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Vasomotor symptoms in menopause: physiologic condition and central nervous system approaches to treatment

  • Andrea J. Rapkin
    Correspondence
    Reprint requests: Andrea J. Rapkin, MD, Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, 10833 LeConte Ave, Los Angeles, CA 90095-1740
    Affiliations
    Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA.
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      Objective

      The decline in concentrations of gonadal hormones during menopause gives rise to a range of physiologic and psychologic changes that may impact a woman’s health and quality of life significantly. Most notable among these are vasomotor symptoms (hot flashes and night sweats) and mood and sleep disturbances.

      Study design

      This article reviews the physiologic condition underlying menopausal vasomotor symptoms and centrally active, nonhormonal therapies that have demonstrated efficacy for their treatment.

      Results

      Despite the emergence of a range of nonhormonal treatments for vasomotor symptoms, a need still exists for safe and effective therapeutic options that directly target the underlying thermoregulatory mechanisms for women who want treatment but prefer to avoid hormone therapy or for whom hormone therapy is contraindicated.

      Conclusion

      The availability of centrally active therapies for menopausal vasomotor symptoms with risks and benefits clearly defined by results from well-designed clinical trials has the potential to allay safety concerns that are associated with the treatment of these common symptoms.

      Key words

      Life expectancy for women is increasing worldwide. The mean lifespan for women in the United States is approximately 80 years,
      United States Life Tables, 2002.
      and women who are currently 75 years old have 12.4 additional years of life expectancy.
      Therefore, most women can expect to spend a significant portion of their lives in a postmenopausal state. It is estimated that approximately 30 million women in the United States are now in or past menopause and that an additional 6 million women will reach this stage during this decade.
      • Hammond C.B.
      HEDIS 2000: strategies for successful menopause management.

      United States Bureau of the Census. Projections of the populations of the United States: 1977 to 2050. In: Current population reports. Washington, DC: US Government Printing Office. p. 25-27.

      The decline in estrogen levels that is associated with menopause results in a wide range of symptoms. The most common are vasomotor symptoms, which include hot flashes (also referred to as hot flushes) and night sweats. Menopausal symptoms may also include dizziness, rapid irregular heartbeat, atrophic vaginitis, bladder irritability, mood changes, sleep disturbances, headaches, myalgias, arthralgias, difficulty concentrating, memory impairment, and general malaise.
      • Freedman R.R.
      Physiology of hot flashes.
      • Miller R.G.
      • Ashar B.H.
      Managing menopause: current therapeutic options for vasomotor symptoms.
      • Stearns V.
      • Ullmer L.
      • Lopez J.F.
      • Smith Y.
      • Isaacs C.
      • Hayes D.
      Hot flushes.
      The North American Menopause Society position statement codified the language that is used to describe vasomotor symptoms of menopause. They define vasomotor symptoms as a global term that encompasses hot flashes and night sweats.
      North American Menopause Society
      Treatment of menopause-associated vasomotor symptoms: position statement of the North American Menopause Society.
      This position statement does not review treatment of mood changes or sleep disturbances along with vasomotor symptoms. However, considering sleep disturbances in the context of hot flashes and night sweats is logical because a number of studies have demonstrated strong relationships between self-reported hot flashes and sleep complaints.
      • Moe K.E.
      Hot flashes and sleep in women.
      In addition, treatments that reduce the frequency of hot flashes can also improve mood,
      • Barton D.L.
      • Loprinzi C.L.
      • Novotny P.
      • et al.
      Pilot evaluation of citalopram for the relief of hot flashes.
      • Saure A.
      • Planellas J.
      • Poulsen H.K.
      • Jaszczak P.
      A double-blind, randomized, comparative study evaluating clinical effects of two sequential estradiol-progestogen combinations containing either desogestrel or medroxyprogesterone acetate in climacteric women.
      which supports the view that these disturbances should be taken into account with the treatment of vasomotor symptoms.
      Menopausal vasomotor symptoms occur in as many as 74% of menopausal women,
      • Kritz-Silverstein D.
      • Goldani V.M.
      • Barrett-Connor E.
      Prevalence and clustering of menopausal symptoms in older women by hysterectomy and oophorectomy status.
      and evidence indicates that these symptoms are present in higher percentages (up to 88%) of perimenopausal women.
      • Dennerstein L.
      • Dudley E.C.
      • Hopper J.L.
      • Guthrie J.R.
      • Burger H.G.
      A prospective population-based study of menopausal symptoms.
      • Feldman B.M.
      • Voda A.
      • Gronseth E.
      The prevalence of hot flash and associated variables among perimenopausal women.
      • Guthrie J.R.
      • Dennerstein L.
      • Taffe J.R.
      • Donnelly V.
      Health care-seeking for menopausal problems.
      These symptoms generally subside within 1 year; however, for some women, the symptoms may persist for more than 30 years.
      • Kronenberg F.
      Hot flashes: epidemiology and physiology.
      Furthermore, they can have a marked negative impact on health-related and global quality of life (QOL)
      • Bobula J.D.
      Vasomotor symptoms and quality of life (QoL) in postmenopausal women.
      • Brazier J.E.
      • Roberts J.
      • Platts M.
      • Zoellner Y.F.
      Estimating a preference-based index for a menopause specific health quality of life questionnaire.
      • Daly E.
      • Gray A.
      • Barlow D.
      • McPherson K.
      • Roche M.
      • Vessey M.
      Measuring the impact of menopausal symptoms on quality of life.
      and often prompt visits to health care professionals.
      • Guthrie J.R.
      • Dennerstein L.
      • Taffe J.R.
      • Donnelly V.
      Health care-seeking for menopausal problems.
      Despite high prevalence and deleterious effects of symptoms on QOL, many women with menopausal symptoms do not seek treatment or receive therapy for these symptoms.
      • Genazzani A.R.
      • Nicolucci A.
      • Campagnoli C.
      • et al.
      Assessment of the QoL in Italian menopausal women: comparison between HRT users and non-users.
      Results from 2 large surveys that were conducted across Europe indicated that most women surveyed believed that they needed more information about hormone replacement therapy,
      • Rozenberg S.
      • Fellemans C.
      • Kroll M.
      • Vandromme J.
      The menopause in Europe.
      • Schneider H.P.
      Cross-national study of women’s use of hormone replacement therapy (HRT) in Europe.
      which underscores the need for physicians to educate women about new and effective therapies for menopausal symptoms and to treat them with medications that meet their individual needs.
      Hormone therapy (HT) has been the cornerstone of the management of menopausal symptoms for many years and has been demonstrated repeatedly to reduce their severity and to improve QOL.
      • Gambacciani M.
      • Ciaponi M.
      • Cappagli B.
      • et al.
      Effects of low-dose, continuous combined hormone replacement therapy on sleep in symptomatic postmenopausal women.
      • Shanafelt T.D.
      • Barton D.L.
      • Adjei A.A.
      • Loprinzi C.L.
      Pathophysiology and treatment of hot flashes.
      • Sikon A.
      • Thacker H.L.
      Treatment options for menopausal hot flashes.
      However, the treatment landscape for menopausal symptoms has changed dramatically since the publication of the Women’s Health Initiative and the Heart and Estrogen/Progestin Replacement Study and follow-up.
      • Hulley S.
      • Grady D.
      • Bush T.
      • et al.
      Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women: Heart and Estrogen/progestin Replacement Study (HERS) research group.
      • Hulley S.
      • Furberg C.
      • Barrett-Connor E.
      • et al.
      Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement study follow-up (HERS II).
      • Rossouw J.E.
      • Anderson G.L.
      • Prentice R.L.
      • et al.
      Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial.
      It has become clear that initial interpretations of Women’s Health Initiative and Heart and Estrogen/Progestin Replacement Study substantially overestimated the risks of HT for the treatment of menopausal symptoms. Both trials were designed to examine long-term effects of HT for the reduction of coronary heart disease in an older postmenopausal population. Their conclusions therefore are not generalizable to short-term treatment of a younger, perimenopausal population.
      • Grodstein F.
      • Manson J.E.
      • Stampfer M.J.
      Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation.
      • Klaiber E.L.
      • Vogel W.
      • Rako S.
      A critique of the Women’s Health Initiative hormone therapy study.
      • Salpeter S.
      Hormone therapy for younger postmenopausal women: How can we make sense out of the evidence?.
      Still, the results from these trials have increased dramatically the interest of health care practitioners and patients in nonhormonal therapies for menopausal symptoms. This article combines a discussion of the physiologic condition that underlies vasomotor symptoms, which includes the interplay between estrogen, serotonin, and norepinephrine, with a review of the currently published clinical trials of neuroactive therapies, including not only the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), but also the α-adrenoceptor antagonists and antidopaminergic agents that have been studied for the treatment of menopausal symptoms.
      Other compounds, which include tibolone, selective estrogen receptor modulators, and phytoestrogens (found in soybeans, black cohosh, whole grains, legumes, and flaxseed), and other alternative nonprescription compounds are also available for the treatment of menopausal symptoms. However, a full discussion of these treatment options has been published previously and is beyond the scope of this review.
      • Kessel B.
      • Kronenberg F.
      The role of complementary and alternative medicine in management of menopausal symptoms.
      • Robertson J.F.
      Selective oestrogen receptor modulators/new antioestrogens: a clinical perspective.
      • Swegle J.M.
      • Kelly M.W.
      Tibolone: a unique version of hormone replacement therapy.

      Literature Search Methods

      A PubMed search that was limited to clinical trials that were published in English was conducted with the search terms hot flash or hot flush or vasomotor symptoms (all fields). We eliminated all references in which vasomotor symptoms were addressed as side effects rather than outcome; in which the test article was a hormone or a hormone modulator, a herbal supplement, soy/isoflavone, or other phytoestrogen; and in which nonmedicinal interventions (eg, magnets, behavioral therapy) were used, because they were considered outside the scope of this review. The remaining articles are summarized in the Table.
      TABLEEffects of centrally active drugs
      The entries are the results of a PubMed literature search on the terms hot flash, hot flush, and vasomotor symptoms, limited to clinical trials published in English. References were eliminated if (1) vasomotor symptoms were side effects rather than an outcome measure; (2) test article was a hormone or a direct hormone modulator, a herbal supplement, soy/isoflavone, or other phytoestrogen; or (3) trials used nonmedicinal interventions.
      on vasomotor symptoms
      DrugPopulation
      Subjects with available data.
      DesignDoseDuration of trialEffectSide effects
      Where reported to be significant.
      Study
      Citalopram (SSRI)Postmenopausal, some with history of breast cancer (n = 18)Prospective pilot trialStepwise, 10 mg, 20 mg5 wkReduced severity, frequency compared with baselineMild nausea, dry mouthBarton et al
      • Barton D.L.
      • Loprinzi C.L.
      • Novotny P.
      • et al.
      Pilot evaluation of citalopram for the relief of hot flashes.
      Women with inadequate benefit from venlafaxine (n = 22)Prospective pilot trialStepwise, 10 mg, 20 mg4 wkReduced severity, frequencyLoprinzi et al
      • Loprinzi C.L.
      • Flynn P.J.
      • Carpenter L.A.
      • et al.
      Pilot evaluation of citalopram for the treatment of hot flashes in women with inadequate benefit from venlafaxine.
      Postmenopausal (n = 150)Placebo-controlled, double-blindStepwise, 10 mg, 20 mg, 30 mg9 moNo effectInsomniaSuvanto-Luukkonen et al
      • Suvanto-Luukkonen E.
      • Koivunen R.
      • Sundstrom H.
      • et al.
      Citalopram and fluoxetine in the treatment of postmenopausal symptoms: a prospective, randomized, 9-month, placebo-controlled, double-blind study.
      Fluoxetine (SSRI)Postmenopausal (n = 150)Placebo-controlled, double-blindStepwise, 10 mg, 20 mg, 30 mg9 moNo effectSuvanto-Luukkonen et al
      • Suvanto-Luukkonen E.
      • Koivunen R.
      • Sundstrom H.
      • et al.
      Citalopram and fluoxetine in the treatment of postmenopausal symptoms: a prospective, randomized, 9-month, placebo-controlled, double-blind study.
      Postmenopausal, some with history of breast cancer (n = 68)Double-blind, randomized, cross-over20 mg/d4 wkReduced severity, frequencyLoprinzi et al
      • Loprinzi C.L.
      • Sloan J.A.
      • Perez E.A.
      • et al.
      Phase III evaluation of fluoxetine for treatment of hot flashes.
      Sertraline (SSRI)Postmenopausal (n = 15)Uncontrolled, retrospective open trial25-50 mg/dNot reportedSubjective amelioration, no statisticsPlouffe et al
      • Plouffe Jr, L.
      • Trott E.A.
      • Largoza M.
      • Hansen K.A.
      An open trial of sertraline for menopausal hot flushes: potential involvement of serotonin in vasomotor instability.
      Fluvoxamine (SSRI)Women with oophorectomy (n = 42)Open trial, compared with estrogen alone50 mg/d, with estrogen8 wkReduced frequencyNagata et al
      • Nagata H.
      • Nozaki M.
      • Nakano H.
      Short-term combinational therapy of low-dose estrogen with selective serotonin re-uptake inhibitor (fluvoxamine) for oophorectomized women with hot flashes and depressive tendencies.
      Paroxetine (SSRI)Men who received androgen ablation (n = 22)Prospective, pilot trial12.5 mg/d, increased to 37.5 mg/d4 wkReduced severity, frequency, increased QOLLoprinzi et al
      • Loprinzi C.L.
      • Barton D.L.
      • Carpenter L.A.
      • et al.
      Pilot evaluation of paroxetine for treating hot flashes in men.
      Women with history of breast cancer (n = 27)Pilot trial10 mg/d, then 20 mg/d5 wkReduced severity, frequency, increased QOLSomnolence, anxietyStearns et al
      • Stearns V.
      • Isaacs C.
      • Rowland J.
      • et al.
      A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil) in controlling hot flashes in breast cancer survivors.
      Postmenopausal (n = 165)Placebo-controlled, double-blind, randomized12.5 mg/d or 25 mg/d6 wkReduced severity, frequencyStearns et al
      • Stearns V.
      • Beebe K.L.
      • Iyengar M.
      • Dube E.
      Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial.
      Women with hot flashes (n = 107)Placebo-controlled, double-blind, randomized, cross-over, stratified10 mg/d, 20 mg/d9 wkReduced severity, frequencyDrowsiness, nauseaStearns et al
      • Stearns V.
      • Slack R.
      • Greep N.
      • et al.
      Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial.
      Women with breast cancer (n = 13)Uncontrolled, open trial20 mg/dApproximately 4 wkReduced severity, improved sleep compared with baselineWeitzner et al
      • Weitzner M.A.
      • Moncello J.
      • Jacobsen P.B.
      • Minton S.
      A pilot trial of paroxetine for the treatment of hot flashes and associated symptoms in women with breast cancer.
      Venlafaxine (SNRI)Women with history of breast cancer, men who underwent androgen ablation (n = 28)Pilot25 mg/d4 wkReduced frequencyLoprinzi et al
      • Loprinzi C.L.
      • Pisansky T.M.
      • Fonseca R.
      • et al.
      Pilot evaluation of venlafaxine hydrochloride for the therapy of hot flashes in cancer survivors.
      Women with history of breast cancer (n = 191)Double-blind, randomized37.5 mg/d, 75 mg/d, 150 mg/d4 wkReduced severity, frequencyAppetite loss, constipation, dry mouthLoprinzi et al
      • Loprinzi C.L.
      • Kugler J.W.
      • Sloan J.A.
      • et al.
      Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial.
      Postmenopausal (n = 102)Open-label continuation phase of Loprinzi et al, 200037.5-150 mg/d8 wkReduced severity, frequency (75 mg/d)Mild appetite loss, dry mouth, dissipating nauseaBarton et al
      • Barton D.
      • LaVasseur B.
      • Loprinzi C.
      • Novotny P.
      • Wilwerding M.B.
      • Sloan J.
      Venlafaxine for the control of hot flashes: results of a longitudinal continuation study.
      Breast cancer (n = 30)Open-label37.5 mg/d8 wkReduced severity, frequency from baselineNausea, dry mouthBiglia et al
      • Biglia N.
      • Torta R.
      • Roagna R.
      • et al.
      Evaluation of low-dose venlafaxine hydrochloride for the therapy of hot flushes in breast cancer survivors.
      Men who underwent androgen ablation (n = 21)Uncontrolled, open trial12.5 mg twice daily5 wkReduced frequency from baselineQuella et al
      • Quella S.K.
      • Loprinzi C.L.
      • Sloan J.
      • et al.
      Pilot evaluation of venlafaxine for the treatment of hot flashes in men undergoing androgen ablation therapy for prostate cancer.
      Postmenopausal (n = 80)Placebo-controlled, double-blind, randomized37.5 mg/d, then 75 mg/d12 wkImproved subjective assessment, no effect on severityDry mouth, sleeplessness, decreased appetiteEvans et al
      • Evans M.L.
      • Pritts E.
      • Vittinghoff E.
      • McClish K.
      • Morgan K.S.
      • Jaffe R.B.
      Management of postmenopausal hot flushes with venlafaxine hydrochloride: a randomized, controlled trial.
      GabapentinBreast cancer (n = 371)Placebo-controlled, double-blind, randomized300 mg/d, 900 mg/d8 wkReduced severity, frequency at 900 mgLoss of appetitePandya et al
      • Pandya K.J.
      • Morrow G.R.
      • Roscoe J.A.
      • et al.
      Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial.
      Breast cancer (n = 22)Uncontrolled, open trial300 mg, 3 times daily8 wkReduced duration, severity, frequency compared with baselinePandya et al
      • Pandya K.J.
      • Thummala A.R.
      • Griggs J.J.
      • et al.
      Pilot study using gabapentin for tamoxifen-induced hot flashes in women with breast cancer.
      Postmenopausal (n = 59)Placebo-controlled, double-blind, randomized900 mg/d, open-label dose escalation to 2700 mg/d after 12 wk12 wkReduced severity at >900 mgPeripheral edema, somnolence, dizzinessGuttuso et al
      • Guttuso Jr, T.
      • Kurlan R.
      • McDermott M.P.
      • Kieburtz K.
      Gabapentin’s effects on hot flashes in postmenopausal women: a randomized controlled trial.
      Postmenopausal, some with history of breast cancer (n = 20)Prospective, single-arm pilotStepwise, 300 to 600 to 900 mg/d5 wkReduced severity, frequency compared with baselineLoprinzi et al
      • Loprinzi L.
      • Barton D.L.
      • Sloan J.A.
      • et al.
      Pilot evaluation of gabapentin for treating hot flashes.
      Clonidine (alpha adrenergic agonist)Postmenopausal (n = 86)Placebo-controlled, double-blind, cross-over25-75 μg twice daily8 wkReduced severity, frequency, durationDry mouthClayden et al
      • Clayden J.R.
      • Bell J.W.
      • Pollard P.
      Menopausal flushing: double-blind trial of a non-hormonal medication.
      Postmenopausal (n = 30)Placebo-controlled, double-blind0.1 mg/d, transdermally10 wkReduced frequencyNagamani et al
      • Nagamani M.
      • Kelver M.E.
      • Smith E.R.
      Treatment of menopausal hot flashes with transdermal administration of clonidine.
      Women with hot flashes (n = 37)Placebo-controlled, double-blind, cross-over0.050- 0.075 mg/d12 wkNo effectNo different from placeboSalmi and Punnonen
      • Salmi T.
      • Punnonen R.
      Clonidine in the treatment of menopausal symptoms.
      Postmenopausal (n =10)Placebo-controlled, dose-response0.1, 0.2, 0.4 mg/d6 wkReduced frequency compared with baselineSevere fatigue, nausea, headaches, irritability, dizzinessLaufer et al
      • Laufer L.R.
      • Erlik Y.
      • Meldrum D.R.
      • Judd H.L.
      Effect of clonidine on hot flashes in postmenopausal women.
      Postmenopausal (n = 14)Placebo-controlled, double-blind, cross-over0.1 mg/d10 wkNo effect on frequencyWren and Brown
      • Wren B.G.
      • Brown L.B.
      A double-blind trial with clonidine and a placebo to treat hot flushes.
      Postmenopausal, tamoxifen-induced (n = 194)Randomized, double-blind, placebo-controlled0.1 mg/d8 wkReduced frequency, increased QOLDifficulty sleepingPandya et al
      • Pandya K.J.
      • Raubertas R.F.
      • Flynn P.J.
      • 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.
      Postmenopausal, tamoxifen-induced (n = 110)Placebo-controlled, double-blind, crossover0.1 mg/d8 wkSmall but significant reduced severity,- frequencyDry mouth, constipation, drowsinessGoldberg et al
      • Goldberg R.M.
      • Loprinzi C.L.
      • O’Fallon J.R.
      • et al.
      Transdermal clonidine for ameliorating tamoxifen-induced hot flashes.
      Postmenopausal (n = 41)Placebo-controlled, double-blind, cross-over0.050 mg twice daily13 wkNo effectLindsay and Hart
      • Lindsay R.
      • Hart D.M.
      Failure of response of menopausal vasomotor symptoms to clonidine.
      Methyldopa (alpha adrenergic agonist)Postmenopausal (n = 28)Placebo-controlled, double-blind, cross-over250-500 mg twice daily60 d, 14 d washoutReduced frequencyNesheim and Saetre
      • Nesheim B.I.
      • Saetre T.
      Reduction of menopausal hot flushes by methyldopa: a double blind crossover trial.
      Postmenopausal (n = 24)Placebo-controlled, double-blind, cross-over375-1125 mg/d8-16 wkNo effect on frequency compared with placebo, subjective improvement in “trouble caused by hot flushes”Andersen et al
      • Andersen O.
      • Engebretsen T.
      • Solberg V.M.
      • Orbo A.
      Alpha-methyldopa for climacteric hot flushes: a double-blind, randomized, cross-over study.
      Veralipride (antidopaminergic)Postmenopausal (n = 29)100 mg/d with raloxifene 60 mg/d6 moReduced hot flashesMorgante et al
      • Morgante G.
      • Farina M.
      • Cianci A.
      • et al.
      Veralipride administered in combination with raloxifene decreases hot flushes and improves bone density in early postmenopausal women.
      Premenopausal, gonadotropin-releasing hormoneagonist-induced hot flashes (n = 36)Randomized, double-blind, placebo-controlled100 mg/d2 moReduced frequency, severityHyperprolactinemiaVercellini et al
      • Vercellini P.
      • Sacerdote P.
      • Trespidi L.
      • Manfredi B.
      • Panerai A.E.
      • Crosignani P.G.
      Veralipride for hot flushes induced by a gonadotropin-releasing hormone agonist: a controlled study.
      Postmenopausal (n = 40)Randomized, double-blind, placebo-controlled100 mg/d30 dReduced frequency, severityMelis et al
      • Melis G.B.
      • Gambacciani M.
      • Cagnacci A.
      • Paoletti A.M.
      • Mais V.
      • Fioretti P.
      Effects of the dopamine antagonist veralipride on hot flushes and luteinizing hormone secretion in postmenopausal women.
      Postmenopausal (n = 47)Randomized, double-blind, placebo-controlled, crossover100 mg/d80 dReduced frequency, severityIncreased estradiol, hyperprolactinemia, galactorrheaDavid et al
      • David A.
      • Don R.
      • Tajchner G.
      • Weissglas L.
      Veralipride: alternative antidopaminergic treatment for menopausal symptoms.
      Gonadotropin-releasing hormone agonist-induced hot flashes (n = 25)Open observational trial100 mg/d28 dReduced frequency, severity, no statistics reportedVercellini et al
      • Vercellini P.
      • Vendola N.
      • Colombo A.
      • Passadore C.
      • Trespidi L.
      • Crosignani P.G.
      Veralipride for hot flushes during gonadotropin-releasing hormone agonist treatment.
      Postmenopausal (n = 40)Double-blind, randomized100 mg/d compared with 1.25 mg/d estrogen20 dReduced frequency, severity, no different than estrogenWesel et al
      • Wesel S.
      • Bourguignon R.P.
      • Bosuma W.B.
      Veralipride versus conjugated oestrogens: a double-blind study in the management of menopausal hot flushes.
      Veralipride bromocriptine Liposom domperdomePostmenopausal (n = 75)Randomized, double-blind, placebo-controlled100 mg/d veralipride, 3.75 mg/d bromocriptine, 40 mg/d im Liposom, 10 mg/d domperdome20 dReduced frequency, severity, all drugs compared with placeboMastodynia, galactorrheaZichella et al
      • Zichella L.
      • Falaschi P.
      • Fioretti P.
      • et al.
      Effects of different dopamine agonists and antagonists on post-menopausal hot flushes.
      MirtazapineWomen with history of breast cancer (n = 22)Prospective, single-arm, pilot7.5 mg/d, then 15 mg/d, then 30 mg/d5 wkReduced severity, frequency, no statisticsIncrease in appetite, dry mouthPerez et al
      • Perez D.G.
      • Loprinzi C.L.
      • Barton D.L.
      • et al.
      Pilot evaluation of mirtazapine for the treatment of hot flashes.
      Moclobemide (monoamine oxidase inhibitor)Postmenopausal (n = 28)Randomized, double-blind, placebo-controlled150 mg/d or 300 mg/d5 wkReduced severityTarim et al
      • Tarim E.
      • Bagis T.
      • Kilicdag E.
      • Erkanli S.
      • Aslan E.
      • Kuscu E.
      Moclobemide in the treatment of hot flashes in postmenopausal women.
      Propranolol (beta blocker)Perimenopausal (n = 25)Prospective, double-blind, randomized40 mg, 3 times daily8 wkNo effectCoope et al
      • Coope J.
      • Williams S.
      • Patterson J.S.
      A study of the effectiveness of propranolol in menopausal hot flushes.
      low asterisk The entries are the results of a PubMed literature search on the terms hot flash, hot flush, and vasomotor symptoms, limited to clinical trials published in English. References were eliminated if (1) vasomotor symptoms were side effects rather than an outcome measure; (2) test article was a hormone or a direct hormone modulator, a herbal supplement, soy/isoflavone, or other phytoestrogen; or (3) trials used nonmedicinal interventions.
      Subjects with available data.
      Where reported to be significant.

      Physiologic Condition of Menopausal Vasomotor Symptoms

      The occurrence of vasomotor symptoms in most women is correlated closely with estrogen withdrawal that occurs with natural or surgical menopause. The key role of estrogen in menopausal symptoms is supported by the fact that hormone replacement is generally acknowledged as the most effective therapy for reducing their occurrence.
      • Gambacciani M.
      • Ciaponi M.
      • Cappagli B.
      • et al.
      Effects of low-dose, continuous combined hormone replacement therapy on sleep in symptomatic postmenopausal women.
      • Shanafelt T.D.
      • Barton D.L.
      • Adjei A.A.
      • Loprinzi C.L.
      Pathophysiology and treatment of hot flashes.
      • Sikon A.
      • Thacker H.L.
      Treatment options for menopausal hot flashes.
      However, estrogen withdrawal alone does not explain the cause of menopausal vasomotor symptoms. This is evidenced by the observation that there is no significant correlation between plasma hormone levels and the occurrence of vasomotor symptoms.
      • Hutton J.D.
      • Jacobs H.S.
      • Murray M.A.
      • James V.H.
      Relation between plasma oestrone and oestradiol and climacteric symptoms.
      Estrogen withdrawal therefore is necessary but not sufficient to explain the occurrence of menopausal symptoms.
      • Freedman R.R.
      Pathophysiology and treatment of menopausal hot flashes.
      A growing body of evidence supports the hypothesis that hot flashes result from the physiologic response to a marked narrowing of the hypothalamic thermoregulatory set point or neutral zone (Figure 1).
      • Freedman R.R.
      Pathophysiology and treatment of menopausal hot flashes.
      This change in set point increases the chances of sensation of intense heat in response to internal and environmental triggers and subsequent activation of heat loss responses, which include cutaneous vasodilation and sweating.
      • Kronenberg F.
      Hot flashes: epidemiology and physiology.
      • Freedman R.R.
      Pathophysiology and treatment of menopausal hot flashes.
      It is assumed that the menopause-associated reduction in circulating levels of gonadal hormones gives rise to this change in hypothalamic function. However, the relationship between these events is complex, and the exact trigger that induces a change in thermoregulatory set point activity in the hypothalamus during menopause is not understood fully.
      • Stearns V.
      • Ullmer L.
      • Lopez J.F.
      • Smith Y.
      • Isaacs C.
      • Hayes D.
      Hot flushes.
      Figure thumbnail gr1
      FIGURE 1Small core body temperature (Tc) elevations that act within a reduced thermoneutral zone trigger hot flashes in symptomatic postmenopausal women.
      Freedman RR. Pathophysiology and treatment of menopausal hot flashes. Semin Reprod Med 2005, 23:117-25. Reprinted with permission of Thieme.

      Thermoregulatory Set Point

      The key role of a change in the hypothalamic thermoregulatory set point or neutral zone in the hot flush cascade is underscored by the fact that these events are preceded by an increase in core body temperature that does not result from peripheral vasoconstriction or elevated metabolic rate.
      • Freedman R.R.
      • Norton D.
      • Woodward S.
      • Cornelissen G.
      Core body temperature and circadian rhythm of hot flashes in menopausal women.
      • Freedman R.R.
      Biochemical, metabolic, and vascular mechanisms in menopausal hot flashes.
      Perspiration and vasodilation are classic mechanisms of heat loss that are activated during hot flashes. These responses contribute to night sweats and are initiated by activity in the medial preoptic area of the hypothalamus.
      • Shanafelt T.D.
      • Barton D.L.
      • Adjei A.A.
      • Loprinzi C.L.
      Pathophysiology and treatment of hot flashes.
      The changes in hypothalamic function that are thought to underlie hot flashes and associated symptoms appear to be related closely to changes in the levels of biogenic amine neurotransmitters that occur in menopausal women.

      Neurotransmitter Changes in Menopause

      Estrogen has complex effects in the central nervous system (CNS). Menopause-associated reductions in circulating estrogen could lead to imbalances in neurotransmitter levels in the hypothalamus and other portions of the CNS and ultimately result in hot flushes in susceptible individuals. It has been suggested that estrogens may alter the activity of both the noradrenergic and serotonergic systems by modulating the levels of these neurotransmitters in the brain. Both norepinephrine and serotonin are thought to be involved in the regulation of temperature homeostasis in the hypothalamus. During menopause, diminished levels of gonadal hormones may lead to instability in CNS concentrations of both norepinephrine and serotonin, which results in alterations in thermoregulation (eg, a reduced neutral zone) and an increased occurrence of hot flashes.
      • Stearns V.
      • Ullmer L.
      • Lopez J.F.
      • Smith Y.
      • Isaacs C.
      • Hayes D.
      Hot flushes.
      • Deecher D.C.
      • Leventhal L.
      • Numan S.
      • et al.
      Desvenlafaxine alleviates vasomotor instability in two rodent models of hot flush.

      Norepinephrine

      A large body of evidence indicates that norepinephrine plays a central role in the pathophysiologic condition of hot flashes (Figure 2).
      • Freedman R.R.
      Pathophysiology and treatment of menopausal hot flashes.
      The involvement of norepinephrine in central thermoregulation and the etiology of hot flashes is supported by results from experimental animal studies that showed that increased CNS levels of norepinephrine are correlated with a narrowing of the thermoneutral zone.
      • Freedman R.R.
      Pathophysiology and treatment of menopausal hot flashes.
      • Bruck K.
      • Hinckel P.
      Thermoregulatory noradrenergic and serotonergic pathways to hypothalamic units.
      Freedman
      • Freedman R.R.
      Biochemical, metabolic, and vascular mechanisms in menopausal hot flashes.
      reported that plasma levels of 3-methoxy-4-hydroxyphenylglycol, a metabolite of brain norepinephrine and an indicator of central noradrenergic activity, increased significantly after a hot flash in 9 menopausal women. This suggests that alterations in CNS levels of this neurotransmitter changed before the onset of this menopausal symptom. This conclusion is consistent with results from another study that showed that yohimbine, an α2-adrenergic antagonist, elevates 3-methoxy-4-hydroxyphenylglycol plasma levels and brain norepinephrine and ultimately triggers hot flashes.
      • Maas J.
      MHPG: basic mechanisms and psychopathology.
      The role of norepinephrine in hot flashes also is supported by clinical results that have been obtained with clonidine, an α2-adrenergic agonist that reduces central noradrenergic activity.
      • Freedman R.R.
      Physiology of hot flashes.
      • Freedman R.R.
      • Woodward S.
      • Sabharwal S.C.
      Alpha 2-adrenergic mechanism in menopausal hot flushes.
      This agent has been used with modest efficacy as a treatment for women with menopausal vasomotor symptoms.
      • Miller R.G.
      • Ashar B.H.
      Managing menopause: current therapeutic options for vasomotor symptoms.
      Figure thumbnail gr2
      FIGURE 2Role of norepinephrine in the development of hot flashes.
      Freedom RR. Pathophysiology and treatment of menopausal hot flashes. Semin Reprod Med 2005;23:117-25. Reprinted with permission of Thieme.

      Serotonin

      Serotonin also appears to play a pivotal role in the hot flash cascade (Figure 3).
      • Stearns V.
      • Ullmer L.
      • Lopez J.F.
      • Smith Y.
      • Isaacs C.
      • Hayes D.
      Hot flushes.
      Estrogen withdrawal may be correlated with a decline in circulating serotonin levels that could increase the sensitivity of hypothalamic serotonin (5-HT2A) receptors. This change may also contribute to a narrowing of the thermoregulatory neutral zone and an increased risk of hot flash occurrences.
      • Berendsen H.H.
      The role of serotonin in hot flushes.
      • Sipe K.
      • Leventhal L.
      • Burroughs K.
      • Cosmi S.
      • Johnston G.H.
      • Deecher D.C.
      Serotonin 2A receptors modulate tail-skin temperature in two rodent models of estrogen deficiency-related thermoregulatory dysfunction.
      After an internal or external thermostimulus, rising concentrations of ligand stimulate the serotonin (5-HT2A) receptor, which results in a change in the thermoregulatory set point and a subsequent hot flash sensation. The importance of serotonin in the hot flash cascade is underscored by results from a comparison of serotonin levels in women with mild vs moderate-to-severe menopausal symptoms that indicates an association between concentration of serotonin and severity of menopausal symptoms.
      • Slopien R.
      • Meczekalski B.
      • Warenik-Szymankiewicz A.
      Relationship between climacteric symptoms and serum serotonin levels in postmenopausal women.
      Figure thumbnail gr3
      FIGURE 3In the premenopausal state, estrogens stabilize the thermoregulatory set point, which results in a normal thermoregulatory response (peripheral vasodilation or constriction) to external thermal stimuli.
      In the menopausal state, estrogen concentrations are decreased, and the set point is unstable, which results in an altered vasodilatory thermoregulatory response to external thermal stimuli. In the absence of pharmacologic intervention, the set point readjusts.
      • Stearns V.
      • Ullmer L.
      • Lopez J.F.
      • Smith Y.
      • Isaacs C.
      • Hayes D.
      Hot flushes.

      Mood and sleep disturbances

      Mood and sleep disturbances are included in the array of menopausal symptoms, and their occurrence may result from changes in CNS transmitters, which include serotonin, norepinephrine, dopamine, and endorphins.
      • Vliet E.L.
      • Davis V.L.
      New perspectives on the relationship of hormone changes to affective disorders in the perimenopause.
      The central importance of the relationship between estrogens and the serotonin system in mood regulation in women with menopause is supported by results from a small-scale study that demonstrates that the blockade of serotonin receptors with metergoline reversed the positive effects of estrogen replacement on mood in perimenopausal women.
      • Rubinow D.R.
      • Schmidt P.J.
      • Roca C.A.
      Estrogen-serotonin interactions: implications for affective regulation.
      Serotonin also plays a key role in the regulation of sleep,
      • Portas C.M.
      • Bjorvatn B.
      • Ursin R.
      Serotonin and the sleep/wake cycle: special emphasis on microdialysis studies.
      and menopause-associated changes in serotonin levels may contribute to sleep disorders. This view is supported by the fact that treatment with an SSRI improves sleep in menopausal women.
      • Stearns V.
      • Isaacs C.
      • Rowland J.
      • et al.
      A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil) in controlling hot flashes in breast cancer survivors.
      Although it has been suggested that disturbed sleep in menopause may be due to hot flashes,
      • Henderson V.W.
      • Klein B.E.K.
      • Resnick S.M.
      Menopause and disorders of neurologic function, mental health, and the eye.
      recent results indicate that this is not entirely the case.
      • Freedman R.R.
      • Roehrs T.A.
      Lack of sleep disturbance from menopausal hot flashes.

      Neuroactive Agents for Menopausal Vasomotor Symptoms

      A wide range of neuroactive agents has been evaluated for the treatment of menopausal symptoms. Most of these medications have been tested in relatively short-term, small-scale clinical trials. However, these drugs have been used extensively for other indications, and the safety of most of them is supported by extensive long-term data.
      The Table summarizes the clinical trials that were conducted on centrally active prescription alternatives to HT. Most are small-scale studies, but several large, randomized, double-blind, placebo-controlled trials have been completed. The classes of drugs that were evaluated include SSRIs, SNRIs, α-adrenoceptor antagonists, and antidopaminergic drugs. Several drugs that fall outside these groups have been examined also.

      SSRIs

      SSRIs have been evaluated extensively as treatment for menopausal mood symptoms and could be considered rational therapy for vasomotor menopausal symptoms, given the well-documented role of serotonin in thermoregulation. Results from small-scale, short-term clinical trials have shown that the administration of SSRIs may be effective in reduction of the frequency and severity of hot flashes.
      • Barton D.L.
      • Loprinzi C.L.
      • Novotny P.
      • et al.
      Pilot evaluation of citalopram for the relief of hot flashes.
      • Stearns V.
      • Isaacs C.
      • Rowland J.
      • et al.
      A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil) in controlling hot flashes in breast cancer survivors.
      • Loprinzi C.L.
      • Flynn P.J.
      • Carpenter L.A.
      • et al.
      Pilot evaluation of citalopram for the treatment of hot flashes in women with inadequate benefit from venlafaxine.
      • Loprinzi C.L.
      • Sloan J.A.
      • Perez E.A.
      • et al.
      Phase III evaluation of fluoxetine for treatment of hot flashes.
      • Loprinzi C.L.
      • Barton D.L.
      • Carpenter L.A.
      • et al.
      Pilot evaluation of paroxetine for treating hot flashes in men.
      • Stearns V.
      • Beebe K.L.
      • Iyengar M.
      • Dube E.
      Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial.
      • Stearns V.
      • Slack R.
      • Greep N.
      • et al.
      Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial.
      • Weitzner M.A.
      • Moncello J.
      • Jacobsen P.B.
      • Minton S.
      A pilot trial of paroxetine for the treatment of hot flashes and associated symptoms in women with breast cancer.
      These treatments also have been demonstrated to improve mood, sleep, anxiety, and QOL in menopausal women and in women who undergo estrogen-deprivation therapy for breast cancer.
      • Barton D.L.
      • Loprinzi C.L.
      • Novotny P.
      • et al.
      Pilot evaluation of citalopram for the relief of hot flashes.
      • Stearns V.
      • Isaacs C.
      • Rowland J.
      • et al.
      A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil) in controlling hot flashes in breast cancer survivors.
      • Stearns V.
      • Beebe K.L.
      • Iyengar M.
      • Dube E.
      Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial.
      SSRIs also have been combined effectively with low-dose HT. Results from a small-scale trial showed that the combination of fluvoxamine (50 mg/d) with low-dose estrogen (0.3125 mg/d) was significantly more effective than estrogen alone in relieving hot flashes and depressive symptoms in women who had undergone oophorectomy (P = .036).
      • Nagata H.
      • Nozaki M.
      • Nakano H.
      Short-term combinational therapy of low-dose estrogen with selective serotonin re-uptake inhibitor (fluvoxamine) for oophorectomized women with hot flashes and depressive tendencies.
      However, it should be noted that clinical results for SSRIs are not uniformly positive. Results from a study of fluoxetine and citalopram (each titrated to a maximum dose of 30 mg/d) indicated no significant benefit of either drug vs placebo in relieving hot flashes in postmenopausal women.
      • Suvanto-Luukkonen E.
      • Koivunen R.
      • Sundstrom H.
      • et al.
      Citalopram and fluoxetine in the treatment of postmenopausal symptoms: a prospective, randomized, 9-month, placebo-controlled, double-blind study.
      Variability in clinical trial results for SSRIs may be related to the selectivity of different agents in this class for the serotonin vs the norepinephrine transporter. Because both neurotransmitters are thought to be involved in thermoregulation and the development of menopausal vasomotor symptoms, it is reasonable to suggest that activity at both transporters may be more effective than high selectivity for only 1 of them. Paroxetine is the SSRI with the highest activity at the norepinephrine transporter,
      • Nemeroff C.B.
      • Owens M.J.
      Pharmacologic differences among the SSRIs: focus on monoamine transporters and the HPA axis.
      and it has been shown repeatedly to be effective for the treatment of menopausal vasomotor symptoms.
      • Stearns V.
      • Isaacs C.
      • Rowland J.
      • et al.
      A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil) in controlling hot flashes in breast cancer survivors.
      • Stearns V.
      • Beebe K.L.
      • Iyengar M.
      • Dube E.
      Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial.
      • Weitzner M.A.
      • Moncello J.
      • Jacobsen P.B.
      • Minton S.
      A pilot trial of paroxetine for the treatment of hot flashes and associated symptoms in women with breast cancer.
      In contrast, fluoxetine and citalopram have much lower affinities for the norepinephrine transporter,
      • Nemeroff C.B.
      • Owens M.J.
      Pharmacologic differences among the SSRIs: focus on monoamine transporters and the HPA axis.
      and each of these SSRIs has been shown to have modest or variable efficacy in decreasing the frequency or severity of hot flashes vs placebo.
      • Barton D.L.
      • Loprinzi C.L.
      • Novotny P.
      • et al.
      Pilot evaluation of citalopram for the relief of hot flashes.
      • Loprinzi C.L.
      • Sloan J.A.
      • Perez E.A.
      • et al.
      Phase III evaluation of fluoxetine for treatment of hot flashes.
      • Suvanto-Luukkonen E.
      • Koivunen R.
      • Sundstrom H.
      • et al.
      Citalopram and fluoxetine in the treatment of postmenopausal symptoms: a prospective, randomized, 9-month, placebo-controlled, double-blind study.
      Although SSRIs generally are well tolerated, their use may be limited by sexual dysfunction that may occur in as many as 30% of women who are treated.
      • Bachmann G.A.
      Menopausal vasomotor symptoms: a review of causes, effects and evidence-based treatment options.
      Treatment with SSRIs also may be associated with weight gain,
      • Masand P.S.
      • Gupta S.
      Selective serotonin-reuptake inhibitors: an update.
      which may decrease adherence to potentially effective therapy. The use of the lowest effective doses can reduce the frequency of their adverse effects.
      • Stearns V.
      • Slack R.
      • Greep N.
      • et al.
      Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial.
      • Masand P.S.
      • Gupta S.
      Selective serotonin-reuptake inhibitors: an update.

      Serotonin-Norepinephrine Reuptake Inhibitors

      Because norepinephrine and serotonin are both involved in the development of menopausal symptoms, it is plausible to expect that an agent that is designed to modulate these systems might be effective in reducing the frequency and severity of these symptoms. Although results from large-scale, long-term clinical studies are lacking, results from smaller-scale, well-controlled trials support the use of agents in this class.
      • Loprinzi C.L.
      • Pisansky T.M.
      • Fonseca R.
      • et al.
      Pilot evaluation of venlafaxine hydrochloride for the therapy of hot flashes in cancer survivors.
      • Loprinzi C.L.
      • Kugler J.W.
      • Sloan J.A.
      • et al.
      Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial.
      • Barton D.
      • LaVasseur B.
      • Loprinzi C.
      • Novotny P.
      • Wilwerding M.B.
      • Sloan J.
      Venlafaxine for the control of hot flashes: results of a longitudinal continuation study.
      • Biglia N.
      • Torta R.
      • Roagna R.
      • et al.
      Evaluation of low-dose venlafaxine hydrochloride for the therapy of hot flushes in breast cancer survivors.
      • Evans M.L.
      • Pritts E.
      • Vittinghoff E.
      • McClish K.
      • Morgan K.S.
      • Jaffe R.B.
      Management of postmenopausal hot flushes with venlafaxine hydrochloride: a randomized, controlled trial.
      • Quella S.K.
      • Loprinzi C.L.
      • Sloan J.
      • et al.
      Pilot evaluation of venlafaxine for the treatment of hot flashes in men undergoing androgen ablation therapy for prostate cancer.
      Evans et al
      • Evans M.L.
      • Pritts E.
      • Vittinghoff E.
      • McClish K.
      • Morgan K.S.
      • Jaffe R.B.
      Management of postmenopausal hot flushes with venlafaxine hydrochloride: a randomized, controlled trial.
      have demonstrated that the SNRI venlafaxine (dosed at 75 mg/d) was significantly superior to placebo in decreasing interference by hot flashes with activities of daily living in a 12-week trial that included 80 menopausal women. Overall, venlafaxine decreased hot flash scores from baseline by 51% vs 15% for placebo. Venlafaxine did not decrease hot flash severity significantly in these patients. Nevertheless, 93% of women on venlafaxine planned to continue treatment after the study concluded. Loprinzi et al
      • Loprinzi C.L.
      • Kugler J.W.
      • Sloan J.A.
      • et al.
      Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial.
      have demonstrated that treatment with venlafaxine for 4 weeks significantly decreased the combined frequency and severity of hot flashes in postmenopausal women who did not want to take HT because of a history of breast cancer or concern about malignancy. In this study of 191 patients (50 women received placebo, and 49, 43, and 49 women were treated with venlafaxine 37.5, 75.0, or 150.0 mg/d, respectively), median hot flash scores (a combination of frequency and severity) were reduced from baseline by 27%, 37%, 61%, and 61%, respectively (P < .001 for the difference between all venlafaxine treatment groups vs placebo). Recently presented results have shown that a metabolite of venlafaxine is also effective in animal models of hot flashes, but its efficacy has yet to be evaluated in clinical trials.
      • Deecher D.C.
      • Leventhal L.
      • Numan S.
      • et al.
      Desvenlafaxine alleviates vasomotor instability in two rodent models of hot flush.
      The efficacy of venlafaxine in reducing hot flash activity must be balanced against possible adverse effects (temporary nausea, decreased appetite, dry mouth, sleeplessness, and constipation) that are seen with this drug.
      • Loprinzi C.L.
      • Kugler J.W.
      • Sloan J.A.
      • et al.
      Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial.
      • Barton D.
      • LaVasseur B.
      • Loprinzi C.
      • Novotny P.
      • Wilwerding M.B.
      • Sloan J.
      Venlafaxine for the control of hot flashes: results of a longitudinal continuation study.
      • Biglia N.
      • Torta R.
      • Roagna R.
      • et al.
      Evaluation of low-dose venlafaxine hydrochloride for the therapy of hot flushes in breast cancer survivors.
      Patients who are treated with venlafaxine may also experience sexual dysfunction.
      • Preskorn S.H.
      Comparison of the tolerability of bupropion, fluoxetine, imipramine, nefazodone, paroxetine, sertraline, and venlafaxine.

      Additional Nonhormonal Therapies

      Neuroactive agents from several other classes have been used for the treatment of hot flashes in menopausal women. Results from a small-scale, short-term controlled clinical trial have demonstrated that the anticonvulsant gabapentin (titrated up to 2700 mg/d) is significantly more effective than placebo in the reduction of composite scores that reflect the frequency and severity of hot flashes.
      • Guttuso Jr, T.
      • Kurlan R.
      • McDermott M.P.
      • Kieburtz K.
      Gabapentin’s effects on hot flashes in postmenopausal women: a randomized controlled trial.
      This study of 59 women indicated that gabapentin 900 mg/d decreased hot flash frequency by 45% and the composite score by 54% (P = .002 and P = .01 vs placebo, respectively). Loprinzi et al
      • Loprinzi C.L.
      • Kugler J.W.
      • Sloan J.A.
      • et al.
      Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial.
      evaluated gabapentin (titrated to 900 mg/d) in 20 women with a history of breast cancer who did not want HT. In this small study, gabapentin decreased the frequency of hot flashes from baseline by 66%.
      In a large-scale, randomized, double-blind, placebo-controlled multiinstitutional trial, Pandya et al
      • Pandya K.J.
      • Morrow G.R.
      • Roscoe J.A.
      • et al.
      Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial.
      examined the efficacy of 2 doses of gabapentin (300 mg/d and 900 mg/d) in women with breast cancer. Gabapentin treatment reduced both the frequency and severity of hot flashes compared with placebo for the higher dose only. At 900 mg/d, the frequency of hot flashes dropped by 41% and 44% at weeks 4 and 8, respectively, significantly greater than placebo (18%, P < .0001; 15%, P = .0002). After 4 weeks of treatment, severity of hot flashes had decreased by 49% for the 900-mg/d group compared with 21% for the placebo group (P =.0001). Hot flash severity was also significantly reduced after 8 weeks of treatment (P = .007), but no further decrease was seen from the week 4 measures (46% decrease from baseline for the 900-mg/d group; 15% decrease for placebo group). Slightly more subjects in the gabapentin groups than in the placebo group withdrew from the study because of side effects; the most common side effect that was cited was somnolence.
      Adverse events (which include somnolence, dizziness, rash, and peripheral edema) have resulted in the discontinuation of therapy by approximately 15% of patients who received this antiepileptic drug for the treatment of menopausal vasomotor symptoms.
      • Stearns V.
      • Loprinzi C.L.
      New therapeutic approaches for hot flashes in women.
      Clinical experience has indicated that the use of this medication in some populations can also lead to weight gain.
      Clonidine is an α-adrenoceptor antagonist that was developed for the treatment of hypertension. Results from a number of small-scale studies of menopausal women and women who were being treated with tamoxifen have demonstrated modest efficacy for this agent.
      • Clayden J.R.
      • Bell J.W.
      • Pollard P.
      Menopausal flushing: double-blind trial of a non-hormonal medication.
      • Nagamani M.
      • Kelver M.E.
      • Smith E.R.
      Treatment of menopausal hot flashes with transdermal administration of clonidine.
      • Salmi T.
      • Punnonen R.
      Clonidine in the treatment of menopausal symptoms.
      • Wren B.G.
      • Brown L.B.
      A double-blind trial with clonidine and a placebo to treat hot flushes.
      • Goldberg R.M.
      • Loprinzi C.L.
      • O’Fallon J.R.
      • et al.
      Transdermal clonidine for ameliorating tamoxifen-induced hot flashes.
      • Laufer L.R.
      • Erlik Y.
      • Meldrum D.R.
      • Judd H.L.
      Effect of clonidine on hot flashes in postmenopausal women.
      • Pandya K.J.
      • Raubertas R.F.
      • Flynn P.J.
      • 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.
      Clonidine must be used with care because it is a potent antihypertensive. Nevertheless, results from 1 controlled study indicated no adverse hemodynamic effects of a 0.1-mg/d oral clonidine dose in women who experienced tamoxifen-associated hot flashes.
      • Pandya K.J.
      • Raubertas R.F.
      • Flynn P.J.
      • 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.
      The overall tolerability of oral clonidine is relatively poor, with a 40% discontinuation rate because of adverse events among 10 women who were treated for menopausal symptoms.
      • Laufer L.R.
      • Erlik Y.
      • Meldrum D.R.
      • Judd H.L.
      Effect of clonidine on hot flashes in postmenopausal women.
      A transdermal clonidine (0.6 mg transdermal therapeutic system) preparation has better tolerability than the oral drug,
      • Fujimura A.
      • Ebihara A.
      • Ohashi K.
      • et al.
      Comparison of the pharmacokinetics, pharmacodynamics, and safety of oral (Catapres) and transdermal (M-5041T) clonidine in healthy subjects.
      but it appears to have very limited usefulness for the treatment of hot flashes because it provides only a 10% reduction from baseline in symptom severity.
      • Goldberg R.M.
      • Loprinzi C.L.
      • O’Fallon J.R.
      • et al.
      Transdermal clonidine for ameliorating tamoxifen-induced hot flashes.
      A second α-adrenoceptor antagonist, methyldopa, also has been examined in 2 small trials.
      • Nesheim B.I.
      • Saetre T.
      Reduction of menopausal hot flushes by methyldopa: a double blind crossover trial.
      • Andersen O.
      • Engebretsen T.
      • Solberg V.M.
      • Orbo A.
      Alpha-methyldopa for climacteric hot flushes: a double-blind, randomized, cross-over study.
      Both studies found that methyldopa was more effective than placebo in reducing hot flashes, but in other studies, the drug has been found to have serious potential side effects that include reduced blood pressure, positive Coombs test, hemolytic anemia, and liver disorders.
      North American Menopause Society
      Treatment of menopause-associated vasomotor symptoms: position statement of the North American Menopause Society.
      Veralipride, a benzamide derivative antidopaminergic drug, has been tested in small trials, mainly outside the United States.
      • Morgante G.
      • Farina M.
      • Cianci A.
      • et al.
      Veralipride administered in combination with raloxifene decreases hot flushes and improves bone density in early postmenopausal women.
      • Vercellini P.
      • Sacerdote P.
      • Trespidi L.
      • Manfredi B.
      • Panerai A.E.
      • Crosignani P.G.
      Veralipride for hot flushes induced by a gonadotropin-releasing hormone agonist: a controlled study.
      • Melis G.B.
      • Gambacciani M.
      • Cagnacci A.
      • Paoletti A.M.
      • Mais V.
      • Fioretti P.
      Effects of the dopamine antagonist veralipride on hot flushes and luteinizing hormone secretion in postmenopausal women.
      • David A.
      • Don R.
      • Tajchner G.
      • Weissglas L.
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      At a dose of 100 mg/d, it has been shown to reduce the frequency and severity of hot flashes in postmenopausal women and women who receive gonadotropin-releasing HT for menorrhagia or endometriosis. However, side effects of veralipride included increases in prolactin levels and galactorrhea.
      Several additional agents have been the subjects of single trials. Mirtazapine (a tetracyclic piperinoazepine analog of mianserin with activity at histaminergic, serotonin, and α2-adrenoceptors) has been shown to be effective for the treatment of hot flashes in an open-label study that enrolled 22 subjects. However, 18% of the women in this trial withdrew because of intolerable adverse events (excessive somnolence, dry mouth, headache, flu-like symptoms, and muscle ache).
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      Pilot evaluation of mirtazapine for the treatment of hot flashes.
      The monoamine oxidase inhibitor moclobemide was examined in a small (n = 28) randomized, double-blind, placebo-controlled trial.
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      Moclobemide was tested at 2 doses, 150 mg/d and 300 mg/d, in the 5-week trial. The 150-mg/d group showed the greatest decrease in hot flash severity score, with a 69.8% reduction from baseline compared with 24.4% for placebo. Propranolol, a potent beta-1 and beta-2 adrenergic antagonist, was tested in 25 perimenopausal women.
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      A 40-mg dose given 3 times daily was no more effective than placebo at controlling hot flashes.
      In its 2004 position statement, the North American Menopause Society recommended venlafaxine, paroxetine, fluoxetine, or gabapentin for women with moderate to severe vasomotor symptoms who have concerns about or contraindications for HT.
      North American Menopause Society
      Treatment of menopause-associated vasomotor symptoms: position statement of the North American Menopause Society.
      The statement described clonidine and methyldopa as having “only moderate efficacy combined with a relatively high rate of adverse events.” An evidence-based review published as part of the National Institutes of Health 2005 State-of-the-Science Conference on Management of Menopausal Symptoms made similar recommendations.
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      The review concluded that venlafaxine and paroxetine were the most effective of the newer antidepressants for the treatment of hot flashes but added a caveat that paroxetine may interfere with tamoxifen in patients with breast cancer. Citalopram may be effective for women whose condition does not respond to venlafaxine. Gabapentin was also considered effective.
      For all drugs, the reviews of both the North American Menopause Society and National Institutes of Health recommended doses at the low end of the ranges that were tested in clinical trials (Table).
      North American Menopause Society
      Treatment of menopause-associated vasomotor symptoms: position statement of the North American Menopause Society.
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      The SSRIs/SNRIs effectively reduce numbers of hot flashes at doses lower than those that are used for antidepressant therapy, and lower doses are associated with fewer and milder side effects. The North American Menopause Society specifically recommended venlafaxine at 37.5 to 75 mg/d, paroxetine at 12.5 to 25 mg/d, and fluoxetine at 20 mg/d, starting at lower doses and increasing after 1 week. SSRIs and SNRIs have been approved for long-term use in patients with mood disorders (major depressive disorder and anxiety disorders); it is well-known that relief from mood disorder symptoms may not occur until treatment has continued for 4 to 8 weeks. However, time-to-onset of efficacy and duration of treatment have not been established in patients who are treated for vasomotor symptoms. The reports of both the North American Menopause Society and National Institutes of Health recommended tapering the dose at the termination of treatment to minimize posttreatment emergent adverse events, which may be similar to treatment emergent adverse events.

      Comment

      The physiologic mechanisms underlying menopausal vasomotor symptoms are still not completely understood, but an increasing body of evidence links these symptoms to an alteration in hypothalamic thermoregulation and changes in neuromodulatory systems that are evoked by decreased levels of circulating estrogen. Understanding what is known about the probable roles of norepinephrine and serotonin in menopausal vasomotor symptoms and how their actions are influenced by nonhormonal therapies may help physicians when they discuss these treatment options with their patients.
      Although no current treatment for menopausal vasomotor symptoms is ideal, neuroactive agents that interact with both norepinephrine and serotonin systems would appear to be a rational choice for treatment, given the involvement of both of these amines in thermoregulation. These agents have some undesirable adverse effects and may have other actions that are unrelated to menopausal vasomotor symptoms. An ideal treatment should be directed at the thermoregulatory dysfunction that gives rise to these symptoms and has minimal unwanted effects in the body. It should be orally bioavailable, safe, and have low potential for interactions with other medications that are likely to be taken by middle-aged and older women.
      Many menopausal women experience troubling symptoms that can include hot flashes, night sweats, mood changes, and sleep disturbances. These symptoms are believed to be related to a dysfunction in CNS thermoregulatory circuitry. For many years, HT has been the mainstay of treatment for menopausal vasomotor symptoms, and results from clinical trials have demonstrated its efficacy repeatedly. Recent concerns about long-term safety of standard-dose HT have prompted careful reanalysis of the risks and benefits that are associated with this therapy and heightened interest in other treatments for menopausal vasomotor symptoms. Treatment of these symptoms with either SSRIs or SNRIs is supported by results from multiple well-controlled clinical trials. Less evidence supports the use of other drugs (eg, gabapentin, clonidine). An unmet need exists for safe and effective therapeutic options that directly target thermoregulatory mechanisms that underlie menopausal symptoms for women who want treatment but who prefer to avoid HT. The availability of new therapies with risks and benefits clearly defined by results from well-designed clinical trials has the potential to allay safety concerns that are associated with the current treatments for menopausal vasomotor symptoms.

      Acknowledgment

      I thank Dr Mary E. Hanson for assistance in the preparation of this manuscript.

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