Given the problems associated with hormonal therapy, and the prominent problem of hot flashes in menopausal women, there is a need for nonhormonal agents to alleviate hot flashes. Several compounds that appear to act on the central nervous system have been investigated. Potential mechanisms for their effects on hot flashes have been described. Bellergal (no longer available on the US market, where it was known as Bellergal-S), a combination preparation sedative that consists of low-dose phenobarbital, ergotamine tartrate, and levorotatory alkaloids of belladonna, is an old agent that was popular approximately 20 years ago; however, there is limited suggestion of efficacy for this agent. Clonidine, an older antihypertensive drug, is another centrally active agent that has been studied. Randomized trials have demonstrated that it clearly works for reducing hot flashes, but the magnitude of efficacy is somewhat limited. Toxicity from this agent limits its utility in the clinic. Methyldopa is another centrally active agent that has been studied but to a more limited degree. It appears to have minimal efficacy and too much toxicity to make it clinically useful. Anecdotal observations from a number of sources suggested that newer antidepressants can alleviate hot flashes. This led to pilot trials of venlafaxine and paroxetine, with results suggesting benefit from both drugs. Subsequently, randomized, placebo-controlled, double-blind clinical trials of venlafaxine, paroxetine, and fluoxetine were conducted. All 3 of these clinical trials demonstrated statistically significant reductions in hot flashes with these newer antidepressants compared with placebo. Pilot trials of citalopram and mirtazapine, 2 other newer antidepressants, have also suggested efficacy. Toxicity evaluations have suggested that these agents are, again, well tolerated by the majority of patients. A recent trial, however, was unable to demonstrate any benefit for fluoxetine or citalopram over a placebo. Anecdotal observations also suggested that gabapentin was helpful for alleviating hot flashes. This led to pilot trials that again suggested efficacy. Subsequently, 2 large placebo-controlled, randomized, double-blind clinical trials were conducted. Both of these demonstrated statistically significant efficacy for gabapentin compared with a placebo. This drug is relatively well tolerated by most patients. Thus, centrally active nonhormonal agents clearly do decrease hot flashes in women. The most efficacious and clinically appropriate agents for use are newer antidepressants and gabapentin. Continued evaluation of the efficacy and toxicity of these agents is ongoing.
aMayo Clinic College of Medicine, Rochester, Minnesota, USA
bThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
Requests for reprints should be addressed to Charles L. Loprinzi, MD, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905.
The opinions offered at the National Institutes of Health (NIH) State-of-the-Science Conference on Management of Menopause-Related Symptoms and published herein are not necessarily those of the National Institute on Aging (NIA) and the Office of Medical Applications of Research (OMAR) or any of the cosponsoring institutes, offices, or centers of the NIH. Although the NIA and OMAR organized this meeting, this article is not intended as a statement of Federal guidelines or policy.
Publication of the online supplement was made possible by funding from the NIA and the National Center for Complementary and Alternative Medicine of the NIH, US Department of Health & Human Services.
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