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Home » Medications for Fibromyalgia

Medications for Fibromyalgia

December 1, 2008
From The Carlat Psychiatry Report
Issue Links: Learning Objectives | Editorial Information | PDF of Issue
Daniel Carlat, MD

Recently, the FDA gave its first two approvals for medications to treat fibromyalgia (FM): first Lyrica (pregabalin) and then Cymbalta (duloxetine). While it is nice that FM is receiving some attention from big pharma, the badge of FDA approval should be taken with a grain of salt. Tricyclic antidepressants have been used with benefit in FM for some time, and will likely never receive FDA approval. (They are available generically, and generic companies don’t pursue FDA approval because they cannot recoup the high cost of the clinical trials and application process.) Nonetheless, most rheumatologists still recommend tricyclics as the agents of first choice (Abeles M et al., Am J Med 2008;121:555-61). As we have noted in the past, older meds often have advantages, including longer safety records and more usage experience among clinicians. In general, when approaching medication treatment of fibromyalgia, bear in mind the four most common presenting symptoms as outlined by Dr. Daniel Clauw in this month’s interview – pain, fatigue, insomnia, and memory problems – as well as the frequently comorbid major depression. Choose medications to target these symptoms, and track the response over time to determine if meds need to be changed or if polypharmacy seems necessary.

Tricyclics

Tricyclics are effective for pain, insomnia, and overall well-being in fibromyalgia. In one double-blind study, FM patients randomly assigned to amitriptyline, with or without the NSAID naproxen, did better than patients on placebo. Patients who were assigned to naproxen alone did not improve more than placebo (Goldenberg DL et al., Arthritis Rheum 1986;29:1371-7).

The most studied tricyclics are amitriptyline (Elavil) and cyclobenzaprine (Flexeril). While most studies of amitriptyline have tested doses of 25-50 mg QHS, many rheumatologists will begin at a very low dose of 5 or 10 mg QHS, and will increase by 5 mg every week or so until the patient feels better or begins to experience troublesome side effects (Goldenberg DL, Best Pract Res Clin Rheumatol 2007;21:499-511). Side effects to watch out for include dry mouth, constipation, urinary retention and confusion. The elderly are more vulnerable to these side effects than younger patients.

Flexeril is often prescribed as a “muscle relaxant” to patients with back pain, but it is a tricyclic and is effective for FM. As opposed to amitriptyline, Flexeril is sometimes dosed during the day. Start with 10 mg QHS, and increase to 10 mg TID as needed.

While desipramine and nortriptyline have fewer anticholinergic side effects than other tricyclics, they have been less well studied, and may or may not work as well as amitriptyline or Flexeril.

SSRIs

In most clinical trials, SSRIs have been found effective for FM. The problem is that many of these have been relatively small trials, and the largest one yielded mixed results. According to one review (Uceyler N et al., Arthritis Rheum 2008;59:1279-98), fluoxetine has the most consistent evidence, with a placebo-controlled study showing a benefit in FM patients when titrated up to 80 mg QD, and another study showing that fluoxetine plus amitriptyline was more effective than either drug alone. But a recent large placebo-controlled trial of Paxil CR (controlled release paroxetine), funded by GlaxoSmithKline, found that Paxil CR 12.5-62.5 mg/day yielded a 25.8% response rate on a Fibromyalgia symptom scale (the FIQ), not quite statistically superior to the 13.7% response to placebo. Furthermore, Paxil CR did not outperform placebo for treating pain (Patkar AA et al., Am J Med 2007;120:448-54).

SNRIs

Cymbalta (duloxetine) was the first medication to be approved for FM. Three large randomized double blind studies have been reported, the largest of which was published quite recently (Russell IJ et al., Pain 2008;136:432-44). In this study, 520 patients with FM were randomized to Cymbalta (20mg/day vs. 60 mg/day vs. 120 mg/day) vs. placebo for 6 months. Patients assigned to Cymbalta 60 mg/day and 120 mg/day had significantly greater reductions in pain severity compared to placebo. Looking at the efficacy in terms of response rates (50% improvement in the average pain severity score from baseline to the 3-month endpoint), the results were: Cymbalta 120 mg/day, 40.1%; 60 mg/day, 34%; placebo, 23.7%. Only the 120 mg/day dose separated significantly from placebo on response rate. Another study of 207 patients on Cymbalta 60 mg BID yielded response rates of 27.7% for Cymbalta and 16.7% for placebo, which just missed statistical significance (p = 0.06) (Arnold LM et al., Arthritis Rheum 2004;50:2974-84).

What about Effexor? One might imagine that it would be as effective for FM as Cymbalta, as they have the same mechanism of action, but in the largest study published (only 90 patients), it was not more effective than placebo (Zijlstra TR et al., Arthritis Rheum 2002;46 (suppl 19):S105).

Finally, you should be aware that milnacipran, an SNRI antidepressant approved for use in some European countries, may win FDA approval for fibromyalgia in the near future. It will be co-marketed by Cypress Bioscience and Forest Laboratories, and you can find a summary of their clinical trials on Cypress’s website (http://www.cypressbio.com/products/milnacipranPhase3.php). If it gains approval, it will likely be dosed in the 100-200 mg/day range.

Novel Anticonvulsants

Lyrica (pregabalin) and Neurontin (gabapentin) are closely related molecules in the category of “novel anticonvulsants.” However, if you want to be trendy, you should refer to them as “alpha-2-delta ligands,” a name based on their presumed mechanism of analgesia, which is their ability to bind to the alpha-2-delta subunit of voltagegated calcium channels in the brain and spinal cord.

At any rate, both of them seem to work for FM. In one of the major studies, 529 patients were assigned to Lyrica (150 mg, 300 mg, or 450 mg/day) or placebo for 8 weeks (Crofford LJ et al., Arthritis Rheum 2005;52:1264-73). Only those receiving the 450 mg dose showed a statistically better response rate (50% improvement in pain) than placebo (28.9% vs. 13.2%). The 300 mg dose yielded only an 18.9% response rate, but it did significantly improve measures of sleep, fatigue, and quality of life. In large trials for FM, the major side effects of Lyrica have been dizziness, sedation, and about a 10% incidence of weight gain. Considering that the vast majority of FM sufferers are women, Lyrica’s weight gain liability can be a problem, and you should inform your patients of this risk.

The major study of Neurontin randomized 150 patients to either Neurontin 1200-2400 mg/day or placebo. In this case, the response rate was defined as a 30% improvement in pain after 12 weeks (rather than the 50% improvement cited in other studies), and Neurontin bested placebo 51% to 31% (Arnold LM et al., Arthritis Rheum 2007;56:1336-44). Dizziness and sedation were the most common side effects.

Bottom Line

There are many potential treatments available for FM, but the response rates tend to be rather small and of marginal clinical significance. By all means try them, but view them as only one part of a multimodal package of treatment, which should include exercise and cognitive behavior therapy.
General Psychiatry
    www.thecarlatreport.com
    Issue Date: December 1, 2008
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    Table Of Contents
    Diagnosis and Non-Drug Management of Fibromyalgia
    Medications for Fibromyalgia
    Cymbalta For Physical Pain in Depression: Fact or Fiction?
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