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Therapeutic Approaches to Pain and Disability Associated with 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.

71st Annual Meeting of the American College of Rheumatology

Boston, Massachusetts / November 6-11, 2007

Fibromyalgia affects patients in many different domains, with its symptoms of pain and fatigue, but also its broader effects on the mental health, well-being and quality of life of patients, stated Dr. Lesley M. Arnold, Associate Professor of Psychiatry and Director, Women’s Health Research Program, University of Cincinnati College of Medicine, Ohio.

She described the challenges of diagnosing and managing patients with fibromyalgia. “As a first-line approach for those with severe to moderate levels of pain, we use an evidence-based approach to treatment,” Dr. Arnold told delegates. “We select medications based on the evidence, and then we also decide what to choose based on comorbidities and their symptom domains.”

Because fibromyalgia is marked by enhanced pain perception, pharmacologic management (as supported by evidence) may include a serotonin-norepinephrine reuptake inhibitor (SNRI), tricyclic antidepressant or an alpha-2-delta ligand such as pregabalin, Dr. Arnold noted. As meeting attendees heard in a scientific session, however, one SNRI, duloxetine, was found in a 27-week, phase III clinical trial to be no better than placebo at reducing mean pain severity or ameliorating Patient Global Impression of Improvement (PGI-I) scores. As measured by the Brief Pain Inventory, the mean reduction in pain severity at the end of treatment was 1.62 points with duloxetine vs. 1.13 points with placebo, a difference that was not statistically significant, reported researcher Dr. Amy Chappell, Indianapolis, Indiana.

A second SNRI, milnacipran, showed more promise in phase III studies also presented at the ACR. About 25% of patients treated with a 200-mg daily dose met the study’s criteria for fibromyalgia syndrome response, defined as a pain response plus at least a 6-point improvement on the Short Form (SF)-36 Physical Component Summary. However, 45.6% of patients in this group were classified as pain responders, with at least a 30% reduction in pain scores, as recorded by patients in an electronic diary, and scores of “very much improved” or “much improved” on a 7-point patient-rated scale. At a 100-mg daily dose, 24.6% of patients were syndrome responders and 38.6% were pain responders, reported Dr. Robert H. Palmer, Forest Research Institute, Jersey City, New Jersey.

Regarding a different class of agents, the alpha-2-delta ligands, Dr. Arnold cited study results she and colleagues had originally presented at the 2007 meeting of the American Pain Society in Washington, DC. She noted there was a rapid onset of action with pregabalin, a sustained duration of effect out to 14 weeks in the two highest dose groups (450 mg and 600 mg/day), and a significant effect compared with placebo for the 300-mg dose at all time points except at week 11.

Symptomatic Relief

Similar results were seen in a randomized, placebo-controlled trial of pregabalin monotherapy in patients with fibromyalgia, results of which were reported by Dr. Erdal Diri, Division of Rheumatology, Trinity Health Center, Minot, North Dakota.

Patients assigned to receive one of three doses reported significantly greater pain relief than controls, beginning at one week and continuing at nearly all time points and at all doses through 14 weeks, Dr. Diri reported in a scientific oral abstract session. “Pregabalin monotherapy demonstrated clinically meaningful symptomatic relief of fibromyalgia.”

The trial was a randomized, double-blind, placebo-controlled study in 745 patients with fibromyalgia who met ACR criteria, which included a score of 40 mm on a pain visual analog scale (VAS) of 0 to 100, and a less than 30% reduction in pain VAS score during a one-week, single-blind, placebo run-in phase.

After the run-in, patients were randomly assigned to receive placebo or active therapy in doses of either 300, 450 or 600 mg/day, delivered twice daily in divided doses, or placebo for 14 weeks, including a two-week dosage escalation phase and a 12-week fixed-dosage phase.

There were significant differences from placebo in the mean change from baseline to study end point for the mean pain score, at -0.71 in the 300-mg group (P=0.0009), -0.98 in the 450-mg group (P<0.0001) and -1.00 in the 600-mg group (P<0.0001).

The mean differences from placebo at end point over the entire treatment period (duration adjusted average change) were -0.38 in the 300-mg group (P=0.0200), -0.62 in the 450-mg group (P=0.0001) and -0.57 in the 600-mg group.

In a mixed model repeated measurements (MMRM) analysis, there was pain relief among patients in all three active treatment groups by week 1 and at all other weekly measurements, with the exception of one treatment group at the 11-week interval only.

For all active treatment groups, the MMRM mean scores (week 14) were significantly improved compared with placebo, Dr. Diri noted. The difference from baseline was -0.63 for the 300-mg group (P=0.0051), -0.90 for the 450-mg group (P<0.0001) and -0.96 for the 600-mg cohort (P<0.0001).

FREEDOM Findings

Several studies presented here at the 2007 ACR underlined the efficacy of pregabalin over the long term. For example, in the FREEDOM (Fibromyalgia Relapse Evaluation and Efficacy for Durability of Meaningful Relief) trial involving 1051 patients, it significantly prolonged the time to loss of therapeutic response (as measured by pain VAS) and delayed worsening of outcomes related to Patient Global Impression of Change (PGIC) scores and Fibromyalgia Impact Questionnaire (FIQ) responses, as well as measures of sleep quality and fatigue (Figure 1).

The authors found that while 50% of placebo patients had lost their therapeutic responses by day 19, an equal percentage of actively treated patients retained their therapeutic responses through at least six months, at the end of the double-blind phase.

In addition, “pregabalin was generally well tolerated in this population of patients and across all indications,” the authors noted. “The safety profile was consistent with that seen in other studies and did not raise any new safety concerns.”

Durability of Response at One Year

An even longer response duration was seen in a study reported by Hana Florian, PhD, New York, New York, and colleagues.

In an open-label extension study of pregabalin for the long-term treatment of pain associated with fibromyalgia, the authors found that fibromyalgia patients who were treated for up to one year, for a total of 303 subject-years, had improvements in the SF-McGill Pain Questionnaire VAS and Present Pain Intensity (PPI) index measured on a 6-point scale. As in the FREEDOM study, the compound was generally well-tolerated, the authors found (Figure 2).

“We see that patients who were enrolled in this one-year, open-label extension actually maintained an effect for up to one year, and we see an improvement in their adverse-event profiles, in that the dizziness and somnolence that are the most common adverse events in our double-blind trials tend to go away over time,” reported study co-investigator Jeannette A. Barrett, PhD.

Finally, an analysis of pooled data from two randomized, placebo-controlled trials involving a total of 1493 patients revealed that pregabalin at each of three doses showed “robust” efficacy in the management of fibromyalgia.

The investigators reported that differences from placebo in mean change from baseline to end point in pain score were -0.55 for patients on 300 mg/day (P=0.0003), -0.71 for those on 450 mg/day (P<0.001) and -0.82 for patients on the 600 mg/day dose (P<0.0001).

In addition, the two higher doses were associated with significant improvements in the FIQ total score. PGIC scores were also significantly better than placebo in all dose groups (P£0.0002).

The response was generally dose-related, with nearly 50% of patients on the 450-mg or 600-mg dose showing a response of 30% or better, compared with only 32.6% of those on placebo. Similarly, whereas only 17.4% of fibromyalgia patients on placebo had a ³50% response, the responses of patients on pregabalin 300, 450 and 600 mg/day were 24.5%, 26.3% and 28.6%, respectively.

Summary

No single treatment approach may be right for every patient with fibromyalgia. Yet as Dr. Arnold noted, it is encouraging to know that there is growing evidence for improved options in the treatment of fibromyalgia, and she expressed the hope that there would be more of such agents in the coming year. She added, “We’ve worked so very hard to identify better treatments for our patients with fibromyalgia, and this is a very significant step forward.”

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

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