Nonhormone treatments for vasomotor symptoms

WHY IS IT IMPORTANT TO ALLEVIATE VASOMOTOR SYMPTOMS? Vasomotor symptoms (VMS) are sudden, transitory rushes of intense heat like a blowtorch inside. They can begin before, during, or after perimenopause. According to the Study of Women's Health Across the Nation, a multiethnic, multiracial prospective longitudinal study of women transitioning through menopause, VMS can persist for 10 years on average.1 When left untreated, VMS can be frequent, severe, disruptive to quality of life,2 and associated with poorer cardiovascular health,3 lost work productivity,4 and higher healthcare utilization and costs.4 WHAT NONHORMONE PRESCRIPTION MEDICATIONS ARE APPROVED BY NATIONAL AGENCIES FOR TREATING VASOMOTOR SYMPTOMS? The US FDA approved two nonhormone prescription medications for the treatment of VMS: the selective serotonin reuptake inhibitor (SSRI) paroxetine salt 7.5 mg daily and the neurokinin 3 receptor antagonist fezolinetant 45 mg daily.5 In Canada and Mexico, paroxetine is available for off-label management of VMS, but fezolinetant is not yet available. Multiple published randomized, placebo-controlled trials of these medications show their efficacy in reducing VMS compared with placebo, although placebo effects can be substantial (20%-50% reduction in some studies). Paroxetine salt has the added benefit of improving sleep without negatively affecting weight or libido. Fezolinetant, developed to directly target the underlying neurophysiology of VMS, also improves sleep.5,6 Fezolinetant adverse events (AEs) include elevation of liver transaminases; thus, baseline testing and repeat evaluation are recommended every 3 months during the first year of therapy. For a medication to be approved by the FDA to treat hot flashes a placebo arm should be included during the research design. WHAT OTHER NONHORMONE MEDICATIONS HAVE STRONG EVIDENCE FOR USE IN TREATING VASOMOTOR SYMPTOMS? Multiple rigorous, controlled clinical trials show the superiority of medications over placebo for treating VMS: SSRIs (paroxetine 10-25 mg daily, escitalopram 10-20 mg daily, citalopram 10-20 mg daily), selective serotonin-norepinephrine reuptake inhibitors (SSNRIs; venlafaxine 37.5-150 mg daily, desvenlafaxine 100-150 mg daily), gabapentin 900 to 2,400 mg daily, and oxybutynin 2.5 to 15 mg daily. Adverse events vary, and clinicians should take into consideration a patient's overall health status and use of other medications when engaging in shared decision-making. FOR WOMEN WHO DO NOT WANT TO TAKE A DAILY MEDICATION FOR VASOMOTOR SYMPTOMS, WHAT OTHER TREATMENT OPTIONS HAVE STRONG EVIDENCE? Cognitive-behavioral therapy (CBT) and clinical hypnosis show benefit over placebo in reducing VMS.5 Multiple controlled studies have shown CBT provided in a group setting, individually in person, or via the internet reduces VMS. One study also showed that CBT reduced depressed mood in women with VMS. Trials have shown clinical hypnosis performed in person with a therapist or using a self-guided program reduces VMS. There are no AEs associated with either treatment. ARE THERE ANY OTHER EVIDENCE-BASED THERAPIES FOR TREATING VASOMOTOR SYMPTOMS? Based on the review of evidence in the 2023 nonhormone therapy position statement of The North American Menopause Society (now The Menopause Society), two other therapies were recommended.5 These include weight loss and stellate ganglion block. Weight loss through behavioral interventions (as little as 5 kg or a 1-point change in body mass index) or medication (selective serotonin 2C receptor agonist) has been shown to improve VMS in a small number of studies. Stellate ganglion block has been shown in small studies to reduce VMS. This procedure, typically performed by an anesthesiologist, involves injection of an anesthetic into the anterior neck targeting the sympathetic chain at C6 or C7 to block the flushing and sensation of heat associated with VMS. Beneficial effects have been found to last 6 weeks to several months. Because of its invasive nature and potential risks, shared decision-making with patients is essential. Both weight loss and stellate ganglion block are recommended nonhormone therapies for VMS, although the position statement also acknowledged that additional research on these treatments is needed. IS THERE A ROLE FOR COMBINATION THERAPY USING THESE APPROACHES? Using a combination of approaches seems reasonable, yet evidence is limited. Some evidence suggests additive benefits from combination therapy should not be assumed. In one randomized, controlled, factorial trial, women received venlafaxine with clinical hypnosis, venlafaxine with sham (placebo) hypnosis, placebo pill with clinical hypnosis, or placebo pill with sham hypnosis.7 Venlafaxine and clinical hypnosis equally reduced VMS; however, their combination did not yield a greater reduction in VMS. If combination therapy is being considered, before starting a second therapy, clinicians should consider: other concurrent menopause symptoms and medical issues, allowing enough time for benefits of the first treatment to occur (eg, 1-2 weeks for SSRIs or SSNRIs), avoiding possible drug-drug interactions, and counseling women to avoid over-the-counter treatments that do not have placebo-controlled trial evidence of efficacy.5 WHAT IS IMPORTANT TO CONSIDER WHEN COUNSELING WOMEN ABOUT NONHORMONE VASOMOTOR SYMPTOMS TREATMENT OPTIONS? Clinicians should consider and prepare women that informed choices about VMS treatment options are made in a complex, iterative process, which is influenced by several factors. Decisions about VMS treatment are not single-event, once-and-done decisions. Rather, women repetitively evaluate whether to initiate, continue, or discontinue treatment over time in relation to their VMS experience. The process can include trial and error because not all evidence-based treatments will work for all women. Women often try one treatment after another before deciding on one that works to alleviate VMS, has tolerable AEs, and may have secondary benefits for other symptoms, such as sleep or mood disturbance. As symptoms change throughout the menopause transition, ongoing reevaluation of treatment choice is recommended. In this way, women continually decide whether to do nothing, do something, and which something(s) to use to treat VMS. Factors affecting women's decisions about treating VMS include their individual characteristics (eg, demographics, menopause experience, symptom experience, concurrent medical concerns) and values (eg, attitudes, beliefs, and preferences about VMS and VMS treatment options, importance of quality of life, and tolerance for risks and AEs).8 Women also make decisions based on facts and information (eg, amount, type, source, credibility, and availability) and clinician context (eg, trust, communication, availability/time, knowledge, and relationship).8 Thus, shared decision-making between prescribers and patients should also be complex and iterative, with multiple discussions over time that take into account changes in symptoms, concurrent medical concerns, values, and other factors affecting decision-making. KEY SUMMARY POINTS On average, vasomotor symptoms can negatively affect women's lives for a decade or longer. Several nonhormone vasomotor symptom treatments are available to help reduce their frequency, severity, and impact. Paroxetine and fezolinetant are the only two nonhormone medications approved by the US FDA to reduce vasomotor symptoms. Other prescription medications shown to reduce vasomotor symptoms include selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, gabapentin, and oxybutynin. Additional therapies that reduce vasomotor symptoms are cognitive-behavior therapy, clinical hypnosis, weight loss, and stellate ganglion block. CLINICAL RECOMMENDATIONS Recognize that vasomotor symptoms can have a major impact on midlife women's lives and health. Counsel patients who seek nonhormone relief of vasomotor symptoms about all evidence-based and recommended treatment options. Educate patients that use of two or more therapies concurrently may not have any added benefits. Iteratively engage in shared decision-making with patients to determine the best nonhormone vasomotor symptoms treatment option for each patient, monitor response, and adjust recommendations accordingly. Coming next in the Step-by-Step series: Steven Goldstein, MD, professor, Department of Obstetrics and Gynecology at NYU Grossman School of Medicine, discusses the common clinical conundrum of what action (if any) must be taken (and when) for spotting, staining, or bleeding for perimenopausal and postmenopausal women.This article is part of the ongoing series Menopause Step-by-Step, a monthly Menopause education feature.9 The Editors of this series are Dr. Cynthia Stuenkel, Dr. Cheryl Cox Kinney, and Dr. Isaac Schiff.

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