What are the treatment options for hot flashes in menopausal women?

Treatment of Hot Flashes in Menopausal Women

For menopausal women with moderate to severe hot flashes, start with nonhormonal pharmacologic therapy—specifically gabapentin 900 mg at bedtime or venlafaxine 37.5-75 mg daily—reserving menopausal hormone therapy (MHT) for women who fail nonhormonal options and have no contraindications. 1

First-Line Nonhormonal Pharmacologic Treatment

The National Comprehensive Cancer Network recommends nonhormonal pharmacologic treatments as first-line therapy, with hormonal therapies considered only after weighing individual risks and benefits. 1

Gabapentin (Preferred Initial Option)

• Start with gabapentin 900 mg/day at bedtime, which reduces hot flash severity by 46% compared to 15% with placebo—efficacy equivalent to estrogen. 1
• Gabapentin has no known drug interactions and no absolute contraindications, making it safer than SSRIs/SNRIs in complex medication regimens. 1
• Side effects (somnolence, fatigue) occur in up to 20% of patients but improve after the first week and largely resolve by week 4. 2, 1
• Particularly useful for patients with concurrent sleep disturbance from hot flashes, those on multiple medications, or those taking tamoxifen. 1

Venlafaxine (Alternative First-Line)

• Start at 37.5 mg daily, increase to 75 mg after 1 week if greater symptom control is desired. 2
• Reduces hot flash scores by 37-61%, with 68% of patients preferring it over gabapentin despite similar efficacy. 1
• Choose venlafaxine when rapid onset is prioritized or if gabapentin is ineffective or not tolerated. 1
• Common side effects include dry mouth, reduced appetite, nausea, and constipation, with increased prevalence at higher doses. 2

Paroxetine

• Paroxetine 7.5-20 mg daily reduces hot flash frequency and severity by 62-65% and decreases nighttime awakenings. 1
• CRITICAL WARNING: Avoid paroxetine (and fluoxetine) in women taking tamoxifen due to CYP2D6 inhibition, which decreases plasma levels of endoxifen, an active metabolite of tamoxifen. 2, 1
• Use venlafaxine, citalopram, or gabapentin instead for women on tamoxifen. 1

Fezolinetant (Newer Option)

• Consider fezolinetant as first-line for women seeking non-hormonal therapy or with contraindications to hormone therapy. 3
• Avoids the 10-20% treatment withdrawal rate seen with SSRIs/SNRIs and doesn't require gradual discontinuation to prevent withdrawal symptoms. 3
• No drug interactions with tamoxifen through CYP2D6 inhibition, making it suitable for breast cancer survivors. 3
• Significant improvements seen by week 4. 3

Treatment Monitoring

• Review efficacy at 2-4 weeks for SSRIs/SNRIs and 4-6 weeks for gabapentin; if intolerant or ineffective, switch to another nonhormonal agent. 1

Nonpharmacologic Approaches (Adjunctive)

Effective Interventions

• Acupuncture is safe and effective, with some studies showing equivalence or superiority to venlafaxine or gabapentin. 1
• Weight loss ≥10% of body weight may eliminate hot flash symptoms; smoking cessation improves frequency and severity. 1
• Hypnosis showed a 59% decrease in daily hot flashes and significant improvement in quality of life measures including work, social activities, sleep, mood, concentration, and sexuality. 1
• Paced respiration training and structured relaxation techniques (20 minutes daily) show significant benefit. 1
• Cognitive behavioral therapy (CBT) may reduce perceived burden of hot flashes. 1

Limited Efficacy Options

• Vitamin E 800 IU daily has limited efficacy but is reasonable for patients requesting "natural" treatment; however, doses >400 IU/day are linked to increased all-cause mortality and should be avoided. 1

Menopausal Hormone Therapy (Second-Line)

When to Consider MHT

• MHT is the most effective treatment, reducing hot flashes by approximately 75% compared to placebo (80-90% reduction in symptoms). 1, 4, 5
• Use only when nonhormonal options fail, at the lowest effective dose for the shortest duration possible (not more than 3-5 years). 1, 6
• Initiation soon after menopause is safer than initiation many years after menopause, which is associated with excess coronary risk. 6

Formulation Preferences

• Transdermal estrogen formulations are preferred due to lower rates of venous thromboembolism (VTE) and stroke. 1
• Micronized progestin may be preferred over medroxyprogesterone acetate due to lower rates of VTE and breast cancer risk. 1
• Women with a uterus using estrogen must also take a progestogen to reduce the risk of endometrial cancer. 4

Absolute Contraindications to MHT

• History of hormonally mediated cancers (breast, endometrial) 1
• Abnormal vaginal bleeding 1
• Active or recent history of thromboembolic events 1
• Pregnancy 1
• Active liver disease 1

Relative Contraindications (Use with Caution)

• Coronary heart disease 1
• Hypertension 1
• Current smokers 1
• Increased genetic cancer risk 1

Critical Risk Information

• Combined estrogen/progestogen therapy increases breast cancer risk when used for more than 3-5 years and increases the risk of stroke and VTE. 1, 4

Special Populations

Breast Cancer Survivors

• Avoid estrogen and tibolone as they may increase recurrence risk. 1
• First-line options: venlafaxine, gabapentin, or fezolinetant. 1, 3
• Avoid paroxetine if on tamoxifen due to CYP2D6 inhibition. 1
• For women with advanced breast cancer or severe symptoms affecting quality of life, estrogen may be considered after fully informed discussion of risks. 1

Women on Tamoxifen

• Avoid paroxetine and fluoxetine; use venlafaxine, citalopram, or gabapentin instead. 2, 1
• Gabapentin is particularly advantageous due to no drug interactions. 1

Treatment Algorithm

1. Start with gabapentin 900 mg at bedtime if patient has sleep disturbance, is on multiple medications, or is taking tamoxifen. 1
2. Alternatively, start with venlafaxine 37.5-75 mg daily if rapid onset is prioritized or patient prefers based on tolerability profile. 1
3. Consider fezolinetant for women with inadequate response or intolerable side effects with SSRIs/SNRIs, or those on tamoxifen. 3
4. Add nonpharmacologic adjuncts (weight loss, acupuncture, CBT, hypnosis) to enhance efficacy. 1
5. Reserve MHT for women who fail nonhormonal options, have no contraindications, and are recently menopausal with good cardiovascular health. 1, 6

Common Pitfalls to Avoid

• Do not use paroxetine or fluoxetine in women on tamoxifen—this is a critical drug interaction. 2, 1
• Do not prescribe vitamin E >400 IU/day—linked to increased all-cause mortality. 1
• Do not use MHT as first-line therapy—nonhormonal options should be tried first. 1
• Do not forget to add progestogen when prescribing estrogen to women with a uterus—this prevents endometrial cancer. 4
• Recognize the robust placebo response (up to 70% in some studies) when evaluating treatment efficacy. 1