RESEARCH - Duloxetine shows efficacy in fibromyalgia with or without concurrent major depression

[Guest guest]

Duloxetine shows efficacy in fibromyalgia with or without concurrent

major depression

Rheumawire

Sep 14, 2004

Janis

Cincinnati, OH - Duloxetine (Cymbalta, Eli Lilly & Co), a drug that

inhibits both norepinephrine (NE) and serotonin (5-HT) reuptake and is

currently marketed for depression, has shown a significant improvement

in a wide range of fibromyalgia syndrome (FMS) symptoms, including pain

and tender point scores, and this effect was independent of whether or

not the patient had major depression [1].

The results, from a double-blind, placebo-controlled trial involving 207

patients sponsored by the manufacturer, are reported in the September

2004 issue of Arthritis & Rheumatism.

" I would say the weight of the evidence shows that duloxetine leads to

sustained relief of pain, especially in the female subjects, who

improved on all pain outcomes, " principal investigator Dr Lesley M

Arnold (University of Cincinnati College of Medicine, OH) tells

rheumawire.

" Are we then on the brink of a new era of fibromyalgia syndrome

management? " asks an accompanying editorial [2]. " The future does seem

positive in regard to significant improvement in FMS symptoms with these

new potential therapies, " writes Dr Geoffrey O Littlejohn (Monash

Medical Centre, Clayton, Australia). " However, it is wise to continue to

reflect on the FMS process and to recognize that social and

psychological factors, even everyday life stressors, can dramatically

affect FMS neurobiology. "

The duloxetine study is part of an effort to improve on results with

tricyclic antidepressants, which are widely used in FM in doses lower

than those typically used in mood disorders, Arnold et al explain. The

tricyclics produce some improvement in FM-related fatigue and in sleep,

overall well-being, and pain severity but have less effect on

tenderness. These drugs reduce both NE and 5-HT reuptake but also have

varied effects on choloinergic and histamine activities and on other

mechanisms that modulate pain.

Separating out the effect on reuptake inhibition has not been useful.

Targeted inhibition of NE reuptake with venlafaxine (Efexor, Wyeth) and

selective inhibition of 5-HT reuptake with fluoxetine (Prozac, Eli &

Lilly Co) have both been relatively ineffective in FM [3, 4]. The

duloxetine study combines both approaches by using a combination

reuptake inhibitor to elevate levels of both NE and 5-HT, but without

the other effects of the tricyclics.

The multicenter study enrolled 207 subjects meeting the American College

of Rheumatology (ACR) criteria for primary fibromyalgia. Patients were

randomized to placebo (n=103, including 92 women) or to duloxetine 60 mg

bid (n=104, including 92 women). In the placebo group, 42/103 patients

had major depressive disorder. In the duloxetine group, 37/104 patients

had major depressive disorder.

The double-blind treatment phase continued for 12 weeks and included

weekly visits for the first 2 weeks, then visits every 2 weeks.

The 2 primary outcome measures were pain severity as measured by the

Fibromyalgia Impact Questionnaire (FIQ) pain item and the FIQ total

score, reflecting the overall impact of FM. Secondary end points

included the FIQ items for fatigue, morning tiredness, and stiffness,

and tender point assessment.

Other secondary end points were the Clinical Global Impressions of

Severity scale, the Patient Global Impression of Improvement scale, the

Brief Pain Inventory (short form), the Beck Depression Inventory, the

Beck Anxiety Inventory, the Medical Outcomes Study Short Form 36

(SF-36), the Quality of Life in Depression Scale, and the Sheehan

Disability Scale. All of them were assessed on an intention-to-treat

analysis.

" The FIQ score was improved at week 12. Only the FIQ pain score was not

significantly improved at week 12, although it was improved at week 4.

Another pain score, the Brief Pain Inventory, was significantly improved

at week 12, as was the SF-36 bodily pain score. Furthermore, the female

subjects improved on all pain outcomes (including the FIQ pain score) at

week 12, " Arnold tells rheumawire.

There was a striking improvement in the FIQ total score for the entire

duloxetine group, which became significant at week 4 and continued

through week 12 (p=0.027). The group difference in the other primary end

point, the FIQ pain score, became significant at week 4 but was not

significant at week 12 (p=0.130). Response rates, defined as a <50%

decrease in FIQ pain score, were 27.7% for duloxetine vs 16.7% for

placebo at week 12 (p=0.06).

Arnold points out that the improvement in tender point measures was

particularly important, since previous studies using tricyclic

antidepressants found little improvement in tender points.

The duloxetine-treated patients also had significant improvements in

general activity, mood, walking ability, normal work, sleep, and

enjoyment of life, as measured on the Brief Pain Inventory.

Duloxetine was equally effective in patients with or without major

depressive disorder, Arnold notes. " I was not surprised that the

improvement in fibromyalgia symptoms with duloxetine was independent of

the presence or absence of depression. Duloxetine may have an effect on

the descending pain pathways that involve serotonin and norepinephrine

that is independent of its effect on mood. "

Although the numbers are small, the data also suggest that there may be

a sex difference in response to duloxetine for FM. The investigators

found that duloxetine-treated women improved significantly more than

placebo-treated women on both the primary and secondary end points,

while male subjects treated with duloxetine did not have significantly

better responses than the placebo-treated men on either primary or

secondary efficacy measures.

" I was surprised by the lack of effect in men. I think the power was not

great enough to show an effect in men. We need to study a larger group

of men before coming to any firm conclusion about duloxetine in the

treatment of men with fibromyalgia, " Arnold says.

Sources

Arnold LM, Lu Y, Crofford LJ, et al. A double-blind,

multicenter trial comparing duloxetine with placebo in the treatment of

fibromyalgia patients with or without major depressive disorder.

Arthritis Rheum 2004; 50:2974-2984.

Littlejohn GO. Balanced treatments for fibromyalgia.

Arthritis Rheum 2004; 50:2725-2729.

Zijlstra TR, Barendregt PJ, van de Laar MA.

Venlafaxine in fibromyalgia: results of a randomized,

placebo-controlled, double-blind trial [abstract]. Arthritis Rheum

2002; 46(Suppl 9):S105

Wolfe F, Cathey MA, Hawley DJ. A double-blind placebo

controlled trial of fluoxetine in fibromyalgia. Scand J Rheumatol

1994; 23:255-259.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org