Electroacupuncture Versus Gabapentin for Hot Flashes Among Breast Cancer Survivors: A Randomized Placebo-Controlled Trial
Authors: Mao, J; Bowman, MA; Xie SX; Bruner D; DeMichele A; Farrar JT. Source: Title Journal of Clinical Oncology, August 24, 2015; DOI:10.1200/JCO.2015.60.9412.
Hot flashes are a common and debilitating symptom among survivors of breast cancer.
This study aimed at evaluating the effects of electroacupuncture (EA) versus gabapentin (GP) for hot flashes among survivors of breast cancer, with a specific focus on the placebo and nocebo effects.
Patients and Methods We conducted a randomized controlled trial involving 120 survivors of breast cancer experiencing bothersome hot flashes twice per day or greater. Participants were randomly assigned to receive 8 weeks of EA or GP once per day with validated placebo controls (sham acupuncture [SA] or placebo pills [PPs]). The primary end point was change in the hot flash composite score (HFCS) between SA and PP at week 8, with secondary end points including group comparisons and additional evaluation at week 24 for durability of treatment effects.
Results By week 8, SA produced significantly greater reduction in HFCS than did PP (−2.39; 95% CI, −4.60 to −0.17). Among all treatment groups, the mean reduction in HFCS was greatest in the EA group, followed by SA, GP, and PP (−7.4 v −5.9 v −5.2 v−3.4; P = < .001). The pill groups had more treatment-related adverse events than did the acupuncture groups: GP (39.3%), PP (20.0%), EA (16.7%), and SA (3.1%), with P = .005. By week 24, HFCS reduction was greatest in the EA group, followed by SA, PP, and GP (−8.5 v −6.1 v −4.6 v −2.8; P = .002).
Conclusion: Acupuncture produced larger placebo and smaller nocebo effects than did pills for the treatment of hot flashes. EA may be more effective than GP, with fewer adverse effects for managing hot flashes among breast cancer survivors; however, these preliminary findings need to be confirmed in larger randomized controlled trials with long-term follow-up.
Commentary by Ting Bao
Over the past three months, there have been a number of acupuncture clinical trials published. Among them, the electroacupuncture clinical trial conducted by Mao et al1 and published in the Journal of Clinical Oncology is the most innovative and thought-provoking.
In this trial, investigators randomized 120 breast cancer survivors suffering from hot flashes at least twice daily into four arms: electroacupuncture (EA), sham acupuncture (SA), gabapentin (GP), and placebo pills (PP) for 8 weeks. Unlike other acupuncture efficacy trials, however, the primary end point was the change in hot flash composite scores (HFCS) between SA and PP at week 8, with secondary end points including post-treatment comparisons of all groups at different time points and to examine treatment durability at week 24.
The emphasis on SA and PP outcomes and their placebo versus nocebo effects stems from the paradox that while some trials indicate similar results with real and sham acupuncture for hot flashes, 2-4 real acupuncture also produces responses equivalent with pharmacologic treatments such as venlafaxine, but without adverse effects.
Therefore, investigators further identified the value in learning the extent to which sham acupuncture may or may not also perform better than a corresponding GP placebo pill, based on gabapentin efficacy.
In Mao et al1, SA produced significantly greater reductions in HFCS than PP by week 8, indicating a greater placebo effect with SA. Compared with baseline scores, although all arms experienced HFCS reductions, SA produced significantly better results than both GP and PP interventions (EA −7.4, SA −5.9, GP −5.2, and PP −3.4). In addition, SA had a smaller nocebo effect than PP, as evidenced by the significantly higher percentage of reported adverse events for PP compared with SA (20.0% vs 3.1%, respectively).
An intriguing finding is the more durable effect in HFCS reductions produced at week 24 (16 weeks post-treatment) with both EA and SA treatments (EA −8.5 , SA −6.1) than with gabapentin (GP −2.8), suggesting that both types of acupuncture may elicit underlying physiologic changes not induced by pharmacologic intervention. On the other hand, the effect size of EA compared with SA was small at week 8 (Cohen’s d = 0.21) but got bigger at week 24 (Cohen’s d = 0.31), suggesting EA may produce additional or longer-lasting physiological effects than SA.
This is the one of the few studies comparing the placebo and nocebo effects of acupuncture with pills. These findings may help to explain the lack of statistically significant differences between treatment arms in many trials evaluating true acupuncture versus sham controls, since the placebo effect has now been determined to be larger with SA than PP interventions. Designing a sham acupuncture-controlled trial may require a much bigger sample size than placebo pill-controlled trials due to significant larger placebo in SA than PP. This study validates the importance of determining how and the extent to which SA differs from pharmacologic placebos as well as its performance against both types of active interventions. Further, the demonstrated durability with EA and to a lesser extent SA, 16 weeks post-intervention vis-à-vis the lack of durability with GP bears special mention and should influence design considerations of future acupuncture trials, as longer follow-up is warranted.
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