Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

70th Annual Meeting of the American College of Rheumatology

Washington, DC / November 10-15, 2006

The syndrome of fibromyalgia is characterized by widespread musculoskeletal pain, disturbed sleep and fatigue. The etiology and pathophysiology of fibromyalgia remain incompletely understood, although the symptoms have been associated with central nervous system (CNS) abnormalities in the perception and processing of pain stimuli. Population studies worldwide have demonstrated a fibromyalgia prevalence of 0.5 to 4.0% (Dadabhoy D, Clauw DJ. Nat Clin Pract Rheumatol 2006;2:364-72). In the US, fibromyalgia is the most common generalized pain condition, affecting an estimated six million people.

As detailed by Dr. Leslie Crofford, Chief, Division of Rheumatology, University of Kentucky, Lexington, currently fibromyalgia has no approved therapy. Several different forms of treatment have been tried with varying degrees of success, including NSAIDs and tricyclic antidepressants. Certain compounds have proven effective in some patients, but tolerability frequently has been a problem. In addition, no treatment for fibromyalgia has been evaluated in long-term clinical studies.

As an alpha2-delta protein which is a subunit of the voltage-dependent calcium channel in the CNS, pregabalin has demonstrated promise as a treatment for several types of pain disorders. Originally developed as an antiepileptic drug, it has approved indications for post-herpetic neuralgia and diabetic neuropathy in Canada and the US. Clinical evaluation also has yielded evidence of efficacy for treatment of fibromyalgia. In an eight-week, placebo-controlled trial, pregabalin 450 mg/day significantly reduced pain, sleep disturbance and fatigue and improved global measures of change (Crofford et al. Arthritis Rheum 2005;52:1264-73).

Long-term Findings

Here at the ACR meeting, Dr. Crofford presented results of a long-term study of pregabalin in fibromyalgia patients. The primary objective of the trial was to evaluate the efficacy of pregabalin vs. placebo for durability of effect in the treatment of fibromyalgia-associated pain among patients who initially responded to open-label pregabalin.

Eligibility for the trial included a fibromyalgia diagnosis by ACR criteria, pain associated with the syndrome for at least three months, pain in at least 11 of 18 specific tender points, and a visual analog scale (VAS) pain score of at least 40 mm on a scale of 0 to 100. Exclusions included use of medications for relief of fibromyalgia-associated pain or insomnia or retinotoxic medications; creatinine clearance £60 mL/min; use of prohibited medications without appropriate washout; and the presence of rheumatologic disorders, severe depression or unstable medical or psychiatric conditions.

The primary efficacy variable was the time to loss of therapeutic response (LTR), which was defined in two ways: <30% reduction in VAS pain score relative to the open-label baseline value at two consecutive visits during the double-blind phase; and worsening of fibromyalgia symptoms necessitating an alternative treatment.

Investigators at 99 sites in the US enrolled 1051 patients in the initial six-week, open-label phase. During the first three weeks, patients began pregabalin at 150 mg/day, which was titrated to 300 mg/day and then to 450 and 600 mg/day, as tolerated. The dosage could be reduced once during the first three weeks of the open-label phase. For the remaining three weeks of the open-label evaluation, patients remained on their individually selected optimum dose.

At the end of the open-label phase, patients who responded to active treatment were eligible for the 26-week placebo-controlled, double-blind phase. Response was defined as ³50% reduction in the average pain score and a patient global change rate of “much improved” or “very much improved.” Dr. Crofford reported that 663 patients (63%) completed the open-label evaluation and 566 (85%) were eligible for randomized treatment.

Patients were randomized to their optimum individualized dose of active treatment or placebo. The optimum dose was defined as 600 mg/day in 50% of cases, 450 mg/day in 25% and 300 mg/day in 25%. For statistical analysis, all three active dosages were considered together.

By the end of the double-blind phase, 174 placebo patients (61%) had LTR compared to 32% of patients on active treatment, which represents almost a 50% reduction. Each of six sensitivity analyses confirmed the robustness of the primary analysis (P<0.0001).

“Patients who were randomized from an effective dose of the active treatment to placebo very quickly lost therapeutic response, with 25% of patients losing response by seven days and another 25% losing therapeutic response by approximately 24 days,” indicated Dr. Crofford. “In contrast, for those patients who remained on the agent, the mean time to LTR in those who lost therapeutic response was 34 days. Patients who passed the 34- to 40-day interval had maintenance of therapeutic response for the entire six-month duration of the study.”

Separate analyses of patients treated with each of the three active doses demonstrated a highly statistically significant benefit compared to placebo in terms of LTR, she added. Analysis of secondary efficacy measures consistently revealed significant differences (P<0.0001) in favour of active treatment. The secondary measures were patient global impression of change, fibromyalgia impact questionnaire, a standardized sleep scale, multidimensional assessment of fatigue, and all eight domains of the SF-36 health-related quality-of-life instrument.

Adverse events (AEs) occurred in about 80% of patients during the open-label phase of the study, and most were mild or moderate in severity, remarked Dr. Crofford. During double-blind treatment, 62% of pregabalin patients and 45% of placebo patients experienced AEs, and 82% of the AEs were mild or moderate in severity. During the double-blind phase, the most common AEs were insomnia, sinusitis, nausea, arthralgia, anxiety, influenza, and weight increase, which occurred in similar proportions of patients in the placebo and the active treatment groups. Dr. Crofford reported that 7% of placebo patients discontinued treatment because of AEs as did 17% of patients in the active treatment group. More than half of the discontinuations in the active treatment group involved AEs that first emerged during open-label treatment. Serious AEs occurred in 2% of patients over the course of the entire trial. During double-blind treatment, three placebo patients and seven pregabalin patients had serious AEs, all of which were judged to be unrelated to study medication.

“This 26-week study demonstrated durability of pain relief in fibromyalgia for patients who responded to pregabalin during open-label treatment,” Dr. Crofford concluded. “Pregabalin significantly delayed the time to LTR. By the end of double-blind treatment, nearly twice as many placebo patients had lost therapeutic response compared to pregabalin-treated patients. Pregabalin was generally well tolerated during both open-label and double-blind treatment.”

Dr. Lesley Arnold, Assistant Professor of Medicine, University of Cincinnati College of Medicine, Ohio, reviewed emerging therapeutic options for fibromyalgia and identified selective serotonin and norepinephrine reuptake inhibitors as potentially promising. Nonpharmacologic interventions (including exercise, cognitive behavioural therapy, education, and social support) also have demonstrated benefits. Dr. Arnold concluded that many fibromyalgia patients likely would benefit from a combination of pharmacologic and nonpharmacologic therapies (Arnold LM. Arthritis Res Ther 2006;8(4):212).

Summary

New hope for pain relief is emerging for fibromyalgia patients. There has been some progress in the understanding of the disorder and although no agent is currently approved for treatment, the anticonvulsant pregabalin is showing promising results for long-term use.

Note: At the time of printing, pregabalin is not indicated for fibromyalgia or for epilepsy in Canada.