What is the first-line treatment for hot flashes?

First-Line Treatment for Hot Flashes

For moderate to severe hot flashes, nonhormonal pharmacologic therapy with SSRIs/SNRIs or gabapentin is the first-line treatment, with gabapentin being particularly advantageous due to its lack of drug interactions and equivalent efficacy to estrogen. 1, 2, 3

Primary Nonhormonal Options

Gabapentin (Preferred First-Line)

• Gabapentin 900 mg/day reduces hot flash severity by 46% compared to 15% with placebo and is the only nonhormonal treatment demonstrating equivalent efficacy to estrogen. 1, 3
• Dose at bedtime to leverage somnolence as a therapeutic benefit for patients with sleep disturbance from hot flashes. 1
• No known drug interactions and no absolute contraindications, making it safer than SSRIs/SNRIs in complex medication regimens. 1
• Side effects (dizziness, unsteadiness, drowsiness) affect up to 20% but markedly improve after the first week and largely resolve by week 4. 1
• Discontinuation rates due to side effects are lower (10%) compared to SSRIs/SNRIs (10-20%). 1

SSRIs/SNRIs (Alternative First-Line)

• Venlafaxine 37.5 mg daily, increasing to 75 mg after 1 week, reduces hot flash scores by 37-61% and is preferred by 68% of patients over gabapentin despite similar efficacy. 1, 2
• Paroxetine 7.5-20 mg daily reduces hot flash frequency, severity, and nighttime awakenings by 62-65%. 1, 3
• Lower doses than those used for depression are required, with faster response times (typically within 1 week). 1, 2
• Review efficacy at 2-4 weeks; if ineffective, switch to another nonhormonal agent. 3

Critical Drug Interaction Warning

In women taking tamoxifen, avoid paroxetine and fluoxetine due to CYP2D6 inhibition that blocks conversion of tamoxifen to active metabolites; use venlafaxine, citalopram, or gabapentin instead. 1, 2, 3

• Conflicting evidence exists: one database of 17,000 breast cancer survivors found no increased recurrence with concurrent paroxetine and tamoxifen 1, while another study of 2,430 survivors found increased cancer death risk. 1
• The NCCN panel recommends alternative therapy when available given this uncertainty. 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, 2
• Patient has concerns about sexual dysfunction (SSRIs/SNRIs cause this, gabapentin does not) 1

Step 2: Use venlafaxine 37.5-75 mg daily if:

• Rapid onset is prioritized (faster effect than clonidine) 1
• Patient prefers this based on tolerability profile 1
• Gabapentin is ineffective or not tolerated 1

Step 3: Consider paroxetine 10-20 mg daily if:

• Patient is NOT on tamoxifen 1, 2
• Venlafaxine is ineffective or not tolerated 1

Step 4: Clonidine 0.1 mg/day (oral or transdermal) for mild-moderate symptoms if:

• Other agents are contraindicated or not tolerated 1
• Reduces hot flashes by up to 46% but has higher discontinuation rates (40%) due to side effects (dry mouth, insomnia/drowsiness) 1

Important Contraindications and Cautions

SSRIs/SNRIs are contraindicated in women taking monoamine oxidase inhibitors and should be avoided in bipolar disorder due to risk of inducing mania. 1

• Gradual taper required on discontinuation to minimize withdrawal symptoms, especially with short-acting agents (venlafaxine, paroxetine). 1
• Common side effects include dry mouth, decreased appetite, fatigue, nausea, constipation, and sexual dysfunction. 1, 2

When Hormonal Therapy Should Be Considered

Menopausal hormone therapy (MHT) reduces hot flashes by approximately 75% and is the most effective treatment, but should only be used after nonhormonal options fail, at the lowest effective dose for the shortest duration (not more than 3-5 years). 3, 4, 5

• Absolute contraindications to MHT: history of hormone-related cancers, abnormal vaginal bleeding, active/recent thromboembolic events, pregnancy, active liver disease. 1, 3
• Combined estrogen/progestogen therapy increases breast cancer risk when used >3-5 years and increases stroke and venous thromboembolism risk. 3, 5

Nonpharmacologic Adjuncts

• Acupuncture is safe and effective, with some studies showing equivalence or superiority to venlafaxine or gabapentin. 1, 3
• Weight loss ≥10% of body weight may eliminate hot flash symptoms. 1, 3
• Smoking cessation and limiting alcohol intake may reduce symptoms. 3
• Cognitive behavioral therapy and yoga may improve quality of life but have limited direct effect on hot flash frequency. 1, 3