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Sept. 10, 2004 — Duloxetine, a serotonin and norepinephrine
reuptake inhibitor, is effective for the treatment of fibromyalgia
with or without major depressive disorder, according to the results
of a randomized trial published in the September issue of Arthritis
& Rheumatism. This was one of the largest clinical trials in
fibromyalgia conducted to date, and the only trial to evaluate the
impact of comorbid major depressive disorder on treatment response.
"Our results suggest that duloxetine improves pain and tenderness,
the hallmark characteristics of fibromyalgia," lead author
Lesley M. Arnold, MD, from the Duloxetine Fibromyalgia Trial Group,
says in a news release. "The effect of duloxetine on the reduction
of pain appears to be independent of its effect on mood."
The Food and Drug Administration (FDA) has not approved any treatments
for fibromyalgia.
Because 5-hydroxytryptamine (5-HT) and norepinephrine are thought
to be key mediators of descending pain pathways, duloxetine has
been investigated in animal models of persistent and neuropathic
pain and found to be effective in reducing pain-related behaviors.
In this double-blind, parallel-group study conducted in 18 U.S.
outpatient research centers, 207 outpatients meeting the American
College of Rheumatology (ACR) criteria for primary fibromyalgia
with or without current major depressive disorder were enrolled.
Mean age was 49 years, 89% of subjects were female, 87% were white,
and 38% had current major depressive disorder. After one week of
single-blind placebo treatment, subjects were randomized to receive
duloxetine, 60 mg, twice daily or placebo for 12 weeks.
Primary outcome measures were the Fibromyalgia Impact Questionnaire
(FIQ) total score (score range, 0 to 80, with 0 indicating no impact)
and FIQ pain score (score range, 0 to 10). Secondary outcomes were
mean tender point pain threshold, number of tender points, FIQ fatigue,
tiredness on awakening, and stiffness scores; and Clinical Global
Impression of Severity scale, Patient Global Impression of Improvement
scale, Brief Pain Inventory (short form), Medical Outcomes Study
Short Form 36, Quality of Life in Depression Scale, and Sheehan
Disability Scale.
Compared with subjects receiving placebo, those taking duloxetine
had greater improvement on the FIQ total score (treatment difference,
-5.53; 95% confidence interval, -10.43 to -0.63). Improvement on
the FIQ pain score was similar in both groups (P = .13).
The duloxetine group also fared better than the placebo group in
Brief Pain Inventory average pain severity score (P = .008), Brief
Pain Inventory average interference from pain score (P = .004),
number of tender points (P = .002), and FIQ stiffness score (P =
.048). Improvement was greater with duloxetine than with placebo
for mean tender point pain threshold (P = .002), Clinical Global
Impression of Severity (P = .048), Patient Global Impression of
Improvement (P = .03), and several quality-of-life measures.
Compared with women receiving placebo, those taking duloxetine
had significantly greater improvement on most efficacy measures.
However, men treated with duloxetine did not improve significantly
on any efficacy measure.
"The reasons for the sex differences in response are unclear,"
says Dr. Arnold. "Because the male subgroup was small, reflecting
the much higher prevalence of fibromyalgia in women, the results
of the study may not be generalizable to all men with fibromyalgia.
There may also be sex differences in fibromyalgia that affect treatment
response."
Independent of baseline status of major depressive disorder, duloxetine
treatment improved fibromyalgia symptoms and pain severity, and
the treatment effect on significant pain reduction in women was
independent of the effect on mood or anxiety. Duloxetine was safe
and well-tolerated in this study.
Study limitations include predominance of women limiting generalizability
to men, problems with the FIQ pain score related to retrospective
rating of pain, limited treatment duration, and study dropout by
about 40% of all subjects. Other problems were exclusion of individuals
with several forms of lifetime psychopathology, those with secondary
fibromyalgia and unstable medical or psychiatric illness, and those
previously shown to be resistant to antidepressant treatment.
Dr. Arnold recommends further research on larger samples of men
and in other groups with fibromyalgia.
Eli Lilly and Company, the maker of duloxetine, supported this
study, employs two of its authors and the wife of one of the authors,
and has provided consulting fees or honoraria to two of the authors.
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