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.