Pregabalin

Oral pregabalin, a calcium channel α₂δ-subunit ligand with analgesic, anxiolytic and antiepileptic activity, has shown efficacy in the treatment of fibromyalgia. It has a multidimensional effect in the treatment of this complex condition, and is associated with rapid and clinically significant improvements in several outcome measures relating to core symptoms of the syndrome, including pain and sleep, in patients with long-standing fibromyalgia. Pregabalin treatment is also associated with improvements in the overall health status of these patients. The beneficial effects of pregabalin are durable in patients with an initial response to the drug. The most common adverse events associated with the drug are dizziness and somnolence, which are generally mild to moderate in intensity and are tolerated by many patients. Pregabalin is, therefore, a valuable option in the first-line treatment of patients with fibromyalgia.

Pregabalin selectively binds with high affinity to the α₂δ subunit of voltage-gated calcium channels, which are widely distributed throughout the central and peripheral nervous systems. This modulates calcium influx in presynaptic nerve terminals to reduce excessive release of several excitatory neurotransmitters. Pregabalin demonstrates beneficial effects on the key symptoms and co-morbidities associated with fibromyalgia (i.e. pain, anxiety and sleep).

Oral pregabalin is absorbed rapidly (peak plasma concentrations occur within 1.5 hours) and exposure is dose proportional. Metabolism of pregabalin is negligible, with most of the drug being excreted unchanged in the urine. In healthy volunteers, the mean apparent elimination half-life is 6.3 hours. Clearance of pregabalin is directly related to creatinine clearance; dosage adjustments are required in patients with impaired renal function.

Oral pregabalin was generally associated with improvements from baseline in mean pain scores in short-term, randomized, double-blind, placebo-controlled, multicentre trials in patients with fibromyalgia. In three 8-, 13- or 14-week trials conducted in the US, relative to placebo recipients, pregabalin 450 or 600 mg/day recipients demonstrated significant improvements from baseline in endpoint mean pain numerical rating scale (NRS) scores (primary endpoint), with pregabalin 300 mg/day recipients also showing significant improvements in two of the trials. Mean pain NRS scores for all pregabalin arms were significantly different from those with placebo as early as week 1, with significant improvements generally sustained through most or all weeks of the treatment period in the pregabalin 300, 450 and 600 mg/day arms.

Improvements from baseline in Fibromyalgia Impact Questionnaire (additional co-primary endpoint) total scores in the pregabalin 450 and 600 mg/day groups were significantly better than those in the placebo groups in the 14-week trial, but there was no significant difference between placebo and any of the pregabalin groups in the 13-week trial. Patient-rated overall status, as assessed by response on the Patient Global Impression of Change scale (additional co-primary end-point), improved in patients with fibromyalgia receiving pregabalin 300, 450 or 600 mg/day in the 13- and 14-week US trials.

Relative to placebo, pregabalin 300, 450 and 600 mg/day was associated with improvements in several sleep parameters in the short-term trials. Significant differences between pregabalin and placebo were reported for only some of the other secondary endpoints and were generally not consistent across trials.

Continued treatment with pregabalin was effective in prolonging the efficacy of open-label pregabalin in patients with fibromyalgia who had shown initial response to open-label pregabalin. In the FREEDOM trial, patients who had an initial response to pregabalin during a 6-week open-label phase were randomized to a further 26 weeks of treatment with their optimized dosage of pregabalin or placebo. Based on Kaplan-Meier estimates, the time to loss of therapeutic response was significantly longer in the pregabalin 300–600 mg/day group than in the placebo group. Sensitivity analyses, which tested the validity of the primary assumptions, confirmed the superiority of pregabalin over placebo.

The tolerability profile of pregabalin in patients with fibromyalgia is consistent with the known adverse effects the drug. Although adverse events were frequently reported in the pregabalin and placebo groups in clinical trials in patients with fibromyalgia, most events were of mild to moderate intensity and were often of limited duration.

The treatment-emergent adverse events most frequently associated with pregabalin were dizziness and somnolence. These events were generally reported shortly after the initiation of pregabalin therapy, were mild to moderate in intensity and occurred more frequently at higher dosages, but led to discontinuation of pregabalin therapy in only some patients.