Non-Hormonal and Alternative Treatments for Vasomotor Symptoms in Menopause
Hot flashes can influence the daily lives of women going through menopause, with 50-82% experiencing them at some point.1 Of these women, 87% experience hot flashes on a daily basis, and 33% experience >10 hot flashes per day.1 These symptoms can often interfere with daily life, disturb sleep, and may last for years.1 Vasomotor symptoms (VMS) often begin 1-2 years before the final menstrual period and can last up to 12 years after it.2
The most efficacious treatment for VMS is hormone replacement therapy (HRT) using either estrogen alone or a combination pill of estrogen plus progestin. Women using HRT saw a 75% decrease in weekly hot flashes.3 With such great results, this has long been used as the therapy of choice for symptomatic perimenopausal women. The Woman’s Health Initiative (WHI) demonstrated some negative effects of these therapies including increased risk of breast cancer as well as various cardiovascular concerns with the combination pill.4 Estrogen alone did not have as many of the same risks, although it did demonstrate an increased risk of stroke.4 These adverse effects have made many providers and patients more cautious about using HRT. It is important to note that the WHI was only looking at postmenopausal women using HRT as a preventative therapy, not perimenopausal women and not solely for the treatment of menopause symptoms.1 This is why current guidelines for treating VMS still recommend the use of HRT, but for the shortest amount of time at the lowest effective dose.1 It is even recommended that its use be limited to those <60 years old or who are <10 years away from menopause.5 For women who prefer not to use HRT or are unable to, there are non-hormonal medications that effectively reduce VMS. These include certain selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), clonidine, and gabapentin.1 These drugs are more effective than placebo in reducing VMS, but less effective than HRT.1
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
SSRIs are a group of antidepressant drugs. Currently, the only non-hormonal drug approved for the treatment of VMS is the SSRI paroxetine.1 In one divided study by Simon of over one thousand participants, paroxetine decreased the mean number of hot flashes significantly at 4 and 12 weeks in both portions of the study.6 Severity ratings varied between the two portions of the study, but when the results were pooled, severity of VMS was significantly decreased at both week 4 and week 12.6 This study also found that 47.5% of women were still responding to paroxetine at 24 weeks compared to 36.3% responding to the placebo.6 Paroxetine should be used with caution in women being treated with tamoxifen because paroxetine is a strong inhibitor of the cytochrome isoenzyme that is needed to convert tamoxifen to its active form.7 Three other SSRIs are commonly being used off-label for the treatment of VMS, fluoxetine, citalopram, and escitalopram.8 In one study published in 2005, fluoxetine and citalopram did not perform better than the placebo.9 However, in two more recent studies of citalopram, it reduced both the frequency of symptoms and overall severity of VMS, with hot flash scores decreasing by 37% compared to 13% with placebo in one study10 and a decrease of 49-55% compared to 23% in the other.11 Escitalopram also demonstrated a decrease in the frequency and severity of VMS in comparison to placebo in a trial by Freeman with a decrease of at least 50% reported by 55% of women using escitalopram vs 37% of those using placebo.12 Some adverse effects of SSRIs include weight loss, prolonged QT interval, headache, agitation, and increased risk of suicide.8
SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS
SNRIs are another group of antidepressant medications. The two SNRIs that have been used for the treatment of VMS in menopause are venlafaxine and desvenlafaxine. In a study of breast cancer patients with either natural or induced menopause, venlafaxine reduced hot flash scores compared to a placebo, although the reduction was only significant in weeks 1-8 and borderline not significant during weeks 9-12.13 At the end of 12 weeks, venlafaxine reduced hot flash scores by 41% compared to 29% in the placebo group.13 In a study comparing venlafaxine to gabapentin, patients preferred venlafaxine despite similar decreases in hot flash scores.14 Desvenlafaxine has also recently been shown to be effective in the reduction of VMS number and severity in the short term as well as after a year of treatment.15 Some side effects experienced by women taking SNRIs for VMS include nausea, appetite loss, constipation, dizziness, fatigue, dry mouth, and drowsiness.13,15 Concerns about cardiovascular events and hepatotoxicity have been raised about desvenlafaxine8, but a recent study by Archer showed no significant difference in severe adverse effects between desvenlafaxine and placebo.16
Clonidine is an antihypertensive medication.1 A meta-analysis conducted in 2006 found mixed results in the efficacy of clonidine in treating VMS.17 However, a more recent study showed a significant reduction in VMS frequency and severity of those receiving clonidine in comparison to participants receiving a placebo during weeks 6-12 of the 12 week trial.13 The evidence for clonidine use is not as strong as the evidence for SSRIs, SNRIs, and Gabapentin.5 Common side effects of clonidine include dry mouth, somnolence, and trouble sleeping.1
Gabapentin is an anti-convulsant medication.1 It has demonstrated greater efficacy than placebo in reducing both number of VMS and severity with hot flash scores decreasing by 51% in the treatment group compared to a 26% decrease in the placebo group.18 Gabapentin is potentially advantageous because it has no known drug interactions and no absolute contraindications.18 Possible side effects include dizziness, drowsiness, unsteadiness, peripheral edema, and increased risk of suicide.18,8
While SSRIs, SNRIs, clonidine, and gabapentin have demonstrated the ability to reduce vasomotor symptoms8, many women still prefer to try alternative treatments; currently 19% of women in the US experiencing VMS are using soy products as an alternative therapy.19 Unfortunately many alternative therapies lack support from randomized, controlled studies, and many studies demonstrate a large placebo effect.19 Phytoestrogens are derived from soy products and are similar in structure to estrogen.1 Because of this similar structure, caution should be used in breast cancer survivors.5
A 2013 Cochrane Database review found that, in general, most phytoestrogens are not supported by research.19 Many trials with various phytoestrogens did not have statistically different results when compared to a placebo.19 Several of the studies analyzed did show a positive benefit, but these studies were often plagued by small sample size, researcher bias, or not using an “intention to treat model”.19 However, there were a few studies that focused on genistein, a type of phytoestrogen, that showed some promise. One such study by Evans used a single dose of genistein and observed patient’s vasomotor symptoms over 12 weeks. At 12 weeks, the average number of vasomotor symptoms had decreased by 51% in the treatment group compared with 27% in the placebo group.20 The most common side effect of phytoestrogens are gastrointestinal complaints, and no significant differences in breast and endometrial cancer were observed between placebo and phytoestrogens in a meta-analysis.21 Because the average study length in the meta-analysis was only 6 months, there is a need for studies of longer duration assessing safety.21
ADDITIONAL ALTERNATIVE TREATMENTS
Black cohosh is an herb native to America historically used to treat menopause symptoms.22 Currently there is little evidence supporting the use of black cohosh for treating VMS based on a Cochrane Database review.22 Safety concerns have been raised about the potential hepatotoxicity of black cohosh1, but a study examining its safety and efficacy for one year did not find any difference in adverse effects between black cohosh and placebo.23
There have been many other alternative treatment options studied including vitamin E, evening primrose oil, acupuncture, exercise, stellate ganglion block, yoga and mind/body therapies, and hypnosis.1,8 Most of these treatments are either lacking in evidence, or there is only limited support.1,8
There are multiple treatment options available for women experiencing VMS. The most effective and well-studied option is HRT.1 If women are hesitant to take these medications there are non-hormonal medications available. The only FDA approved non-hormonal medication for the treatment of VMS is the SSRI Paroxetine1. Multiple studies have found other SSRIs, SNRIs, clonidine, and gabapentin to be effective in reducing VMS as well1,8, but none of these alternatives are as efficacious as HRT.1 Deciding on an appropriate medication involves weighing the patient’s needs as well as the side effect profiles for the various medications. Currently there is not enough evidence to recommend non-traditional medications to women, but certain phytoestrogens do show some promise for future research.19
- ACOG Practice Bulletin No. 141. Obstet Gynecol. 2014;123(1):202-216. doi:10.1097/01.aog.0000441353.20693.78.
- Politi MC, Schleinitz MD, Col NF. Revisiting the Duration of Vasomotor Symptoms of Menopause: A Meta-Analysis. J Gen Intern Med. 2008;23(9):1507-1513. doi:10.1007/s11606-008-0655-4.
- Al-Safi ZA, Santoro N. Menopausal hormone therapy and menopausal symptoms. Fertil Steril. 2014;101(4):905-915. doi:10.1016/j.fertnstert.2014.02.032.
- Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal Hormone Therapy and Health Outcomes During the Intervention and Extended Poststopping Phases of the Women’s Health Initiative Randomized Trials. JAMA. 2013;310(13):1353. doi:10.1001/jama.2013.278040.
- Stuenkel CA, Davis SR, Gompel A, et al. Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(11):3975-4011. doi:10.1210/jc.2015-2236.
- Simon JA, Portman DJ, Kaunitz AM, et al. Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms. Menopause. 2013;20(10):1027-1035. doi:10.1097/gme.0b013e3182a66aa7.
- Sassarini J, Lumsden MA. Non-hormonal management of vasomotor symptoms. Climacteric. 2013;16(sup1):31-36. doi:10.3109/13697137.2013.805525.
- Tan O, Pinto A, Carr BR. Hormonal and Non-Hormonal Management of Vasomotor Symptoms: A Narrated Review. J Endocrinol Diabetes Obes. 2013;1(2):1-15.
- Suvanto-Luukkonen E, Koivunen R, Sundstrom H, et al. Citalopram and fluoxetine in the treatment of postmenopausal symptoms: a prospective, randomized, 9-month, placebo-controlled, double-blind study. Menopause. 2005;12(1):18-26. doi:10.1097/00042192-200512010-00006.
- Kalay A, Demir B, Haberal A, Kalay M, Kandemir O. Efficacy of citalopram on climacteric symptoms. Menopause. 2007;14(2):223-229. doi:10.1097/01.gme.0000243571.55699.4a.
- Barton DL, LaVasseur BI, Sloan JA, et al. Phase III, Placebo-Controlled Trial of Three Doses of Citalopram for the Treatment of Hot Flashes: NCCTG Trial N05C9. J Clin Oncol. 2010;28(20):3278-3283. doi:10.1200/jco.2009.26.6379.
- Freeman EW, Guthrie KA, Sternfield B, et al. Efficacy of Escitalopram for Hot Flashes in Healthy Menopausal Women. JAMA. 2011;305(3):267. doi:10.1001/jama.2010.2016.
- Boekhout AH, Vincent AD, Dalesio OB, et al. Management of Hot Flashes in Patients Who Have Breast Cancer With Venlafaxine and Clonidine: A Randomized, Double-Blind, Placebo-Controlled Trial. J Clin Oncol. 2011;29(29):3862-3868. doi:10.1200/jco.2010.33.1298.
- Bordeleau L, Pritchard KI, Loprinzi CL, et al. Multicenter, Randomized, Cross-Over Clinical Trial of Venlafaxine Versus Gabapentin for the Management of Hot Flashes in Breast Cancer Survivors. J Clin Oncol. 2010;28(35):5147-5152. doi:10.1200/jco.2010.29.9230.
- Pinkerton JV, Constantine G, Hwang E, Cheng RF. Desvenlafaxine compared with placebo for treatment of menopausal vasomotor symptoms. Menopause. 2013;20(1):28-37. doi:10.1097/gme.0b013e31826421a8.
- Archer DF, Pinkerton JV, Guico-Pabia CJ, Hwang E, Cheng RF. Cardiovascular, cerebrovascular, and hepatic safety of desvenlafaxine for 1 year in women with vasomotor symptoms associated with menopause. Menopause. 2013:1. doi:10.1097/gme.0b013e3182775fe9.
- Nelson HD, Vesco KK, Haney E, et al. Nonhormonal Therapies for Menopausal Hot Flashes. JAMA. 2006;295(17):2057. doi:10.1001/jama.295.17.2057.
- Butt DA, Lock M, Lewis JE, Ross S, Moineddin R. Gabapentin for the treatment of menopausal hot flashes. Menopause. 2008;15(2):310-318. doi:10.1097/gme.0b013e3180dca175.19.
- Lethaby A, Marjoribanks J, Kronenberg F, Roberts H, Eden J, Brown J. Phytoestrogens for menopausal vasomotor symptoms. Cochrane Database of Syst Rev. 2013:1-22. doi:10.1002/14651858.cd001395.pub4.
- Evans M, Elliott JG, Sharma P, Berman R, Guthrie N. The effect of synthetic genistein on menopause symptom management in healthy postmenopausal women: A multi-center, randomized, placebo-controlled study. Maturitas. 2011;68(2):189-196. doi:10.1016/j.maturitas.2010.11.012.
- Tempfer CB, Froese G, Heinze G, Bentz E, Hefler L, Huber J. Side Effects of Phytoestrogens: A Meta-analysis of Randomized Trials. The Am J Med. 2009;122(10):939-946.e9. doi:10.1016/j.amjmed.2009.04.018.
- Leach MJ, Moore V. Black cohosh ( Cimicifuga spp.) for menopausal symptoms. Cochrane Database of Syst Rev. 2012. doi:10.1002/14651858.cd007244.pub2.
- Geller SE, Shulman LP, van Breemen RB, et al. Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms. Menopause. 2009;16(6):1156-1166. doi:10.1097/gme.0b013e3181ace49b.