What is the best non‑hormonal treatment for menopausal vasomotor symptoms?

Best Non-Hormonal Treatment for Menopausal Vasomotor Symptoms

For moderate to severe menopausal hot flashes, start with gabapentin 900 mg daily at bedtime or venlafaxine 37.5-75 mg daily, as these are the most effective non-hormonal pharmacologic options with the strongest evidence base. 1, 2

First-Line Pharmacologic Options

Gabapentin (Preferred for Most Patients)

• Gabapentin 900 mg/day reduces hot flash severity by 46% compared to 15% with placebo, with efficacy equivalent to estrogen. 1
• Take at bedtime, particularly beneficial when sleep is disturbed by night sweats. 3, 1
• No drug interactions and no absolute contraindications, making it safer than SSRIs/SNRIs in complex medication regimens. 1
• Side effects occur in up to 20% of patients but improve after the first week and largely resolve by week 4. 1
• Optimal choice for women taking tamoxifen since it has no CYP2D6 interactions. 1, 2

Venlafaxine (Preferred When Rapid Onset Needed)

• Start at 37.5 mg daily, increase to 75 mg after 1 week if needed. 1, 2
• Reduces hot flash scores by 37-61% depending on dose. 1
• 68% of patients prefer venlafaxine over gabapentin despite similar efficacy, likely due to tolerability profile. 1, 2
• Common side effects include dry mouth, nausea, constipation, headache, and sexual dysfunction (10-20% discontinuation rate). 2
• Must taper gradually on discontinuation to minimize withdrawal symptoms. 1

Paroxetine (FDA-Approved but Use with Caution)

• Paroxetine 7.5 mg daily is the only FDA-approved non-hormonal treatment for moderate to severe vasomotor symptoms. 4, 5
• Reduces hot flash frequency, severity, and nighttime awakenings by 62-65%. 3, 1
• CRITICAL WARNING: Avoid paroxetine in women taking tamoxifen due to CYP2D6 inhibition, which reduces tamoxifen conversion to active metabolites. 1, 2
• Use venlafaxine, citalopram, or gabapentin instead for women on tamoxifen. 1

Treatment Algorithm

Start with gabapentin 900 mg at bedtime if:

• Patient has concurrent sleep disturbance from hot flashes 1
• Patient is on multiple medications (no drug interactions) 1
• Patient is taking tamoxifen 1, 2

Start with venlafaxine 37.5-75 mg daily if:

• Rapid onset is prioritized 1
• Patient prefers it based on tolerability profile 1
• Gabapentin is ineffective or not tolerated 1

Review efficacy at 2-4 weeks for SSRIs/SNRIs and 4-6 weeks for gabapentin; if intolerant or ineffective, switch to another non-hormonal agent. 3

Alternative Pharmacologic Options

Clonidine

• Reduces hot flash frequency and severity in postmenopausal women, including those on tamoxifen. 1, 2
• May have slower effect than venlafaxine but is often better tolerated. 1
• Side effects include sleep difficulties, dry mouth, fatigue, dizziness, and nausea (40% discontinuation rate). 2

Fezolinetant (Newest Option)

• Recommended as first-line for women with hormone therapy contraindications (history of breast cancer, VTE, stroke, or coronary heart disease). 1
• Shows significant reduction in vasomotor symptom frequency compared to other non-hormonal therapies. 6
• More expensive; affordability and access may be limiting factors. 6

Non-Pharmacologic Approaches (Adjunctive)

Strongly Recommended

• Cognitive-behavioral therapy (CBT) reduces perceived burden of hot flashes even if frequency remains unchanged. 1, 5
• Clinical hypnosis showed 59% decrease in daily hot flashes and significant improvement in quality of life measures including work, social activities, sleep, mood, and sexuality. 1
• Weight loss ≥10% of body weight may eliminate hot flash symptoms entirely. 1, 5
• Smoking cessation improves frequency and severity of hot flashes. 1

Moderately Recommended

• Acupuncture is safe and effective, with some studies showing equivalence or superiority to venlafaxine or gabapentin. 1, 2
• Paced respiration training (structured breathing exercises for 20 minutes daily) shows significant benefit. 1
• Structured relaxation techniques for 20 minutes daily show significant beneficial effect. 1

Environmental Modifications

• Dress in layers, maintain cool room temperatures, wear natural fibers. 1, 2
• Use cold packs intermittently and avoid identified triggers (spicy food, caffeine, alcohol, hairdryers). 1, 2
• Keep a hot flash diary to identify personal triggers. 1

Special Population: Breast Cancer Survivors

Treatment hierarchy for breast cancer survivors: 1, 2

1. Lifestyle modifications (weight loss, smoking cessation, environmental adjustments)
2. Gabapentin 900 mg at bedtime (first-line pharmacologic)
3. Venlafaxine 37.5-75 mg daily (alternative first-line)
4. Acupuncture or CBT (adjunctive)

Avoid estrogen and tibolone in breast cancer survivors due to potential increased recurrence risk. 1, 2

What NOT to Use

Not Recommended (Insufficient Evidence)

• Vitamin E 800 IU daily has limited efficacy, and doses >400 IU/day are linked to increased all-cause mortality. 1
• Black cohosh shows no benefit in randomized trials with breast cancer survivors and has reports of liver failure. 1
• Multibotanicals with soy worsened symptoms in randomized trials. 1
• Phytoestrogens, dietary supplements, and herbal remedies have mixed or limited evidence. 2, 5
• Paced respiration alone (without structured training) is not recommended. 5

Critical Drug Interactions and Contraindications

SSRIs/SNRIs are contraindicated in:

• Women taking monoamine oxidase inhibitors (risk of serotonin syndrome) 1
• Bipolar disorder (risk of inducing mania) 1

Do not screen patients for CYP2D6 despite theoretical concerns about SSRI-tamoxifen interactions, as negative impact on breast cancer outcomes has not been conclusively demonstrated. 1

Common Pitfalls to Avoid

• Do not abruptly discontinue SSRIs/SNRIs; always taper gradually to minimize withdrawal symptoms. 1
• Do not prescribe paroxetine or fluoxetine to women on tamoxifen; use venlafaxine, citalopram, or gabapentin instead. 1, 2
• Recognize the robust placebo response (up to 70% in some studies) when evaluating treatment efficacy. 3, 1
• Many hot flashes improve spontaneously over time with ongoing treatment. 1
• Hot flashes are more severe in overweight women, making weight reduction particularly impactful. 1