A randomised trial of electro-acupuncture for arthralgia related to aromatase inhibitor use

https://doi.org/10.1016/j.ejca.2013.09.022Get rights and content

Abstract

Background

Arthralgia is a common and debilitating side-effect experienced by breast cancer patients receiving aromatase inhibitors (AIs) and often results in premature drug discontinuation.

Methods

We conducted a randomised controlled trial of electro-acupuncture (EA) as compared to waitlist control (WLC) and sham acupuncture (SA) in postmenopausal women with breast cancer who self-reported arthralgia attributable to AIs. Acupuncturists performed 10 EA/SA treatments over 8 weeks using a manualised protocol with 2 Hz electro-stimulation delivered by a TENS unit. Acupuncturists administered SA using Streitberger (non-penetrating) needles at non-traditional acupuncture points without electro-stimulation. The primary end-point was pain severity by Brief Pain Inventory (BPI) between EA and WLC at Week 8; durability of response at Week 12 and comparison of EA to SA were secondary aims.

Findings

Of the 67 randomly assigned patients, mean reduction in pain severity was greater in the EA group than in the WLC group at Week 8 (−2.2 versus −0.2, p = 0.0004) and at Week 12 (−2.4 versus −0.2, p < 0.0001). Pain-related interference measured by BPI also improved in the EA group compared to the WLC group at both Week 8 (−2.0 versus 0.2, p = 0.0006) and Week 12 (−2.1 versus −0.1, p = 0.0034). SA produced a magnitude of change in pain severity and pain-related interference at Week 8 (−2.3, −1.5 respectively) and Week 12 (−1.7, −1.3 respectively) similar to that of EA. Participants in both EA and SA groups reported few minor adverse events.

Interpretations

Compared to usual care, EA produced clinically important and durable improvement in arthralgia related to AIs in breast cancer patients, and SA had a similar effect. Both EA and SA were safe.

Introduction

Arthralgia, or joint pain, is a debilitating side-effect of aromatase inhibitors (AIs) among postmenopausal women with hormone receptor positive breast cancer taking these drugs [1]. Nearly half of AI-users in the clinical setting report arthralgia attributable to AIs [2]. Arthralgia ranks as the top symptom associated with AIs discussed in online breast cancer-specific message boards [3] and often results in poor adherence, or discontinuation [4]. Premature discontinuation negatively impacts disease free and overall breast cancer survival [5].

There is emerging evidence [6] and acceptance [7] for acupuncture, a practice in Traditional Chinese Medicine, as a component of pain management. Many breast cancer patients desire the integration of acupuncture into their conventional cancer care [8] and 60% of National Cancer Institute designated comprehensive cancer centres in the United States (U.S.) recommend acupuncture as an approach for patient symptom management [9]. Despite growing interest from patients and cancer centres, rigorous research is needed to guide its evidence-based integration into cancer care to improve patient outcomes.

A few studies have suggested that acupuncture may be safe and effective for managing AI-related arthralgia [10], [11], [12]. However, lack of controls, small sample sizes and high drop-out levels in intervention arms limit the interpretation of these results. Additionally, lack of comparison with usual care makes it difficult to evaluate the clinical relevance of the overall effect of acupuncture for this condition. To more definitively test the clinical effect of acupuncture, we conducted a Phase-II randomised controlled trial (RCT) to evaluate the short term effects and safety of electro-acupuncture (EA) for AI-related arthralgia compared to usual care. We chose EA because animal research has demonstrated its clear physiological effect on the endogenous opioid system (enkaphalin, beta-endorphin and endomorphin) and pain reduction [13]. Our primary hypothesis was that patients receiving EA would have a greater reduction in arthralgia and improved function at Week 8 compared to the Waitlist Control (WLC) ‘usual care’ group. As secondary aims, we evaluated the durability of response with a repeated measure at Week 12 and evaluated the magnitude of response to sham acupuncture (SA) to inform the design of a future Phase-III trial.

Section snippets

Study participants

We conducted a three arm RCT (EA, SA and WLC) from September 2009 through May 2012 at the Abramson Cancer Center of the Hospital of the University of Pennsylvania, a tertiary care academic medical centre in Philadelphia. The institutional review board of the University of Pennsylvania approved the study protocol. Eligible patients were women with a history of early stage breast cancer (stages I–III) who were currently receiving an aromatase inhibitor (Anastrozole, Letrozole or Exemestane), had

Results

Between September 2009 and May 2012, we screened 159 patients. Of the 76 patients who qualified for baseline evaluation, nine were further excluded (seven had patient-reported pain level lower than inclusion criteria, one had severe pain unrelated to AIs and another did not want to participate), and the 67 eligible participants were randomly assigned to EA, SA or WLC. Among participants, 21 (95.4%) in the EA group and 20 (90.5%) in the SA group received all 10 treatments. Four (6%) and eight

Discussion

This randomised controlled trial met its primary end-point, demonstrating that EA produced statistically significant and clinically important improvements in pain severity, pain-related interference and functional outcomes in both upper and lower extremities when compared to WLC usual care. The effects were observed at Week 8 when intervention completed, and persisted at the Week 12 follow-up visit. SA also produced a similar magnitude of change in pain-related outcomes that were significantly

Author contributions

All authors participated in study design, writing of and approving the final manuscript. J.J.M. obtained funding and managed trial and data collection process. S.X.X. performed data analysis and data interpretation. J.T.F., C.T.S., M.A.B., D.B. and A.D. provided expertise during study design, data interpretation and revision of the manuscript.

Funding source

This study is supported by grants from the National Institutes of Health/National Center for Complementary and Alternative Medicine (NCCAM) R21 AT004695. Dr. Mao is a recipient of the NCCAM K23 AT004112 award. The funding agencies had no role in the design or conduct of the study. Dr. Mao had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Conflict of interest statement

Dr. Mao has consulted for Pfizer on issues unrelated to aromatase inhibitors. Dr. Farrar has consulted for Pfizer and AstaZeneca on issues that are unrelated to aromatase inhibitors. The other co-authors had no conflict of interest to declare.

Acknowledgements

We thank our acupuncturists, Lorna Lee and Adam Schreiber, for delivering the interventions. We thank Christina Seluzicki, Rana Leed, Courtney Penn, Shawn Fernandes, Xiaoyan Han and Qing S. Li for their dedication to clinical trial coordination, data collection and management and statistical programming. We thank Brian Strom MD MPH for valuable feedback on the manuscript. Sincere thanks also go to the patients, oncologists, nurse practitioners and clinical staff for their support of this study.

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