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Review | Clinician's Corner

Nonhormonal Therapies for Menopausal Hot Flashes Systematic Review and Meta-analysis

Heidi D. Nelson, MD, MPH; Kimberly K. Vesco, MD; Elizabeth Haney, MD; Rongwei Fu, PhD; Anne Nedrow, MD; Jill Miller, MD; Christina Nicolaidis, MD, MPH; Miranda Walker, BA; Linda Humphrey, MD, MPH
JAMA. 2006;295(17):2057-2071. doi:10.1001/jama.295.17.2057.
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Published online

Context Concern regarding the adverse effects of estrogen and other hormones for treating menopausal symptoms has led to demand for other options; however, the efficacy and adverse effects of nonhormonal therapies are unclear.

Objective To assess the efficacy and adverse effects of nonhormonal therapies for menopausal hot flashes by reviewing published randomized controlled trials.

Data Sources MEDLINE (1966-October 2005), PsycINFO (1974-October 2005), and the Cochrane Controlled Clinical Trials Register Database (1966-October 2005) were searched for relevant trials that provided data on treatment of menopausal hot flashes using 1 or more nonhormonal therapies.

Study Selection All English-language, published, randomized, double-blind, placebo-controlled trials of oral nonhormonal therapies for treating hot flashes in menopausal women measuring and reporting hot flash frequency or severity outcomes.

Data Extraction Trials were identified, subjected to inclusion and exclusion criteria, and reviewed. Data on participants, interventions, and outcomes were extracted and trials were rated for quality based on established criteria. A meta-analysis was conducted for therapies with sufficient trials reporting hot flash frequency outcomes.

Data Synthesis From 4249 abstracts, 43 trials met inclusion criteria, including 10 trials of antidepressants, 10 trials of clonidine, 6 trials of other prescribed medications, and 17 trials of isoflavone extracts. The number of daily hot flashes decreased compared with placebo in meta-analyses of 7 comparisons of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) (mean difference, −1.13; 95% confidence interval [CI], −1.70 to −0.57), 4 trials of clonidine (−0.95; 95% CI, −1.44 to −0.47), and 2 trials of gabapentin (−2.05; 95% CI, −2.80 to −1.30). Frequency was not reduced in meta-analysis of trials of red clover isoflavone extracts and results were mixed for soy isoflavone extracts. Evidence of the efficacy of other therapies is limited due to the small number of trials and their deficiencies. Trials do not compare different therapies head-to-head and relative efficacy cannot be determined.

Conclusion The SSRIs or SNRIs, clonidine, and gabapentin trials provide evidence for efficacy; however, effects are less than for estrogen, few trials have been published and most have methodological deficiencies, generalizability is limited, and adverse effects and cost may restrict use for many women. These therapies may be most useful for highly symptomatic women who cannot take estrogen but are not optimal choices for most women.

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Figure 1. Search and Selection of Trials
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RCTs indicates randomized controlled trials; SSRIs, selective serotonin reuptake inhibitors; SNRIs, serotonin norepinephrine reuptake inhibitors. Articles identified from database searches were subjected to inclusion and exclusion criteria for the systematic review and meta-analysis.
*Some trials had more than 1 reason for exclusion.

Figure 2. Trials of Selective Serotonin Reuptake Inhibitors (SSRIs) or Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)
Graphic Jump Location

CI indicates confidence interval; SERM, selective estrogen receptor modulator. Six trials of 4 SSRIs or SNRIs provided data for meta-analysis.22,23,2932
*Controlled release forms of paroxetine and extended release forms of venlafaxine.
†Data for 150-mg/d dose were not included because this dose was substantially higher than the other dosages.
‡Data for 20-mg/d dose at 3 months of follow-up were included to improve consistency with the other trials.
§Includes references 29-32.
∥Includes references 22 and 23.

Figure 3. Trials of Clonidine
Graphic Jump Location

CI indicates confidence interval; SERM, selective estrogen receptor modulator. Four trials of clonidine provided data for meta-analysis: 3 trials used 0.1-mg/d dose41,45,46 and 1 trial used a range of doses (0.05-0.15 mg/d).38
*Includes references 45 and 46.
†Includes references 38 and 41.

Figure 4. Trials of Red Clover Isoflavone Extracts
Graphic Jump Location

CI indicates confidence interval. Six trials of 2 types of red clover isoflavones provided data for meta-analysis.5358

Figure 5. Trials of Soy Isoflavone Extracts
Graphic Jump Location

CI indicates confidence interval. Six trials of soy isoflavone extracts provided data for meta-analysis.59,61,6568
*Participants have breast cancer, with 78% taking tamoxifen.

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