New Potential Drug Therapy for AI-Associated Arthralgia

Randomized, Multicenter, Placebo-Controlled Clinical Trial of Duloxetine Versus Placebo for Aromatase Inhibitor Associated Arthralgias in Early-Stage Breast Cancer: SWOG S1202

Henry NL, Unger JM, Schott AF, et al
J Clin Oncol. 2014 Nov 14. [Epub ahead of print]

Study Summary

Aromatase inhibitors for adjuvant therapy of early-stage breast cancer are very effective but adherence is limited by musculoskeletal symptoms. Lifestyle interventions such as exercise, as well as nonpharmacologic interventions such as acupuncture, have demonstrated a benefit in reduction of side effects. Duloxetine is an antidepressant with demonstrated improvement in pain. The investigators of this multicenter trial hypothesized that a short course of treatment with duloxetine would improve average joint pain compared with placebo.

SWOG researchers conducted a randomized, double-blind phase 3 study of postmenopausal women with breast cancer treated with curative intent. Eligible patients scored their pain as 4/10 and were assigned to take duloxetine or placebo for 13 weeks.

The study enrolled 299 patients, and among those evaluable for the primary analysis, 127 were treated with duloxetine and 128 received placebo. By 12 weeks, average joint pain (including stiffness) was 0.82 points lower for patients on duloxetine. Adverse events (mainly fatigue, dry mouth, and headache) caused 21 patients receiving duloxetine and 19 patients on placebo to discontinue. More patients on duloxetine reported that it was beneficial despite adverse effects and that the benefit occurred quickly, within 2 weeks of starting the medication. The benefit did not persist in either group after the drug was discontinued.

Results of this study show that duloxetine was superior to placebo in treating musculoskeletal symptoms, including pain and stiffness, that are associated with aromatase inhibitors, although it resulted in more low-grade toxicities.

Viewpoint

The study addresses an important topic for clinicians treating women with early-stage breast cancer. There is strong evidence to support the use of adjuvant endocrine therapy with aromatase inhibition for postmenopausal women for 5 years or more, depending on recurrence risk and tolerance to the medication. The overall effectiveness of this therapy depends on adherence, which remains a stubborn problem for patients and clinicians.

Studies have demonstrated beneficial effects from lifestyle interventions such as exercise, as well as nonpharmacologic specialized interventions such as acupuncture, in ameliorating troublesome side effects like joint pain and stiffness, which affect quality of life and function.

This trial was rigorously designed to test the benefit of a pharmacologic intervention of duloxetine, a drug that was developed to treat depression but which also has analgesic properties. A 14-item pain questionnaire and several other instruments to assess musculoskeletal symptoms were used to survey patients on many aspects of quality of life and function across multiple time points.

The results are fascinating and show a clear benefit from the medication, as well as expected adverse events associated with the drug. Of note, the authors reported that almost as many patients receiving placebo discontinued the medication due to grade 3 adverse events (mostly fatigue, dry mouth, and headache), and this speaks strongly to the "nocebo" effect—the anticipation of discomfort that accompanies receiving information about possible adverse events while taking a placebo.

The take-home message is that duloxetine proved superior to placebo and showed a significant reduction in symptoms quite early in the treatment course, and that this benefit did not persist after discontinuing the drug. Of note, the improvement of pain was not due to inadvertent treatment of mood and depression, suggesting a specific pharmacologic effect mediating tolerance and perception of pain.

A final comment about lessons learned from this study: Drug trials have a significant placebo response that is on the order of 30%-50%, and this is not found in lifestyle or acupuncture studies—an important concept to bear in mind as we learn more about supportive care interventions to help women adhere to adjuvant endocrine therapy.

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