Sheets on, sheets off. A bed drenched with sweat and any chance of an amorous sex life literally washed away. This can be the nightly routine for many as they go through menopause, and while hot flushes and night sweats may be considered an annoying rite of passage for some, they may have a darker side when it comes to long-term health.
Vasomotor symptoms have not only been associated with poor sleep, day time fatigue and brain fog, they’ve also been linked to an increase in the risk of heart disease, bone loss, depression and potentially neurodegenerative changes.
While menopausal hormone therapy (MHT) is the gold standard for treating vasomotor symptoms, not all patients can take, or wish to take, hormones. So, what are other options are there?
The Menopause Society (formerly known as the North American Menopause Society or NAMS) has done a comprehensive review of the literature on treatments for vasomotor symptoms, revised and republished this year.
The panel assessed the current literature based on three levels of evidence:
When it comes to pharmacological interventions, they made a few changes since the review was first published eight years ago, including removing clonidine from the list of recommended treatments and adding some newcomers like Oxybutinin to consider when treating vasomotor symptoms.
There were limited trials comparing non-hormone prescription therapies head-to-head with hormone therapy, and many of the studies had limitations in terms of size and structure. The authors looked at both drugs specifically for vasomotor symptoms as well as off-label use of other medications.
The statement says “evidence exists that SSRIs and SNRIs are associated with mild to moderate improvements in vasomotor symptoms, regardless of whether menopause is natural or surgical”.
When it comes to achieving significant reductions in vasomotor symptoms, paroxetine, escitalopram, citalopram, venlafaxine and desvenlafaxine have been shown to perform well in large, double-blind RCTs. Smaller studies suggest duloxetine is effective.
“Hot flash reductions vary from 25% to 69% with these treatments, with improvements in composite hot flash severity and frequency from 27% to 61%.”
However, sertraline and fluoxetine did not show statistically significant improvements, and as such are not recommended.
A pooled analysis of three randomised controlled studies found that 10 mg to 20 mg of escitalopram, 0.5 mg of oral 17β-estradiol, and 75 mg of venlafaxine daily all led to similar reductions in the frequency of vasomotor symptoms.
A low-dose paroxetine salt (7.5 mg/d) produced improvements in vasomotor symptom severity and frequency for up to two years, Sleep was also improved and there was no weight gain or negative effects on libido.
Improvements are generally seen within a couple of weeks, the position statement says.
However they remind practitioners that SNRIs and SSRIs are contraindicated in patients who have prior neuroleptic syndrome, serotonin syndrome, or who are taking monoamine oxidase inhibitors.
They advise caution in patients who have:
For patients on tamoxifen safer options include venlafaxine, desvenlafaxine, escitalopram, or citalopram. This is because these have less of an effect on the CYP2D6 Enzyme, the authors wrote.
You can find suggested dosing ranges for SSRIs and SNRIs in Table 1 of the position statement.
Gabapentin is commonly used to treat diabetic neuropathy and postherpetic neuralgia but several trials studying a dose of 900 mg (300 mg three times a day) showed an improvement in the frequency and severity of vasomotor symptoms, the advisory panel found.
But it warns there are possible adverse events including:
These are typically seen in the first week but should resolve within a month.
Gabapentin tritated to doses as high 2400 mg/d performed as well as the older form of conjugated equine estrogens at 0.625 mg/d estrogen in reducing hot flash severity scores but the statement said the adverse events limited its potential benefits.
However, it suggested that bedtime use may be beneficial for those who experience poor or disrupted sleep.
There are black box warnings for uncommon suicidal thoughts or behaviours that prescribers should take into account.
This one is a left-of-field recommendation as its effectiveness in treating vasomotor symptoms was picked up as a ‘side effect’ of its traditional use as a treatment for overactive bladder and urge incontinence.
Oxybutynin is an antimuscarinic, anticholinergic therapy that one prospective study and two randomised, double-blind studies showed significantly improved vasomotor symptoms in people who experienced moderate to severe flushes and/or sweats.
The studies involved postmenopausal women who used doses ranging from 2.5 mg or 5 mg twice daily up to 15 mg extended-release daily.
There were, however, dose dependent adverse events including a dry mouth and urinary difficulties.
The authors warned that long-term use of anticholinergics may be associated with cognitive decline, particularly in older people.
Pregabalin, used for the management of neuropathic pain and seizures, has been shown in one small RCT to reduce the frequency of vasomotor symptoms but there were reports of dizziness and cognitive difficulties.
The panel said that due to limited studies, associated adverse events such as weight gain, and because it’s a Schedule V controlled substance due to the potential for abuse, “pregabalin is not recommended”.
Clonidine has traditionally been suggested as an effective treatment for VMS but the position statement now says no. It is a blood pressure drug (α-2 adrenergic agonist) that has been shown to be modestly more beneficial than placebo but less beneficial than SSRIs, SNRIs, and gabapentin in reducing VMS, the panel concluded.
It comes with its own list of adverse events including hypotension, light-headedness, headache, dry mouth, dizziness, sedation, and constipation. Suddenly stopping can cause significant elevations in blood pressure.
“Because there are other more effective therapies with fewer adverse events, clonidine is not recommended,” the statement said.
For people who have trouble with night sweats suvorexant may be useful, but the position statement has opted not to recommend it.
It says it’s a “dual orexin-receptor antagonist that blocks the effects of the hypothalamic neuropeptide orexin-A.” Post menopausal women have three times the serum amount of hypothalamic neuropeptide orexin-A than their pre-menopausal counterparts. It promotes wakefulness, the statement says, and may contribute to sleep disruption and impaired thermoregulation.
While suvorexant plays a role in reducing insomnia a small study showed that it also reduced vasomotor frequency at night when compared to placebo, but there was no improvement in daytime symptom frequency.
The statements says there is not enough data to support its use.
The TGA is currently evaluating a new nonhormone therapy, fezolinetant, which is a first in class neurokinin antagonist. The FDA recently approved fezolinetant and studies show it is effective and well tolerated. It works by selectively blocking the neurokinin 3 receptor which regulates sense of temperature. As estradiol levels decline they increase activity in neurokinin B.
“This nonhormone approach directly targets the neural mechanism underlying [vasomotor symptoms] VMS,” the statement says. It adds that although fezolinetant appears to be effective and offers a viable alternative for those who can’t take HRT, it may not confer the benefits of oestrogen when it comes to other menopause related concerns or health conditions.
“Early evidence suggests benefit for quality of life and VMS-related distress, nocturnal awakenings, and sleep quality. Further effect on VMS-related mood and genitourinary, sexual, cardiovascular, metabolic, and bone health are lacking,” the panel wrote.
As they say, further studies are needed on larger population groups.
To read about the evidence for non-pharmacological strategies for managing vasomotor symptom, check out this article.
References:
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