What are the treatment options for hot flashes, particularly in the context of menopause, including hormone replacement therapy (HRT) and non-hormonal medications like selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs)?

Medication for Hot Flashes

First-Line Treatment Recommendation

For menopausal hot flashes, start with nonhormonal pharmacologic therapy: gabapentin 900 mg/day at bedtime is the preferred first-line agent, particularly if sleep disturbance is present, followed by venlafaxine 37.5-75 mg daily if rapid onset is prioritized or gabapentin fails. 1

Nonhormonal Pharmacologic Options (First-Line)

Gabapentin

• Reduces hot flash severity by 46% compared to 15% with placebo 1
• Optimal dosing: 900 mg/day, typically taken at bedtime 2, 1
• Particularly advantageous because it has no known drug interactions and no absolute contraindications, making it safer than SSRIs/SNRIs in complex medication regimens 1
• Side effects (somnolence, dizziness, fatigue) affect up to 20% of patients but improve after the first week and largely resolve by week 4 1
• Especially useful for patients with concurrent sleep disturbance from hot flashes 2, 1

SNRIs (Venlafaxine and Desvenlafaxine)

• Venlafaxine reduces hot flash scores by 37% at 37.5 mg/day and 61% at 75 mg/day (compared to 27% placebo reduction) 2
• Start at 37.5 mg daily, increase to 75 mg after 1 week if needed 1, 3
• Preferred by 68% of patients over gabapentin despite similar efficacy, often due to tolerability profile 1
• Side effects include dry mouth, decreased appetite, nausea, and constipation (dose-related) 2
• Use caution in hypertension as SNRIs can increase blood pressure 4
• Desvenlafaxine is an effective alternative SNRI 2, 3

SSRIs

• Paroxetine (controlled release) 12.5 mg daily reduces hot flash composite score by 62-65% and decreases frequency, severity, and nighttime awakenings 2, 1
• CRITICAL WARNING: Avoid paroxetine and fluoxetine in women taking tamoxifen due to CYP2D6 inhibition, which interferes with tamoxifen metabolism 1, 4, 5
• Alternative SSRIs: escitalopram, citalopram (though long-term efficacy not demonstrated for citalopram) 2, 3
• Fluoxetine decreased hot flash composite score by 50% versus 36% for placebo, but with marked variability (27% had worse hot flashes) 2
• Side effects: headache, nausea, gastrointestinal disturbance, dry mouth, anxiety, sleep disturbance, sexual dysfunction—typically mild and short-lived 2
• 10-20% of patients discontinue due to adverse events 2
• Must taper gradually when discontinuing to prevent withdrawal symptoms, particularly with short-acting agents like paroxetine and venlafaxine 2

Clonidine (Alpha-Agonist)

• Can reduce hot flash frequency and severity 1
• May have slower effect than venlafaxine but is often better tolerated 1

Treatment Algorithm

Step 1: Start with gabapentin 900 mg/day 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

Step 2: Use 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

Step 3: Consider SSRIs (escitalopram, citalopram, or paroxetine if NOT on tamoxifen) if SNRIs and gabapentin fail 1

Step 4: 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

Hormonal Therapy (Second-Line)

When to Consider

• Menopausal hormone therapy (MHT) is the most effective treatment, reducing hot flashes by approximately 75% compared to placebo and by 80-90% overall 2, 1, 6
• Should only be used when nonhormonal options fail 1
• Use at the lowest effective dose for the shortest duration possible 2, 7
• Transdermal estrogen formulations are preferred due to lower rates of venous thromboembolism and stroke 1

Absolute Contraindications to MHT

• History of hormone-related cancers (breast, endometrial) 2, 1
• Abnormal vaginal bleeding 2, 1
• Active or recent thromboembolic events 2, 1
• Active liver disease 2, 1
• Pregnancy 2, 1

Important Risks

• Combined estrogen/progestogen therapy increases breast cancer risk when used for more than 3-5 years 2, 7
• Increases risk of stroke and venous thromboembolism 2, 7
• In Women's Health Initiative: estrogen plus progestin increased invasive breast cancer, stroke, pulmonary embolism; decreased colorectal cancer and hip fracture 2
• Women with a uterus must take progestogen with estrogen to reduce endometrial cancer risk 7
• Micronized progestin may be preferred over medroxyprogesterone acetate due to lower rates of VTE and breast cancer risk 1

Nonpharmacologic Approaches (Adjunctive)

Evidence-Based Options

• Cognitive behavioral therapy (CBT) significantly reduces the perceived burden of hot flashes 2, 1
• Acupuncture is safe and effective, with some studies showing equivalence or superiority to venlafaxine or gabapentin 1
• Avoid acupuncture in breast cancer survivors with prior axillary surgery on the affected arm 1
• Paced respiration training and structured relaxation techniques (20 minutes daily) show significant benefit 1
• Hypnosis showed a 59% decrease in daily hot flashes and significant improvement in quality of life 1

Lifestyle Modifications

• Weight loss of ≥10% of body weight may eliminate hot flash symptoms 2, 1
• Smoking cessation improves frequency and severity of hot flashes 2, 1
• Limit alcohol intake if it triggers hot flashes 2
• Yoga may improve quality of life but effects on hot flash frequency are inconsistent 1

Special Populations

Breast Cancer Survivors

• Avoid estrogen and tibolone as they may increase recurrence risk 1
• First-line options: venlafaxine, gabapentin, or citalopram 1
• Avoid paroxetine if taking tamoxifen 1
• For advanced breast cancer or severe symptoms affecting quality of life, estrogen may be considered after fully informed discussion, with decision resting with patient 1

Limited Efficacy Options

• Vitamin E 800 IU daily has limited efficacy but is reasonable for patients requesting "natural" treatment 1, 6
• However, doses >400 IU/day are linked to increased all-cause mortality and should be avoided 1

Common Pitfalls

• Recognize the robust placebo response (up to 70% in some studies) when evaluating treatment efficacy 1
• Do not use sertraline as first-line—mixed results and substantial variability in response 2
• Mirtazapine has encouraging pilot data but tolerance is limited by somnolence and weight gain 2
• SSRIs/SNRIs are contraindicated in women taking monoamine oxidase inhibitors 1
• Avoid SSRIs/SNRIs in bipolar disorder due to risk of inducing mania 1
• Physical activity does not specifically improve hot flash symptoms, though it should still be recommended for overall health benefits 2