Introduction
Vasomotor symptoms are the most widely recognized menopause symptoms in Western nations, with over three-quarters of women reporting hot flashes or night sweats during or after the menopause transition. Many women struggle to choose between available treatments, given the lack of data on head-to-head comparisons of different treatments, concerns about both short-term side effects and longer-term treatment risks, and confusion about complementary or alternative remedies with unclear evidence of benefit.
Hormonal treatment
Estrogen therapy is the oldest U.S. Food and Drug Administration (FDA) approved vasomotor symptom treatment and has the most robust evidence of efficacy, given an average 75% reduction in symptom frequency relative to placebo. However, unopposed estrogen causes endometrial cancer, and patients with an intact uterus must take a progestogen to prevent this risk. Long-term use of estrogen-plus-progestogen therapy increases the risk of breast cancer as well as cardiovascular and venous thromboembolic events, particularly in older postmenopausal women,2 and even without progestogen therapy, long-term systemic estrogen increases the risk of stroke and thromboembolism in older women. While the benefits of estrogen therapy in younger women with high symptom burden outweigh the risks, this review focuses on nonhormonal treatments (Table), since many women are not candidates for or prefer to avoid hormone therapy.
Table.
Evidence-Based Nonhormonal Vasomotor Symptom Treatments
| Treatment and Dosages | Reported Efficacya | Potential Limitations |
|---|---|---|
| Selective serotonin or norepinephrine reuptake inhibitor medications | ||
| Paroxetine, oral 7.5 mg mesylate nightly (FDA-approved) or higher doses of paroxetine HCl (off-label) | ~10%-25% greater reduction in any symptom frequency versus placebo3 | AEs: drowsiness, weight gain, decreased libido; interactions with tamoxifen, hypertension |
| Citalopram, oral 10-30 mg daily (off label) | ~5-35% greater reduction in any symptom frequency versus placebo3 | AEs: drowsiness, weight gain, decreased libido, hypertension |
| Desvenlafaxine, oral 100 mg daily (off label) | ~15%-25% greater reduction in moderate-to-severe symptom frequency versus placebo5,6 | AEs: insomnia, nausea, decreased libido, hypertension |
| Escitalopram, oral 10-20 mg daily (off label) | ~20% greater reduction in any symptom frequency versus placebo 3,4 | AEs: drowsiness, weight gain, decreased libido, hypertension |
| Venlafaxine, oral 37.5-75 mg daily | ~10%-25% greater reduction in any symptom frequency versus placebo4 | AEs: insomnia, nausea, decreased libido, hypertension |
| Neurokinin 3 receptor antagonist medications | ||
| Fezolinetant, oral 45 mg daily | ~20-25% greater reduction in moderate-to-severe symptom frequency versus placebo7 | Limited long-term safety data; FDA box warning to check liver enzymes |
| Anticonvulsant medications | ||
| Gabapentin, oral 300 to 800 mg 3 times a day, or bedtime only (not tested in controlled trials) | ~10%-20% greater reduction in any symptom frequency versus placebo (dosed at 300 mg 3 times a day)10 | AEs: dose-dependent drowsiness, weight gain, and dizziness |
| Pregabalin, oral 75-150 mg twice daily | ~15%-25% greater reduction in any symptom frequency versus placebo10 | AEs: dry mouth, dizziness, constipation, drowsiness |
| Other pharmacologic treatments | ||
| Oxybutynin, oral 2.5-5.0 mg twice daily, or extended-release formulations | ~30%-50% greater reduction in any symptom frequency versus placebo (depending on dose)9 | AEs: dry mouth, constipation, and drowsiness; possible delirium or cognitive dysfunction in older adults; only a few moderate-sized trials conducted |
| Clonidine, oral 0.025 to 0.1 mg daily | ~10-20% greater reduction in any symptom frequency versus placebo | AEs: dizziness or low blood pressure |
| Behavioral therapies | ||
| Cognitive behavioral therapy, multiple forms (weekly 2-hour group sessions with psychologists, self-help booklets) | ~15%-25% greater reduction in any symptom frequency, and ~40% more patients reporting meaningful improvement, versus usual care or no treatment | Limited availability of trained therapists; limited comparison to attention controls |
| Clinical hypnosis, weekly 45-minute sessions | ~45%-55% greater reduction in any symptom frequency versus a structured attention control | Limited availability of trained therapists; studies conducted by only one research team |
Based on results of published randomized trials reporting benefit compared to placebo or other non-active interventions, not weighted by size or quality indicators
AE: Adverse effects
Nonhormonal pharmacotherapies
For patients seeking to avoid hormone therapy, the selective serotonin reuptake inhibitor (SSRI) paroxetine is an FDA-approved nonhormonal treatment option, formulated as a daily low-dose oral 7.5 mg tablet. Although trials indicate a modest 10%-25% reduction in vasomotor symptom frequency relative to placebo,3 low-dose paroxetine may also offer ancillary benefits for sleep and mood disturbances that often overlap with vasomotor symptoms. To address overlapping symptoms, higher doses of paroxetine are sometimes prescribed off-label. However, lower-dose treatment is less likely to cause side effects of paroxetine such as weight gain or decreased libido.
Other SSRI and serotonin-norepinephrine reuptake inhibitor (SNRI) medications are also used off-label for vasomotor symptoms, based on trials reporting varying magnitudes of reduction in symptom burden compared to placebo (specifically citalopram, desvenlafaxine, escitalopram, and venlafaxine).4–6 Few head-to-head trials have compared SSRIs/SNRIs to estrogen therapy, but similar reductions in hot flash frequency have been observed with 10-20 mg daily escitalopram and 75 mg daily venlafaxine compared with low-dose oral estradiol (0.5 mg daily).4 When relevant, potential weight gain, decreased libido, and short-term SSRI/SNRI side effects should be discussed with patients, along with rare side effects such as uncontrolled hypertension.
A newer nonhormonal pharmacologic option is fezolinetant, a neurokinin 3 receptor antagonist approved by the FDA in 2023, believed to modulate thermoregulatory mechanisms underlying vasomotor symptoms by targeting hypothalamic neurokinin receptor activity. Published trials report 20%-25% decreases in moderate-to-severe symptom frequency relative to placebo.7 Currently, fezolinetant has little long-term safety data, and based on a post-marketing case of serious liver injury and other cases of moderate liver enzyme elevation, a 2024 FDA boxed warning recommends liver function testing pre-treatment, monthly for the first 3 months of treatment, and again at months 6 and 9 of treatment. Although it is not yet clear whether fezolinenant offers a more favorable benefit-to-safety profile than other nonhormonal treatments, other agents aiming to achieve greater symptom relief by suppressing activity of multiple neurokinin receptors are now under investigation.7
The antimuscarinic medication oxybutynin is another off-label pharmacologic option, based on moderate-sized trials reporting 30%-50% improvement in vasomotor symptom frequency with 2.5 to 5 mg twice daily and other formulations compared to placebo.8,9 Because antimuscarinic medications can decrease overactive bladder symptoms that are also common in midlife, oxybutynin may appeal to patients experiencing both vasomotor and bladder symptoms. However, side effects including dry mouth and constipation limit its usage, and concerns about potential longer-term cognitive risks of antimuscarinic agents have led to recommendations to avoid their use in patients over age 65.
The anticonvulsant medication gabapentin is another nonhormonal, off-label pharmacologic option. Doses of 300 mg taken 3 times a day result in modest reductions in symptom frequency of 10%-20% relative to placebo.10 Higher doses of 800 mg 3 times a day may have efficacy similar to standard-dose estrogen therapy but cause substantial drowsiness and dizziness. Limiting gabapentin to bedtime may reduce night sweats and trouble sleeping while minimizing side effects, although controlled trials have not tested the efficacy of this approach.
While other nonhormonal drugs such as clonidine and pregabalin have also been found effective in reducing vasomotor symptoms, poor tolerability and availability of other options limit their usage.8,10
Behavioral and complementary therapies
Cognitive behavioral therapy has demonstrated efficacy in alleviating vasomotor symptoms,8 although studies have used a variety of comparators (usual care, waitlist, and other active controls) and outcome measures, limiting comparisons to pharmacologic treatments. Clinical hypnosis has also been reported to reduce vasomotor symptom frequency compared to no treatment.8 Although these strategies once depended on repeated, intensive sessions with specialists trained in these techniques, self-delivered versions have also been created. To date, potentially more accessible behavioral strategies such as paced respiration, mindfulness strategies, or yoga have not been found effective for vasomotor symptoms.
Many women express interest in using supplemental and herbal treatments for menopause symptoms, including cannabis, soy products, black cohosh, ammonium succinate, rhubarb, and probiotics. However, evidence of vasomotor symptom reduction with these products is poor or inconsistent. Currently, none of these can be recommended as evidence-based therapies.8
Conclusions
Vasomotor symptoms are among the most common complaints of menopausal women, and hormone therapy remains the most effective treatment strategy. Selected nonhormonal medications such as SSRIs/SNRIs, gabapentin, and oxybutynin offer modest efficacy when taken in well-tolerated doses. Pharmacotherapy should be based on patients’ symptom severity (with consideration of estrogen therapy for those with greater symptom burden), age (with older age associated with more adverse effects with estrogen and oxybutynin), and comorbidity profile (including opportunities for co-treatment of other menopause-related symptoms with estrogen, mood symptoms with SSRIs/SNRIs, bladder symptoms with oxybutynin, and sleep disturbance with gabapentin). Patients with access to behavioral treatments such as cognitive behavioral therapy should consider these strategies, given that these have minimal risks, but supplements and herbs cannot be recommended as effective treatments.
Acknowledgments
AJH was supported by National Institutes of Health grant K24AG068601 during the preparation of this manuscript.
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