Pregabalin for fibromyalgia: Some relief but no cure
ABSTRACTWhat is the role of pregabalin (Lyrica) in the treatment of fibromyalgia? In this article the authors explore the putative pathophysiology of fibromyalgia, pregabalin’s mechanism of action and evidence of efficacy, and its emerging role in treating this challenging disease.
KEY POINTS
- Several lines of evidence point to functional abnormalities in the central nervous system as being responsible for fibromyalgia.
- Clinical trials found pregabalin superior to placebo. Nevertheless, patients need to have reasonable expectations of its possible benefit.
- 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.
- Research with pregabalin enhances our understanding of fibromyalgia and may point the way to future treatments.
PREGABALIN
Pregabalin is an alpha-2-delta ligand similar to GABA, but it does not act on GABA receptors. Rather, it binds with high affinity to the alpha-2-delta subunit of voltage-gated presynaptic calcium channels, resulting in reduction of calcium flow through the channels, which subsequently inhibits the release of neurotransmitters including glutamate, norepinephrine, and substance P.15–17 Animal studies suggest that the decrease in the levels of these excitatory neurotransmitters is the mechanism of action of pregabalin, resulting in its analgesic, anticonvulsant, and anxiolytic benefit.15 Another potential mechanism of pregabalin is enhancement of slow-wave sleep, demonstrated in one study in healthy human subjects.18
Besides fibromyalgia, pregabalin is also approved for the treatment of diabetic peripheral neuropathy, postherpetic neuralgia, generalized anxiety disorder, and social anxiety disorder, and as adjunctive therapy for partial-onset seizure in adults.
Pharmacokinetics
Pregabalin is quickly absorbed, primarily in the proximal colon (bioavailability > 90%), and has highly predictable and linear pharmacokinetics.15 Food consumption does not affect its absorption or elimination but can delay its peak plasma concentration, which occurs at 1.5 hours. Its elimination half-life is approximately 6 hours.15 Because it does not bind to plasma proteins, it freely crosses the blood-brain barrier. The drug reaches its steady-state concentration within 2 days of starting therapy.
Its clearance is not affected by the sex or race of the patient, but its total clearance may be lower in the elderly because of age-related loss of renal function. Patients on hemodialysis may require a supplemental dose after dialysis because hemodialysis removes the pregabalin.
The drug is not metabolized by the P450 system in the liver, so it interacts only minimally with drugs that do use the P450 system. However, its clearance may be decreased when it is used concomitantly with drugs that can reduce the glomerular filtration rate, such as nonsteroidal anti-inflammatory drugs, aminoglycosides, and cyclosporine.15
Efficacy
The efficacy of pregabalin in fibromyalgia was evaluated in several recent trials.19
Crofford et al16 assessed pregabalin’s effects on pain, sleep, fatigue, and health-related quality of life. Some 529 patients with fibromyalgia were randomized in a double-blind fashion to four treatment groups: placebo, and pregabalin 150 mg/day, 300 mg/day, and 450 mg/day. The baseline mean pain scores (a 0-to-10 scale derived from daily diary ratings) were 6.9 in the placebo group, 6.9 for the pregabalin 150 mg/day group, 7.3 for the pregabalin 300 mg/day group, and 7.0 for the pregabalin 450 mg/day group.
The pain scores declined in all groups, but at 8 weeks, the mean score had declined 0.93 points more in the group receiving pregabalin 450 mg/day than in the placebo group (P ≤ .001). The scores in the groups taking pregabalin 150 mg/day and 300 mg/day were not significantly different from those in the placebo group. Significantly more patients in the 450-mg/day group (29%, vs 13% in the placebo group) had at least 50% improvement in pain at the end of the study. Patients in both the 300-mg/day group and the 450-mg/day had statistically significant improvement in their quality of sleep, in fatigue, and on the Patient Global Impression of Change (PGIC) scale.
Arnold et al20 conducted a trial with 750 patients in which three doses of pregabalin were compared with placebo: 300 mg/day, 450 mg/day, and 600 mg/day. The primary end point was also the change in pain score from baseline (using the 0-to-10 scale derived from a daily pain diary). The mean baseline pain score was 6.7.
At 14 weeks, the mean pain score was lower than at baseline in all the groups, but it had declined 0.71 more in the pregabalin 300-mg/day group than in the placebo group, 0.98 points more in the 450-mg/day group, and 1.0 points more in the 600-mg/day group. All three pregabalin groups also showed significant improvement on the PGIC scale, and patients in the 450-mg/day and 600-mg/day groups showed statistically significant improvement in the Fibromyalgia Impact Questionnaire (FIQ) score. All three pregabalin treatment groups also had significantly better patient-reported sleep outcomes than in the placebo group, both in measures of overall sleep and quality of sleep. With the exception of a significant improvement of anxiety on 600 mg/day, there was no significant difference between the treatment and placebo groups in the secondary outcomes of depression and anxiety symptoms and fatigue.
Duan et al21 presented a pooled analysis of this and a similarly designed double-blind, placebo-controlled trial (the results of which were not available individually) at the 71st annual meeting of the American College of Rheumatology in November 2007. The analysis included 1,493 patients with a mean baseline pain score of 6.9. Compared with the mean pain score in the placebo group, those in the pregabalin groups had declined more by the end of the study: 0.55 points more with 300 mg/day, 0.71 points more with 450 mg/day, and 0.82 points more with 600 mg/day. This pooled analysis also showed significant improvement in PGIC score with all pregabalin doses and in the FIQ score with 450 mg/day and 600 mg/day.
The FREEDOM trial22 (Fibromyalgia Relapse Evaluation and Efficacy for Durability of Meaningful Relief) evaluated the durability of effect of pregabalin in reducing pain and symptoms associated with fibromyalgia in 1,051 patients who initially responded to the drug.
The patients received 6 weeks of open-label treatment with pregabalin and then 26 weeks of double-blind treatment (dose adjustment was allowed based on efficacy and tolerability for the first 3 weeks). The time to loss of therapeutic response was significantly longer with pregabalin than with placebo. Loss of therapeutic response was defined as worsening of pain for two consecutive visits or worsening of fibromyalgia symptoms requiring alternative therapy.
By the end of the double-blind phase, 61% of those in the placebo group had loss of therapeutic response compared with only 32% in the pregabalin group. The time to worsening of the FIQ score was also significantly longer in the pregabalin group than in the placebo group.
