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Chris Stubbs, MD (PGY-2), Lisa Mattingly, MD (PGY-3), Steven A. Crawford, MD, Elizabeth A. Wickersham, MD, Jessica L. Brockhaus, BA, and Laine H. McCarthy, MLIS
Corresponding Author: Elizabeth Wickersham, MD, Assistant Professor, research study Division, department of family & precautionary Medicine, college of Oklahoma health and wellness Sciences Center, 900 NE 10th St., Oklahoma City, ok 73104. (405) 271-2370. Ude.cshuo

Clinical Question

In menopausal women who experience consistent hot flashes, go treatment with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) mitigate the frequency and/or severity of warm flashes?


Answer

Yes. Review of the literature says that treatment with SSRIs or SNRIs to reduce the frequency and severity of hot flashes in menopausal and post-menopausal women. Researches demonstrated the paroxetine (Paxil), citalopram (Celexa) and escitolapram (Lexapro) to be the most efficient SSRIs, and venlafaxine (Effexor) to be the many effective very first line SNRI, with desvenlafaxine as a second option. The most common side results reported because that both SSRIs and also SNRIs are nausea and constipation, with many resolving within the first week the treatment. SNRIs have been connected with increased blood press in part patients and should be offered with fist in women through hypertension. Women v a background of breast cancer and also taking tamoxifen need to avoid SSRIs, which have been presented to interfere with tamoxifen metabolism. SNRIs room the most safe drugs because that this population. Treatment choice should be patient-specific and begin with the lowest sheep available.

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Level of evidence for the Answer

A


Search Terms

SSRI, SNRI, hot flashes, vasomotor symptoms, menopause


Search Conducted

August 2014, February 2016 and August 2016


Inclusion Criteria

menopausal, perimenopausal or postmenopausal women 18 year of period or enlarge with regular and/or severe vasomotor symptoms, meta-analyses, methodical reviews, randomized managed trials, cohort studies.


Exclusion Criteria

pre-menopause, anxiety, depression, panic disorder, bipolar disorder, co-morbid conditions.


Summary of the Issues

Between 80% and also 90% the perimenopausal and menopausal ladies will experience vasomotor symptom (VMS), frequently called hot flashes. Depending upon severity and also frequency, warm flashes might adversely affect a woman"s quality of life from 5 to 7 year or more.1-4 hot flashes are the an outcome of diminished estrogen levels associated with menopause.1,2 Hormone replacement treatment (HRT) is considered the gold conventional treatment for warm flashes.1,3 However, HRT is attached to boosted risk the estrogen-dependent pathologies, consisting of breast cancer, endometrial cancer, cardiovascular an illness and thromboembolism.2 females experiencing hot flashes who either cannot take HRT or who would favor other alternatives are looking to nonhormonal therapies to control the frequency and severity of menopausal vasomotor symptoms.1-3

Research right into nonhormonal options has concentrated on two significant categories the nonestrogen therapy: nonpharmaceutical and pharmaceutical. Nonpharmaceutical therapies encompass lifestyle changes, together as practice weight loss; yoga and other mindfulness or relaxation techniques; cognitive behavioral therapy; a range of vitamins and supplements; and over-the-counter natural remedies, together as black cohosh, ginseng and mix botanical remedies. Although few of these therapies have actually demonstrated some level of efficacy – load loss and mindfulness stress reduction techniques, for instance – in general, these alternatives “may no be the finest for women with significant VMS or those seeking prompt relief.”3

Several nonestrogen pharmaceutical, or prescription, therapies have also been evaluate for warm flashes. These incorporate clonidine, an alpha-adrenergic agonist, the anticonvulsant gabapentin, selective serotonin reuptake inhibitors (SSRIs) and also serotonin-norepinephrine reuptake inhibitors (SNRIs). Clonidine and also gabapentin have both demonstrated some effectiveness. However, each have far-ranging adverse side effects that might make lock impractical alternatives for plenty of women. Gabapentin is associated with dizziness, drowsiness, peripheral edema, loss of balance and also suicidal thoughts. Side impacts from clonidine are similar and incorporate dizziness, sedation, headache and also a far-reaching elevation in blood through abrupt cessation.1-4

SSRIs and/or SNRIs have demonstrated promise for reducing both the frequency and also severity of hot flashes there is no the risks of HRT or the more severe side impacts of the various other prescription medicine studied.1-4 This brief review examines the existing evidence to recognize if SSRIs and/or SNRIs might be effective and also safe choices to HRT for reducing the frequency and/or severity of warm flashes in menopausal women.


Summary that the Evidence

In 2013, Shams et al. Released a organized review and also meta-analysis assessing the effectiveness of 5 SSRIs – escitalopram, paroxetine, sertraline, citalopram and also fluoxetine – because that reducing vasomotor symptoms (hot flashes) in healthy and balanced perimenopausal women.5 The testimonial analyzed 11 randomized regulated trials (RCTs) v rigorous methodology published in between 2003 and also 2012. The studies had 2,069 women in between 36 and also 76 years of period who were followed for a duration of 1 come 9 months, depending on the study. Meta-analyses verified that treatment through an SSRI led to a far-ranging decrease in the average variety of daily warm flashes in ~ 4 to 8 weeks, under from 10 per day to 9 (95% CI -1.49 to -0.37) contrasted to placebo. In this study, escitolapram (Lexapro) to be the most effective SSRI because that reducing the everyday frequency of hot flashes. Attendees in the SSRI group also reported a palliation in severity the residual warm flashes contrasted to placebo. The most typical side impacts reported consisted of nausea, fatigue and also drowsiness yet were not considerably different native placebo. The investigators concluded that SSRIs space a reasonable substitute because that HRT.5

A 2015 systematic review by Handley and Williams examined 18 RCTs published in between 2000 come 2012 that contrasted SSRIs/SNRIs come placebo for reducing peri- and also postmenopausal warm flashes.6 entrants were healthy women in between the eras of 27 and also 78 years who reported suffering an mean of 46 come 76 hot flashes per week, relying on the study. All studies assessed warm flash frequency and also severity using a self-reported day-to-day hot flash diary. The severity rating and also frequency were multiplied to yield a composite score, with higher scores representing an ext severe symptoms. SSRIs/SNRIs decreased hot flash symptom by as much as 65% compared to placebo. Potential an initial line SSRIs were paroxetine (Paxil), paroxetine ER (Paxil CR), citalopram (Celexa) and also escitalopram (Lexapro). Venlafaxine (Effexor XR) was determined as a potential first line SNRI. Paroxetine ER prove the best statistically far-ranging reduction in hot flash frequency at both 12.5mg/day (62%, p=0.007) and 25mg/day (64%, p=0.03). Venlafaxine noted more immediate symptom relief 보다 the SSRIs, but had a higher incidence of side effects, many notably nausea and also constipation. SNRIs may boost blood pressure and also should be supplied with caution in hypertensive patients.6

In 2015, The phibìc American Menopause society (NAMS) exit a position statement regarding nonhormonal administration of menopause-associated vasomotor symptoms.3 panel members searched 5 databases because that high-level evidence write-ups (RCTs or organized reviews) concentrated on nonhormonal therapies for hot flashes. The search figured out 340 initial research articles and also 105 methodical reviews suitable for additional evaluation. NAMS dashboard members reviewed every articles and also assigned level of evidence. A restricted number the head-to-head RCTs comparing HRT to various other pharmacological agents to be identified. One such research reported that the SNRI venlafaxine (Effexor) demonstrated similar effectiveness for reducing VMS symptoms contrasted to a low-dose estradiol. A limitation of the RCT was that the protocol go not include a to compare of the 2 therapies v up-dosing.

After review of the evidence, the NAMS panel concluded that multiple nonhormonal therapies are suitable considerations for menopausal and also post-menopausal warm flashes. Recommendations incorporate the following SSRIs and also SNRIs:paroxetine salt 7.5mg/day (Brisdelle®); paroxetine or paroxetine ER 10–25mg/day; escitalopram 10–20mg/day; citalopram 10–20mg/day; desvenlafaxine 50–150mg/day; and also venlafaxine XR 37.5–150mg/day. Patients need to be started at the lowest obtainable dose and also titrated up as needed. Brisdelle® is only obtainable in 7.5mg and is right now the just drug FDA-approved for hot flashes. 3 The Table summarizes the efficacy, safety and also costs associated with SSRI/SNRI treatment.


SSRI/SNRI Safety, Efficacy and also Cost for treatment of hot Flashes5,6

To avoid side effects, patients have to be started on the lowest dose obtainable and gradually increased as essential to control hot flashes. Drugs are listed by course in the stimulate of demonstrated safety and also effectiveness. Prices are for generic drugs where accessible and space for reference purposes only. Actual expenses will differ dependent top top pharmacy and also insurance coverage.

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Generic (Brand Name) Recommended very first Line medicines for hot FlashesDaily DosesAppropriate for Tamoxifen usersApproximate price of 30 job supply
Selective Serotonin Reuptake Inhibitors (SSRIs)
1. Paroxetine (Paxil)
 Paroxetine salt (Brisdelle®) (FDA authorized for warm flashes)7.5mgNo$150-$200+
 Paroxetine (Paxil)10mg20mgNoNo$5.00+$5.00+
 Paroxetine ER (Paxil CR)12.5mg25mgNoNo$40-$250$40-$250
2. Citalopram (Celexa)20mgNo$4.00-$12.00
3. Escitalopram (Lexapro)10mgNo$8.00-$10.00
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
1. Venlafaxine (Effexor XR)37.5mgYes$6.00-$12.00+
2. Desvenlafaxine ER (Pristiq)50mgYes$140-$240+

Conclusion

HRT is still considered the most effective treatment because that reducing warm flashes in menopausal and also post-menopausal women. However, pertains to that HRT deserve to increase the risks of estrogen-dependent pathologies have actually led to studies investigating various other treatments for vasomotor symptoms. Based upon the proof reviewed, SSRIs and SNRIs minimize the frequency and severity the menopause-associated vasomotor symptoms by 10% to 64%, relying on the study. Side results from SSRIs and SNRIs, which consisted of nausea, constipation, and also dry mouth, were generally not severe and often subsided in ~ the first week.3,4 SSRIs escitalopram and paroxetine ER and also SNRI venlafaxine XR were displayed to it is in the many effective.3-5 return less reliable than HRT, SSRIs/SNRIs room demonstrated to reduce warm flashes and also may it is in recommended for women who wish to protect against the threats of HRT. Additional placebo-controlled researches are required to evaluate risks, benefits and also dosing. Women with a background of breast cancer who are taking tamoxifen must avoid SSRIs. Studies have actually demonstrated that part SSRIs inhibit the activity of the enzyme CYP2D6, which can an outcome in lower therapeutic levels of tamoxifen. The SNRIs venlafaxine and also desvenlafaxine show up to have small or no impact on tamoxifen task and have to be taken into consideration as the very first line treatment for this patients.5,6


The authors say thanks to Zsolt J. Nagykaldi, Ph.D., because that reading and commenting ~ above this paper. E.A.W. And also L.H.M. Room supported in part or in full by Oklahoma mutual Clinical & Translational resources (OSCTR) provide NIGMS U54GM104938, NIGMS/NIH.


1. Freedman RR. Menopausal hot flashes: mechanisms, endocrinology, treatment. J Steroid Biochem Mol Biol. 2014;142:115–20.
2. Imai A, Matsunami K, Takagi H, Ichigo S. New generation nonhormonal monitoring for warm flashes. Gynecol Endocrinol. 2013;29(1):63–6.
3. Nonhormonal monitoring of menopause-associated vasomotor symptoms: 2015 position statement that The north American Menopause Society. Menopause. 2015;22(11):1–18.
4. Krause MS, Nakajima ST. Hormonal and nonhormonal threatment of vasomotor symptoms. Obstet Gynecol Clin N Am. 2015;42:163–79.
5. Shams T, Firwana B, Habib F, et al. SSRIs for warm flashes: a systematic review and also meta analysis of randomized trials. J Gen Intern Med. 2013;29(1):204–13.
6. Handley A, Williams M. The efficacy and tolerability that SSRI/SNRIs in the treatment of vasomotor symptoms in menopausal women: a methodical review. J to be Assoc Nurse Pract. 2015;27(1):54–61.