Meta-analysis of these 13 published, good quality, randomized, placebo-controlled trials suggests that antidepressants reduce the symptoms of fibromyalgia. While most individual studies were not individually statistically significant, all published results graphically fell on the side of effectiveness and pooled results showed a significant benefit of antidepressants. On meta-regression, there was no variable or study which had a significant independent effect on the overall effect size, thereby minimizing what few qualitative differences there were in these studies.
The probability of benefit is clinically appealing. Patients treated with antidepressants were more than four times as likely to improve. From a different analysis, using pooling of the risk difference, the number needed to treat was 4; in other words, 4 individuals would need treatment with antidepressants to improve 1 patient's symptoms.
The magnitude of benefit also appeared clinically significant. Study patients experienced a range of improvement in various symptoms of fibromyalgia, from 0.2 standard deviation units improvement in the number of trigger points to over one-half standard deviation improvement in average pain scores. To put this finding into context, effect sizes of 0.2, 0.5, and 0.8 standard deviations are commonly considered mild, moderate, and large treatment effects.31
When original units could be combined, there was evidence of substantial relative improvement: from 9% fewer trigger points to 26% less pain. Therefore, the symptomatic benefits of antidepressants appear to be mild for fatigue and number of trigger points, and moderate for sleep, overall well-being, and pain severity. Of the 5 continuous measures of fibromyalgia symptoms, only the number of trigger points was not statistically improved.
Although the syndrome of fibromyalgia is well described, its etiology and pathophysiology are poorly understood.32–34
There is some evidence that patients with fibromyalgia have a heightened pain response,35–37
as well as abnormal sleep patterns.38–41
Neurohormonal abnormalities, physical or emotional trauma, psychological stress, and infectious causes have also been postulated, although no single etiologic factor has been identified.2
Thus, there may be several mechanisms by which antidepressants improve fibromyalgia symptoms, such as pain control, mood stabilization, and improved sleep. Disturbed sleep is particularly interesting, as this may be both a causative factor as well as a symptom of disease. If abnormal sleep precedes the development of fibromyalgia, the effect of antidepressants may be primarily associated with improved sleep.
Traditional methods of pain control such as nonsteroidal anti-inflammatory medications (NSAIDs), while the mainstay of treatment for degenerative and inflammatory musculoskeletal disorders, have not been very effective in the treatment of fibromyalgia. Several studies have compared NSAIDS to tricyclics and have found no benefit in symptoms with NSAIDs alone, and no synergy when used with antidepressants.2,18
Only 3 of the trials assessed the effectiveness of SSRIs on fibromyalgia.23–25
While we found no difference in the efficacy of SSRIs and the other drug classes studied, the small sample size of studies makes it difficult to assess relative efficacy. Other meta-analysis of the efficacy of SSRIs for symptoms have included headache,42
and psychogenic pain.43
These also found no differences between tricyclic antidepressants and SSRIs, although these meta-analyses were also hampered by the paucity of trials using SSRIs. One large meta-analysis evaluating antidepressant effectiveness in chronic, unexplained pain found tricyclic antidepressant studies to be more likely to show benefit than SSRIs.44
Tricyclics have been found to be more effective than SSRIs in treatment of neuropathic pain.9
One of the trials in this review found that the combination of tricyclics with SSRIs was more effective than either alone.23
Well-designed, randomized, controlled trials are needed to assess the relative efficacy of different classes of antidepressants in fibromyalgia.
Does responsiveness to antidepressants then imply that psychological factors also play a role in fibromyalgia? There have been numerous studies demonstrating that patients with underlying psychological disorders are more likely to seek medical care for their symptoms.45–47
In addition, patients with depressive or anxiety disorders tend to rate their physical symptoms as more severe.45–47
Most trials (10/13) in our review included some baseline measure of psychological disorders. The Beck Depression Inventory or Hamilton Rating Scale were the tools used most frequently in reporting depressive symptoms in study subjects. However, this assessment was only included in the analysis of 5 trials.15,23,24,26,27
Four of the 5 trials which did do such an analysis found no relationship between improvement of fibromyalgia symptoms and change in the depression scores.15,23,24,26
Since most studies treated patients with subtherapeutic doses of antidepressants and for relatively short duration, it seems unlikely that the benefit is entirely due to antidepressant properties of these drugs. However, without fully controlling for the effects of antidepressants on psychological disorders, it is impossible to know if the efficacy observed with antidepressants in fibromyalgia is mediated through or independent of an effect on depression.
This literature has several limitations. One limitation, common to many studies, was the question of adequate blinding. Most studies either reported no measure of blinding or provided evidence that adequate blinding was not achieved (). Given the side effect profile of antidepressants it is easy to understand how blinding would be difficult to attain, regardless of the use of identical placebos. Inadequate blinding in previous randomized trials has led to erroneous conclusions regarding treatment, such as vitamin C's benefits for the common cold.48,49
A second limitation is that included studies were relatively short in duration, only 8.7 weeks. This is a particular concern in a syndrome such as fibromyalgia that tends to have a chronic course. The short duration of study treatment limits the ability to know whether the benefit will persist over time, or what the optimal duration of treatment should be.
Despite these limitations, our analysis suggests that antidepressants are effective in fibromyalgia. Physicians can expect to see improvement in 1 patient for every 4 treated, with over one-half standard deviation of improvement in pain severity. The myriad facets of fibromyalgia appear to be generally improved with the use of antidepressants. Further research is needed to assess the relative efficacy of different classes of antidepressants, as well as whether such efficacy is independent of an effect on depression.