Evidence-Based Reviews

Antidepressants for fibromyalgia: Latest word on the link to depression and anxiety

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Tricyclics In randomized, controlled trials, tricyclic medications (including the muscle relaxant cyclobenzaprine) appear to be moderately effective in improving fibromyalgia symptoms. Two meta-analyses of trials of tricyclic medications (amitriptyline, dothiepin, cyclobenzaprine, clomipramine, and maprotiline) have found similar results.30,31 Our group found the greatest effect on measures of sleep improvement, which may be due in part to tricyclics’ sedative properties.30 Many patients with fibromyalgia, however, cannot tolerate the sedative and other side effects associated with tricyclic agents, even though low dosages (e.g., 25 mg/d of amitriptyline) have typically been used in clinical trials.

SSRIs. Selective serotonin reuptake inhibitors, although likely to be better tolerated than tricyclics, have been examined in only five placebo-controlled trials in fibromyalgia: two with citalopram, and three with fluoxetine. One citalopram study found no significant differences in efficacy between citalopram and a placebo,32 but the other reported significant improvement in one measure of pain and a significant decrease in depressive symptoms compared with the placebo group.33 No significant differences were found between groups in the global assessment of improvement.

The initial fluoxetine trial in fibromyalgia treatment did not reveal a significant therapeutic effect over a placebo,34 although the study was limited by a high (57%) placebo dropout rate, small sample size (42 subjects), brief duration (3 to 6 weeks after treatment), and restriction of fluoxetine dosage to 20 mg/d. In the two other controlled trials, including one which we recently conducted, fluoxetine was superior to a placebo in reducing pain and other fibromyalgia-associated symptoms.35,36

In our 12-week investigation (a randomized, placebocontrolled, parallel-group, flexible-dose trial), 60 subjects with fibromyalgia received fluoxetine 20 to 80 mg/d or a placebo.36 Those receiving fluoxetine (mean dosage 45 ±25 mg/d) displayed significantly greater reduction in pain, fatigue, and depression compared with those receiving the placebo. The effect of fluoxetine on pain remained significant after we adjusted for change in depression.

Sertraline was evaluated in an open study of 47 fibromyalgia patients at dosages of 25 to 200 mg/d for 6 weeks. Nearly two-thirds (63%) assessed the efficacy of sertraline as good or very good in the treatment of their symptoms.37 Paroxetine effectively reduced fibromyalgia symptoms in a single-blind study at dosages of 20 mg/d for 3 months.38

SNRIs Venlafaxine, a dual serotonin and norepinephrine reuptake inhibitor, has shown promise in the treatment of fibromyalgia in a preliminary open trial conducted by our group.39 Venlafaxine at a mean dosage of 167 mg/d resulted in significant improvement in fibromyalgia symptoms and quality of life compared with baseline. Notably, lifetime comorbid depressive and anxiety disorders were common in this sample, and their presence predicted response of fibromyalgia symptoms to venlafaxine.

Gabapentin Although no studies have been published on fibromyalgia treatment with this anticonvulsant, gabapentin has been found to exert substantial analgesic effects in controlled studies of other kinds of pain, including diabetic neuropathy, post-herpetic neuralgia, and migraines.40-42 There are also anecdotal reports of its successful use in fibromyalgia.2

Nonpharmacologic treatment

Cardiovascular fitness training, regional sympathetic block, electromyographic biofeedback, hypnotherapy, and electroacupuncture have been reported to have modest efficacy for fibromyalgia symptoms in short-term, randomized controlled trials.43-46 Other studies, however, have not replicated the efficacy of these treatments.

Cognitive-behavioral therapy has shown promise in preliminary studies.47,48 Cognitive restructuring techniques that challenge negative thoughts and promote an active, positive, problem-solving approach to pain were found to be important components of fibromyalgia therapy, as were relaxation training, aerobic exercise and stretching, pacing of activities, and family education.47


Based on our group’s experience and the limited data available, the following are recommendations for the pharmacologic treatment of fibromyalgia:

  • Consider a trial of antidepressant medication for patients with a history of mood (unipolar) or anxiety disorders. First try an SSRI or an SNRI because many patients do not tolerate tricyclics. Use antidepressant therapeutic dosages and an adequate duration of treatment (at least 6 weeks).
  • If symptoms do not respond to an adequate trial of first-line medications, treatment with tricyclics appears warranted. Although studies have focused mostly on tertiary amine tricyclics (e.g., amitriptyline), secondary amine agents (e.g., nortriptyline) may be just as effective and better tolerated, allowing for titration to higher dosages.
  • Consider combination therapy when needed. For example, in patients who experience relief of pain, fatigue, and depressed mood with fluoxetine but continue to have insomnia, gabapentin can be added at night. Begin with 100 mg/d and increase by 100 mg/d until you see improvement or intolerance. Another option is trazodone, beginning with 50 mg hs. If you add a low-dose tricyclic to an SSRI, be aware of pharmacokinetic interaction and monitor tricyclic levels.
  • Gabapentin alone, although it has not been studied in controlled trials of fibromyalgia, may be an option for patients who do not respond to antidepressants. Other pain conditions treated with gabapentin have required dosages of 1,600 to 2,400 mg/d to achieve substantial analgesic effects.

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