Managing Vasomotor Symptoms in Women After Cancer

Climacteric

ISSN: 1369-7137 (Print) 1473-0804 (Online) Journal homepage: https://www.tandfonline.com/loi/icmt20

Managing vasomotor symptoms in women after cancer

J. V. Pinkerton & R. J. Santen

To cite this article: J. V. Pinkerton & R. J. Santen (2019) Managing vasomotor symptoms in women after cancer, Climacteric, 22:6, 544-552, DOI: 10.1080/13697137.2019.1600501 To link to this article: https://doi.org/10.1080/13697137.2019.1600501

Published online: 13 May 2019.

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Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=icmt20 CLIMACTERIC 2019, VOL. 22, NO. 6, 544–552 https://doi.org/10.1080/13697137.2019.1600501

REVIEW Managing vasomotor symptoms in women after cancer

J. V. Pinkertona and R. J. Santenb aDivision of Midlife Health, University of Virginia Health System, Charlottesville, VA, USA; bDivision of Endocrinology and Metabolism, University of Virginia Health System, Charlottesville, VA, USA

ABSTRACT ARTICLE HISTORY Women with estrogen-sensitive cancer or survivors of these neoplasms are generally not candidates Received 15 March 2019 for systemic menopausal hormone therapy or tibolone for the treatment of bothersome vasomotor Accepted 22 March 2019 symptoms (hot flashes or night sweats). However, menopausal symptoms negatively affect quality of Published online 13 May life and need to be addressed by clinicians. For mild vasomotor symptoms, optimizing lifestyle 2019 – changes or mind brain behavior may be sufficient. For women with moderate to severe vasomotor KEYWORDS symptoms unresponsive to these measures, non-hormone pharmacologic therapy may be needed. Non-hormone pharmaco- Randomized controlled trials have shown efficacy for vasomotor symptoms with selective serotonin therapies; menopause; reuptake inhibitors (paroxetine, citalopram, and escitalopram) and serotonin–norepinephrine reuptake selective serotonin reuptake inhibitors (venlafaxine and desvenlafaxine), as well as gabapentin, pregabalin, and clonidine. Therapies inhibitor; serotonin–norepi- in development include neurokinin B inhibitors (neurokinin 3 receptor), stellate ganglion blockade, nephrine reuptake inhibitor; and a natural estrogen, estetrol. Individualizing therapy is important. As the physiology of menopausal gabapentin; clonidine; hot hot flashes becomes better understood, it will drive development of future non-hormone flashes; neurokinins; estetrol pharmacotherapies.

Introduction with breast cancer. Premenopausal women who are treated with chemotherapy or artificially induced menopause with Vasomotor symptoms (VMS) defined as hot flashes and gonadotropin-releasing agonists may develop premature sweating are the most frequent complaints associated with ovarian insufficiency or early menopause associated with menopause, occurring in up to 75% of women and bother- VMS. Notably, early surgical menopause has been associated some in the majority of them (i.e. 75%). Hot flashes were with more severe VMS. Postmenopausal women with hor- previously considered to begin around the time of meno- mone-dependent cancer may receive medications such as pause and cease a few years afterward. However, in the tamoxifen or aromatase inhibitors which may worsen pre- Penn Ovarian Aging Study, up to one-third of women contin- existing hot flashes. ued to experience moderate to severe hot flashes for 10 years after the final menstrual period with a mean duration of moderate/severe hot flashes of 4.9 years1. Pathophysiology Surprisingly, hot flashes may persist in some women for a much longer time, with one study finding 8% of women Hot flashes occur as a result of alterations in the central experiencing hot flashes more than 20 years after meno- thermoregulatory system. With an increase in core body tem- pause2. In the Study of Women across the Nation (SWAN)3,a perature, neuroregulatory mechanisms are initiated to induce median duration of 7.4 years was found for hot flashes, with sweating and vasodilatation as a means to reduce the core a median persistence of 4.5 years after the last menstrual temperature. When the core temperature falls below a cer- period. African American women had the longest duration at tain level, neuroregulatory-induced shivering and vasocon- 10.1 years, while Hispanic and Chinese had the shortest at striction occur. The zone of thermoneutrality is defined as 5 years. In the SWAN, four trajectories of hot flash onset and ‘the range of temperatures that do not elicit thermoregula- 4 duration were observed (Figure 1), including early onset tory effector responses’ . During menopause, the thermo- (18.4%), late onset (29%), low frequency (27%), and high fre- regulatory neutral zone is narrowed as a result of lowered quency (25.5%). In the latter group, hot flashes started estrogen levels. As studied by Freedman and Woodward5,a before the final menstrual period and continued unabated to mean increase in body temperature of 1.5 ± 0.20 C induced the end of the observation period (i.e. 14 years after the final sweating in premenopausal women but an increase of only menstrual period). 0.8 ± 0.09 C induced sweating in postmenopausal women In the subset of menopausal women during treatment of (p < 0.006). This concept provides a biologic basis for why their cancer or after completion of treatment, VMS occur in a dressing in layers of clothing which can be discarded during large proportion and appear more problematic for women a hot flash relieves hot flashes in women.

CONTACT J. V. Pinkerton [email protected] Division of Midlife Health, University of Virginia Health System, Charlottesville, VA, USA ß 2019 International Menopause Society CLIMACTERIC 545

Figure 1. Trajectories of vasomotor symptoms over the menopause transition. Probability of VMS represents the average observed probability of VMS at each time point within each trajectory subgroup. No factors were included in the model. VMS, vasomotor symptoms. Reproduced with the permission of the publishers from Avis et al. 3.

Studies by Yen and others several years ago correlated recommended for relief of bothersome VMS. These include the onset of hot flashes with pulses of luteinizing hormone dressing in layers, wearing breathable clothing, avoiding (LH). These observations lead to the conclusion that the neu- heavy clothing or down comforters, or wearing clothes that roregulatory mechanisms controlling pulsatile LH and hot wick moisture away. Fans may be used to circulate cool air flashes must be similar. The neuroregulatory mechanisms including hand fans, electric fans, ceiling fans, or bed fans involve the kisspeptin, neurokinin B, and dynorphin (KNDy) that blow air under the sheets. Avoiding hot or spicy foods, class of neurons in the hypothalamus. Each of these neuronal drinking cold beverages, placing reusable cold packs under mediators acts in response to estradiol and contains estro- pillows, keeping the air temperature at night between 65 gen receptors6. Evidence for the role of neurokinin B in trig- and 68 C, or taking cold showers before bed may be helpful gering hot flashes and in pulsatile LH secretion is provided for some women. by experiments with neurokinin B inhibitors in study Lifestyle measures which are often suggested without patients. Clinical trials with neurokinin B inhibitors for hot clear clinical trial data include non-sweating exercise, stop- flashes are ongoing and appear very promising (detailed ping smoking, or trying deep controlled breathing. The later in the article). Melbourne Women’s Midlife Health Project found no signifi- Serotonergic agents such as selective serotonin reuptake cant association between alcohol intake and VMS7. Alcohol is inhibitors (SSRIs) and serotonin–norepinephrine reuptake often listed as a trigger, but this may be due to dehydration inhibitors (SNRIs), which modulate neuroregulatory pathways, and disrupted sleep. have been shown to reduce the frequency and severity of hot flashes. While these agents are commonly used to treat mood, they appear to increase serotonergic tone which inter- Weight loss and exercise acts with estrogen or norepinephrine receptors in the brain, Of the healthy lifestyle suggestions, studies suggest that leading to widening of the thermoneutral zone. weight loss has been associated with a reduction in 8,9 Gabapentenoid agents work through calcium channel activity hot flashes . in the hypothalamus by blocking neurotransmitter release In a pilot randomized clinical trial (RCT) of a behavioral 8 and possibly through peripheral effects on vasodilation or weight loss program , women in the weight loss group vasoconstriction. reported fewer hot flashes. Improvement of hot flashes was a major motivator for their weight loss. In the Women’s Health Initiative dietary intervention study, women with Non-pharmacologic options symptoms at baseline who lost 10 lbs or lost 10% of their baseline body weight between baseline and year 1 were Behavioral changes more likely to eliminate VMS than those who maintained Despite the lack of clinical trial data to support their efficacy, weight10. Although weight loss was not associated with a behavioral changes that lower core temperature are often change in VMS in the SWAN, body mass index and waist 546 J. V. PINKERTON AND R. J. SANTEN circumference were positively related to VMS in early meno- Mind–brain–body pause, while negatively related in late menopause9. Cognitive behavioral therapy (CBT) and hypnosis have been Exercise has shown mixed results in randomized trials, shown to be of benefit in RCTs and thus are recommended with a meta-analysis showing insufficient evidence to recom- 11 for relief of hot flashes based on the degree of scien- mend evidence for VMS . Exercise training leading to 14 improved cardiorespiratory fitness reduced self-reported hot tific evidence . flashes12, believed to be due to greater thermoregulatory control as the core temperature increases with exercise train- Cognitive behavioral therapy ing. Exercise may increase the core body temperature and 21 trigger hot flashes, but longer term relief may depend on Hunter and Liao developed a CBT program to decrease the the fitness level, and cancer patients may have improve- impact of hot flashes and night sweats which incorporated ments in mood, sleep, or quality of life13. information about symptoms, triggers, relaxation and stress management, cognitive restructuring of unhelpful assump- tions and automatic thoughts, and encouragement of helpful Supplements behavioral strategies to improve coping. A group-based ver- Although supplements are often touted as improving hot sion of this CBT program has been shown to reduce meno- flashes, it has been difficult to prove effectiveness in RCTs pausal complaints, although effectiveness was limited by beyond the 50% improvement seen with placebo. These missed appointments. An Internet-based CBT program for include over-the-counter black cohosh, dong quai, Chinese management of menopausal symptoms has shown positive 22 herbs, oral dehydroepiandrosterone, and red clover isofla- pilot data . vones14,15. Although generally safe, they cannot be recommended for effective hot flash relief based on current data. Hypnosis One RCT showed a reduction of one hot flash per day for users of 800 IU vitamin E per day16, but additional trials have Hypnosis is characterized by a state of deep relaxation and not shown further significant efficacy. heightened focus, with improved awareness and suggestibil- Phytoestrogens are estrogen-like substances which appear ity allowing improved concentration on specific feelings, to function as weak estrogens. A meta-analysis of clinical tri- images, thoughts, and sensations, and is used primarily to als suggested that composite and specific phytoestrogen relieve stress, anxiety, and pain. Hypnosis has been studied supplementations modestly reduced the frequency of hot in small pilot trials of breast cancer survivors. An RCT of 23 flashes but there was no significant reduction in night symptomatic menopausal women (n ¼ 187) found that clin- sweats17. In a meta-analysis and systemic review18, supple- ical hypnosis reduced hot flashes by 74.2%, compared with a menting equol with equol non-producers was found to sig- 17.1% reduction for structured attention control (p < 0.001). 24 nificantly lower the incidence and/or severity of hot flashes A systematic review by Cramer et al. of three trials of hyp- in menopausal women. Overall, studies on isoflavones are nosis on women with a history of breast cancer and those heterogeneous and suboptimal. Further research is needed with menopause-associated VMS showed a significant on effectiveness and safety in women with estrogen-sensitive decrease in hot flash frequency compared with no treatment, cancers. with no difference found in the hypnosis arm compared with gabapentin treatment. In a more recent RCT pilot study25, hypnosis alone reduced hot flashes as well as 75 mg of ven- Acupuncture lafaxine alone, but the combination of hypnosis and venla- Traditional acupuncture has been studied for its effect on faxine was no more effective than either treatment alone. hot flashes in women with breast cancer, but data have While there are small trial data supporting the use of hypno- been inconclusive. In a systemic review and meta-analysis of sis in women with breast cancer, usefulness may be limited RCTs on the effect of acupuncture on relief of hot flashes in due to a lack of available trained hypnotists and individual breast cancer survivors, Wang et al.19 found that women responsiveness. benefited similarly from both real acupuncture and sham acupuncture. Relaxation, yoga, and tai chi A pooled analysis of data from three RCTs of interventions for hot flashes (two acupuncture trials, one yoga trial) of Although early research suggested improvements in meno- women with 4 hot flashes/day on average using the Daily pausal symptoms with mind–body therapies26, there is no Diary of Hot Flashes found that acupuncture, yoga, and high-quality evidence that yoga, paced respiration, relaxation health and wellness education classes demonstrated similar therapy, or tai chi reduces hot flashes better than controls. effectiveness in reduction of hot flash frequency compared There are few good-quality studies to assess their efficacy. with controls, improved over those in the waiting list Paced respiration refers to a form of slow, controlled deep group20. Thus, both acupuncture and sham acupuncture breathing, while applied relaxation involves the practice of appear to work better than being on a waiting list, with min- progressive muscle relaxation in specific situations. An RCT imal harm. of paced respiration using electronic hot flash diaries, hot CLIMACTERIC 547 flash interference, and menopausal symptom questionnaires arterial or venous injection of the anesthetic agent, pneumo- did not show efficacy over the control27. thorax, or vocal cord paralysis. SGB, where available, may be A meta-analysis28 of mind–body and behavioral therapy a helpful therapy for hot flashes when hormone therapy is for VMS found that nine trials met the inclusion criteria for contraindicated. exercise, relaxation breathing, progressive muscle relaxation, audiotape relaxation, stress management and menopause education, and counseling support. Four of the nine trials Serotonergic medications were of poor quality while the other studies did not improve symptoms significantly. Women who are experiencing mild Heat production is increased acutely by the catecholamines VMS could use these measures, recognizing limited epinephrine and norepinephrine, and both SSRIs and SNRIs effectiveness. reduce this. A number of preparations have been shown in Yoga cannot be recommended for effective hot flash relief prospective RCTs to be superior to placebo for the manage- 29 as a systematic review of yoga for menopausal symptoms ment of VMS. found insufficient evidence to suggest that yoga was an effective intervention for hot flashes, although yoga may have other benefits on sleep, mood, or quality of life. SSRIs and SNRIs Paroxetine mesylate is the only drug approved by the US Mindfulness-based stress reduction Food and Drug Administration (FDA) for treating moderate- The goal of mindfulness-based stress reduction training for to-severe VMS and for improved sleep quality. In two RCTs, breast cancer survivors is to decrease emotional reactivity 12 and 24 weeks in duration with 1184 postmenopausal and negative thinking to encourage approaching thoughts women, a 7.5 mg formulation of paroxetine was found to be 30 and feelings in an accepting, non-reactive manner . effective in treating VMS37. Mindfulness training to decrease stress and improve Although used off label, many other SSRIs and SNRIs have menopausal symptoms has been evaluated in small stud- shown efficacy in the reduction of hot flashes in RCTs (see 31 ies . Higher mindfulness and lower perceived stress corre- Figure 2). Venlafaxine 75 mg, desvenlafaxine 50–100 mg, lated independently with lower menopausal symptom paroxetine 20 mg, citalopram 10–20 mg, and escitalopram scores, with the magnitude of association larger as the self- 20 mg have proven effective in short-term RCTs in the treat- reported stress increased. Self-help cognitive behavior was ment of hot flashes (see later for a full discussion)14. For shown to improve menopausal symptoms compared to a 32 SSRIs and SNRIs, the reduction in hot flash frequency ranges randomized no treatment group . A cross-sectional cohort from 25 to 69%, while the reduction in hot flash severity study33 of 1744 women aged 40–65 years found that higher ranges from 27 to 61%14. Lower doses than those needed mindfulness and lower stress correlated independently with for mood management are effective at reducing hot flashes, lower menopausal symptom scores. The higher the perceived with fewer resultant side effects of nausea, headache, jitteri- stress scores, the more mindfulness correlated with lower ness, or dizziness which often subside within several weeks menopausal rating scores. Further studies are needed before of initiating treatment14. Less consistent results on reduction mindfulness-based stress reduction can be recommended as of hot flashes have been seen with the SSRIs sertraline and an effective treatment for hot flashes. fluoxetine38. Desvenlafaxine is not approved in the United States for Stellate ganglion block VMS but is approved at 100 mg in Mexico and Thailand39–41. Dose-increase titration in the first week minimizes nausea, The stellate ganglion is a sympathetic ganglion located vomiting, and dizziness, while a down-titration minimizes below the subclavian artery. The stellate ganglion block withdrawal symptoms of anxiety, depression, and moodiness. (SGB), using local anesthetic, has been used for relief of chronic sympathetic mediated pain of the head, neck, and In an 8-week double-blind RCT of 339 perimenopausal and upper extremity. Early pilot studies, case reports, and small postmenopausal women, venlafaxine 75 mg extended release RCTs showed a reduction in hot flashes. A 12-week pilot and low-dose oral estradiol (0.5 mg) demonstrated similar study in 13 breast cancer survivors found a reduction in hot efficacy in treating VMS, with both agents more effective 42 flash frequency and severity, with reduced nighttime awak- than placebo . Contraindications to SNRIs include prior ening and minimal adverse events, and a continued decrease neuroleptic syndrome, serotonin syndrome, and concurrent in symptoms with a second blockade 11 weeks later34,35. use of a monamine oxidase inhibitor. Side effects include A small comparative study (n ¼ 40) of Iranian breast cancer fatigue, drowsiness, dry mouth, headache, nausea, and other survivors36 with menopausal symptoms randomly assigned gastrointestinal symptoms. to either SGB performed under sonography guidance using For women with breast cancer, SSRIs and SNRIs may be 10 ml of 0.5% bupivacaine or 7.5 mg of paroxetine daily for good options to reduce hot flashes or make them more tol- 6 weeks found that both treatments similarly improved hot erable. Caution is needed for women taking tamoxifen as flashes and night disturbances. Potential complications of SSRIs can interfere with CYP2D6 metabolism of tamoxifen, SGB include Horner’s syndrome (oculosympathetic palsy), most notably fluoxetine and paroxetine. 548 J. V. PINKERTON AND R. J. SANTEN

Figure 2. Hot flash frequency and composite score with non-hormonal prescription therapies for relief of VMS. Upper panel, effect on frequency of VMS; lower panel, effect on composite score (severity frequency; best representation of effect). Open bars, placebo; colored bars, therapies; length of bars, ranges in studies; horizontal bars, means. VMS, vasomotor symptoms. Reproduced with the permission of the publishers from Stuenkel et al. 67.

Gabapentenoid medications for management transport process through a transporter called LAT 1 (large of VMS neutral amino-acid transporter). Based on its non-linear absorption kinetics, intra-individual variability in absorption Gabapentin and variability in transporter action, the tissue bioavailability Gabapentin is classified as a gabapentinoid and acts as a lig- of gabapentin is variable with a coefficient of variability of – 43–45,47–49 and of the a2d subunit site of specific voltage-dependent cal- 20 30% . cium channels43. In spite of its name, gabapentin does not Gabapentin has been found clinically to be very effective bind to gamma-aminobutyric acid receptors. The main action and well tolerated when used for treatment of nocturnal hot of gabapentin is to block the release of excitatory neuro- flashes that awaken the patient at night50. Several physio- transmitters in the brain43. Several RCTs have demonstrated logic and pharmacologic factors favor the use of gabapentin its efficacy when compared to placebo. When used at a total in this setting. Nocturnal hot flashes appear to occur primar- dose of 2400 mg per day, gabapentin is as effective as estro- ily in the first 4 h of sleep, whereas rapid eye movement gen44–47. A clinically important caveat is that the doses of sleep in the subsequent 4 h suppresses hot flashes51. gabapentin must be individually titrated in each patient due Accordingly, an agent exerting its effect predominantly over to the complex pharmacokinetics of gabapentin43. this time interval would be favorable. A single dose of gaba- The oral bioavailability of gabapentin is approximately pentin given 1 h before sleep results in peak levels at 1.7–4h 80% at a dose of 100 mg every 8 h but decreases to 27% at depending upon the dose given, with a rapid reduction of a 1600 mg dose when dosed every 8 h43. The half-life of levels occurring subsequently due to renal clearance. As a clearance is 5–7 h depending on the dose and renal function. result, the drug blood levels would be expected to largely This agent readily enters the brain via an active, saturable, dissipate by the time of awakening, thus obviating morning CLIMACTERIC 549 side effects. The standard, short-acting formulation of gaba- comparative trials between gabapentin and pregabalin are pentin would then be preferable to the extended release needed to determine superiority on relief of hot flashes and form, which would not be cleared as rapidly46. As gabapen- side effects. tin induces drowsiness, its action is both to induce sleep and Each of these agents exerts a substantial placebo effect to abrogate hot flashes. In women whose hot flashes occur ranging from 20 to 50% but specific pharmacologic actions primarily at night, the authors have found that a single dose of them statistically significantly improve efficacy. On a prac- of gabapentin given 1 h before bedtime often relieves the tical basis, women do not distinguish placebo from drug hot flashes that awaken patients from sleep. The authors effects and the overall efficacy is what is important. Figure 2 suggest starting with 100 mg 1 h before bedtime and increas- illustrates well the differences between placebo and over- ing by 100 mg every three nights until relief of hot flashes, all effects. side effects, or a maximum of 1200 mg. At much higher doses and use during the daytime, gaba- Oxybutynin pentin may be as effective as estrogen but is limited by its side effects. In one trial (20 patients per arm) of women The anti-cholinergic agent oxybutynin (ditropanVR ) is generally receiving gabapentin (dose titrated up to 2400 mg over used for ‘hyperactive bladder’ and urinary leakage in postme- 12 days), conjugated estrogen (0.625 mg), or placebo, both nopausal women. Three RCTs have shown this agent to be gabapentin and estrogen reduced the hot flash severity effective in the treatment of hot flashes56–58. The largest RCT score to a similar degree when compared with placebo randomized 150 women to placebo or 2.5 and 5.0 mg oxybu- (72%, 71%, and 54%, respectively)44,46. However, at this dose, tynin twice daily56. Using a hot flash composite score of fre- gabapentin caused significant side effects including head- quency and severity, the 2.5 mg twice daily group reported a ache, dizziness, and disorientation. Because of these side decrease of 10.6 (standard deviation 7.7) and those on effects, the use of gabapentin during the daytime should be 5 mg twice daily a decrease of 16.9 (standard deviation considered as a second-line approach with the SSRI/SNRI 15.6), compared to a decrease for those on placebo of 5.7 class of agents as the first line. (standard deviation 10.2). Side effects of dry mouth and diffi- Combined therapy with gabapentin and an antidepressant culty urinating were related to the anti-cholinergic effects. (SSRI or venlafaxine) does not appear to be more effective Additional studies are needed to determine oxybutynin’s for hot flashes than gabapentin alone in patients with inad- relative role among other agents. equate control of their hot flashes with an antidepressant alone52. When switching from an antidepressant to gabapentin, it might be best to continue the antidepressant for the Clonidine first 2 weeks and then titrate down to avoid withdrawal Clonidine, an a-adrenergic agonist that reduces central sym- symptoms from discontinuing the antidepressant, which the pathetic activation, in doses of 50 lg two or three times daily patient might inappropriately attribute to the newly initi- has been shown to reduce hot flashes modestly compared ated gabapentin. to placebo in short-term trials. This agent is FDA approved A trial comparing gabapentin during the daytime to ven- for hypertension and used off label infrequently for reduc- lafaxine found overall relief of hot flashes, with both agents tion of hot flashes, limited by orthostatic hypotension or having a similar 66% reduction of the hot flash score. other side effects59. Interestingly, 68% of patients preferred venlafaxine and 32% preferred gabapentin53. Venlafaxine was more effective in the subgroup preferring this agent, with a 95% reduction of Neurokinins hot flash severity and an 84% reduction in frequency. In Data are emerging about the effectiveness of neurokinin B those preferring gabapentin, the reduction of hot flash sever- antagonists in the treatment of menopausal hot flashes. ity was 94% and the reduction of frequency was 94%. While data remain limited, these neurokinin antagonists appear to have a remarkably fast onset of action, within the Pregabalin first 1 or 2 days of administration, and have a significant effect on both daytime flashes and night sleep disturbance. Pregabalin, like gabapentin, is used for a number of indica- If safety and long-term efficacy are confirmed, these new tions, including seizures, neuropathic pain, and postherpetic agents will be an important advance in non-hormone ther- neuralgia, and is effective in relieving hot flashes54. In favor apy for hot flashes. The neurokinin B pathway is involved in of pregabalin is the lesser degree of biologic variability, physiological regulation of the control of gonadotropin- 10–15% versus gabapentin (20–30%), and the lesser need for releasing hormone secretion in men and women, and is a individual dose titration43,48,55. For neuropathic pain in key mediator of hot flashes. Neurokinin B antagonists have patients with diabetes, pregabalin is more effective than shown remarkable rapid efficacy in reducing hot flash fre- gabapentin, but no comparative data are available with quency, for both daytime and nighttime hot flashes60. respect to hot flashes. Pregabalin at the recommended dose In a placebo-controlled crossover RCT, MLE4901, a specific of 300 mg three times daily is reasonably well tolerated. antagonist of the neurokinin 3 receptor, led to a marked Gabapentin is suggested over pregabalin as it has been bet- decreased in daytime and nighttime hot flashes in postme- ter studied for hot flashes and is less expensive. However, nopausal women61. This particular drug was halted in 550 J. V. PINKERTON AND R. J. SANTEN development due to slight elevations of liver function62. The of hot flashes. In general, these preparations reduce the fre- effect on hot flashes was extremely rapid, with a significant quency and severity of hot flashes by 50–60%, which reduction in hot flash frequency by the second day of drug appears acceptable to many women who wish to avoid hor- administration62. mones. In comparison, standard-dose estrogen reduces hot Drugs in development include Fesolinetant (ESN364), with flashes by 80–90%. New therapies in development which rapid and highly effective suppression of hot flashes, and appear promising include neurokinin receptor blockades, NT-814, which is a dual neurokinin 1 and neurokinin 3 recep- oxybutynin, and estetrol. tor antagonist60. Functional magnetic resonance imaging data presented in abstract form at the International Potential conflict of interest J-VP: none for past 12 months. Menopause Society meeting in 2018 suggested that the neu- RJS: research funding from Panterhei Bioscience. rokinin B pathway is involved in the perception of hot flashes, as well as affecting hot flash frequency. Thus, the frequency and perception of severity or unpleasantness may Source of funding Nil. turn out to be a benefit in the treatment of hot flashes63. Neurokinin B antagonists show rapid onset of action and effi- References cacy similar to hormone therapy in reducing hot flash frequency and hold promise as the first truly effective non- 1. Freeman EW, Sammel MD, Sanders RJ. Risk of long-term hot hormone pharmacologic treatment. flashes after natural menopause: evidence from the Penn Ovarian Aging Study cohort. Menopause 2014;21:924–32 2. Huang AJ, Grady D, Jacoby VL. Persistent hot flushes in older postmenopausal women. Arch Intern Med 2008;168:840 Estetrol 3. Avis NE, Crawford SL, Greendale G, et al. 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