Brigitte L. Sicat, Pharm.D.; Deborah K. Brokaw, Pharm.D.

Pharmacotherapy 24(1):79-93, 2004. © 2004 Pharmacotherapy Publications

Posted 02/09/2004

Abstract

Objective: To review the literature on clonidine, venlafaxine, selective serotonin reuptake inhibitors, and gabapentin for the treatment of hot flashes.
Data Sources: A MEDLINE search (January 1966–July 2003) was conducted to identify English-language literature available on the treatment of hot flashes that focused on clonidine, venlafaxine, selective serotonin reuptake inhibitors, and gabapentin. These articles, relevant abstracts, and additional references listed in articles were used to collect pertinent data.
Study Selection: All controlled and uncontrolled trials were reviewed.
Data Synthesis: In women unable or unwilling to take hormonal therapies, several nonhormonal alternatives have been evaluated in small controlled and uncontrolled trials. Oral and transdermal formulations of clonidine are moderately effective in reducing hot flashes. Results of studies evaluating venlafaxine, paroxetine, and gabapentin suggest greater reductions in hot-flash frequency and severity compared with those of clonidine. Fluoxetine appears to display a modest benefit compared with paroxetine, although no comparative trials have been conducted. Most women studied in these trials had a history of breast cancer, and many were taking concurrent tamoxifen. All of these agents were fairly well tolerated.
Conclusions: Clonidine, venlafaxine, paroxetine, fluoxetine, and gabapentin are nonhormonal agents that have demonstrated efficacy in small controlled and uncontrolled trials in reducing hot flashes and should be considered in patients unwilling or unable to take hormonal therapies.

Introduction

Hot flashes affect approximately 75% of postmenopausal women and are one of the most distressing symptoms women experience as they enter menopause. Symptoms typically begin a few years before natural menopause and usually continue for 0.5–5 years, although a small percentage of women may have symptoms for up to 15 years.^[1,2] Hot flashes occur not only in women undergoing natural menopause, but also in women experiencing premature menopause due to bilateral oophorectomy or cytotoxic chemotherapy. This abrupt decline in estrogen often results in hot flashes that are more frequent and severe than those associated with natural menopause. In addition, 50% of postmenopausal women with breast cancer who are receiving tamoxifen experience hot flashes as an adverse effect of the drug.^[3]

Hormone replacement therapy effectively reduces hot-flash symptoms by 80–90%^[4,5]; however, many patients may be unable or unwilling to undergo hormonal treatment. Patients with a history of endometrial cancer, venous thromboembolism, or breast cancer, or with a family history of breast cancer often are advised to avoid hormonal agents. Although several recent reports suggest some breast cancer survivors may be safely treated for hot flashes with estrogen or progesterone,^[6–8] their use remains controversial because of concerns about stimulating cancer growth. In addition, the estrogen and progestin arm of the Women's Health Initiative^[9] and other recent reports^[10–12] suggest that hormone replacement therapy may increase the risk for coronary heart disease events, strokes, venous thromboembolism, and invasive breast cancer. Many expert groups recommend that combination hormonal therapy for the management of vasomotor symptoms should be limited to the shortest duration consistent with treatment goals and benefits versus risks for individual women.^[13–15] All of these concerns have generated interest in nonhormonal treatment of hot flashes.

Numerous nonhormonal alternatives for the treatment of hot flashes have been evaluated, including clonidine, belladonna-ergotamine-phenobarbital, methyldopa, vitamin E, and complementary and alternative agents.^[16–18] However, adverse effects or insufficient efficacy limits the use of these agents. Accumulating evidence suggests that several antidepressants including venlafaxine and selective serotonin reuptake inhibitors (SSRIs), as well as gabapentin, may be effective in reducing hot flashes. We conducted a MEDLINE search (January 1966–July 2003) to identify English-language literature available on the treatment of hot flashes that focused on clonidine, venlafaxine, selective serotonin reuptake inhibitors, and gabapentin. These articles, relevant abstracts, and additional references listed in articles were used to collect pertinent data.

Hot flashes are characterized by a sudden sensation of heat or burning, which typically starts in the chest and rises to the neck and head. They often are accompanied by profuse sweating, palpitations, and red blotching of the skin. The exact mechanism of hot flashes is complex and not well understood. Perspiration and vasodilation are classic mechanisms of heat loss that are activated during a hot flash.^[19] The thermoregulatory center in the hypothalamus activates these mechanisms to maintain core body temperature within a normal thermoregulatory zone. Results of recent studies suggest that hot flashes may be preceded by a rise in core body temperature.^[20,21] It has been theorized that women susceptible to hot flashes have both a dysfunction of the central thermoregulatory center and a temperature regulating zone that is shifted downward and is narrower compared with that in women who do not have hot flashes. Thus, a small rise in core body temperature in conjunction with a narrow thermoregulatory zone may trigger the heat-loss mechanisms that result in a hot flash.^[22]

Although estrogen withdrawal is thought to be the central change that leads to hot flashes, accumulating evidence suggests that complex neuroendocrine pathways involving norepi-nephrine, estrogen, testosterone, serotonin, and endorphins all play a role in regulating the thermoregulatory center and are possible sites where dysfunction may occur. Blood levels of norepinephrine are increased both before and during hot flashes, and norepinephrine can increase core body temperature and induce a heat-loss response.^[20] Norepinephrine in the thermoregulatory center is inhibited by endorphins and catecholestrogen, a metabolic byproduct of estrogen metabolism.^[22] In addition, testosterone and androgens can inhibit norepinephrine by their ability to stimulate endorphin production.^[22] Recent evidence suggests that serotonin also may play a role in the pathogenesis of hot flashes. Estrogen withdrawal has been associated with decreased blood serotonin levels and an upregulation of serotonin receptors in the hypothalamus.^[22] The role of serotonin is very complex, as the effect of serotonin varies depending on the type of receptor activated. Activation of the serotonin 5-HT_2A receptor has been shown to precipitate heat loss, whereas activation of the 5-HT_2C receptor can exert negative feedback on 5-HT_2A.^[23]

Most studies evaluating the efficacy of pharmacologic therapy for hot flashes obtain patient data by using daily hot-flash diaries or questionnaires. Information collected often includes hot-flash frequency, severity, and duration. A hot-flash score or activity frequently is used as an additional efficacy measure and is calculated by multiplying average hot-flash frequency by average hot-flash severity. Other outcome measures may include quality of life, depression, sleep quality, and patient global impression-of-change scores. Most clinical trials evaluating the efficacy of nonhormonal treatments for hot flashes included patients with a history of breast cancer, many of whom were taking concurrent tamoxifen.

When evaluating the efficacy of pharmacologic therapy for hot flashes, the placebo effect must be considered. Placebo-controlled trials have demonstrated a relatively consistent 20–30% reduction in hot-flash symptoms in women treated with placebo for 4 weeks.^[24,25] This highlights the importance of critically analyzing uncontrolled trials that claim efficacy in reducing hot flashes. In addition, the United States Food and Drug Administration is revising its 1995 Guidance for Industry regarding clinical evaluation of hormonal therapy for vasomotor symptoms.^[26]

Clonidine

Clonidine is an α₂-adrenergic agonist that reduces sympathetic outflow from the central nervous system and is indicated primarily for the treatment of hypertension. It has been hypothesized that since hot flashes may be associated with an excess of norepinephrine, clonidine may be useful in their treatment.^[21] Several studies have evaluated clonidine for the treatment of hot flashes due to both natural and surgically induced menopause, as well as in women receiving tamoxifen as adjunctive therapy for breast cancer. These studies have shown conflicting results, as well as questionable clinical significance.

Postmenopausal Hot Flashes. In a multicenter, randomized, double-blind, placebo-controlled, crossover trial, oral clonidine was studied in 86 postmenopausal women with hot flashes that were sufficient enough for treatment.^[27] Subjects were aged 41–62 years (mean 50 yrs) and had experienced hot flashes for a median of 2 years (2 wks–23 yrs). Before the start of the trial, all drugs for hot flashes were discontinued for at least 2 weeks. Baseline data on hot flashes were gathered during a 1-week placebo run-in. Patients were then randomly assigned to receive clonidine 0.025 mg twice/day for 4 weeks followed by placebo for 4 weeks, or vice versa. Depending on the occurrence of hot flashes, the clonidine dosage could be titrated up to a maximum of 0.075 mg twice/day. Data on the frequency, severity, and duration of hot flashes were gathered by daily entries in a patient diary, as well as through weekly interviews for the 9 weeks. A placebo effect was seen in both placebo groups during the first week of treatment. A reduction in the mean number of hot flashes/week was greater in both groups during the clonidine treatment period compared with placebo (clonidine before placebo p<0.05, placebo before clonidine p<0.001). Hot-flash frequency, severity, and duration were significantly improved with clonidine treatment when it was given as the first treatment compared with placebo. When patients received placebo first followed by clonidine, these improvements were still seen when compared with placebo; however, they did not reach statistical significance. It also was noted that women who experienced hot flashes for more than 1 year tended to have a greater placebo response than did women with hot flashes for less than 1 year. More than half the patients in both the placebo-first group and the clonidine-first group were receiving the maximum dosage of clonidine at the end of the treatment periods.

The effects of clonidine 0.05 mg twice/day versus placebo were studied in 66 postmenopausal women (mean age 47 yrs) for 8 weeks in a double-blind, placebo-controlled, crossover trial.^[28] At the end of the trial, patients randomly assigned to receive clonidine experienced statistically significant reductions of 78%, 89%, and 88% in hot-flash frequency, severity, and duration, respectively, compared with the placebo group.

Another single-blind, placebo-controlled, dose-response study was conducted in 10 post-menopausal women with frequent hot flashes.^[29] Each patient was given placebo for 2 weeks and then was given clonidine at total daily doses of 0.1, 0.2, and 0.4 mg, as one tablet twice/day for 2 weeks at each dose. Patients were blinded to the order and dose of the clonidine and placebo. Hot flashes were recorded at baseline and at the end of each of the four treatment periods. This was done through a continuous recording of finger temperature and skin resistance for 8 hours, as well as by evidence of flushing and perspiration reported by the patient. A hot flash was defined in the study as the recording of the subjective symptoms, a finger temperature of greater than 1°C, and a decrease in skin resistance, all of which began within 5 minutes of each other. At the onset of a subjective hot flash, the patient would push a button, which would record the occurrence. Baseline recordings revealed a rate of 0.84 hot flash/hour in the treatment groups, which was not statistically significantly different from that in the placebo phase. In the six women who completed the trial, a dose-response relationship was observed. Increasing doses of clonidine were associated with significant reductions in hot flashes compared with baseline (p<0.005) and placebo (p<0.05). The 0.4-mg dose produced a 46% mean reduction in hot flashes from baseline. No other information was given regarding the other clonidine strengths. Four patients withdrew from the study because of adverse effects from clonidine, which included severe fatigue, nausea, headaches, irritability, and dizziness.

Three trials failed to find clonidine effective in reducing symptoms of hot flashes in post-menopausal women. A 13-week randomized, double-blind, placebo-controlled, crossover trial was conducted in 41 women with severe menopausal symptoms.^[30] After a baseline assessment, the women were given clonidine 0.05 mg twice/day or placebo for 6 weeks, which was followed by the opposite treatment for another 6 weeks. Clonidine could be increased to 3 times/day after 1 week if symptoms were not controlled. The women ranged in age from 35–60 years and had menopausal symptoms present for a mean of 1.6 years. Interviews and patient diaries were used to gather symptoms and adverse effects. A reduction in hot-flash frequency was significant for both the clonidine and the placebo groups compared with baseline; however, clonidine was not shown to be any more effective than placebo. In a similar crossover trial, 14 postmenopausal women (mean age 50 yrs) were randomly assigned to receive clonidine 0.05 mg twice/day followed by placebo each given for 2 weeks, or vice versa.^[31] Compared with placebo, clonidine was not associated with fewer hot flashes. No effects were seen on blood pressure, heart rate, or gonadotropin levels during the trial. Another study found no difference in hot flashes when clonidine 0.025–0.075 mg twice/day was compared with placebo after 6 weeks of treatment.^[32] As with other clonidine trials, a placebo effect was noted.

Transdermal clonidine also has been evaluated for the treatment of hot flashes in postmenopausal women. In a randomized, placebo-controlled, double-blind trial, 30 postmenopausal women experiencing 10–100 hot flashes/week were randomly assigned to receive either transdermal clonidine 0.1 mg/24 hours or placebo for 8 weeks.^[33] Baseline data were collected for 2 weeks before treatment. Patient diaries were used to record hot-flash frequency, severity, and duration, as well as adverse effects, throughout the trial. One patient withdrew from the placebo group and was not included in the statistical analysis. Compared with baseline, clonidine significantly reduced hot-flash frequency, severity, and duration. Twelve (80%) of the 15 patients in the clonidine group reported a reduction in the frequency of hot flashes over baseline compared with five patients in the placebo group (p<0.04). By the end of 8 weeks, hot flashes completely resolved in 4 of the 12 patients who reported improvements with clonidine, whereas the remaining 8 patients had a 60% or less reduction in the number of hot flashes. In the placebo group, significant reductions were noted in hot-flash frequency during weeks 5 (p<0.05), 6 (p<0.05), and 8 (p<0.04) only.

In all of the previous trials, women with hypertension were excluded. The effects of clonidine 0.075 and 0.15 mg/day in 12 post-menopausal women with hypertension were studied in a randomized, double-blind, placebo-controlled, crossover trial.^[34] Patients received each treatment for 2 weeks and recorded daily hot-flash frequency, severity, and duration in a diary. No significant effect was seen with the lower dosage of clonidine compared with placebo; however, both groups improved when compared with baseline hot-flash frequency. In the higher dosage arm, the clonidine 0.15 mg/day group and placebo group were associated with a significant reduction in hot-flash frequency compared with baseline measures, but not compared with each other. The effects of clonidine on blood pressure were not reported.

Tamoxifen-Induced Hot Flashes. Another population that experiences hot flashes is women receiving tamoxifen for breast cancer. Hot flashes are one of the most common adverse effects associated with tamoxifen and have been reported in clinical trials as occurring in approximately 50% of women treated with tamoxifen.^[3,35] Two randomized, double-blind, placebo-controlled trials evaluated clonidine in reducing the frequency, severity, and duration of hot flashes in women with breast cancer who were receiving tamoxifen.

The effect of transdermal clonidine 0.1 mg/24 hours was studied in 110 women experiencing seven or more hot flashes/week for at least 1 month.^[24] In this crossover trial, patients were stratified by age, duration of tamoxifen therapy, duration of hot-flash symptoms, and average frequency and severity of hot flashes. Baseline information on hot flashes was gathered during a 1-week placebo run-in. Patients were then randomly assigned to receive a clonidine patch 0.1 mg/24 hours for 4 weeks followed by a placebo patch for 4 weeks, or vice versa. Hot-flash frequency and severity were assessed through daily self-administered questionnaires, and the combined hot-flash score was calculated by multiplying the mean frequency by the mean severity. The median age of the population was 54 years (range 30–76 yrs), and most of the women experienced four to nine hot flashes/day, had experienced hot flashes 9 years or more, and had received tamoxifen therapy for more than 12 months. During the baseline placebo run-in week, the median frequency of hot flashes was six to seven hot flashes/day, whereas the median severity was rated as moderate. Compared with placebo, clonidine was associated with a significantly greater reduction in hot-flash frequency by approximately 20% (p<0.0001) and severity by approximately 10% (p=0.006). An apparent placebo effect only on hot-flash frequency was noted during the first treatment period for both groups. During the second treatment phase, patients who crossed over to the placebo group reported a higher number of hot flashes and greater severity as compared with those of the first treatment period. When questioned about which patch worked best to reduce hot flashes, 48% of the patients selected the clonidine patch, 25% selected the placebo, and 27% could not tell a difference between the patches.

A randomized, double-blind, placebo-controlled trial was conducted in 194 women, aged 35–77 years, to evaluate the effectiveness of oral clonidine for the treatment of tamoxifen-associated hot flashes in postmenopausal women with breast cancer.^[36] Patients were eligible for inclusion if they had experienced at least one hot flash/day and had been receiving tamoxifen for at least 1 month. After a 1-week placebo run-in, the women were randomly assigned to receive clonidine 0.1 mg or placebo at bedtime for 8 weeks. Patients were required to keep a daily diary during the placebo run-in week, the 4th and 8th weeks of treatment, and the 4th week after the end of treatment to assess frequency, severity, and duration of symptoms. Quality of life and toxicity were also assessed during these weeks. At baseline, patients experienced an average of 7.4–8.0 hot flashes/day, which were rated as moderate and lasted approximately 3 minutes. Withdrawal rates were similar in both groups; however, patients who withdrew had a significantly shorter mean duration of hot flashes at baseline compared with those who completed the trial. Compared with the placebo group, patients receiving clonidine reported a greater decrease in hot-flash frequency at week 4, 37% versus 20% (95% confidence interval [CI] 7–27%, p=0.001), and at week 8, 38% versus 24% (95% CI 3–27%, p=0.006). This translated to approximately 2.2 fewer hot flashes/day in the clonidine group. Hot-flash severity and duration also improved in the clonidine group; however, the percentage change compared with the placebo group was not statistically significant at weeks 4, 8, or 12. Significant improvement was seen in the quality-of-life scores for the clonidine group at weeks 4 and 8 compared with that of the placebo group; however, the median difference in all groups was zero. No difference was noted between the clonidine and placebo groups with regard to hot-flash frequency, severity, and duration or quality-of-life scores at week 12.

The authors of both of these trials concluded that clonidine could be a useful treatment for hot flashes associated with tamoxifen in women with breast cancer. However, results were conflicting with respect to improvements in hot-flash severity and duration between the trials, as well as to occurrence of adverse effects. Since the efficacy of clonidine in these trials was modest and some patients experienced adverse effects, this may outweigh the benefits of clonidine on hot-flash reduction. Therefore, the clinical utility of clonidine in this patient population remains unclear.

Adverse Effects. The adverse effects reported in the clinical trials were minimal and, for the most part, not significantly different from those when patients took placebo. The adverse effects included rash, nausea, gastrointestinal disturbances, sedation, and dry mouth and were associated with higher dosages of clonidine (>/= 0.1 mg/day). However, one trial did find that difficulty sleeping was significantly higher in the clonidine group than in the placebo group (p<0.002).^[36] In addition, the clonidine patches were associated with a higher frequency of itching and erythema compared with the placebo patches. Blood pressure also was assessed during each of the trials, and no significant effect was noted. This is to be expected since the dosage of clonidine administered in the trials was lower than the dosage typically given for treating hypertension.

Although clonidine has been shown efficacious in reducing the frequency, duration, and severity of postmenopausal hot flashes, the results have been modest at the dosages administered in the trials. It may be useful in women with coexistent hypertension, although higher dosages would need to be given since the dosages administered in the trials did not show a significant effect on blood pressure. However, if higher dosages are given, patients may experience adverse effects associated with the clonidine therapy. It is also hard to determine what the optimal dosage and duration are for treatment of hot flashes and what long-term effects are associated with this treatment.

Venlafaxine

Venlafaxine and its active metabolite, O-desmethylvenlafaxine, are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Although the recommended dosing range for venlafaxine for the treatment of depression and various anxiety disorders is 75–225 mg/day, evidence suggests that the pharmacologic properties of the drug changes as the dosage is increased within the dosing range. Serotonin reuptake inhibition is present at both low and high dosages; however, the inhibition of norepinephrine reuptake occurs more profoundly at higher dosages, somewhere at or above 150 mg/day.^[37] While giving venlafaxine for other clinical conditions, clinicians noted an improvement in patients experiencing hot flashes. Based on these positive anecdotal experiences, several pilot studies and one randomized clinical trial were conducted to evaluate the efficacy of venlafaxine for the treatment of hot flashes.

In a phase II evaluation of venlafaxine for the treatment of hot flashes, 28 women with a history of breast cancer or men undergoing androgen-deprivation therapy received oral venlafaxine 12.5 mg twice/day for 4 weeks.^[38] To be eligible, patients had to have experienced 14 or more bothersome hot flashes/week for at least 1 month. Patients receiving antineoplastic chemotherapy, androgens, estrogens, progestational agents, or antidepressants were excluded; tamoxifen therapy was allowed. Before treatment, patients recorded the occurrence of hot flashes in a diary for 1 week to collect baseline data. Efficacy measures included the average number of daily hot flashes in 1 week, the weekly hot-flash score, the proportion of patients who thought the drug was helping them, and the proportion of patients who wanted to continue taking venlafaxine at the end of the trial. After 4 weeks, a greater than 50% reduction in hot-flash scores compared with baseline was seen in 58% of patients who completed the study. Median weekly hot-flash scores were reduced by 55% from baseline. Overall, 68% of patients thought that venlafaxine helped reduce hot-flash activity and 64% wished to continue taking the drug after completion of the study. Venlafaxine appeared to be well tolerated and to result in an improvement in fatigue, dry mouth, sweating, trouble sleeping, and nervousness, although statistically significant improvements were seen only for fatigue (p<0.01) and sweating (p<0.03).

Based on the results of this open-label trial,^[38] a 4-week double-blind, placebo-controlled, randomized study compared placebo with three dosages of extended-release venlafaxine (37.5, 75, and 150 mg/day) in 191 women with a history of breast cancer or who were worried about taking estrogen for fear of breast cancer.^[25] Subjects were aged 18 years or older, experienced 14 or more troublesome hot flashes/week, and had hot flashes severe enough to desire therapeutic intervention. Patients were excluded if they had taken venlafaxine in the past, any antidepressant within 2 years, or other agents to treat hot flashes within 2 weeks or if they had uncontrolled hypertension. Patients could not be taking antineoplastic chemotherapy, androgens, estrogens, progestogens, antidepressants, clonidine, or belladonna-ergotamine-phenobarbital, although patients could be taking tamoxifen. The primary end point was average daily hot-flash score calculated from daily hot-flash questionnaires. Global quality-of-life score^[39] and a Beck Depression Inventory^[40] were also measured. Patients were randomly assigned to one of four treatments: 37.5 mg/day for 28 days; 37.5 mg/day for 7 days, then 75 mg/day for 21 days; 37.5 mg/day for 7 days, 75 mg/day for 7 days, then 150 mg/day for 14 days; or placebo for 28 days. After week 4 of treatment, when each titration group had been taking the assigned maximum dosage for at least 2 weeks, the median hot-flash scores were reduced from baseline by 27% (95% CI 11–34%), 37% (95% CI 26–54%), 61% (95% CI 50–68%), and 61% (95% CI 48–75%) in the placebo and the extended-release venlafaxine 37.5-, 75-, and 150-mg groups, respectively. Changes in hot-flash scores within an individual in groups assigned escalating dosages during the titration reflected a similar pattern in that there were significant decreases in hot-flash scores from baseline to 37.5 mg/day (p=0.01) and from 37.5 to 75 mg/day (p=0.01), but not when the dosage was increased from 75 to 150 mg/day (p=0.74). In addition, significant decreases in hot-flash scores occurred within the first week and reduction in hot-flash activity was unrelated to baseline depression. Overall quality-of-life score increased from baseline to week 4 by an average of three points in the three venlafaxine groups and decreased three points in the placebo group (p=0.02). Adverse effects including decreased appetite, dry mouth, constipation, and nausea were dose related. Dry mouth occurred significantly more with all venlafaxine doses than with placebo (p<0.05), although the 150-mg dose caused significantly more dry mouth than did the two lower doses (p=0.0006 for 37.5 mg, p=0.02 for 75 mg). Decreased appetite and nausea both occurred significantly more with the 75- and 150-mg doses than with placebo (p<0.05); constipation was only significantly higher in the venlafaxine 150-mg group (p<0.05). This trial mainly studied women with breast cancer who were experiencing at least 14 hot flashes/week. Whether these findings can be generalized to postmenopausal women without breast cancer or with less frequent hot flashes requires further study. Furthermore, 69% of patients in this trial were taking tamoxifen. Although stratification of patients according to tamoxifen therapy did not reveal any differences in hot-flash frequency, since only 30% of subjects in each group were not taking tamoxifen, the study had limited power to ensure that there was no tamoxifen effect. Finally, given the short duration of the trial, further investigation is needed to determine if venlafaxine continues to alleviate hot flashes long term.

An 8-week, open-label continuation phase of the previously mentioned study^[25] examined extended efficacy and toxicity data for 102 evaluable patients continuing with extended-release venlafaxine therapy.^[41] During this study, women could self-titrate the venlafaxine dosage anywhere from 37.5–150 mg/day for optimal effectiveness. Overall, this study demonstrated that the reduction in hot flashes reported in the randomized trial phase was maintained during the open-label study, and no additional benefits were seen with venlafaxine dosages higher than 75 mg/day. In addition, toxicity did not increase over time.

Venlafaxine appears to be effective in reducing hot-flash frequency and severity. Most subjects in the published venlafaxine studies had a history of breast cancer, and many were taking tamoxifen. The 75-mg dose appears to have the best ratio of benefits to adverse effects. However, since some patients will respond adequately to 37.5 mg/day, it may be prudent to start with a daily dose of 37.5 mg and increase the dosage to a maximum of 75 mg/day after 1 week if optimal results are not achieved. The dose-dependent efficacy of venlafaxine may be related to its pharmacology, as the reduction in hot flashes is mainly seen at lower dosages where serotonin reuptake is inhibited but not at higher dosages where norepinephrine reuptake is also inhibited.

Selective Serotonin Reuptake Inhibitors

The SSRIs are prescribed for a number of psychiatric conditions, including depression, anxiety disorders, obsessive-compulsive disorder, panic disorder, and bulimia. The antidepressant, anti–obsessive-compulsive, and antibulimic effects of SSRIs are presumed to be due to their inhibition of central neuronal uptake of serotonin. This potentiation of serotonin may also be responsible for the reduction in hot flashes that have been seen with several SSRIs in two pilot studies and two controlled trials.

An open-label trial of paroxetine was conducted in 30 survivors of breast cancer who experienced 14 or more hot flashes/week for at least 1 month.^[42] Women completed daily diaries for 1 week while receiving no therapy and then received paroxetine 10 mg/day for 1 week followed by 4 weeks of paroxetine 20 mg/day. Women completed hot-flash daily diaries throughout the study and a health-related symptom assessment questionnaire and a quality-of-life scale at weeks 1 and 6. Twenty-seven women completed the 6-week study. The reductions in hot-flash frequency and severity scores were 67% (95% CI 56–79%) and 75% (95% CI 66–85%), respectively. Statistically significant improvements were noted in depression, sleep, anxiety, and quality-of-life scores. Twenty-five (83%) of the 30 participants chose to continue paroxetine at the end of the study. The most common adverse effects associated with paroxetine were somnolence and dry mouth, which occurred in 60% and 43% of patients, respectively.

Another pilot trial was conducted to evaluate the efficacy of paroxetine for the treatment of hot flashes and associated symptoms in 13 women with breast cancer.^[43] Subjects received paroxetine 10 mg/night for 3 nights and then 20 mg/night. After 5 weeks of treatment, hot-flash ratings decreased in severity from a mean of 3.62 (hot flashes rated "quite a bit" or "extremely severe") to 2.08 (hot flashes rated "moderately severe"). At end point, 11 patients (85%) were still experiencing hot flashes, although the percentage of patients still rating their hot flashes as quite a bit or extremely severe had declined from 100% to 38% (p=0.008). In addition, significant improvements were seen in general, emotional, and mental fatigue, as well as in the occurrence of clinical depression.

Although the results of these pilot trials are intriguing, they are limited by their uncontrolled design and small sample. The largest study to investigate paroxetine for the treatment of menopausal hot flashes was conducted in 165 menopausal women aged 18 years or older from 17 sites in the United States.^[44] After a 1-week placebo run-in phase, this double-blind, placebo-controlled, parallel-group trial randomized women experiencing at least two to three hot flashes/day to receive paroxetine controlled release (CR) 12.5 mg/day, 25 mg/day, or placebo. Women must have discontinued any hormone replacement therapy at least 6 weeks before screening. Subjects with signs of active cancer or receiving chemotherapy or radiation therapy were excluded. Treatment with selective estrogen receptor modulators (e.g., tamoxifen) was permitted if therapy had been started at least 3 months before screening and the dosage remained unchanged throughout the study. At week 6, the mean placebo-adjusted reductions in hot-flash composite scores (frequency x severity) were -4.7 (95% CI -8.1 to -1.3, p=0.007) comparing paroxetine CR 12.5 mg/day with placebo and -3.6 (95% CI -6.8 to -0.4, p=0.03) comparing paroxetine CR 25 mg/day with placebo. This corresponded to median reductions of 62.2% in the 12.5-mg group and 64.6% in the 25-mg group versus 37.8% for the placebo group. By week 6, the median daily hot-flash frequency was reduced from 7.1 to 3.8 (mean reduction 3.3) in the paroxetine CR 12.5-mg group, from 6.4 to 3.2 (mean reduction 3.2) for the paroxetine CR 25-mg group, and from 6.6 to 4.8 (mean reduction 1.8) for the placebo group. As in studies of related agents,^[25,45] the reduction in hot-flash scores were seen within 1 week and benefits were largely independent of any effect that paroxetine CR may have had on mood or anxiety symptoms. The most frequently reported adverse events for paroxetine CR were headache, nausea, and insomnia, with fewer reports from patients in the paroxetine CR 12.5-mg group, and 89% of these events were mild or moderate in severity. Although this study is limited by the low proportion of African-American and Asian women, unlike previous studies, this is the first study of an SSRI in treating menopausal vasomotor symptoms in a group of women who were not primarily breast cancer survivors (7.3%).

The efficacy of fluoxetine for the treatment of hot flashes was evaluated in a placebo-controlled, double-blind, crossover trial.^[45] Eighty-one women with a history of breast cancer or a perceived increased risk of breast cancer were randomly assigned to receive fluoxetine 20 mg/day or placebo for 4 weeks. Subjects then crossed over to the alternative treatment arm for an additional 4 weeks. Women had at least 14 bothersome hot flashes/week and were allowed to continue tamoxifen if they had been receiving therapy for at least 1 month and were planning to continue therapy for the duration of the study. Patients taking fluoxetine or other antidepressants for 2 years before study entry were excluded. Women reported occurrence of hot flashes in a diary for 1 week without study drug and during the 8-week study period. At baseline, 56% and 53% of patients in the placebo-to-fluoxetine and fluoxetine-to-placebo groups, respectively, were receiving concurrent tamoxifen, and the median hot-flash occurrence was 7 and 7.4, respectively. At the end of the first treatment period (4 wks), median hot-flash frequency decreased by 3.4 hot flashes/day (42%) in the fluoxetine group versus 2.5 hot flashes/day (31%) in the placebo group (p=0.54). Hot-flash scores decreased by 50% in the fluoxetine arm versus 36% in the placebo arm (p=0.35). Crossover analysis indicated that patients taking fluoxetine experienced a median improvement of 1.5 hot flashes/day (19%) and 3.1 hot-flash score units/day (24%) versus placebo (p=0.01 and 0.02, respectively). No significant differences were noted in any of the checklist-determined toxicities (appetite loss, sleeplessness, nausea, dizziness, constipation, nervousness, mood changes, fatigue, and abnormal sweating) between the two study arms during the first randomized period. After the 9 weeks, when patients were still blinded to the study arm and asked which treatment period was more efficacious, 47% of patients thought the fluoxetine period was superior, 22% thought the placebo period was superior, and 31% could not tell (p=0.14). Fluoxetine resulted in a modest improvement in hot flashes.

Two pilot studies and two controlled trials suggest immediate-release paroxetine 20 mg, paroxetine CR 12.5 and 25 mg, and fluoxetine 20 mg daily may reduce hot flashes effectively. The reduction in hot-flash activity with fluoxetine appeared more modest compared with the benefits seen with paroxetine; however, direct comparison trials are needed to determine if there are any clinically meaningful differences between the various SSRIs. In addition, dose-seeking trials are needed to help determine the optimum dosage since in one paroxetine trial, patients noted an almost immediate reduction in hot-flash frequency and severity at 10 mg/day before the dosage was titrated to 20 mg/day. Although the mechanism of action of this class of drugs is still not clear, the benefit may be a result of increased neuronal serotonin concentrations. Furthermore, the benefit of SSRIs on hot flashes appears to apply to women with and those without a history of breast cancer.

Gabapentin

Gabapentin is approved in the United States as an anticonvulsant, although it also has demonstrated efficacy in treating other conditions such as migraine headaches and neuropathic pain. Gabapentin is structurally similar to the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Its mechanism of action remains unclear, as it appears to have GABA-mimetic properties, although it does not bind to GABA receptors or influence the neural uptake of GABA.

After a case series reported that six patients receiving gabapentin experienced a reduction in the frequency of hot flashes,^[46] a phase II trial was conducted to evaluate gabapentin's efficacy and toxicity in the management of hot flashes.^[47] Twenty-four women with a history of breast cancer and at least 14 bothersome hot flashes/week were enrolled. Subjects underwent a 1-week baseline period during which they took no study drug, followed by a gabapentin dosage titrated from 300 mg/night for 1 week to 300 mg twice/day for 1 week, then to 300 mg 3 times/day for 2 weeks. Participants were allowed to take antidepressants and/or vitamin E as long as they had been taking a stable dosage for 3 months and had no plans to change their treatment during the study. They also were allowed to continue taking tamoxifen, raloxifene, or aromatase inhibitors. After 4 weeks of gabapentin, the 16 patients completing the trial experienced a 66% and 70% reduction in hot-flash frequency and scores, respectively, compared with baseline. At the end of the study, 88% chose to continue taking gabapentin. Five patients were taking venlafaxine concurrently, and four additional patients were taking other antidepressants. The reduction in hot flashes in these patients was at least as robust as that observed in patients who were not taking venlafaxine, suggesting that the gabapentin effect may be additive to the antidepressant effect. Dizziness was noted in 31% of patients during week 1 of gabapentin treatment and seemed to improve over time despite increasing dosages of gabapentin. The mean severity of dizziness during week 4 of gabapentin was 1 on a scale of 0–10, with 10 being "as bad as it can be." In addition, from baseline to week 4, dizziness remained unchanged in eight patients, worsened in four, and improved in four. Of note, 70% of patients were taking concurrent tamoxifen.

Another open-label pilot study was conducted in 19 women with breast cancer to investigate gabapentin's efficacy in reducing tamoxifen-induced hot flashes.^[48] Women received gabapentin 300 mg 3 times/day for 4 weeks. In the 14 women completing the study, the mean decrease in hot-flash duration was 70% (p=0.058), frequency 42% (p=0.000), and severity 50% (p=0.000). Ten women reported about 21% improvement in quality of life (p=0.013). The authors reported that the drug was well tolerated except for mild dizziness and drowsiness.

A randomized, double-blind, placebo-controlled trial was conducted in 59 postmenopausal women with seven or more hot flashes/day.^[49] Patients taking estrogen, progestin, leuprolide, or tamoxifen within the last 2 months were excluded. After a 2-week baseline assessment, women were randomly assigned to 12 weeks of treatment with gabapentin 300-mg capsules 3 times/day or placebo. After 12 weeks, gabapentin resulted in a 45% decrease in mean hot-flash frequency and a 54% decrease in mean hot-flash composite score from baseline compared with a 29% (p=0.02) and a 31% (p=0.01) decrease, respectively, in the placebo group. These differences were statistically significant after the first week of treatment. In addition, 67% of gabapentin-treated patents experienced a 50% reduction in hot-flash composite score versus 38% of placebo-treated patients during week 12. No significant differences between groups were noted in the Short Form-36 Health Survey,^[50] Profile of Mood States,^[51] Patient Global Impression of Change Scale Measures,^[52] or Pittsburgh Sleep Quality Index^[53] at 12 weeks. At the end of the randomized trial, patients were given the option to enroll in a 5-week, open-label treatment phase during which all patients received gabapentin. Patients could increase the dosage to 2700 mg/day, if needed. Of the 50 patients who completed the open-label study, mean reductions in hot-flash frequency and composite scores were 54% and 61–67%, respectively, at week 17. In addition, 72% of patients experienced a greater than 50% reduction in hot-flash composite scores. Forty-four (81.5%) patients who started the open-label study requested to continue gabapentin after the open-label study ended. Of these patients, 25% requested a dosage of 900 mg/day or less, 61.4% requested a dosage of 900–1800 mg/day, and 13.6% requested a dosage of 1800–2700 mg/day. Patients requesting higher dosages tended to have a higher frequency of hot flashes at baseline. The most common adverse events during the double-blind study were somnolence (20%), dizziness (13.3%), and rash (6.7%), none of which occurred in the placebo group. Four patients (13.3%) in the gabapentin group and one (3%) in the placebo group withdrew because of adverse events. Higher gabapentin dosing during the open-label study was not associated with increased adverse events. This trial included women experiencing more frequent hot flashes (>/= 7 hot flashes/day); previous venlafaxine and gabapentin trials included women with 14 or more hot flashes/week. In addition, this trial enrolled postmenopausal women, whereas previous trials included mostly women with a history of breast cancer, many of who were treated with tamoxifen.

Several uncontrolled reports in patients with a history of breast cancer and one small controlled trial in postmenopausal women not taking tamoxifen suggest gabapentin 300 mg 3 times/day may reduce hot flashes effectively. Benefits were seen within 1 week and were maintained over 12 weeks in one study.^[49] Additional controlled trials are needed to determine if lower dosages of gabapentin are efficacious or if a dose-response effect exists. Gabapentin's mechanism of action in unknown; however, further studies may provide more insight into the causation and resolution of hot flashes.

Table 1 summarizes the above-discussed studies for clonidine, venlafaxine, SSRIs, and gabapentin.

Herbal Therapies

Herbal products are among the most popular complementary and alternative medicine (CAM) therapies that are being used. According to a national survey conducted in 1997, women are taking CAM therapies more often than men in the United States.^[54] Herbal products such as dong quai, black cohosh, evening oil of primrose, red clover, and dietary phytoestrogens have been taken for menopausal symptoms. Unfortunately, most of the trials that assess efficacy for the treatment of menopausal symptoms are conflicting or show either modest to no benefit. In addition, many of these studies are not placebo controlled, which can pose a problem since many trials have demonstrated a placebo response when assessing menopausal symptoms. There is also uncertainty regarding their effects on breast, vaginal, and uterine tissues, as well as long-term safety. Currently, clinical trials using a rigorous study design are under way to help answer some of these questions. The specific effects of herbal therapies on menopausal symptoms have been reviewed elsewhere^[55] and are beyond the scope of this article.

Several nonhormonal agents have shown positive results for the treatment of hot flashes. These agents have expanded the options for clinicians treating patients with a contra-indication to hormonal therapy or for those patients unwilling to take hormones. Venlafaxine results in a significant improvement in hot flashes, and studies suggest paroxetine provides a similar benefit. Clonidine and fluoxetine also improve hot flashes, although their effect may be more modest than that seen with venlafaxine. Small studies with gabapentin have shown positive results. Many of these studies were conducted in women with a history of breast cancer, many of who were being treated concurrently with tamoxifen. Further studies should be conducted in postmenopausal women without a history of breast cancer and not taking tamoxifen. These studies also should help clarify the optimum dosage and duration for treatment of hot flashes. In addition, comparative studies should be conducted to help differentiate among these agents and to determine if combination therapies will result in an additive benefit in reducing hot flashes or if there is cross-resistance between hormonal agents and nonhormonal agents. Although the exact mechanism of action of these agents for improving hot flashes is unknown, further investigations of pharmacologic agents may help sort out which neurotransmitters are responsible in the pathophysiology of hot flashes to enable better selection of pharmacologic agents.

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Reprint Address

Address reprint requests to Brigitte L. Sicat, Pharm.D., BCPS, Department of Pharmacy, School of Pharmacy, Virginia Commonwealth University, 410 North 12th Street, Richmond, VA 23298.

From the Department of Pharmacy, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia (both authors).