The American Journal of Medicine
Volume 118, Issue 12, Supplement 2 , Pages 118-123, 19 December 2005

Centrally active nonhormonal hot flash therapies

  • Charles L. Loprinzi, MD

      Affiliations

    • Mayo Clinic College of Medicine, Rochester, Minnesota, USA
    • Corresponding Author InformationRequests for reprints should be addressed to Charles L. Loprinzi, MD, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905.
    • ,
  • Vered Stearns, MD

      Affiliations

    • The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
    • ,
  • Debra Barton, PhD, RN

      Affiliations

    • Mayo Clinic College of Medicine, Rochester, Minnesota, USA

Article Outline

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.

Keywords:  Hot flashes , Newer antidepressants , Nonhormonal therapies

 

Hot flashes are a major problem in many women as they approach menopause. Hormone therapy (HT) has been the most long-standing efficacious therapy for treatment of hot flashes. Nonetheless, concerns about using HT have limited the use of hormones in women in general. More specifically, they have limited the use of hormones in patients with a history of breast cancer.

Clearly, alternative methods of treating hot flashes are desired. There are several centrally acting compounds that have been investigated as a means of alleviating hot flashes in women (Table 1).1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 Potential mechanisms for their efficacy have been described in detail. 15 The present article delineates the histories of several of these classes of agents in the order in which they were first investigated.

Table 1. Summary of studies
Hot Flash Reduction (score or frequency, %)
DrugStudy Type, DurationNPopulationActive DrugPlaceboSide Effects Significantly Different from Placebo
Bellergal 2 pills/day1RPCT, 6 wk72MW——Dry mouth, skin rash, dizziness
Bellergal 2 pills/day2RPCT, 12 wk71MW7568Dry mouth, dizziness, sleepiness
Clonidine 0.1 mg/day (oral)4RPCT, 8 wk194BC, tamoxifen3824Difficulty sleeping
Clonidine 0.1 mg/day (transdermal)3RPCT, 4 wk110BC, tamoxifen5630Dry mouth, constipation, drowsiness, itchy under patch
Methyldopa 250 mg/day5RPCT, 4 wk9MW3415Fatigue, weakness, dizziness, nausea
Venlafaxine ER6PRCT, 4 wk191MW, BC Nausea, decreased appetite, mouth dryness
37.5 mg/day⁎ 3727
75 mg/day⁎ 6127
150 mg/day⁎ 6127
Venlafaxine ER7 75 mg/day⁎RPCT, 12 wk61MW51†15†Dry mouth, sleeplessness decreased appetite
Paroxetine CR8RPCT, 6 wk139MW None
12.5 mg/day 6238
25 mg/day 6538
Paroxetine9RPCT, 4 wk151BC, MW Nausea
10 mg/day 4614
20 mg/day 5629
Fluoxetine 20 mg/day10RPCT, 4 wk68BC, MW50%36%—
Sertraline 50 mg/day11RPCT, 6 wk47BC, tamoxifen———
Citalopram12 10→20→30 mg/dayRPCT, 9 mo150MW76‡64‡—
Fluoxetine12 10→20→30 mg/day 81‡64‡
Gabapentin 300 mg tid13RPCT, 12 wk59MW5431Light-headed, dizzy, mild peripheral edema, decreased serum albumin
Gabapentin14RPCT, 8 wk360BC —
100 mg tid 3018
300 mg tid 4618

BC = women with a history of breast cancer; CR = controlled release; ER = extended release; MW = menopausal women; RPCT = randomized placebo-controlled trial.

⁎ All doses titrated upward initially from 37.5 mg/day for 1 week.

† Patient-determined hot flash scores by these authors were defined based on a 5-point Likert scale.

‡ Estimated from Figure 2 provided in Menopause.12

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Bellergal 

Bellergal (known as Bellergal Spacetabs in Canada and Bellergal-S in the United States Sandoz Pharmaceuticals/Novartis, Princeton, NJ; no longer available on the US market) is a combination preparation sedative including low-dose phenobarbitol, ergotamine tartrate, and levorotatory alkaloids of belladonna. Its potential mechanism of action has not been defined. A double-blind, placebo-controlled, crossover trial published in 1969 reported that it decreased hot flashes compared with placebo. 1 This study reported that participants received 2 pills per day of the fixed combination. In addition, authors reported a 30% withdrawal rate in the study, which initially accrued 72 women. Eligibility criteria were not specified. The outcome measure was an interview at the end of each 6-week phase in which the interviewer classified the participant as a “success” or “failure.” Participants also rated their hot flash severity as absent (0), moderate (1), or severe (2). In another randomized, double-blinded, placebo-controlled trial in 71 naturally postmenopausal women published in 1987, 2 a significantly reduced incidence of hot flashes was seen after 4 weeks of therapy. The primary outcome measure was the mean number of hot flashes per 24-hour period. Hot flashes were reported to be reduced in incidence by 75% in the active arm and by 68% in the placebo arm. Nonetheless, there was no statistically significant difference between the active and placebo groups at 8 or 12 weeks. Once again, >30% of women withdrew before the study ended owing to a lack of response and to toxicity. Toxicities seen in these trials included dry mouth, dizziness, skin rash, and sleepiness. Given the limited efficacy of this agent, its toxicity, and the availability of newer agents, this drug is not generally recommended for use for hot flashes at this time.

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Clonidine 

Clonidine, a centrally acting α-adrenergic agonist, has been used primarily to treat hypertension. Reports of studies related to clonidine for treatment of hot flashes date back to the 1970s. 16, 17, 18, 19 It has been reported that clonidine reduced norepinephrine release, raised the sweating threshold, and reduced the incidence of hot flashes in women. 20 Large placebo-controlled clinical trials have recently been conducted to examine its efficacy on hot flashes. 3, 4 Both studies accrued >100 women who were being treated with tamoxifen for breast cancer. These trials demonstrated that clonidine statistically significantly reduced the incidence of hot flashes, but only by a moderate degree. The primary outcome of these trials included hot flash frequency, severity, and a score combining both severity and frequency. Overall, with respect to frequency of hot flashes, clonidine statistically significantly reduced hot flash frequency 14% to 20% more than did placebo, for an overall decrease of about 38% to 40%. In both of these trials, clonidine caused statistically significant toxicities, with side effects including mouth dryness, constipation, drowsiness, and insomnia. In 1 trial, patients did not prefer clonidine over placebo, in part due to toxicity. 3 In a double-blind, randomized, placebo-controlled crossover trial of transdermal clonidine in 70 men with hot flashes related to prostate cancer treatment, this drug did not have statistically significant efficacy on the frequency or severity of hot flashes. 21 In total, clonidine has limited clinical efficacy due to its only moderate reduction of hot flashes and its toxicities.

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Methyldopa 

Methyldopa is another antihypertensive agent that has been evaluated for treatment of hot flashes. In the 1980s, 2 studies related to the efficacy of methyldopa on hot flashes were reported. 5, 22 These 2 placebo-controlled, double-blind, randomized clinical trials reported that the drug decreased hot flashes to a modest degree. One of the trials 5 included only women who were either naturally or surgically postmenopausal. Efficacy with 250 mg of methyldopa in this trial was illustrated by a 30% to 37% reduction in the frequency of hot flashes compared with a placebo response of 10% to 20%. In this study, 50% of participants taking methyldopa reported fatigue, weakness, dizziness, and nausea. The conclusion was that this agent has little role for the treatment of hot flashes in clinical practice.

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Newer antidepressants 

In the 1990s, anecdotal information from a number of sources suggested that newer antidepressants can alleviate hot flashes in women using these drugs for other reasons. This led to the conduct of pilot trials evaluating venlafaxine (a serotonin/norepinephrine reuptake inhibitor [SNRI]) and paroxetine (a selective serotonin reuptake inhibitor [SSRI]). Published results from the pilot studies of venlafaxine and paroxetine were promising, 23, 24 suggesting the drugs were efficacious and well tolerated.

Subsequently, a placebo-controlled, double-blind, dose-finding randomized trial was conducted to evaluate venlafaxine in 191 women with hot flashes who either were survivors of breast cancer or who did not want to take HT for fear of breast cancer. 6 This trial evaluated doses of 37.5 mg versus 75 mg versus 150 mg per day, with all arms beginning at 37.5 mg for the first week and then titrating up to the target dose. The median hot flash score (a measure of mean frequency times mean severity) was reduced after 4 weeks of therapy by 27% in the placebo group compared with 40% in the 37.5 mg/day venlafaxine group and 60% in the 2 higher venlafaxine dose groups (P ≤0.008). There was no evidence in this study that increasing the drug dosage to 150 mg/day added any efficacy. Although this drug was well tolerated in most patients, there was evidence of some toxicity, with patients receiving venlafaxine experiencing nausea/vomiting, decreased appetite, mild mouth dryness, and constipation (the latter only at the highest dosage of 150 mg/day). Nausea/vomiting appeared to be the most significant toxicity leading to drug discontinuation, affecting approximately 10% of patients. However, in patients reporting nausea but who continued to take venlafaxine, this adverse effect largely abated over 1 or 2 weeks. A subsequent publication, reporting on patients from the prior trial who continued to take venlafaxine for an extended period, provided information to suggest that this drug did continue to control hot flashes for ≥3 months. 25 Two additional placebo-controlled trials recently were reported regarding the use of venlafaxine for hot flashes. The first of these investigations had 61 evaluable postmenopausal women without breast cancer who were treated for 12 weeks. 7 This trial did not report a statistically significant difference in hot flash scores between the active treatment and placebo groups. However, the authors concluded that the study results were positive based on patient self-reported hot flash scores that were determined using a 5-point Likert scale. Also seen in this study were statistically significant improvements in both mental health and vitality in the venlafaxine group, with 93% of patients in this group choosing to continue the drug at the end of the study. In the other trial, published only in abstract form at the time of this writing, 60 women were randomized to placebo or to venlafaxine at either 37.5 mg/day or 75 mg/day for 4 weeks. 26 Hot flashes increased by 10% in the placebo group compared with decreases of 65% and 51% in the venlafaxine-treated patients. A subset of the venlafaxine-treated patients continued on the 37.5 mg dose for 4 months more. Hot flashes at 5 months reportedly decreased by 2% in the placebo group compared with a 79% decrease in those continuing on venlafaxine. Eligibility criteria and the definition of this reported decrease were not included in the published abstract.

A double-blind, placebo-controlled, dose-finding clinical trial of controlled-release paroxetine was also conducted. 8 This study evaluated 2 doses of paroxetine, 12.5 mg/day and 25 mg/day, in 139 naturally and surgically postmenopausal women. The paroxetine statistically significantly reduced hot flashes, compared with the placebo group, with similar efficacy seen with both paroxetine doses. The mean hot flash scores were reduced, at 6 weeks, by 38% in the placebo group and by 62% to 65% in the paroxetine arms. Paroxetine was well tolerated in this trial, with the placebo group reporting more toxicities than did the paroxetine groups. There was, however, a trend for the highest-dose paroxetine treatment to be associated with more nausea (P = 0.06), insomnia (P = 0.141), lethargy (P = 0.12), and constipation (P = 0.12). A second double-blind placebo-controlled trial with a crossover design of immediate-release paroxetine 10 mg/day or 20 mg/day was reported. 9 This study enrolled 151 women, primarily breast cancer survivors, with 60% taking antiestrogen therapy (i.e., tamoxifen). Paroxetine was reported to reduce average hot flash frequency by 41% and average hot flash score by 46% at the 10-mg dose and by 52% (frequency) and 56% (score) at the 20-mg dose in the crossover analysis. The placebo effect in this study was a 14% reduction in the 10-mg arm and a 28.5% reduction in the 20-mg arm for average hot flash scores. 9 The only statistically significant side effect between paroxetine and placebo was nausea associated with the 20-mg dose. The authors recommended that paroxetine 10 mg/day be used in practice, given the efficacy and toxicity information from this trial.

A placebo-controlled clinical trial of another newer antidepressant, fluoxetine, was also reported. This trial was also double-blinded and had a crossover component. A total of 68 women, who had ≥14 hot flashes per week and who did not wish to take HT or who had a history of breast cancer, were treated with 4 weeks of fluoxetine (20 mg/day) or placebo, followed by 4 weeks of the alternative therapy. 10 In this trial, there was a statistically significant reduction in median hot flash score seen with fluoxetine compared with placebo (50% vs. 36%, respectively). This reduction in hot flash score, however, was less impressive than that reported in the trials evaluating venlafaxine and paroxetine. Fluoxetine was well tolerated in this clinical trial, with mouth dryness the only toxicity with a trend for being more prominent in the fluoxetine arm (23% vs. 45%, P = 0.07).

Preliminary results (reported only in abstract form at the time of this writing) of a small and probably underpowered randomized clinical trial were unable to confirm the pre-study hypothesis that sertraline (an SSRI) may be more effective than placebo in reducing hot flashes, although the trial reported a trend for hot flash improvement in the treated group. 11

Findings from pilot trials of 2 other newer antidepressants, mirtazapine and citalopram, suggested that they also are efficacious and well tolerated. 27, 28 Nonetheless, significant efficacy was not reported in a recent trial that looked for long-term effects of fluoxetine and citalopram, compared with placebo, in 150 postmenopausal women with hot flashes. 12 In this trial, the women must not have had a surgical menopause because they were required to have ≥1 ovary. Menopause was defined as amenorrhea for 6 months, with levels of follicle-stimulating hormone >30 IU/L (>30 mIU/L). None of the subjects had a history of malignant disease. In this 9-month trial, no statistically significant difference was seen among the 3 treatment arms. However, all arms experienced a significant decrease in hot flash frequency, with the reduction in the placebo arm an estimated 64%. It is not clear from this report why the placebo effect was so great. However, there was a fairly large drop-out rate in the study over the course of the 9 months, with a 40% discontinuation rate in the placebo group. One can hypothesize that only strong responders continued to take the placebo for the 9 months and therefore the placebo rate may be expected to be high. It is not clear how the patients who withdrew (presumably treatment failures) were handled statistically. If they had been included in the analysis in an intent-to-treat fashion, the results may have looked different. The reductions in hot flashes for the fluoxetine and citalopram groups are also higher than those seen in other placebo-controlled trials with drugs in this class. This also may be related to the drop-out of patients and to the long duration of follow-up.

In aggregate, results of the clinical trials reported to date suggest that newer antidepressants, especially venlafaxine and paroxetine, are effective in reducing the incidence or severity of hot flashes and are fairly well tolerated. Importantly, most SSRIs are metabolized through the cytochrome P-450 isoenzyme 2D6 (CYP 2D6), an enzyme instrumental for converting tamoxifen to a clinically active product. A small study suggested that paroxetine, a potent CYP 2D6 inhibitor, results in decreased concentrations of the active antiestrogenic tamoxifen metabolite endoxifen. 29, 30 A study that included a larger cohort of women who were administered tamoxifen confirmed that the presence of a variant CYP 2D6 gene (which reflects an enzyme with reduced or no activity) was associated with lower concentrations of endoxifen compared with women who had a wild-type gene. 31 Importantly, newer data have reported that women with a history of breast cancer and who are receiving tamoxifen to try to reduce breast cancer recurrence, but who have reduced activity of this enzyme, have a higher chance of breast cancer recurrence than do women with normal levels of this enzyme. 32 Thus, current wisdom dictates that paroxetine should be avoided in patients receiving tamoxifen. Early study findings demonstrate that levels of CYP 2D6 are moderately depressed with sertraline but not substantially influenced by therapeutic doses of venlafaxine. 31

Whether women whose symptoms did not respond to a particular SSRI/SNRI may have a response to a different agent is not known. However, pilot information suggests that citalopram will decrease the incidence or severity of hot flashes in women who have inadequate hot flash control with venlafaxine. 33

Last, pilot information on men with prostate cancer who have hot flashes related to androgen-deprivation therapy suggest that newer antidepressants relieve hot flashes in these patients to a degree similar to that in menopausal women. 34, 35, 36

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Gabapentin 

Gabapentin was anecdotally noted to decrease hot flashes, as reported in a case series published in 2000. 37 Subsequently, 2 prospective pilot trials looked at this agent for treating hot flashes in women who were breast cancer survivors, both reporting results that appear promising. 38, 39 The potential mechanism of action of gabapentin for alleviating hot flashes has not been clarified, but it has been proposed that it may be related to gabapentin’s ability to modulate calcium currents. 37 In 2 placebo-controlled, double-blind, randomized clinical trials, investigators demonstrated that gabapentin does reduce hot flashes in women with and without a history of breast cancer. 13, 14 Mean hot flash score reduction in 1 of these studies 13 with 59 postmenopausal women was 54% compared with a 31% reduction with placebo. In the other trial, 14 involving 360 women, a 30% reduction in hot flash scores after 8 weeks was reported for patients receiving gabapentin 100 mg 3 times daily compared with a 46% reduction for 300 mg 3 times daily and an 18% reduction with placebo. Gabapentin appears to be relatively well tolerated by most patients. Side effects include light-headedness and dizziness; cases of mild peripheral edema associated with decreased serum albumin levels also were reported in some patients. 13

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Hot flashes in survivors of breast cancer compared with other women 

Because estrogen has long been contraindicated in women with breast cancer, many of the trials investigating nonhormonal agents for treating hot flashes have been conducted in survivors of breast cancer. The question arises as to whether the efficacy of treatments for these women is different from that in women without a history of breast cancer.

Although one may propose that there can be differences in the physiology of hot flashes between women with or without a history of breast cancer, the bulk of information available to date suggests that there is little to no difference. First, most of the women with a history of breast cancer who were involved in hot flash trials had no evidence of residual breast cancer, with many of them likely cured of their prior breast cancer. The women in these trials did not concomitantly receive chemotherapy. Although some of these women received tamoxifen, subset analyses suggest that the efficacy of the hot flash therapies is not different in women who are receiving tamoxifen from that in women who are not. 6, 10 In addition, some of the clinical trials 8, 13 largely included women who specifically did not have a history of breast cancer, demonstrating similar efficacy to that seen in patients with a history of breast cancer in other trials. 6, 9, 10, 14

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Summary 

In total, data demonstrate that centrally acting nonhormonal agents reduce hot flashes significantly more than does placebo. The most active and best tolerated of these agents are the newer antidepressants and gabapentin; ongoing studies are further evaluating their efficacy and toxicity. Nonetheless, they are appropriate for clinical use at this time. When these agents are used, it is important to start patients with low doses and titrate upward. When it is decided to discontinue the use of these agents, patients should be titrated off them as opposed to being stopped abruptly.

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References 

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 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.

PII: S0002-9343(05)00903-4

doi:10.1016/j.amjmed.2005.09.045

The American Journal of Medicine
Volume 118, Issue 12, Supplement 2 , Pages 118-123, 19 December 2005

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