
Ozerbil O, Okudan N, Gökbel H, Levendoğlu F. Comparison of the effects of two antidepressants on exercise performance of the female patients with fibromyalgia.  Clin Rheumatol. 2006;25(4):495-497
PubMed   |  Link to Article
Ataoğlu S, Ataoğlu A, Erdoğan F, Saraç J. Comparison of paroxetine, amitriptyline in the treatment of fibromyalgia.  Turk J Med Sci. 1997;27:535-539
Çapaci K, Hepgüler S. Comparison of the effect of amitriptyline and paroxetine in the treatment of fibromyalgia syndrome.  Pain Clin. 2002;14:223-228
Link to Article
Carette S, Bell MJ, Reynolds WJ,  et al.  Comparison of amitriptyline, cyclobenzaprine, and placebo in the treatment of fibromyalgia: a randomized, double-blind clinical trial.  Arthritis Rheum. 1994;37(1):32-40
PubMed   |  Link to Article
Giordano N, Geraci S, Santacroce C, Mattii G, Battisti E, Gennari C. Efficacy and tolerability of paroxetine in patients with fibromyalgia syndrome: a single-blind study.  Cur Ther Res. 1999;60:696-702
Link to Article
Goldenberg DL, Felson DT, Dinerman H. A randomized, controlled trial of amitriptyline and naproxen in the treatment of patients with fibromyalgia.  Arthritis Rheum. 1986;29(11):1371-1377
PubMed   |  Link to Article
Scudds RA, McCain GA, Rollman GB, Harth M. Improvements in pain responsiveness in patients with fibrositis after successful treatment with amitriptyline.  J Rheumatol Suppl. 1989;19:98-103
PubMed
Anderberg UM, Marteinsdottir I, von Knorring L. Citalopram in patients with fibromyalgia: a randomized, double-blind, placebo-controlled study.  Eur J Pain. 2000;4(1):27-35
PubMed   |  Link to Article
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.  Am J Med. 2002;112(3):191-197
PubMed   |  Link to Article
Arnold LM, Lu Y, Crofford LJ,  et al.  A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder.  Arthritis Rheum. 2004;50(9):2974-2984
PubMed   |  Link to Article
Arnold LM, Rosen A, Pritchett YL,  et al.  A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder.  Pain. 2005;119(1-3):5-15
PubMed   |  Link to Article
Carette S, McCain GA, Bell DA, Fam AG. Evaluation of amitriptyline in primary fibrositis: a double-blind, placebo-controlled study.  Arthritis Rheum. 1986;29(5):655-659
PubMed   |  Link to Article
Carette S, Oakson G, Guimont C, Steriade M. Sleep electroencephalography and the clinical response to amitriptyline in patients with fibromyalgia.  Arthritis Rheum. 1995;38(9):1211-1217
PubMed   |  Link to Article
Ginsberg F, Joos E, Geczy J, Bruhwyler J, Vandekerckhove K, Famaey JP. A pilot randomized placebo-controlled study of pirlindole in the treatment of primary fibromyalgia.  J Musculoskeletal Pain. 1998;6:6-17
Link to Article
Ginsberg F, Mancaux A, Joos E, Vanhove P, Famaey JP. A randomized placebo-controlled trial of sustained-release amitriptyline in primary fibromyalgia.  J Musculoskeletal Pain. 1996;4:37-47
Link to Article
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 Rheum. 1996;39(11):1852-1859
PubMed   |  Link to Article
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.  Br J Rheumatol. 1998;37(12):1279-1286
PubMed   |  Link to Article
Heymann RE, Helfenstein M, Feldman D. A double-blind, randomized, controlled study of amitriptyline, nortriptyline and placebo in patients with fibromyalgia: an analysis of outcome measures.  Clin Exp Rheumatol. 2001;19(6):697-702
PubMed
Nørregaard J, Volkmann H, Danneskiold-Samsoe B. A randomized controlled trial of citalopram in the treatment of fibromyalgia.  Pain. 1995;61(3):445-449
PubMed   |  Link to Article
Patkar AA, Masand PS, Krulewicz S,  et al.  A randomized, controlled trial of controlled release paroxetine in fibromyalgia.  Am J Med. 2007;120(5):448-454
PubMed   |  Link to Article
Vitton O, Gendreau M, Gendreau J, Kranzler J, Rao SG. A double-blind placebo-controlled trial of milnacipran in the treatment of fibromyalgia.  Hum Psychopharmacol. 2004;19:(suppl 1)  S27-S35
PubMed   |  Link to Article
Wolfe F, Cathey MA, Hawley DJ. A double-blind placebo controlled trial of fluoxetine in fibromyalgia.  Scand J Rheumatol. 1994;23(5):255-259
PubMed   |  Link to Article
Yavuzer G, Küçükdeveci A, Arasli T, Elhan A. Moclobemid treatment in primary fibromyalgia syndrome.  Eur J Phys Med Rehabil. 1998;8:35-38
Kempenaers C, Simenon G, Vander Elst M,  et al.  Effect of an antidiencephalon immune serum on pain and sleep in primary fibromyalgia.  Neuropsychobiology. 1994;30(2-3):66-72
PubMed   |  Link to Article
Russell IJ, Mease PJ, Smith TR,  et al.  Efficacy and safety of duloxetine for treatment of fibromyalgia in patients with or without major depressive disorder: results from a 6-month, randomized, double-blind, placebo-controlled, fixed-dose trial.  Pain. 2008;136(3):432-444
PubMed   |  Link to Article
 Living with fibromyalgia, drugs approved to manage pain. US Food and Drug Administration consumer updates. http://www.fda.gov/consumer/updates/fibromyalgia062107.html. Accessed December 10, 2008
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses.  BMJ. 2003;327(7414):557-560
PubMed   |  Link to Article
Knapp G, Biggerstaff BJ, Hartung J. Assessing the amount of heterogeneity in random-effects meta-analysis.  Biom J. 2006;48(2):271-285
PubMed   |  Link to Article
Terrin N, Schmid CH, Lau J, Olkin I. Adjusting for publication bias in the presence of heterogeneity.  Stat Med. 2003;22(13):2113-2126
PubMed   |  Link to Article
Uceyler N, Häuser W, Sommer C. A systematic review on the effectiveness of treatment with antidepressants in fibromyalgia syndrome.  Arthritis Rheum. 2008;59(9):1279-1298
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Study Selection
Graphic Jump Location

FMS indicates fibromyalgia syndrome.

Place holder to copy figure label and caption
Figure 2. Effectiveness of Antidepressants in Fibromyalgia for the Outcome Pain
Graphic Jump Location

CI indicates confidence interval; SMD, standardized mean difference.

Place holder to copy figure label and caption
Figure 3. Effectiveness of Antidepressants in Fibromyalgia for the Outcome Fatigue
Graphic Jump Location

CI indicates confidence interval; SMD, standardized mean difference.

Place holder to copy figure label and caption
Figure 4. Effectiveness of Antidepressants in Fibromyalgia for the Outcome Sleep
Graphic Jump Location

CI indicates confidence interval; SMD, standardized mean difference.

Place holder to copy figure label and caption
Figure 5. Effectiveness of Antidepressants in Fibromyalgia for the Outcome Depressed Mood
Graphic Jump Location

CI indicates confidence interval; SMD, standardized mean difference.

Place holder to copy figure label and caption
Figure 6. Effectiveness of Antidepressants in Fibromyalgia for the Outcome Health-Related Quality of Life
Graphic Jump Location

CI indicates confidence interval; SMD, standardized mean difference.

Tables

Table Graphic Jump LocationTable 1. Effect Sizes of the Different Classes of Antidepressants on Selected Outcome Variables

References

Gran JT. The epidemiology of chronic generalized musculoskeletal pain.  Best Pract Res Clin Rheumatol. 2003;17(4):547-561
PubMed   |  Link to Article
Wolfe F, Smythe HA, Yunus MB,  et al; Report of the Multicenter Criteria Committee.  The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia.  Arthritis Rheum. 1990;33(2):160-172
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Bennett RM, Jones J, Turk DC, Russell IJ, Matallana L. An internet survey of 2,596 people with fibromyalgia.  BMC Musculoskelet Disord. 2007;8:27
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Häuser W, Zimmer C, Felde E, Kollner V. What are the key symptoms of fibromyalgia? results of a survey of the German Fibromyalgia Association [in German].  Schmerz. 2008;22(2):176-183
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Wolfe F, Anderson J, Harkness D,  et al.  Work and disability status of persons with fibromyalgia.  J Rheumatol. 1997;24(6):1171-1178
PubMed
Boonen A, van den Heuvel R, van Tubergen A,  et al.  Large differences in cost of illness and wellbeing between patients with fibromyalgia, chronic low back pain, or ankylosing spondylitis.  Ann Rheum Dis. 2005;64(3):396-402
PubMed   |  Link to Article
Penrod JR, Bernatsky S, Adam V, Baron M, Dayan N, Dobkin PL. Health services costs and their determinants in women with fibromyalgia.  J Rheumatol. 2004;31(7):1391-1398
PubMed
Henriksson CM, Liedberg GM, Gerdle B. Women with fibromyalgia: work and rehabilitation.  Disabil Rehabil. 2005;27(12):685-694
PubMed   |  Link to Article
Robinson RL, Jones ML. In search of pharmacoeconomic evaluations for fibromyalgia treatments: a review.  Expert Opin Pharmacother. 2006;7(8):1027-1039
PubMed   |  Link to Article
Henningsen P, Zipfel S, Herzog W. Management of functional somatic syndromes.  Lancet. 2007;369(9565):946-955
PubMed   |  Link to Article
Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia syndrome.  JAMA. 2004;292(19):2388-2395
PubMed   |  Link to Article
Carville SF, Arendt-Nielsen S, Bliddal H,  et al; EULAR.  EULAR evidence-based recommendations for the management of fibromyalgia syndrome.  Ann Rheum Dis. 2008;67(4):536-541
PubMed   |  Link to Article
O’Malley PG, Balden E, Tomkins G, Santoro J, Kroenke K, Jackson JL. Treatment of fibromyalgia with antidepressants: a meta-analysis.  J Gen Intern Med. 2000;15(9):659-666
PubMed   |  Link to Article
Arnold LM, Keck PE Jr, Welge JA. Antidepressant treatment of fibromyalgia: a meta-analysis and review.  Psychosomatics. 2000;41(2):104-113
PubMed   |  Link to Article
Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement: Quality of Reporting of Meta-analyses.  Lancet. 1999;354(9193):1896-1900
PubMed   |  Link to Article
Bero L, Rennie D. The Cochrane Collaboration: preparing, maintaining, and disseminating systematic reviews of the effects of health care.  JAMA. 1995;274(24):1935-1938
PubMed   |  Link to Article
Robinson KA, Dickersin K. Development of a highly sensitive search strategy for the retrieval of reports of controlled trials using PubMed.  Int J Epidemiol. 2002;31(1):150-153
PubMed   |  Link to Article
Smythe HA, Moldofsky H. Two contributions to understanding of the ‘fibrositis’ syndrome.  Bull Rheum Dis. 1977;28(1):928-931
PubMed
Yunus MB. Primary fibromyalgia syndrome: a critical evaluation of recent criteria developments.  Z Rheumatol. 1989;48(5):217-222
PubMed
Mease PJ, Arnold LM, Crofford LJ,  et al.  Identifying the clinical domains of fibromyalgia: contributions from clinician and patient Delphi exercises.  Arthritis Rheum. 2008;59(7):952-960
PubMed   |  Link to Article
van Tulder M, Furlan A, Bombardier C, Bouter L.Editorial Board of the Cochrane Collaboration Back Review Group.  Updated method guidelines for systematic reviews in the Cochrane Collaboration Back Review Group.  Spine. 2003;28(12):1290-1299
PubMed
Jadad AR, Moore RA, Carroll D,  et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary?  Control Clin Trials. 1996;17(1):1-12
PubMed   |  Link to Article
 Review Manager (RevMan) version 4.2.10 [computer program]. The Nordic Cochrane Centre, The Cochrane Collaboration; 2003
Altman DG, Bland JM. Standard deviations and standard errors.  BMJ. 2005;331(7521):903
PubMed   |  Link to Article
Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, OK: Lawrence Erlbaum Assoc; 1988
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test.  BMJ. 1997;315(7109):629-634
PubMed   |  Link to Article
Orwin RG. A fail-safe N for effect size in meta-analysis.  J Stat Educat. 1983;8:157-159
Link to Article
Rosenthal R. The “file drawer problem” and tolerance for null results.  Psychol Bull. 1979;86:638-641
Link to Article
Hayashino Y, Noguchi Y, Fukui T. Systematic evaluation and comparison of statistical tests for publication bias.  J Epidemiol. 2005;15(6):235-243
PubMed   |  Link to Article
Bibolotti E, Borghi C, Pasculli E. The management of fibrositis: a double-blind comparison of maprotiline (Ludiomil) and placebo.  Clin Trials J. 1986;23:269-280
Gendreau RM, Thorn MD, Gendreau JF,  et al.  Efficacy of milnacipran in patients with fibromyalgia.  J Rheumatol. 2005;32(10):1975-1985
PubMed
Jaeschke R, Adachi J, Guyatt G, Keller J, Wong B. Clinical usefulness of amitriptyline in fibromyalgia: the results of 23 N-of-1 randomized controlled trials.  J Rheumatol. 1991;18(3):447-451
PubMed
Cantini F, Bellandi F, Niccoli L, Di Munno O. Fluoxetin combined with cyclobenzaprine in the treatment of fibromyalgia [in Italian].  Minerva Med. 1994;85(3):97-100
PubMed
Isomeri R, Mikkelsson M, Latikka P, Kammonen K. Effects of amitriptyline and cardiovascular fitness training on pain in patients with primary fibromyalgia.  J Musculoskel Pain. 1993;1:253-260
Link to Article
Fors EA, Sexton H, Gotestam KG. The effect of guided imagery and amitriptyline on daily fibromyalgia pain: a prospective, randomized, controlled trial.  J Psychiatr Res. 2002;36(3):179-187
PubMed   |  Link to Article
Gonzalez-Viejo MA, Avellanet M, Hernandez-Morcuende MI. A comparative study of fibromyalgia treatment: ultrasonography and physiotherapy versus sertraline treatment [in French].  Ann Readapt Med Phys. 2005;48(8):610-615
PubMed   |  Link to Article
Gür A, Karakoç M, Nas K, Çevik R, Saraç J, Ataoğlu S. Effects of low power laser and low dose amitriptyline therapy on clinical symptoms and quality of life in fibromyalgia: a single-blind, placebo-controlled trial.  Rheumatol Int. 2002;22(5):188-193
PubMed   |  Link to Article
Sencan S, Aki S, Karan A, Müslümanoglu L, Ozcan E, Berker E. A study to compare the therapeutic efficacy of aerobic exercise and paroxetine in fibromyalgia syndrome.  Back Musculoskeletal Rehabil. 2004;17(2):57-61
Targino RA, Imamura M, Kaziyama HH,  et al.  A randomized controlled trial of acupuncture added to usual treatment for fibromyalgia.  J Rehabil Med. 2008;40(7):582-588
PubMed   |  Link to Article
Ozerbil O, Okudan N, Gökbel H, Levendoğlu F. Comparison of the effects of two antidepressants on exercise performance of the female patients with fibromyalgia.  Clin Rheumatol. 2006;25(4):495-497
PubMed   |  Link to Article
Ataoğlu S, Ataoğlu A, Erdoğan F, Saraç J. Comparison of paroxetine, amitriptyline in the treatment of fibromyalgia.  Turk J Med Sci. 1997;27:535-539
Çapaci K, Hepgüler S. Comparison of the effect of amitriptyline and paroxetine in the treatment of fibromyalgia syndrome.  Pain Clin. 2002;14:223-228
Link to Article
Carette S, Bell MJ, Reynolds WJ,  et al.  Comparison of amitriptyline, cyclobenzaprine, and placebo in the treatment of fibromyalgia: a randomized, double-blind clinical trial.  Arthritis Rheum. 1994;37(1):32-40
PubMed   |  Link to Article
Giordano N, Geraci S, Santacroce C, Mattii G, Battisti E, Gennari C. Efficacy and tolerability of paroxetine in patients with fibromyalgia syndrome: a single-blind study.  Cur Ther Res. 1999;60:696-702
Link to Article
Goldenberg DL, Felson DT, Dinerman H. A randomized, controlled trial of amitriptyline and naproxen in the treatment of patients with fibromyalgia.  Arthritis Rheum. 1986;29(11):1371-1377
PubMed   |  Link to Article
Scudds RA, McCain GA, Rollman GB, Harth M. Improvements in pain responsiveness in patients with fibrositis after successful treatment with amitriptyline.  J Rheumatol Suppl. 1989;19:98-103
PubMed
Anderberg UM, Marteinsdottir I, von Knorring L. Citalopram in patients with fibromyalgia: a randomized, double-blind, placebo-controlled study.  Eur J Pain. 2000;4(1):27-35
PubMed   |  Link to Article
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.  Am J Med. 2002;112(3):191-197
PubMed   |  Link to Article
Arnold LM, Lu Y, Crofford LJ,  et al.  A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder.  Arthritis Rheum. 2004;50(9):2974-2984
PubMed   |  Link to Article
Arnold LM, Rosen A, Pritchett YL,  et al.  A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder.  Pain. 2005;119(1-3):5-15
PubMed   |  Link to Article
Carette S, McCain GA, Bell DA, Fam AG. Evaluation of amitriptyline in primary fibrositis: a double-blind, placebo-controlled study.  Arthritis Rheum. 1986;29(5):655-659
PubMed   |  Link to Article
Carette S, Oakson G, Guimont C, Steriade M. Sleep electroencephalography and the clinical response to amitriptyline in patients with fibromyalgia.  Arthritis Rheum. 1995;38(9):1211-1217
PubMed   |  Link to Article
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