Omega-3 fatty acids similar to placebo for aromatase inhibitor–induced musculoskeletal pain

The placebo effect is related to patient expectations and perceptions of treatment. It is heightened with a supportive patient-provider relationship and typically diminished in blinded clinical trials where patients do not know if they are receiving the active drug. However, in clinical trials that have evaluated symptom management, substantial placebo effects were more common. This observation points to the importance of placebo-controlled, randomized trials vs. uncontrolled trials for symptom management therapies.

The larger-than-expected placebo response in the Hershman et. al. study may have resulted from several factors, including O3-FA supplementation causing placebo contamination, ingredients within the placebo capsule, the natural history of AIMSS, and patient selection.

Because O3-FAs are readily available as supplements, placebo contamination should be considered. The authors examined a surrogate marker for exposure, longitudinal change in triglycerides, and found only the active arm had decreased triglyceride levels. This observation suggests that participants in the placebo arm were not significantly exposed to O3-FAs.

The ingredients of the placebo capsule, soybean oil or other components, may have contributed to symptom improvement. If AIMSS is related to estrogen deprivation, estrogenic compounds in the placebo may have affected symptoms.

Previous studies indicate that many patients do not spontaneously improve over time, as would be the case if the natural history of AIMSS accounted for the high placebo effect.

Regarding the patients enrolled in the study, there is no way to definitively determine if their pain and stiffness was caused by AIs; distinguishing between AIMSS and worsening of osteoarthritis in this patient population with high baseline joint pain is difficult. It is possible that patients with preexisting musculoskeletal pain not related to AIs participated in this study, particularly since there is a low perceived toxicity of the drug.

Patients enrolled in this trial may have experienced symptom improvement solely due to the expectation of benefit by participation in the trial. A similar placebo response was reported in a controlled trial of modafinil for fatigue.

The results of this well-conducted SWOG trial clearly demonstrate that acknowledging and controlling for placebo effects is crucial to high-quality research in the field of symptom management.

Dr. N. Lynn Henry is assistant professor in the division of hematology/oncology, department of internal medicine, at the University of Michigan, Ann Arbor. Dr. Jennifer Griggs is professor of medicine in the division of hematology/oncology and director of the breast cancer survivorship program at the University of Michigan Comprehensive Cancer Center, Ann Arbor. Dr. Henry reported receiving research funding from Sanofi-Aventis, BioMarin, and Celldex. These comments were taken from an editorial accompanying the report by Hershman et al. (J. Clin. Onc. 2015 May 4 [doi:10.1200/JCO.2015.61.1004]).