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Confronting the Pain Paradigm of Fibromyalgia

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.

8th Annual European Congress of Rheumatology (EULAR)

Barcelona, Spain / June 13-16, 2007

According to Dr. Jordi Carbonell Abelló, Head, Rheumatology Unit, Hospitales del Mar y de la Esperanza, Barcelona, Spain, fibromyalgia is a common chronic pain condition with a great need for improved treatment options. He stressed the necessity of a multidisciplinary approach by the health team and the importance of patient education. He also noted that patients are frequently dissatisfied with the results of their care, often shifting treatment and exercise approaches and seeking out complementary therapies offered on the Internet and through other channels (BMC Musculoskeletal Disord 2007;8:27). This state of affairs exposes the need for improvement in the management of fibromyalgia, Dr. Carbonell Abelló added.

Implications of the Central Nervous System

As affirmed by Dr. Eva Kosek, Assistant Professor, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden, compounds that target the underlying mechanism will improve outcomes in fibromyalgia. Her own research has shown that an abnormal processing of nociceptive stimuli could be a key factor in fibromyalgia. In contrast to healthy controls, affected patients have increased cerebral activity in response to painful pressure stimulation (Pain 1996;68(2-3):375-83, Pain 2000; 88(1):69-78).

While current treatments include non-narcotic analgesics, NSAIDs and soft-tissue injection, this understanding of central nervous system (CNS) involvement has led researchers to investigate whether new approaches may help improve outcomes in fibromyalgia. As reported by Dr. Leslie Crofford, Gloria W. Singletary Professor of Women’s Health Research, Division of Rheumatology, University of Kentucky, Lexington, these include serotonin-norepinephrine reuptake inhibitors.

In a double-blind, 12-week study, patients with fibromyalgia with or without major depressive disorder were randomized to duloxetine 60 mg b.i.d. or placebo.Treatment was associated with significant improvement of several measures of pain compared to placebo.

Preliminary results of another study demonstrated that among the newer compounds, modafinil appears to be as effective as amitryptiline in the treatment of fibromyalgia. Further studies may confirm its potential use in this disease.

While the search for more effective compounds continues, Dr. Crofford stressed, like Dr. Carbonell Abelló, the importance of incorporating medical therapy for fibromyalgia into a comprehensive regimen that includes patient education, exercise and cognitive behavioural therapy.

Fibromylagia symptoms include sleep disturbance and fatigue, both elements of the pain triad common to this and other functional somatic syndromes such as chronic fatigue and neuropathic pain.

Findings from FREEDOM

Dr. Crofford cited results from the recent FREEDOM (Fibromyalgia Relapse Evaluation and Efficacy for Durability of Meaningful Relief) trial (Arthritis Rheum 2006;54:4118). Patients who met the 1990 American College of Rheumatology (ACR) criteria for fibromyalgia were eligible for enrolment in a multiphase, double-blind, placebo-controlled, randomized discontinuation trial. It consisted of a one-week screening period, a six-week open-label period and a 26-week double-blind period. In the open-label period, investigators established patients’ optimal pregabalin dosages as 300, 450 or 600 mg/day. Patients who completed the six-week, open-label period with at least a 50% reduction compared to their baseline pain Visual Analog Scale (VAS) score and a Patient Global Impression of Change (PGIC) rating of at least “much improved” could then be randomized to active treatment or placebo.

The primary outcome was time to loss of therapeutic response (LTR), which investigators defined as <30% reduction from the start of the open-label period in the pain VAS score during two consecutive visits or a subjective worsening of fibromyalgia. They included the Multidimensional Assessment of Fatigue (MAF) scale and the Medical Outcomes Study (MOS)-Sleep Scale as secondary end points to evaluate the time to loss of response for associated fatigue and sleep disturbance.

Findings indicated that of the patients who responded to pregabalin, two-thirds continued to have sustained benefits.

Among the 1051 patients who entered the open-label period, 663 completed it and 566 were eligible to participate in the randomization phase. In this phase, 279 patients were assigned to pregabalin and 287 to placebo. The time to LTR for pain was significantly longer for active treatment than for placebo (P<0.0001) (Table 1).

Table 1. Durability of Effect in Double-blind Phase


The most common adverse events with active treatment during the open-label period were dizziness (36%) and somnolence (22%). During the double-blind treatment, these were sinusitis (5% vs. 3%), and arthralgia and anxiety (5% vs. 2%), in the pregabalin and placebo cohorts, respectively.

Measuring Relief Through VAS Score

As discussed by Dr. Lesley M. Arnold, Associate Professor, Department of Psychiatry, University of Cincinnati, Ohio, these findings are consistent with an analysis of pooled data of 1493 patients from two prior trials using a similar double-blind, placebo-controlled, parallel-group design as in FREEDOM. Eligible patients who met 1990 ACR criteria for fibromyalgia were randomized to pregabalin at 300 mg/day, 450 mg/day, 300 mg b.i.d. or placebo, consisting of a one- or two-week dosage-escalation period followed by 12 weeks of fixed-dose treatment.

The average reduction from a mean baseline VAS score of 6.9 to end point was significantly greater for all active doses compared to placebo (each P<0.0001) observing an “almost linear” reduction from 300 to 450 to 600 mg/day treatment arms, Dr. Arnold noted. The 300 mg/day arm had a mean treatment difference of -2.47 points on the Fibromyalgia Impact Questionnaire (P=0.0707) with the strongest improvements in the 450- mg and 600-mg arms. Furthermore, a significantly greater proportion of patients on active treatment reported clinically meaningful improvement on the PGIC: 38% (P=0.0002), 44% and 45% (both P<0.0001) in those on 300, 450 and 600 mg/day, respectively. A 29% improvement was observed in placebo patients.

Patients tolerated active treatment generally well, with most adverse events mild to moderate in severity and tending to resolve with continued treatment. The most common treatment-emergent adverse effects (i.e. somnolence and weight gain) occurred at a rate of 31%, 41%, 45% and 8% in patients receiving 300, 450, 600 mg/day and placebo, respectively. Treatment discontinuation due to adverse events occurred in 18%, 22% and 29% of patients on 300, 450 and 600 mg/day, respectively.

Summary

The underlying pathophysiology of fibromyalgia appears to involve overly active pain processing at the CNS level. Strategies that inhibit the processing of pain at this level offer key advantages. Along with physical and cognitive behavioural therapy, newer options may contribute to improved functions in a condition with historically limited options.

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