To review the efficacy and safety of pregabalin, an alpha2-delta (a2-d) ligand, for the management of fibromyalgia (FM).
Review of 2 pivotal phase 3 trials that evaluated the efficacy and safety of pregabalin for the management of FM.
Results: FM is a chronic condition that is characterized by widespread musculoskeletal pain and has a greater prevalence in women than in men. In a 14-week, randomized, double-blind trial, pregabalin at all 3 doses (300, 450, and 600 mg daily) resulted in significantly greater improvements in pain and function relative to placebo. Parallel with these improvements, greater proportions of patients in the pregabalin groups reported improvement in global disease status compared with placebo. In a second study designed to evaluate the durability of response, patients were randomized to up to 6 months of treatment with pregabalin or placebo after a 6-week, open-label, dose-optimization treatment phase. Based on predefined criteria for loss of therapeutic response, patients treated with pregabalin were observed to maintain a therapeutic response for a significantly longer duration than patients treated with placebo. Pregabalin was tolerated by most patients in both trials; the incidence of the most commonly reported adverse events (dizziness, somnolence, weight gain, headache, dry mouth) appeared to be dose-related.
Pregabalin has been demonstrated to be efficacious and well-tolerated for the management of FM.
Fibromyalgia (FM) is a chronic pain condition that, by recent estimates, affects at least 5 million individuals in the United States, primarily women, among whom the prevalence is 6 to 9 times higher than in men.1 Current concepts of FM pathophysiology suggest an underlying dysfunction in central nociceptive processing, with evidence of the involvement of several pathways of neurotransmission, including altered dopaminergic, serotonergic, and noradrenergic activity; increased glutamate levels; and upregulation of substance P, resulting in increased nociceptive signaling and diminished inhibitory control in central pain pathways.2-7
This central dysfunction may account for the characteristic symptoms of persistent and recurring widespread musculoskeletal pain and tenderness that has been recognized as the clinical hallmarks of FM in the American College of Rheumatology (ACR) classification criteria.8 However, patients with FM also frequently report a constellation of other symptoms, including fatigue, sleep and mood disturbances, and cognitive dysfunction.9,10 These symptoms additionally contribute to reduced function and quality of life as well as increased healthcare resource utilization that have been reported among patients with FM.11-17
Pregabalin was the first pharmacologic therapy to be approved by the US Food and Drug Administration for the management of FM. Pregabalin is a structural analogue of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) that has anticonvulsant and analgesic activity. Similar to gabapentin, to which it is related, it neither binds to GABAA or GABAB receptors nor alters GABA uptake or degradation through interaction with GABA transporters.18 The analgesic activity of pregabalin is mediated through its high affinity binding to the alpha2-delta (α2-δ) subunits of voltage-gated calcium channels in the central nervous system.19 Although the mechanism of action of pregabalin has not been fully elucidated, in vitro studies have shown that pregabalin reduces the release of neurotransmitters including glutamate20,21 and substance P,22 putatively by modulating the calcium-dependent release of presynaptic vesicles.23
PREGABALIN EFFICACY AND SAFETY
The efficacy and safety of pregabalin have been demonstrated in 2 randomized, double-blind, phase 3 trials, and although there were a number of end points evaluated in the trials in addition to those reported here, they were not included in the US prescribing information for pregabalin and thus are not discussed in this article.24,25 The first of the 2 trials was a 14-week study conducted at 84 centers in the United States that evaluated 745 patients with FM who were randomized to placebo (n = 184) or pregabalin at doses of 300 (n = 183), 450 (n = 190), and 600 mg/day (n = 188).24 For inclusion in this trial, patients were required to have met the ACR criteria for FM (ie, widespread pain for a duration of at least 3 months and pain in at least 11 of 18 specific tender point sites),8 and to have a minimum level of pain indicative of at least moderate pain severity. These levels were predefined by a score of 40 mm or more on the 100-mm pain visual analog scale (VAS) at screening, and a mean pain score of 4 or more on an 11-point numeric rating scale (NRS; 0 = no pain; 10 = worst possible pain) during the 1-week, single-blinded, placebo run-in phase. Additionally, since this was a monotherapy trial, patients had to agree to discontinue all other medications for FM.
Patients meeting the above criteria were initiated on treatment during a 2-week dose-escalation phase following a 1-week placebo run-in period. Dose escalation was followed by a 12-week fixed-dose phase. Efficacy was determined by the change from baseline at end point in NRS pain scores (primary outcome), change in total score on the Fibromyalgia Impact Questionnaire (FIQ), and Patient's Global Impression of Change (PGIC). The FIQ is a 20-item, patient- reported questionnaire that captures the impact of FM on daily activity and function,26 and the PGIC provides a global assessment of change from the patient's perspective.27
Relative to placebo, all 3 active-treatment groups (pregabalin 300, 450, and 600 mg daily) resulted in significantly greater improvement in pain at end point, as indicated by reductions in score on the NRS (P <.001) (). Significant differentiation from placebo in pain scores was observed as early as 1 week after initiating treatment for all pregabalin groups, and this significant improvement was maintained until the end of the treatment period at week 14, with the exception of 300 mg/day at week 11. Furthermore, the proportion of patients achieving 30% and 50% reductions in pain were significantly greater in the pregabalin groups compared with placebo (). Both of these levels of pain reduction are recommended for assessment in chronic pain trials, with the former representing an improvement of moderate clinical importance and the latter being of substantial importance.28 There was no evidence of a greater effect on pain scores at 600 mg daily relative to 450 mg daily.
At end point, significantly greater improvement was observed on the FIQ total score for pregabalin 450 mg and 600 mg relative to placebo (P <.005) (). Improvements in pain and function were paralleled by the patient's perceptions of global improvement as assessed on the PGIC. Compared with placebo (48%), significantly greater proportions of patients in the pregabalin groups reported global improvement (); 68% (P <.01), 78% (P <.001), and 66% (P <.001) of patients treated with pregabalin 300 mg, 450 mg, and 600 mg, respectively.
The second study was a randomized withdrawal study that evaluated the durability of response of pregabalin relative to placebo among 566 patients with FM who responded to pregabalin in a 6-week open-label phase.25 This study was performed at 95 centers in the United States and enrolled patients with FM who met ACR criteria8 and had pain at a level of 40 mm or more on a 0-100 mm VAS.
During the open-label phase, 1061 patients were optimized to a pregabalin daily dose of 300, 450, or 600 mg. Patients were considered to be responders if they met both of 2 criteria, including a 50% or more reduction in pain on a 0-100 mm VAS and rated their overall improvement on the PGIC as "much improved" or "very much improved."
In the double-blind phase, patients who completed the open-label phase and responded to pregabalin were randomized to either placebo (n = 287) or the pregabalin dose achieved in the open-label phase (n = 279), with treatment up to 6 months following randomization. Efficacy was assessed by time to loss of therapeutic response, which was defined as either a less than 30% pain reduction from open-label baseline during 2 consecutive visits of the double-blind phase, or a worsening of FM symptoms necessitating an alternative treatment. The 30% threshold was used since that has been reported to be the reduction in pain that is clinically meaningful based on patients' perceptions of feeling "much better" or "very much better" on the PGIC.29
As shown by the Kaplan-Meier survival estimate (), time to loss of therapeutic response according to the above criteria was significantly longer (P <.0001) for patients treated with pregabalin than for patients receiving placebo. The median time to loss of therapeutic response was 19 days in the placebo group, but could not be determined for pregabalin since more than 50% of the patients maintained a response (ie, 68% of patients compared with 39% on placebo). A sensitivity analysis used a 3-part definition of loss of therapeutic response in which all patients who withdrew early due to adverse events were also considered to have loss of therapeutic response in addition to the primary criteria stated above. Using this definition, at 6 months, 53% of pregabalin patients maintained a response compared with 33% on placebo, and the median time for maintaining this response remained significantly longer with pregabalin than with placebo, 158 days versus 17 days (P <.0001). An additional sensitivity analysis considered a stricter definition of loss of therapeutic response that not only included the primary criteria, but also every patient who discontinued for any reason. In this analysis, pregabalin remained statistically significantly superior to placebo, with a median time of 71 days to loss of therapeutic response versus 14 days for placebo (P <.0001).
For secondary end points, when loss of therapeutic response was defined based on the FIQ (a 1-point increase from double-blind baseline in each of the FIQ subscales, and a 5-point increase for the total score), the time to loss of response was still significantly longer with pregabalin, with a median time of 19 days versus 14 days for placebo (P <.0001). Similarly, loss of therapeutic response based on the PGIC and defined as time to a PGIC assessment that no longer indicated "much improved" showed significantly greater durability of response in the pregabalin group; the median time to loss of response was 126 days with pregabalin compared with 20 days for placebo (P <.0001).
Both studies were characterized by a favorable tolerability profile for pregabalin, and in neither of the trials were any clinically relevant safety signals reported. Although a dose-dependent increase in adverse events was noted with pregabalin, the majority of adverse events were of mild or moderate severity. Consistently across both studies, the most commonly occurring adverse events among patients treated with pregabalin (occurring with a frequency of 10% or more for combined doses in any one study) were dizziness (36%-41%), somnolence (18%-24%), weight gain (10%-13%), headache (8%-15%), and dry mouth (5%-11%). Although of less frequency, other recognized adverse events include blurred vision (amblyopia) in up to 12% of patients (600-mg dose) and cognitive effects such as disturbance in attention and memory impairment in up to 6% and 4% of patients, respectively, at the higher doses. Mild cognitive effects, reported as statistically significant negative changes on 3 of 6 cognitive measures, have recently been reported in healthy volunteers treated with the full pregabalin dose of 600 mg/day.30
Within the context of increased weight as an adverse event, pregabalin-associated weight gain was related to dose and duration of exposure, but did not appear to be associated with baseline body mass index, sex, or age. In one study, clinically significant weight gain, defined as an increase in body weight of 7% or more relative to baseline, was reported by 6% of patients in the placebo group, and by 9%, 10%, and 9% of patients treated with pregabalin 300, 450, and 600 mg/day, respectively.24 While 13 patients discontinued treatment due to weight gain, only one of these patients experienced a clinically significant increase in body weight.24
Eleven percent of pregabalin-treated patients in the second study had a clinically significant increase in weight during the open-label phase, and during the double-blind phase 2% to 4% of pregabalin-treated patients reported a clinically significant weight increase compared with more than 1% of placebo-treated patients.25
Discontinuations due to adverse events appeared to be dose-dependent. In one study, these discontinuations were reported as 12% for placebo, 16% for pregabalin 300 mg, 22% for pregabalin 450 mg, and 26% for pregabalin 600 mg,25 and in the other study these discontinuations were 7%, 19%, 18%, and 15% for the treatment groups, respectively.24 The adverse events most frequently resulting in discontinuation were dizziness and somnolence, and were reported as 4% and 3% in one of the studies.24 Peripheral edema was also cited as a reason for discontinuation among 2.1% of patients treated with pregabalin and 0.5% of the control group in the 14-week trial.24 While peripheral edema was not cited as a reason for discontinuation in the other study, it was reported in 8% of individuals during the initial open-label phase, and in 3% and 1% of individuals randomized to pregabalin or placebo, respectively, in the subsequent randomized phase.25
Although not specifically reported in the above 2 studies, it should be noted that there have been postmarketing reports of angioedema as well as hypersensitivity in patients being treated with pregabalin, with the latter occurring shortly after initiation of treatment, and its use should be discontinued in patients with symptoms suggestive of either of these events.31 Similarly, neither was suicidality reported in the 2 FM clinical trials. However, as with other antiepileptic drugs, there is an increased risk of suicidal thoughts or behavior with pregabalin.31 Consequently, there is a need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm, and such behaviors should be reported immediately to healthcare providers.
Chronic widespread musculoskeletal pain is a hallmark characteristic of patients with FM that affects patient function. Pregabalin is a pharmacologic therapy that has been demonstrated to be efficacious and well tolerated for managing FM. Patients treated with pregabalin reported significant improvements in pain, impact of FM, and their perception of global disease status relative to placebo. The therapeutic response of pregabalin was also demonstrated to be of significantly greater duration than placebo. Pregabalin is administered twice daily as oral capsules, and the recommended dose for the management of FM is 300 to 450 mg/day. Dosing is recommended to begin at 75 mg twice daily (150 mg/day) and may be increased to 150 mg twice daily (300 mg/day) within 1 week based on efficacy and tolerability. Patients who do not experience sufficient benefit with 300 mg/day may be further increased to 225 mg twice daily (450 mg/day). No trials have evaluated the safety or efficacy of combining pregabalin with other currently approved therapies for the treatment of FM.
The authors would like to thank E. Jay Bienen for editorial assistance in the preparation of this article, which was funded by Pfizer, Inc.
Author Affiliations: From the University of Cincinnati College of Medicine (LA), Cincinnati, OH; Seattle Rheumatology Associates (PM), Swedish Medical Center, Seattle, WA; and Cedars-Sinai Medical Center, Los Angeles, and University of California (SS), Los Angeles, CA.
Funding Source: Financial support for this work was provided by Pfizer, Inc. This supplement was funded by Pfizer, Inc.
Author Disclosures: None of the authors was compensated for the preparation of this article. Dr Arnold has received grants or research support from Allergan, AstraZeneca, Boehringer Ingelheim, Cypress Bioscience, Forest, Lilly, Pfizer, Inc., and Wyeth Pharmaceuticals. She has been a consultant for Allergan, AstraZeneca, Boehringer Ingelheim, Cypress Bioscience, Forest, Lilly, Pfizer, Inc., sanofi-aventis, Takeda, Theravance, UCB, and Wyeth Pharmaceuticals. She has been on the speakers' bureau for Forest. Dr Silverman served as a consultant/advisory board member, received grants from, and was a lecturer for Lilly and Pfizer, Inc. Dr Mease has received research grants from Allergan, Boehringer Ingelheim, Cypress Bioscience, Forest, Fralex, Lilly, and Pfizer, Inc., and has been a consultant for all of the above. He has also served on the speakers' bureau for Cypress Bioscience, Forest, Lilly, and Pfizer, Inc.
Authorship Information: Concept and design (PM, SS); acquisition of data (LA, PM); analysis and interpretation of data (LA, PM); drafting of the manuscript (PM, SS); and critical revision of the manuscript for important intellectual content (LA, PM, SS).
Address correspondence to: Lesley Arnold, MD, 222 Piedmont Ave, Ste 8200, Cincinnati, OH 45219. E-mail: Lesley.Arnold@uc.edu.
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