Pregabalin for fibromyalgia: Some relief but no cure

Adverse effects: Dizziness, sleepiness, weight gain

Dizziness and sleepiness were the most common adverse events in these studies.

In the 8-week study by Crofford et al,¹⁶ dizziness was dose-related, occurring in 10.7% of those receiving placebo (one patient withdrew because of dizziness), 22.7% of those receiving 150 mg/day (two patients withdrew), 31.3% of those receiving 300 mg/day (four patients withdrew), and 49.2% of those receiving 450 mg/day (five patients withdrew). Somnolence was also dose-related, occurring in 4.6% in the placebo group, 15.9% in the 150-mg/day group (two patients withdrew due to somnolence), 27.6% in the 300-mg/day group (three withdrew), and 28.0% in the 450-mg/day group (five withdrew).

The 14-week study by Arnold et al²⁰ also showed higher frequencies of adverse events with higher doses. The rates of dizziness were 7.6% with placebo, 27.9% with pregabalin 300 mg/day, 37.4% with 450 mg/day, and 42.0% with 600 mg/day. The rates of somnolence were 3.8% with placebo, 12.6% with 300 mg/day of pregabalin, 19.5% with 450 mg/day, and 21.8% with 600 mg/day. Dizziness and somnolence were also the most common adverse effects that led to discontinuation of pregabalin, with rates of 4% and 3%, respectively.

The open-label phase of the FREEDOM trial showed rates of 36% for dizziness and 22% for somnolence among pregabalin-treated patients.

Weight gain and peripheral edema were also common adverse effects in these studies.²² Definitions of weight gain varied, and edema was not accompanied by evidence of cardiac or renal dysfunction.

Less common side effects seen more frequently in the treated groups included dry mouth, blurred vision, and difficulty with concentration and attention. The package insert also warns of angioedema, hypersensitivity reaction, mild asymptomatic creatine kinase elevation, decreased platelet count (without bleeding), and prolongation of the PR interval on electrocardiography.

Pregabalin is a schedule V controlled substance; in clinical studies, abrupt or rapid discontinuation of the drug led to insomnia, nausea, headache, or diarrhea in some patients, suggesting symptoms of dependence. In clinical studies involving a total of more than 5,500 patients, 4% of patients on pregabalin and 1% of patients on placebo reported euphoria as an adverse effect,¹⁹ suggesting possible potential for abuse.

Dosing

As a result of the above studies, the recommended starting dose of pregabalin for fibromyalgia is 150 mg/day in two or three divided doses, gradually increased to 300 mg/day within 1 week based on tolerability and efficacy. The dose may be increased to a maximum of 450 mg/day. The 600-mg dose was found to have no significant additional benefit, but it did have more adverse effects and therefore is not recommended. It is important to note that in these studies multiple medications for pain and insomnia were prohibited, so data on drug interactions with pregabalin are limited.

Few achieve complete remission, but most patients feel better

Several studies of the natural history of fibromyalgia have shown that very few patients experience complete remission of the disease, even after many years. Therefore, one should try to set up realistic expectations for patients, with the goal of achieving functional improvement in activities of daily living and a return to one’s predisease state.

In the longest follow-up study, 39 patients in Boston, MA, were prospectively followed for over 10 years. No patient achieved complete remission: all of them reported some fibromyalgia-related symptoms at the end of the study.²³ However, 66% of them felt a little to a lot better than when first diagnosed, 55% felt well or very well, and only 7% felt poorly.

Other studies have also shown complete remission to be rare.^24,25 A 5-year follow-up study investigating fibromyalgia patients’ perceptions of their symptoms and its impact on everyday life activities demonstrated that the social consequences of fibromyalgia’s symptoms are severe and constant over time.²⁶

Evidence of favorable outcomes was reported in one study in which 47% of patients reported moderate to marked improvement in overall fibromyalgia status upon 3-year follow-up,²⁷ and in another study, in which remission was objectively identified in 24.2% of patients 2 years after diagnosis.²⁸

OTHER THERAPIES

Although there have been many studies of pharmacologic therapies for fibromyalgia to date, the trials had significant limitations, such as short duration, inadequate sample size, nonstandardized measures of efficacy, question of regression to the mean, and inadequate blinding, resulting in insufficient evidence to recommend one drug over another.

Tricyclic antidepressants. Two meta-analyses and a clinical review have supported the efficacy of tricyclic antidepressants in improving symptoms in fibromyalgia patients.^29–31

Selective serotonin reuptake inhibitors (SSRIs) have not been well studied, and the small size and methodologic shortcomings of these studies make it difficult to draw conclusions about the efficacy of SSRIs in reducing pain in fibromyalgia patients.^30,31

Duloxetine (Cymbalta) and milnacipran (Savella) are serotonin and norepinephrine reuptake inhibitors.^32–34 A randomized, double-blind placebo-controlled trial evaluated duloxetine in 520 fibromyalgia patients with and without major depressive disorder. Pain scores improved significantly over 6 months in duloxetine-treated patients at doses of 60 and 120 mg/day.³³ Duloxetine became the second drug approved for the treatment of fibromyalgia in 2007, and milnacipran became the third in 2009.

WHAT ROLE FOR PREGABALIN?

Pregabalin may reduce pain in some patients with fibromyalgia. However, the presenting symptoms can vary significantly, and symptoms can vary even in individual patients over time. Therefore, in most patients with fibromyalgia, a multidisciplinary approach is used to treat pain, sleep disturbance, and fatigue, along with comorbidities such as neurally mediated hypotension and psychiatric disorders. Because treatment of fibromyalgia often involves multiple drugs in addition to exercise and behavioral therapies, future studies should examine combinations of drugs and the use of drugs in conjunction with nondrug treatments.

Pregabalin advances our knowledge of fibromyalgia through improving the understanding of central sensitization and how brain neurotransmitters control central pain perceptions. Drug treatment must still be part of the comprehensive management of this disease. Physician and patient education about the current understanding of the disease is paramount in setting realistic goals for treatment.¹⁴ Future strategies to manage fibromyalgia will be based on the pathophysiology of this complex condition.