Hot Flash Treatment: 2011

Abstract & Commentary

By William B. Ershler, MD

Synopsis: In a randomized, double-blind, placebo-controlled trial, clonidine and venlafaxine both proved superior to placebo in reducing hot flashes in breast cancer patients. The study was insufficiently powered to prove superiority of one drug over the other. However, venlafaxine produced earlier reductions and it appeared clonidine had more sustained effect (i.e., at 12 weeks of treatment).

Source: Boekhout AH, et al. Management of hot flashes in patients who have breast cancer with venlafaxine and clinidine: A randomized, double-blind, placebo-controlled trial. J Clin Oncol 2011;29:3862-3868.

Hot flashes occur as a common consequence of breast cancer therapy and are quite debilitating for some. Whereas the single most effective treatment is estrogen, this approach is contraindicated in the setting of breast cancer and thus alternative, non-estrogenic approaches have been investigated. Boekhout and colleagues from the Netherlands undertook a double-blind, placebo-controlled randomized trial to compare the efficacy of venlafaxine (Effexor®), clonidine, or placebo in reducing average daily hot flash scores over 12 weeks of treatment.

For this, 102 patients with a history of breast cancer who had been experiencing at least two hot flashes daily were randomly assigned (2:2:1) to venlafaxine 75 mg, clonidine 0.1 mg, or placebo daily for 12 weeks. Patients were stratified by age (< 35, 36-50, or > 51 years), duration of complaints (> 9 months or < 9 months), concurrent endocrine therapy (yes or no), and previous chemotherapy (yes or no). Questionnaires at baseline and during treatment assessed daily hot flash scores, sexual function, sleep quality, anxiety, and depression.

After 12 weeks, a total of 80 patients were evaluable for the primary endpoint. During week 12, hot flash scores were significantly lower in the clonidine group vs placebo (P = 0.03); for venlafaxine vs placebo, the difference was borderline not significant (P = 0.07). However, hot flash scores were equal in the clonidine and venlafaxine groups. Over the course of 12 weeks, the differences between both treatments and placebo were significant (P < 0.001 for venlafaxine vs placebo; P = 0.045 for clonidine vs placebo). Frequencies of treatment-related adverse effects of nausea, constipation, and severe appetite loss were higher in the venlafaxine group.


Both venlafaxine and clonidine previously had been shown to be effective in ameliorating hot flashes,1-3 and it was hoped that this trial comparing the two drugs (or placebo) over 12 weeks would prove one drug superior. However, what it showed was that both drugs essentially were comparable but that toxicity was somewhat greater with venlafaxine. Venlafaxine produced a more prompt response, but by week 12, hot flashes were fewer in those receiving clonidine. As articulated in the accompanying editorial,4 the study was insufficiently powered to differentiate the two drugs. By the editorialists' calculations, somewhat more than 150 patients in each of the treatment arms would be required to have a reasonable chance (80%) to detect a difference if it were there. Another concern was that the venlafaxine starting dose (75 mg) is higher than currently recommended (37.5 mg/day, with escalation as tolerated).

Clinicians encounter patients with hot flashes commonly. Venlafaxine and clonidine are two on the list of several (also paroxetine, citalopram, devenlafaxine, gabapentin, pregabalin to name others). None has risen to the top as most efficacious. Dr. Loprinzi and his group at the Mayo Clinic have recommended that a non-hormonal approach start with an antidepressant (e.g., venlafaxine or devenlafaxine) and proceed to one of the antiseizure drugs (e.g., gabapentin) as second line, and that clonidine be used as third line.4

In addition to defining the optimal first approach, a number of questions regarding hot flash management are still unanswered. These include whether treatment should be different for those experiencing hot flashes but with no history of breast cancer, or for women who are currently taking tamoxifen? Furthermore, should the same approach be used for the management of hot flashes in men undergoing androgen-ablation therapy for prostate cancer? Although there are notable gaps, the data would currently suggest there are enough similarities to embark on similar approaches for both men and women.5


1. Goldberg RM, et al. Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol 1994;12:155-158.

2. Loprinzi CL, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: A randomised controlled trial. Lancet 2000;356:2059-2063.

3. Pandya KJ, et al. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: A University of Rochester Cancer Center Community Clinical Oncology Program study. Ann Intern Med 2000;132:788-793.

4. Loprinzi CL, et al. Nonestrogenic management of hot flashes. J Clin Oncol 2011;29:3842-3846.

5. Loprinzi CL, Wolf SL. Hot flushes: Mostly sex neutral? Lancet Oncol 2010;11:107-108.