For women who cannot or choose not to use hormone replacement therapy, managing hot flashes has historically meant limited options. That changed in May 2023 when the FDA approved fezolinetant (Veozah), the first drug of a new mechanistic class to target vasomotor symptoms directly without hormones.

This article covers the main non-hormonal prescription options, what each does, what the clinical trial evidence shows, and what to weigh when discussing them with your doctor.

Who Needs Non-Hormonal Treatment

The women most likely to need non-hormonal treatment fall into a few groups: those with a personal history of hormone-receptor-positive breast cancer (for whom systemic estrogen is generally contraindicated), those taking tamoxifen or aromatase inhibitors for breast cancer treatment, those with a history of blood clots, and those who prefer not to use hormonal therapy.

Hot flashes in women undergoing breast cancer treatment are often severe, partly because tamoxifen and aromatase inhibitors directly reduce estrogen activity. This population has driven much of the clinical trial evidence for non-hormonal options.

Fezolinetant (Veozah): A New Mechanism

Fezolinetant works on a different pathway than any previous hot flash treatment. The mechanism centres on KNDy neurons in the hypothalamus, the temperature-regulating region of the brain.

During the menopausal transition, declining estrogen increases neurokinin B (NKB) signalling at KNDy neurons. This hyperactivation destabilises the thermoregulatory set point, directly driving vasomotor symptoms. Fezolinetant is a selective neurokinin-3 receptor antagonist: it blocks NKB from binding to its receptor on KNDy neurons, dampening the neuronal overactivation and reducing hot flash frequency.[1]

SKYLIGHT trial results: In the pivotal phase 3 trials, fezolinetant 30 mg reduced VMS frequency from 10.7 events per 24 hours at baseline to 4.5 events at week 12, a 56% mean reduction. The 45 mg dose reduced frequency from 10.4 to 4.1 events per 24 hours, a 61% reduction. These improvements were sustained through 52 weeks.[2]

The liver injury warning. The FDA has added a boxed warning for a rare risk of serious liver injury. Liver function tests are required before starting treatment, after three months, and after six months. The drug should be stopped if signs of liver injury appear: jaundice, dark urine, unusual fatigue, right upper abdominal pain. Women with pre-existing liver disease should not use it. Discuss this with a prescriber before starting.[3]

Fezolinetant is approved for moderate to severe vasomotor symptoms and represents a significant advance for women who need a non-hormonal option, particularly those in cancer treatment. The liver monitoring requirement is a real constraint on access.

Paroxetine (Brisdelle): FDA-Approved Since 2013

Low-dose paroxetine CR (7.5 mg), marketed as Brisdelle, was the first non-hormonal drug specifically approved by the FDA for hot flashes. It is an SSRI at a dose lower than that used for depression.

The mechanism is not fully understood, but SSRIs appear to reduce central noradrenergic activity that contributes to thermoregulatory instability. In clinical trials, paroxetine at this dose reduced hot flash frequency by roughly 37–47% versus 13–24% for placebo.[4]

For breast cancer patients: Paroxetine is a strong CYP2D6 inhibitor and reduces the effectiveness of tamoxifen by blocking its conversion to the active metabolite endoxifen. It should not be used alongside tamoxifen, which rules it out for a significant portion of the women who most need non-hormonal options.

Other SSRIs and SNRIs

Several antidepressants have evidence for reducing hot flash frequency, even though they are not approved for this indication.

Venlafaxine and desvenlafaxine (SNRIs) have the strongest antidepressant-class evidence for vasomotor symptoms. Venlafaxine at 75 mg/day reduces hot flash frequency by around 37–60% in trials.[5] Desvenlafaxine at 100–150 mg/day shows similar results. Both are useful for women who also have mood symptoms, since they address both.

Escitalopram has trial evidence for hot flash reduction at 10–20 mg/day, with fewer drug interactions than paroxetine and better tolerability for many women.

Neither venlafaxine nor escitalopram inhibits tamoxifen metabolism to any clinically relevant degree, making them preferable to paroxetine for women on tamoxifen.

The effect size for SSRIs and SNRIs is smaller than for estrogen. They work, but they are second-tier to hormonal treatment for women without contraindications.

Gabapentin

Gabapentin is an anticonvulsant that reduces hot flash frequency and severity through unclear mechanisms, possibly by stabilising the central autonomic response to temperature changes.

A systematic review and meta-analysis found that gabapentin reduced hot flash frequency and composite scores by 45–71% from baseline across included trials.[6] The effective dose for vasomotor symptoms is typically 900 mg/day, split as 300 mg three times daily or 600 mg taken at night.

Side effects are a real constraint: somnolence, dizziness, and unsteadiness are common, particularly in the first one to two weeks. These generally improve by week four, but the adjustment period deters many women. Nocturnal dosing (a higher dose at bedtime) exploits the sedating effect while concentrating symptom relief during the most disruptive hours.

Gabapentin is most useful when the main problem is night sweats disrupting sleep.

Choosing Between Options

Women with hormone-receptor-positive breast cancer or on aromatase inhibitors: Fezolinetant has the most targeted evidence and mechanism. Venlafaxine or desvenlafaxine are alternatives. Avoid paroxetine and fluoxetine due to tamoxifen interactions.

Women with significant co-occurring mood symptoms: SNRIs address both. Starting an SNRI first is pragmatic when mood is as prominent as vasomotor symptoms.

Women whose main problem is night sweats disrupting sleep: Gabapentin at night, or fezolinetant if liver monitoring is feasible.

Women who prefer not to use hormones but have no specific contraindication: All options above are available. HRT remains more effective than any of these for moderate to severe vasomotor symptoms, but that comparison is irrelevant if HRT is off the table.

None of these options addresses bone density, genitourinary changes, or cardiovascular risk, which systemic HRT can. They are vasomotor symptom treatments, not broader menopausal treatments.

References

[1] Kerber, C., Pinkerton, J. V. (2023). FDA approves Veozah (fezolinetant) for menopausal symptoms: a new nonhormonal option. Journal of the Academy of Consultation-Liaison Psychiatry. https://pmc.ncbi.nlm.nih.gov/articles/PMC12401328/

[2] Fraser, G. L., Bhartiya, D., Gompel, A., et al. (2023). Efficacy and safety of fezolinetant in moderate to severe vasomotor symptoms associated with menopause: a phase 3 RCT. Journal of Clinical Endocrinology & Metabolism. https://pmc.ncbi.nlm.nih.gov/articles/PMC10348473/

[3] FDA Drug Safety Communication. FDA adds warning about rare occurrence of serious liver injury with use of Veozah (fezolinetant) for hot flashes due to menopause. https://www.fda.gov/safety/medical-product-safety-information/fda-adds-warning-about-rare-occurrence-serious-liver-injury-use-veozah-fezolinetant-hot-flashes-due

[4] Simon, J. A., Portman, D. J., Kaunitz, A. M., et al. (2013). Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: two randomized controlled trials. Menopause, 20(10), 1027-1035. https://doi.org/10.1097/GME.0b013e3182a66aa7

[5] Loprinzi, C. L., Sloan, J., Stearns, V., et al. (2009). Newer antidepressants and gabapentin for hot flashes: an individual patient pooled analysis. Journal of Clinical Oncology, 27(17), 2831-2837. https://doi.org/10.1200/JCO.2008.19.6253

[6] Guttuso, T., Kurlan, R., McDermott, M. P., Kieburtz, K. (2003). Gabapentin's effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstetrics and Gynecology, 101(2), 337-345. See also systematic review and meta-analysis: https://www.ncbi.nlm.nih.gov/books/NBK76754/