Park H, Qin R, Smith TJ, et al. North Central Cancer Treatment Group N10C2 (Alliance): a double-blind placebo-controlled study of magnesium supplements to reduce menopausal hot flashes. Menopause. 2015;22(6):627-632.
Four-arm, double-blind, placebo-controlled randomized trial
A total of 289 women were enrolled between December 2011 and March 2013; 267 women were included in the final analysis. All participants were postmenopausal with a history of breast cancer and bothersome hot flashes.
Study Medication and Dosage
The participants were randomized into treatment groups of magnesium oxide 800 mg or 1,200 mg per day or corresponding placebo groups at a 2:2:(1:1) ratio. Patients started with lower doses and titrated up over a period of several weeks. Treatment lasted a total of 8 weeks.
Hot flash frequency and hot flash score (number of hot flashes multiplied by the mean severity) were measured using a validated hot flash diary. A 1-week baseline period preceded initiation of study medication. The primary endpoint was intrapatient difference in mean hot flash score between baseline and treatment periods, comparing each magnesium group with the combined placebo groups using a gatekeeping procedure.
Mean hot flash scores, mean hot flash frequencies, and associated changes during the treatment period were similar for each group. An increased incidence of diarrhea and a corresponding lower incidence of constipation were reported in magnesium arms compared with placebo. No statistically significant difference in other toxicities or quality-of-life measures was observed.
This study indicates we should reconsider the practice of suggesting magnesium oxide to breast cancer patients complaining of menopausal hot flashes.
Hot flashes are a common complaint in menopausal women, especially those with a history of breast cancer who are receiving adjunctive therapies such as tamoxifen or aromatase inhibitors. Two pilot studies have in the past suggested that magnesium oxide might reduce the number and intensity of hot flashes.
Given that bottles of placebo pills are not routinely available, magnesium oxide is an easy-to-obtain and safe choice.
At a 2010 meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Herrada described a pilot study of 22 women who received 400 mg of magnesium oxide 3 times a day for a month. All the women were receiving adjuvant treatment for breast cancer. By the end of the study, 10 (45%) patients achieved a complete resolution of hot flashes and 10 (45%) patients experienced at least 50% fewer hot flashes per day. Two (10%) patients did not experience a change in the number of hot flashes.1
Results of a second pilot study were reported in 2011 by Park et al. A group of 25 breast cancer patients, also receiving some form of adjuvant treatment, were given 400 mg of magnesium oxide per day for 4 weeks, escalating to 800 mg if needed. Hot flash scores were significantly reduced. Of 25 patients, 14 (56%) had a >50% reduction in hot flash score, and 19 (76%) had a >25% reduction. The women also experienced a reduction of fatigue, sweating, and distress.2
These studies in combination seemed clinically significant, and we reviewed the 2011 paper in the August 2011 edition of Natural Medicine Journal.
The lead author of this new, larger, and far more comprehensive placebo-controlled trial is Haeseong Park, who was also the lead investigator in the smaller 2011 pilot study. In this 2015 clinical trial, magnesium oxide did not offer any more benefit than placebo. Both doses of magnesium and also the placebo were associated with similar improvements in hot flashes. They all appear to help equally.
It is not that magnesium wasn’t associated with improvement; it was that the placebo worked just as well, suggesting that the benefit of taking magnesium oxide for hot flashes is a placebo effect. Both of the earlier pilot studies were open-label and without placebo arms.
These studies leave us in something of an ethical quandary. There are 2 ways to interpret and act on these data. We could conclude that if magnesium does not work any better than placebo for hot flashes, we should stop prescribing it for this indication. On the other hand, because magnesium and placebo each appear to be quite effective for hot flashes in this patient population, we should consider them for treating this complaint. Given that bottles of “placebo pills” are not routinely available, magnesium oxide is an easy-to-obtain and safe choice.
Some will note that magnesium oxide is typically not our first choice in magnesium because it is poorly absorbed and tends to have a laxative effect. The fact that magnesium oxide does have this side effect may enhance its placebo effect, and we should think twice before switching to “better forms” of magnesium.
Hot flashes appear to be quite responsive to placebo intervention.3 Several prior randomized studies have reported a placebo benefit. In Boekhout’s 2006 review, about 25% of 1,174 patients who received placebo or the intervention reported hot flashes reduced by at least 50%, and 15% had greater than 75% reduction.4 In Sloan’s 2001 review of 7 randomized trials, the 375 patients who received placebo had an average 25% decrease in hot flash frequency and intensity.5 It seems that hot flashes may be particularly sensitive to placebo effect.
Women with a history of breast cancer whose hot flashes are treated using the commonly prescribed drugs venlafaxine, gabapentin, or clonidine have a high risk for adverse events. A November 2016 Cochrane review of 12 studies with a total of 1,467 participants reports that 81% of women in the treatment group had adverse reactions, compared to only 19% in the control group.6 With this in mind, a trial of magnesium, even if it is only a placebo, may be a safer first option than prescription medications.
- Herrada J, Gupta A, Campos-Gines AF, et al. Oral magnesium oxide for treatment of hot flashes in women undergoing treatment for breast cancer: a pilot study. Chicago: 2010 ASCO Annual Meeting; 2010.
- Park H, Parker GL, Boardman CH, Morris MM, Smith TJ. A pilot phase II trial of magnesium supplements to reduce menopausal hot flashes in breast cancer patients. Support Care Cancer. 2011;19(6):859–863.
- Mahon SM, Kaplan M. Placebo effect in hot flush research. Lancet Oncol. 2012;13(5):e188; author reply e190.
- Boekhout AH, Beijnen JH, Schellens JH. Symptoms and treatment in cancer therapy-induced early menopause. Oncologist. 2006;11(6):641-654.
- Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl H. Methodologic lessons learned from hot flash studies. J Clin Oncol. 2001;19(23):4280-4290.
- Hervik JB, Stub T. Adverse effects of non-hormonal pharmacological interventions in breast cancer survivors, suffering from hot flashes: a systematic review and meta-analysis. Breast Cancer Res Treat. 2016;160(2):223-236.