Pregabalin for Fibromyalgia Syndrome

Researchers from the University of Cincinnati College of Medicine, Ohio, USA e-published an article on June 2nd, ahead of the print in the Journal of Pain, discussing a 14 week trial of pregabalin in patients with Fibromyalgia Syndrome. [1]

In 2007, Pregabalin (brand name Lyrica) was the first medication to be approved by the American Food and Drug Administration (FDA) for "on-label" use as a treatment for Fibromyalgia Syndrome.

Some of the researchers involved in the latest study were also involved in a 13 week Phase III trial of Pregabalin for Fibromyalgia Syndrome that was reported in the Journal of Rheumatology earlier this year. [2]

Both of these randomised, double-blinded, placebo-controlled trials aimed to assess the efficacy and safety of pregabalin in patients with Fibromyalgia Syndrome. They both used end point mean pain scores (as derived from daily diary ratings of pain intensity on an 0 to 10 scale) as the primary outcome variable, with other outcome variables being the Patient Global Impression of Change (PGIC) and the Fibromyalgia Impact Questionnaire (FIQ) total score. Other variables considered were assessments of sleep, fatigue, and mood disturbance. [1][2]

In the latest trial, 750 patients meeting American College of Rheumatology criteria for Fibromyalgia Syndrome had 1 week of single-blinded administration of placebo. After this, the participants were randomly pregabalin (at doses of 300 mg/d, 450 mg/d and 600 mg/d) or placebo, administered twice daily for 14 weeks. [1]

The trial found that, mean changes in pain scores at the end point in pregabalin-treated patients were significantly greater (P < .001: 300 mg/d, -0.71; 450 mg/d, -0.98; 600 mg/d, -1.00), compared with placebo-treated patients. Compared with placebo, significantly more pregabalin-treated patients reported improvement on PGIC (P < .01 for all 3 pregabalin doses) and significant improvements in total FIQ score for the 450 mg/d (P = .004) and the 600 mg/d (P = .003) doses. Compared with placebo, all 3 doses of pregabalin were associated with significant improvement in sleep. [1] This mainly reflects the findings of the Phase III trial [2], except that in that trial, improvements in FIQ-Total Score for the pregabalin groups were numerically but not significantly greater than those for the placebo group.

The most commonly reported pregabalin-related adverse events in both trials were dizziness and somnolence, which tended to be dose-related. [1][2]

The researchers from the latest trial said that:

"This randomized, placebo-controlled trial of 300, 450, and 600 mg/d of pregabalin monotherapy demonstrated that all 3 doses were efficacious for up to 14 weeks for the treatment of fibromyalgia and were well tolerated by most patients. These results provide evidence that pregabalin is an important treatment option for patients with fibromyalgia."

Some of the researchers involved in both trials were also involved in a 6 month trial to evaluate the efficacy of pregabalin monotherapy for durability of effect on the pain from Fibromyalgia Syndrome, the results of which were published in the June edition of the journal pain. [3]

This trial started with a 6-week open-label pregabalin-treatment period, where, during weeks 1-3, 1051 patients received escalating dosages of pregabalin to determine their optimal dosages and, during weeks 4-6, patients received their optimal fixed dosages (either 300, 450 or 600mg/d). To be randomised, patients must have had 50% decrease in pain Visual Analogue Score and a self-rating of "much" or "very much" improved on Patient Global Impression of Change (PGIC) at the end of this 6-week period. [3]

There then followed a 26-week double-blinded trial with participants receiving either placebo (287 partcipants) or their optimal fixed dosage of pregabalin (279 participants). The primary outcome was time to loss of therapeutic response (LTR), defined as a less than 30% reduction in pain (from the open-label baseline) or worsening of the Fibromyalgia Syndrome. [3]

The trial found that time to LTR was longer for pregabalin versus placebo (P<.0001) and that, whereas half the placebo group had LTR by Day 19, half the pregabalin group still had not lost response by the end of the trial. At the end of the trial, 174 (61%) placebo patients met LTR criteria versus 90 (32%) pregabalin patients. [3]

The researchers considered that pregabalin was well tolerated, though 178 (17%) discontinued during the open-label stage for treatment-related adverse events, and more pregabalin than placebo patients discontinued for adverse events during the doubled-blinded stage. [3]

The researchers concluded that:

"In those who respond, pregabalin demonstrated durability of effect for relieving FM pain."

In the trial described above, 54% of initial participants made it through the open-label stage and achieved 50% decrease in pain on the Visual Analogue Score and a self-rating of "much" or "very much" improved on the Patient Global Impression of Change. [3]

When the FDA approved pregabalin (Lyrica) for the treatment of Fibromyalgia Syndrome, Steven Galson MD MPH, director of the FDA's Center for Drug Evaluation and Research, cautioned that the drug was not a panacea because response to the drug was not universal. [4]

Response rates to pregabalin in patients with Fibromyalgia Syndrome have varied widely [4] meaning that, although for some patients Pregabalin is an efficient and well tolerated treatment, there are quite a large proportion of Fibromyalgia Syndrome patients who either do not respond or who suffer from adverse side effects.

References:

1. Arnold LM, Russell IJ, Diri EW, Duan WR, Young JP Jr, Sharma U, Martin SA, Barrett JA, Haig G. A 14-week, Randomized, Double-Blinded, Placebo-Controlled Monotherapy Trial of Pregabalin in Patients With Fibromyalgia. J Pain. 2008 Jun 2. [Epub ahead of print]
2. Mease PJ, Russell IJ, Arnold LM, Florian H, Young JP Jr, Martin SA, Sharma U. A randomized, double-blind, placebo-controlled, phase III trial of pregabalin in the treatment of patients with fibromyalgia. J Rheumatol. 2008 Mar;35(3):502-14. Epub 2008 Feb 15.
3. Crofford LJ, Mease PJ, Simpson SL, Young JP Jr, Martin SA, Haig GM, Sharma U. Fibromyalgia relapse evaluation and efficacy for durability of meaningful relief (FREEDOM): a 6-month, double-blind, placebo-controlled trial with pregabalin. Pain. 2008 Jun;136(3):419-31. Epub 2008 Apr 8.
4. Peck P. Pregabalin (Lyrica) Is First Drug Approved for Fibromyalgia. June 22, 2007. MedPage Today. http://www.medpagetoday.com/ProductAlert/Prescriptions/tb/5992