Tricyclics Top Other Antidepressants for Fibromyalgia

By John Gever, Senior Editor, MedPage Today
Published: January 13, 2009
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine.

SAARBRUECKEN, Germany, Jan. 13 -- Among antidepressant drugs, low-dose tricyclics showed the best efficacy against fibromyalgia symptoms, although long-term data were lacking, researchers here found in a meta-analysis.

Smaller but significant benefits were also shown for the other major classes of antidepressant medications, reported Winfried Hauser, M.D., of the Klinikum Saarbruecken, and colleagues in the Jan. 14 issue of the Journal of the American Medical Association.

The analysis examined data on nine different agents, including two tricyclics, three selective serotonin reuptake inhibitors, two dual inhibitors of serotonin and noradrenaline reuptake, and two monoamine oxidase inhibitors.

Overall, with data pooled from 18 randomized, placebo-controlled studies, antidepressant treatment was associated with the following improvements in fibromyalgia symptoms, expressed as standard mean differences: (see abstract below)

"All effect sizes were small," the researchers noted, except for tricyclics.

For pain, fatigue, and sleep disturbance, the mean differences for tricyclics were ­-1.64, ­-1.12, and ­-1.84, respectively, indicating large effects.

Only tricyclics showed a significant benefit for fatigue symptoms. No significant reduction in fatigue was seen in the pooled data for the other antidepressant classes.

Dr. Hauser and colleagues said amitriptyline could be considered for short-term symptom relief.

Amitriptyline was the agent tested in the seven included studies of tricyclics; one also included a nortriptyline arm.

Dr. Hauser and colleagues found that tricyclic doses in the studies ranged from 12.5 to 50 mg per day, well below the standard for depression treatment but typical for chronic pain therapy.

The finding undercuts one theory of fibromyalgia, which holds that it is a form or offshoot of depression.

The researchers added that duloxetine (Cymbalta), a dual inhibitor of serotonin and noradrenaline reuptake, could also be recommended for treatment of pain and sleep disturbance.

But they based the recommendation less on the magnitude of the drug's efficacy -- effect sizes did not reach ­­­-0.4, which Dr. Hauser and colleagues characterized as small -- than on the number of patients included in the drug's commercially sponsored studies.

More than 700 patients took duloxetine in three studies included in the meta-analysis, compared with 245 active-treated patients in all the studies of tricyclic antidepressants.

Dr. Hauser and colleagues lamented that the randomized trials they found were all short-term. One lasted 28 weeks, another was 16 weeks, and the rest were no more than 12 weeks.

"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 fibromyalgia symptoms and the optimal treatment duration," the researchers said.

And, except for the duloxetine studies, most were small as well. The eight studies of tricyclics included a total of 446 patients; six studies involving SSRIs involved 331 patients; and three studies of monoamine oxidase inhibitors enrolled 290 patients.

Nearly 1,100 patients took part in the three duloxetine trials included in the meta-analysis.

Dr. Hauser and colleagues noted as well that "no study controlled for consumption, dose, or adverse effects of concomitant analgesic medications," which might have affected outcomes.

They advised clinicians who prescribe antidepressant therapy for fibromyalgia to evaluate patients regularly to assess benefits and adverse effects.

Goals of drug therapy should also be clear, they said, given the evidence that symptom reduction -- not cure -- is the best that can reasonably be expected.

External funding for the analysis came from the German Rheumatology League, the German Fibromyalgia Association, the German Ministry of Education and Research, and the German Research Network on Neuropathic Pain.

Study authors reported relationships with Lilly, Pfizer, Boehringer Ingelheim, Genzyme, and Schwarz Pharma.

Primary source: Journal of the American Medical Association
Source reference: Hauser W, et al "Treatment of fibromyalgia syndrome with antidepressants: a meta-analysis" JAMA 2009; 301: 198-209.


"Before treatment is initiated, [accompanying] 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 re-evaluated at regular intervals to determine whether benefits outweigh adverse effects," the authors write. "The identification of patient characteristics associated with positive and negative therapeutic outcomes are needed to better target antidepressant therapy for FMS."


Treatment of Fibromyalgia Syndrome With Antidepressants

A Meta-analysis
Winfried Häuser, MD; Kathrin Bernardy, PhD; Nurcan Üçeyler, MD; Claudia Sommer, MD JAMA. 2009;301(2):198-209.

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.

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).