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#10 It's Getting Hot In Here: Non-Hormonal Therapies for Menopausal Vasomotor Symptoms
104 Plays7 months ago
In this episode of "What's the Proof?" we delve into non-hormonal therapies for menopausal vasomotor symptoms (VMS), commonly known as hot flashes and night sweats. Hormone replacement therapy (HRT) is the most effective treatment for VMS, but it isn't suitable for everyone. Join Bobby, Dawn, and Sandy as they explore alternative treatment options for women who cannot or choose not to use HRT. From lifestyle interventions and mind-body techniques to dietary supplements and prescription medications, we break down the latest evidence and provide practical advice for managing these disruptive symptoms. Whether you're a clinician seeking to expand your treatment toolkit or a patient looking for more information, this episode offers valuable insights into improving quality of life during menopause.
Episode Highlights:
[00:00] Introduction and Overview:
- Welcome and episode introduction by Bobby, Dawn, and Sandy.
- Discussion on the significance of VMS during menopause and the limitations of hormone replacement therapy.
[05:50] Lifestyle Interventions
- Discussion on general health benefits and specific interventions like cooling techniques, avoiding triggers, and yoga.
- Evidence review showing limited effectiveness of these methods for reducing VMS.
[10:42] Mind-Body Techniques
- Examination of Cognitive-Behavioral Therapy (CBT) and its promising results for VMS management.
- Insights into clinical hypnosis as a potential therapy.
- Brief discussion on mindfulness and paced breathing, highlighting the lack of substantial evidence for VMS relief.
[17:05] Dietary Supplements
- Analysis of the mixed results for soy products and black cohosh.
- Summary of current recommendations against these supplements due to limited efficacy.
[19:52] Acupuncture
- Discussion on the effectiveness of acupuncture versus sham acupuncture.
- Conclusion that acupuncture is not recommended for VMS treatment based on current evidence.
[21:00] Prescription Medications
- Review of SSRIs, SNRIs, and gabapentin, discussing their varying degrees of effectiveness.
- Introduction to fezolinetant (Veozah), a new neurokinin B antagonist with promising results but higher costs.
- Practical advice on prescribing these medications and considerations for patient-specific factors.
[40:00] Practical Tips and Closing Remarks
Tune in to learn:
- The specific non-hormonal options available for VMS and their effectiveness based on recent studies.
- Practical tips for incorporating these alternatives into clinical practice.
- Personal insights from our hosts on managing VMS without hormones.
Episode Links:
If you liked this episode, please share it with your colleagues, friends, and patients! Subscribe here to "What's the Proof?" on YouTube for video content, and stay updated with the latest episodes! Share your thoughts and questions with us on Twitter @theproofpodcast or email whatstheproofpodcast@gmail.com.
Credits:
- Hosts: Bobby Scott, MD, FAAFP, DABFM; Sandy Robertson, PharmD; Dawn Caviness, MD, BSN, DABFM
- Production & Cover Art: Bobby Scott, MD, FAAFP, DABFM
- Music: Twisterium, MondayHopes, Muzaproduction, and SergeQuadrado from Pixabay
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Transcript
Introduction and Purpose of Podcast
00:00:00
Speaker
You are listening to the What's the Proof podcast, where we seek to help doctors and other clinicians incorporate the best available evidence into their everyday clinical decision making. The content of this podcast is meant for educational purposes only and should not be construed as personalized medical advice. The views and opinions expressed are those of the host and guest, and no content on this podcast has been approved or sanctioned by Atrium Health.
Hormone Replacement Therapy for Menopause
00:00:24
Speaker
The most effective treatment for vasomotor symptoms in menopause is hormone replacement therapy. However, not all women desire to or are able to take this. So what are other options available for these patients? We'll discuss this and more on today's episode of What's the Proof?
Meet the Hosts and Guests
00:00:55
Speaker
Welcome to What's the Proof, the family medicine podcast that seeks help family physicians and other clinicians incorporate the best available evidence into their everyday clinical decision-making. My name is Bobby Scott. I'm one of the faculty members of the Cabarrus Family Medicine Residency and Assistant Professor, soon to be associate at Wake Forest University School of Medicine. With me today is Sandy Robertson and Dawn Kavanas. Sandy, how are you doing?
00:01:21
Speaker
I'm doing great. How are you, Bobby? I'm excellent. Don, how are you? I'm doing well. I'm doing well. Excited to be here. Yeah, me too. Me too. This is episode 10. We are in double digits now.
00:01:35
Speaker
I know. Does it feel like it's been more though, Bobby? Yeah. I bet. For you, I bet it does because Bobby does all the hard lifting for the audience. Especially after our technical difficulties this morning trying to get this set up. Yeah, it feels sometimes like a lot. I know. Bobby, we're such a joy to work with. I don't even think that is true. It flew by for me.
00:01:59
Speaker
Just for those listening, whenever there's any type of technological issue, Bobby works to fix it and me and Sandy just banter back and forth the whole time. So we're super helpful. It's lovely.
Podcast Available on YouTube
00:02:12
Speaker
It's a wonderful experience.
00:02:15
Speaker
Well, I did want to share some exciting news with the audience. So this episode and new episodes of What's The Proof can now be found on YouTube. So for those of you who prefer to consume your podcast by video, you can now watch us from the comforts of your couch, perhaps with a tasty snack or a favorite beverage. But you can subscribe to our YouTube channel and be the first to know when our new episodes are published. How do you guys like that idea? Well, you know I hate.
00:02:44
Speaker
any kind of video, so it's fine. I've had to learn to deal with it, but I don't think it's fair that we don't have our snack and our favorite beverage. I do realize it's 11 o'clock on a Wednesday and we're at work. I guess it depends on what your favorite beverage is. This could be a lot more fun with my favorite beverage. Yes, it could. Yep. By the end of it. The technical difficulties wouldn't be so bad.
00:03:05
Speaker
That's right. That's right. You got to keep the facial expressions in check. That's right. That's right. Very expressive. Yeah. Yeah. You can't have the resting kind of face. I know. Yeah. Yeah. Anyway, without further ado, let's get started on
Understanding Vasomotor Symptoms in Menopause
00:03:21
Speaker
today's topic. We've got an episode that is jam packed today, so I'm super excited.
00:03:26
Speaker
Okay, so hot flashes. So hot flashes and night sweats are the most common symptom of menopause. I know all of us have had patients come in miserable with these symptoms. And this is what I think is really interesting. Honestly, I did not realize how many women are affected, 80% of women. And it can last, it typically lasting seven to nine years, if you're lucky, if you're lucky, because one third of women experienced this for more than 10 years.
00:03:55
Speaker
I'm going to say that again because I think it's super important. 80% of women lasting seven and nine years and then one third of women for more than 10 years. The highest efficacy rates for treatment of vasomotor symptoms are found, we know this, with hormone therapy. This is considered first-line therapy by the North American Menopause Society for women younger than 60 within 10 years of menopause onset with no contraindications. Sandy has
00:04:22
Speaker
A lot of work around this with our group of physicians trying to help us, you know, get comfortable, again, you know, prescribing hormone therapy as it is first-line therapy. Despite this, hormone therapy is underutilized and there are many reasons for this. And this could be, it's on episode, maybe it should be. That's future discussion. But it definitely could be its own topic and Sandy is expert on this. But today we're going to focus on non-hermonal
00:04:50
Speaker
treatments for women who cannot or choose not to take hormones for vasomotor symptoms. So first, let's review who should not take hormonal therapy for vasomotor symptoms. So contraindications are personal history of estrogen, sensitive cancer, including breast cancer.
00:05:10
Speaker
coronary heart disease, myocardial infarction, stroke, venous thromboembolism, and then of course if they have inherited risk of venous thromboembolism, that would be a contraindication.
00:05:21
Speaker
So in 2023, the North American menopausal society wrote a position statement on this topic and they formed an expert panel to review all pertinent literature and to make recommendations. So you remember level one is kind of good consistent evidence. Level two is kind of limited inconsistent evidence. Level three is more consensus expert opinion.
Exploring Lifestyle Interventions for Menopause
00:05:43
Speaker
Um, so Bobby, you want to dig in here and kind of tell us what's the proof.
00:05:48
Speaker
Yeah, so the NAMS divides these therapies into five different categories, lifestyle, mind-body techniques, dietary supplements, acupuncture, and prescription medications. Let's begin with the evidence for lifestyle interventions. Keep in mind that although most of these things are not recommended as effective treatments for phasomotor symptoms of menopause, most of these recommendations are not harmful and may actually have other health benefits.
00:06:15
Speaker
The first example they give are cooling techniques. This would be like changing your clothes, wearing lighter clothes, ingesting the environment in which you live in. There are only a couple of small trials cited here and they have conflicting results. This is therefore not supported by the evidence at this time.
00:06:37
Speaker
And it's common to counsel women going through these symptoms to avoid potential triggers. So alcohol, caffeine, spicy foods, hot liquids, these are common triggers that are thought to provoke the hot flashes. And really there are no trials looking at this as an intervention. So there's really no evidence to support that as a treatment for this.
00:07:03
Speaker
Now, exercise and yoga, there is more of an evidence base available for this. Evidence from randomized controlled trials indicate that neither exercise nor yoga significantly reduces the frequency or severity of vasomotor symptoms associated with menopause.
00:07:20
Speaker
and studies conducted by the Ms. Flash Network, which I think is a fantastic name. Both a 12-week aerobic exercise program and a yoga intervention focusing on specific poses and breathing techniques showed no significant difference in vasomotor symptom outcomes compared to control groups engaging in usual activities. Pulled data from these trials revealed minimal reductions in vasomotor symptom frequency and bother for both interventions.
00:07:47
Speaker
similar to those observed in the control groups, suggesting that there's a strong placebo effect rather than a true therapeutic benefit. Additionally, Cochrane reviews cited in the NAMS position statement corroborate these findings, showing insufficient evidence to support the effectiveness of exercise and yoga in managing vasomotor symptoms. Thus, despite their general health benefits, exercise and yoga are likely not effective treatments for menopausal vasomotor symptoms.
00:08:17
Speaker
Next is dietary modifications, and there's very little evidence available from clinical trials on this, and the results from what we have in observational studies is inconsistent. Nutrition studies are inherently difficult to conduct in a way that reduces biases to an acceptable degree, and specifically when it comes to treating vasomotor symptoms, there really is no compelling evidence to support any dietary interventions.
00:08:42
Speaker
And then finally is weight loss. Now there are smaller randomized controlled trials suggesting that weight loss may reduce basometer symptoms, which is very promising, but larger trials are needed to say this with any significant level of confidence.
00:08:58
Speaker
bottom line with these lifestyle interventions, you know, lose weight if you need to. And this might help with your hot flashes, but otherwise, there's really no reason to restrict yourself from certain foods or beverages to manage these symptoms. And additionally, carefully weigh the potential effects on your utility bill and on others in your household before you go about setting your thermostat to 60 degrees.
00:09:20
Speaker
That is a great summary, Bobby. You mentioned the placebo effect in the trials on exercise. Let me just tell you, I've experienced a hot flash while doing down facing dog, and it's not fun. It's not fun. I love yoga, and it does calm me.
00:09:41
Speaker
But in the midst of down facing dog when you're having a hot flash, that's not a great moment. Seems like that's going to ruin your flow for sure. A little bit, a little bit. But you can rebound, you can get back at it. Let me go back to this placebo effect. Because placebo effect is seen throughout all kinds of studies. This is not a new thing. But particularly with these vasomotor symptom studies is quite impressive. So the placebo effect is consistently shown to have a 20% to 60% improvement rate
00:10:10
Speaker
in trials for vasomator symptom treatment. And I don't really know what that suggests, but it does appear that a rather robust placebo effect is involved. Additionally, women with higher levels of anxiety over their symptoms, so very, very anxious about their symptoms, have been shown to have a higher placebo response rate, which kind of makes sense. And these are the things worth keeping in mind when evaluating these treatment options.
00:10:34
Speaker
So, Dawn, do you want to start next with the evidence surrounding mind-body techniques? Absolutely. Okay.
Can CBT Reduce Menopausal Symptoms?
00:10:44
Speaker
So, mind-body techniques. So, this includes quite a few things. So, cognitive behavioral therapy, CBT, mindfulness-based interventions, clinical hypnosis, pace, respiration, slow breathing techniques, and relaxation techniques.
00:11:00
Speaker
Let's spend a little bit of time on CBT. So the initial studies done on this were two randomized control trials, menos one, I'm gonna call it menos because it's M-E-N-O-S, which means less in Spanish. I'm using Spanish pronunciation. I think it's quite clever. I don't know how to research this. I think the researchers may have used menos, which means less in Spanish, means less hot flashes. That's what I'm thinking. We'll see. So menos one and menos two,
00:11:26
Speaker
first found benefit from group CBT and breast cancer survivors, while Menos too showed a reduction in vasomator symptoms and problems in perimenopausal and postmenopausal women without breast cancer from both group and self-guided design CBT.
00:11:44
Speaker
So subsequent studies have expanded CBT's application, demonstrating its efficacy across different delivery modes of populations. And this is important. This includes nurse-delivered CBT, online CBT, CBT self-help books, which is really important because this will make it much more accessible, given concerns over availability of CBT therapists and just the cost of formal CBT and just the availability.
00:12:11
Speaker
So overall, the North American Menopause Society gave this a level one rating and declared this a recommended treatment option. And then the other thing I mentioned was clinical hypnosis. And this is new news to me as we were looking over these recommendations. So this is very interesting. I have to say I've never referred to a hypnotist before. So I'm taking this in as I'm sharing it.
00:12:40
Speaker
you know, there is some evidence suggesting benefit. So there were two randomized controlled trials cited, one which looked at breast cancer survivors and another postmenopausal women in general. Both studies showed a reduction in hot flash frequency and severity compared to a control group to reduce the frequency and severity of vasomotor symptoms. The reductions in the second trial, now this was a number, an N of 187,
00:13:09
Speaker
It was substantial with hot flash frequency reported 74% in the control group versus 17% in the hypnosis group, as well as reduced hot flash severity, 80% versus 15%. So they gave this a level one grade and recommended therapy.
00:13:31
Speaker
Wow. Well, while that's very intriguing, I do want to give a word of caution about interpreting those results too strongly. One of the challenges of performing a high quality randomized controlled trial on clinical hypnosis is the difficulty in finding inadequate control. And this is really difficult for any type of procedural intervention because the closest thing you can get to a placebo is a sham procedure.
00:13:56
Speaker
So any other control is going to fall short of that and keep you from being able to double blind. So ideally, the control you would have for hypnosis study is going to be a sham hypnosis session. And from what I understand, there are technical challenges in creating an appropriate sham hypnosis. I can imagine that is the case. The first study on this used no treatment as their control group, which
00:14:22
Speaker
is frankly, to me, useless for drawing any meaningful conclusions other than we should study this again with a better control. The second study though, the one with the strong reduction in symptoms does make a better attempt at an adequate control by using a control group that received five weekly sessions of structured attention control.
00:14:43
Speaker
So they designed those sessions to match the therapeutic environment, the therapist interactions, and the discussion of symptoms that the intervention group got in their five sessions, but the intervention group also got hypnotic induction. So that is definitely a better control
00:15:01
Speaker
But in my opinion, a level one evidence rating is a bit strong based on just those two studies alone. But anyway, I'm done with my soapbox, Dawn, you can continue. In addition to that, I don't know enough about hypnosis. Is there any downsides or any risks? And I need to study on this more.
00:15:19
Speaker
But so thank you, Bobby. Thank you for your input on that. And it's really important to think about that. And it is interesting that it was a level one evidence rating. So next on our mindfulness-based interventions is, next is the mindfulness-based interventions. Ultimately, this has not been studied enough to recommend at this time. Studies looking at paced breathing showed no benefit in alleviating the vasomotor symptoms. And this is not recommended.
00:15:48
Speaker
Evidence for benefit from relaxation techniques is limited and inconsistent, therefore not recommended. Although, again, does it do harm? So it's kind of, you know, that's a shared decision making. If they want to do that, certainly women could do that, but we can't promise that it's going to be much benefit.
00:16:08
Speaker
So bottom line, when in doubt, CBT for everything. It's always the board answer. It's always the board answer. Always the board answer. And for baby motor symptoms, hypnosis also has positive results. I feel badly that I have not scheduled my CBT and my hypnosis and I probably need to do that. It would help me get through my yoga class, right? Do you think?
00:16:34
Speaker
I don't know. Oh, okay. Thank you, Dawn. That is a really good summary. And I will admit to you, just like you admit, you know, I mean, I'm clueless on hypnosis. I wouldn't even know where to refer. But even in the field of CBT, I know exactly who to go to. I know whom I would go to. We have access here. We have fantastic psychologists. But as far as self-guided and nurse, you know, self-instructed, I need to do better at that.
00:17:00
Speaker
So, I'm going to try to look into that for myself. So, I will admit that to you. Okay. Are we ready to go on to dietary supplements? Yes? Yes. Let's do it. Okay. Okay.
Effectiveness of Soy and Black Cohosh for Menopause
00:17:11
Speaker
It's got to be the diet, right? Okay. Soy. That's the big question. So, soy supplements and extracts and also the soy metabolite equa. So, I don't know if you guys have heard about these different terminologies, but there are mixed results for all.
00:17:25
Speaker
is the bottom line. Some of the data suggest that soy is effective, but it needs to be consumed for up to 16 weeks before any expected result. And it's really hard to carry that out and to be consistent to have the same amount of supplement up for that long.
00:17:41
Speaker
It is interesting to me in just reading for this podcast that only 35% of North American women can actually metabolize soy to the form of equa, which is basically a very low potency estrogen. But only 35% of women can actually metabolize that. So that's a huge confounder, a huge, you know, not really a bias. It's just, it's your genetics, but we don't know who those women are going to be. So I found that also very interesting.
00:18:09
Speaker
So small studies do not show an increase in the risk of recurrent breast cancer when you are taking soy supplements or foods or ingested that contain a lot of soy, drinking soy milk. So it's considered safe. And for a while that was even in question. So we do at least have safety data with it, but the efficacy data is very limited. So the North American menopausal society assigns this to level two, and they say it's not recommended just because of inconsistent results. But I can at least say that I feel that it's fairly safe to do.
00:18:39
Speaker
And then black cohosh is the one that we all talk about. It's probably the one that most women have tried before they come in. Everyone talks about it on social media. A 2012 cock and review of over 2,000 peri and postmenopausal patients, women did not show improvements in vasomatous
00:18:56
Speaker
symptoms compared to placebo. So, as much as I hate to say it, black cohosh does not work, and I can't recommend it. But, you know, when I flip it and I look at the safety, I do think that it is safe. And then you put in the placebo effect and you're purchasing something and you believe it's going to help. So, it's in that situation where I'm okay with it when women try it, but as far as
00:19:22
Speaker
me trying to sell it, it gets very difficult for me to sell. Unless I'm just trying to sell placebo and I can, I guess I can get in favor of that. I mean, that's basically what you're, you're doing there is you're taking a placebo. You are. You're taking a placebo. And so I would say maybe in that light, find the cheapest placebo you can find. Yeah. I don't know. The bottom line for this though is save your money. I just, it's really hard for me to recommend it. Um, but if it's, if it's cheap and you want to do it, I think it's fairly safe. So.
00:19:51
Speaker
Okay, the fourth category is acupuncture. And again, I'm so intrigued. This is something that I need to know more about. But traditional acupuncture versus no treatment has some modest benefit. But when compared to sham acupuncture, as Dr. Scott just astutely educated us on sham procedures, the results are the same. So level two, not recommended. So there was really no difference between the sham and the actual procedure.
00:20:16
Speaker
This highlights the caution that you were mentioning earlier, and you have to be kind of careful with that. So the bottom line with acupuncture is we do have positive data. I just put a little plug in for insomnia and pain and certain situations. But when you're looking straight at hot flashes and vasomotor symptoms,
00:20:36
Speaker
It's not effective. And it's about $100 per session. I did find that out. So it's a fairly expensive kind of sham thing. But if you have pain and insomnia and some other reasons, maybe if you change your focus to that, because certainly insomnia can come with menopause as well. So maybe it can be beneficial in that light. Yeah.
00:20:59
Speaker
Okay, are we ready to go to kind of, you know, my favorite, which is the prescription medications?
Non-Hormonal Prescription Medications for Menopause
00:21:05
Speaker
Yeah, we're doctors, we love prescriptions. I'm actually a pharmacist that tries so hard to get patients off of everything that is absolutely necessary. But I'm putting this up there, guys, okay, as a person who actually is taking such medications, it happens to be in the hormone realm, but
00:21:27
Speaker
There's a distinct difference, so I do have a little bit of my own bias here, but we're going to focus on the non-hormonal prescription medications because I'm happy to tell you there is some positive data with it. So some of our strongest data for improvement with vasomator symptoms is with the SSRIs and SNRIs.
00:21:42
Speaker
These trials are fairly well-designed. They are blinded with objective questions and diaries for women to complete. Most of these trials include women with bothersome symptoms and no history of depression or generalized anxiety disorder concurrently. So these are women that you're not just, you know, treating the depression and anxiety and, oh, by the way, it may help the hot flashes. So it's very important to understand that these are non-depressed, non-anxious currently. You know, their PHQ-9 and their GED-7 are showing
00:22:12
Speaker
you know, healthy levels, but they're on SSRIs or SNRIs versus placebo in these trials. So, the only FDA approved antidepressant for vasomator symptoms is paroxetine, 7.5 milligrams, very small dose, but there are other off-label options, and we do off-label all the time, so you know that. Specifically, there are trials with acetalapram, acetalapram, venlafaxine, and deslafenlafaxine that have all shown significantly
00:22:41
Speaker
significant reduction in vasometer symptoms. And these are large, double-blind, randomized control trials. All these women were symptomatic. Diloxetine has also been shown to reduce symptoms, but the trials were smaller. But that is another option that showed some positive results. So collectively, when you pull all these together, hot flash reduction varied from 25% up to 65, or excuse me, 69%.
00:23:05
Speaker
So, and it is hard to kind of discern exactly which one is going to be the most effective. And I don't want to go out on a limb and say that one SSRI or one SNRI is superior than another because they haven't been directly compared to each other. And so they are all considered moderately effective. When you look at a pooled analysis of esitalopram between 10 and 20 milligrams versus venlafaxine 75 milligrams versus estradiols, this is a pooled analysis,
00:23:35
Speaker
But the estradiol dose was only 0.5. So just to make sure, you know, 0.5 is usually the starting dose. One milligram is the typical dose. Some women go up to two milligrams. So that's in the estradiol family. When they did a kind of head-to-head comparison of that data, they showed a daily reduction in hot flashes of 2.3 more than placebo with estradiol and 1.8 more per day within the vaccine and 1.4 more with acetalopram.
00:24:04
Speaker
It all worked in reducing the number of hot flashes, but you can see that it was 2.3 more with estradiol, 1.8 within the vaccine, 1.4 with acetalapram. So these women had to have at least 14 bothersome hot flashes per week to be enrolled.
00:24:23
Speaker
That is not insignificant, but you're going to see in later trials that 14 per week is not the same as like 10 per day. So 14 per week. And I applaud them for including that because it's hard to categorize whether you're having, you know,
00:24:41
Speaker
moderate or severe severity of your vasomotor symptoms, it's so subjective. But I will say this, of note, when the estradiol one milligram dose is studied, it is definitely proven to be more effective in this population with an average of a 75% reduction and bothersome hot flashes. So just know that when you compare estradiol, it was the smaller doses and the higher doses. We all know that hormone therapy is superior
00:25:10
Speaker
But overall, the SSRIs and SNRIs were given a level one recommendation by the North American Menopausal Society. So, I don't know if you noticed in my, you know, naming, spitting off all of these medications that I did not include fluoxetine and sertraline.
00:25:27
Speaker
And that's not insignificant. I just want to kind of bring that up. These two have also been studied, and they did trend towards significance, but it didn't meet statistical significance. Also, you need to think about the side effects and drug interactions with all the SSRIs and SNRIs. You need to specifically look and then specifically look at drug interactions. And the one that I just want to make very
00:25:50
Speaker
clear is that with paroxetine, which is FDA approved, shown to be effective, and fluoxetine, not FDA approved, trending towards significance, both of those are your, you know, strong cytochrome P450, 2D6 inhibitors, right? When you have a breast cancer survivor that is now on tamoxifen,
00:26:14
Speaker
that person needs that 2D6 enzyme to metabolize tamoxifen to his active form. It does not work if you don't have the 2D6 in check. So studies have shown a recurrence of breast cancer in women who take tamoxifen and also take either fluoxetine or paroxetine. So for that reason,
00:26:35
Speaker
you would not want to use those medications. So if you are on tamoxifen, you should not take paroxetine or fluoxetine. So just make sure you're just checking in on those drug interactions. You know, little things like bleeding, hyponatremia, SADH, these are all the things that come with SSRIs. I know we like to think about them being completely safe, and they are safe and effective medications, but you know, it's
00:26:58
Speaker
we forget about sometimes these serious, rare side effects that can come with medications. And I think patients have a right to know kind of what you're gonna be monitoring for and looking for. Okay, so SSRIs, SNRIs, check. Gavapentin.
00:27:12
Speaker
tell you it's all the rage. When in doubt, CBT followed by gabapentin, right? It just seems like it works for everything. But it comes with a cost. Anyway, that's my own bias. It was hard for me to, I can't tolerate gabapentin very well. I got very sedated with it. But gabapentin titrated to 2,400 milligrams a day, which is a pretty hefty dose, has been shown in small trials. So these are about 60 women. To reduce hot flash frequency by 71%
00:27:38
Speaker
compared to 72% with a conjugated equine estrogen 0.625 milligrams. The placebo rate in this trial was 54% though. So it's really interesting. So placebo was 54% reduction and 72% with your doses of conjugated equine estrogen at 0.625 and then 71% with 2400 milligrams of gabapin.
00:28:02
Speaker
So, I don't know. That's kind of hard to look at the difference of that, see how clinically significant that is. And you guys know this better than I do. Headache, dizziness, disorientation, very common with those doses of gabapentin. The number needed to harm has actually been shown in the trials to only be four. So, you only have to treat four women to cause one of these side effects.
00:28:24
Speaker
So the North American Menopausal Society gave Gabapentin a level one recommendation. But my biggest concern is just the frequency of the adverse effects. You just have to really follow it closely and make sure the patient understands. And some people can tolerate it very well. And for that reason, you can you can keep it going. But if they're not tolerating it, I would probably. Yeah, I would be quick to to disarm that. So Pre-Gabalin, well, yeah, sorry, I can't say the brand name. Pre-Gabalin has so sorry. That was like a
00:28:54
Speaker
a pharmacist, wasn't it? I'm sorry. I mean, I like to be bilingual, but people get angry with me for that. It has shown similar results in very small trials, but given the high rate of adverse effects and just the simple fact that it's a controlled substance, I don't know that anybody's jumping on to go that route with vasomotor symptoms. Okay.
Introduction of Fezulinetant for Vasomotor Symptoms
00:29:19
Speaker
Then we have a new class. Are we ready to go to school? Are we ready to go back to medical school? I'm going to do my best. There is a new class of medication that is FDA approved for the treatment of vasomator symptoms called the neurokinin B antagonist.
00:29:36
Speaker
and a pheasant, and I am gonna say the brand name because you need to know it, because people are gonna come asking for Vioza. So it is- It's on TV. It is on TV every day. It's on my Instagram. The fact that it's hearing me right now, I'll have advertisements all afternoon about it. It's the first FDA approved agent in this class. And this really gets to the core of what causes a hot flash, which I find so interesting. And I don't truly understand it, but I'm gonna try to describe it.
00:30:06
Speaker
So, there is a thermoregulatory center in our hypothalamus that becomes disrupted when estradiol levels declines at menopause. Can I get a witness? It happens, okay? You can't will it away, okay? The specific hormone that regulates the center is gonadotropin-releasing hormone, which is regulated by three smaller hormones that we like to call the pacemakers, okay? It's kisspeptin,
00:30:37
Speaker
neurokinin B and dinoorphan. Now, when they refer to this in the studies that I was reading and the review articles, they refer to these three smaller hormones or pacemakers as the candy pacemakers, starting with the candy. Isn't that great? It's a candy problem, right? So specifically, if you look at neurokinin B, that serves as the stimulator in your thermoregulatory center and dinoorphan is the inhibitor
00:31:06
Speaker
of this regulatory center, and it's very disrupted by your estradiol levels going down. So by antagonizing your neurokinin B, there is less hypersecretion to the thermoregulatory center of the brain, and hence, less hot flashes. Yeah? Easy? Easy? Let me see if I have my mind wrapped around this. Okay.
00:31:29
Speaker
Um, so hopefully though, you know, as soon as we have non-clinicians that listen in, um, those of us clinicians that need a little bit more processing, that's also for them too. Um, so to have this straight, um, the hypothalamus is part of the part of your brain that acts like the thermostat for your body temperature.
00:31:50
Speaker
And there's the chemicals, the fancy ones you just named, in our body that act like switches that control this thermostat. Neurokinin B turns the thermostat up while the dino, dinoorphan, right? Dino correct. Turns it down. And so when the estrogen levels fall in menopause, neurokinin B basically goes into overdrive, sporadically turning your thermostat way up.
00:32:15
Speaker
causing hot flashes. So this medication works by blocking the effects of neurokine and B, preventing it from doing this overstimulation of the thermostat and thus totally reducing the hot flashes. Yes. Yes. Okay. Aw, you're such a good student. We're back in medical school.
00:32:37
Speaker
Again, I could go on my soapbox, Bobby, but just to talk about how to describe a hot flash. This is not sweating. This is not me working out. I know exactly what that feels like. This is in your inner core. And when women try to describe it, it's just really hard. But when I think about this internal thermostat and being inside and the disruption of it, that makes me feel a little bit better that people are understanding what I'm trying to
00:33:02
Speaker
describe as the feeling because it's really, really hard. So, very good job of trying to explain that. So, I'm always intrigued when we have a new class of medication. Of course, I'm always very skeptical. You have to really prove to me that something works and you have to prove to me that it's safe before I'm ever going to recommend it. And let me tell you, I have a large inner circle right now of women in their 50s.
00:33:23
Speaker
that are all coming to me. It's personal for me. I really want to make the right call. What is the evidence? Does this actually work? I'm glad that we are talking about the thermostat in our brain, but does it actually work? There is primary evidence
00:33:44
Speaker
that is really coming from industry sponsor, but these are phase three trials. So these are the trials that are required by the FDA in order to get FDA approval. They were called Skylight 1 and Skylight 2, and both of these trials are very similar. They enrolled approximately 500 women with moderate to severe vasomotor symptoms. And so this is where it kind of is different from the SSRI trials. They averaged at least seven episodes per day.
00:34:06
Speaker
So that was, you know, they were having to have a significant amount per day. And they were randomized into three groups. There were two different doses of the phase of... Sorry. Phase of lenitent. Yes, phase of lenitent. So two different doses, the 30 milligrams and the 45 milligrams, and then placebo, of course.
00:34:26
Speaker
The primary outcomes were changes in baseline at four weeks and at 12 weeks in the frequency and the severity of your base emitter symptoms. And at baseline, the mean frequency, just so you know for these studies, the mean frequency was 10 to 11 episodes per day. So they had to have at least seven to be enrolled in the trial, but these women were having 10 to 11 per day, not 14 per week like this in the other studies. That sounds terrible.
00:34:49
Speaker
It is pretty awful. Yeah, I'd like to see how long you would try to suffer through it, right? I lasted a whopping three weeks before I called in reinforcements from my primary care team. Okay, so back to the studies. In Skylight 1,
00:35:07
Speaker
The mean daily frequency of vasomotor symptoms with the 45 milligram daily dose, which is the dose that was ultimately approved by the FDA, was reduced by about 2.55 episodes per day at 12 weeks compared to placebo. So two and a half less episodes per day.
00:35:23
Speaker
In Skylight 2, it showed similar reduction in your average vasomotor symptoms at 12 weeks. So, 7.5 episodes per day was the average. So, compared while placebo reduction was basically 5 episodes per day.
00:35:40
Speaker
So wait, I don't think I made that very clear. Let me repeat that. In Skylight 2, there was a similar reduction, but at 12 weeks, it went down by 7.5 episodes per day versus placebo, which was five episodes per day.
00:35:57
Speaker
So placebo was not better. Okay. Placebo was still worse, but it was a decrease of five. Right. A decrease of five. Yes. Sorry. I kind of butchered that. So in both of these studies, the mean reduction is about 2.5 episodes per day compared to placebo. Okay. When you compare it.
00:36:12
Speaker
But remember, the baseline numbers was pretty high, you know, 11. So you'll get five less due to placebo, an additional two and a half whenever you're on the pheasant line of intent, okay? So when it comes to the reduction in the daily severity of the symptoms, so the ones that are considered the most severe, the mean difference was small at about 0.29 points, which is not likely to be clinically important. So the severity of it didn't change.
00:36:39
Speaker
significantly. But note the difference in the vasomator symptoms in this trial with the SSRIs, which I already kind of talked about. I mean, it is encouraging that there is data that started to trickle out with improved quality of life, nocturnal awakenings, and sleep quality. And I mean, I can attest to this with myself and with my inner circle. You know, we can handle some hot flashes during the day and we can even laugh about it, we can joke about it, we can have a better attitude about it, but when you start interfering with my sleep,
00:37:08
Speaker
And I'm waking up and when you wake up with these night sweats, it's not just a little hot. It's not like you just have to take the blanket off. You have to literally get out of the bed and decide, you know, are you going to take a shower? You're going to definitely change your clothes. Your sheets are completely soaked.
00:37:26
Speaker
You know, I sleep in the same bed with my spouse. He's fast asleep. What am I going to do? So then I put a towel down. I mean, it's a whole, it's a whole thing. And then you finally get settled back down and 45 minutes later it happens again. And that only had to happen to me literally for three weeks until I had to tap out and say, I cannot continue to not get sleep. I was probably sleeping.
00:37:44
Speaker
you know, two to three hours a night. And that's, I can't even pretend to do this job with two or three hours over time. So that's what really called it for me. So bottom line is, well, hold on, let me go back to side effects. So let me talk about safety. Very, very safe. Headache was the most common side effect that was reported in the trials. And I believe that was about
00:38:09
Speaker
2% of patients. And they are, they did see it, you know, the phase two trials, some elevations and LFTs. And I'm not super concerned about it, but I am, I like to be very, very conservative. And I agree with what they recommended. So baseline LFTs, three, six, and nine months.
00:38:29
Speaker
I'm hopeful that throughout time, just like with statins and all the other medications that we learned over years that we don't have to check LFTs as frequently, I hope that's going to follow suit, but for now we need to be very cautious with that. You need to talk about headache as the main side effect, which I know is difficult to ascertain the cause of your headache, and then you have to check liver enzymes for sure.
00:38:53
Speaker
Bottom line for pharmacologic management, prescription medications for vasometric symptoms, venlafaxine, paroxetine, esitalopram, deloxetine, and fezulinatant all have a shot at helping your hot flashes, okay? If it's appropriate, consider these. Paroxetine should not be used in women with tamoxifen, so just another little plug for that.
00:39:14
Speaker
The last thing I'll say, because I do have one friend that's actually doing this, is that we do not have any studies to date on combining any of those SSRIs or SNRIs that I just mentioned with a neurokinin antagonist. But it's reasonable that if you are not getting adequate control with, you know, one of those therapies, say it's venlafaxine and, you know,
00:39:40
Speaker
you want to try, you know, a neurokine and antagonist. I can't think of a pharmacologic reason why that would be a contraindication because it's just hitting different receptors, it's working two different ways. We oftentimes use combination therapies for treatment. So, but it's not, it certainly has not been studied yet. I hope that it will be. Yeah, it seems like that would make sense.
Cost and Effectiveness of New Medications for Menopause
00:40:01
Speaker
Well, to wrap things up, it sounds like we have several non-hormonal pharmacologic options available. When trying to choose one, here's how I guess I would think about it and go and approach this. The big issue at this point is cost. Yes. It's about $600 a month out of pocket for pheasant.
00:40:20
Speaker
Obviously, insurance coverage is going to be variable, but it's a new medication. There is a pharmaceutical savings coupon for this. It's similar to the others. You get your first month free. Your following months can be as low as $30 up to an annual total discount of $4,000. Additionally, like most coupons, these are only for patients with commercial prescription coverage.
00:40:44
Speaker
So, although we don't have any head-to-head trials, fezulinatant seems comparably effective to SSRIs and SNRIs based on the evidence we have thus far, and it seems like it may have a better safety and tolerability profile. So, I think eventually we may see fezulinatant as the first-line non-hormonal option, but practically because of this cost barrier, even though I would likely recommend this over an SSRI or SNRI, most patients are probably not going to be able to afford it right now.
00:41:14
Speaker
Yeah, Bobby, I tend to agree. If costs weren't a consideration, I might lean towards this as a first line option for women who can't or won't take hormones for their vasomotor symptoms that are negatively affected by, you know, their quality of life is bad. And I tend to agree. But they do not currently suffer from depression, anxiety. Then certainly I would go that way. If that is a confounding factor, then I certainly would go lean towards the SSRIs or SNRIs. So you just have to, you know, share decision making and
00:41:43
Speaker
for your first choice. So I think that's why it's, and I guess, Dawn, do you agree with that assessment? So depression, anxiety, some other issues going on, maybe go the SSRI, SNRI, but otherwise, if they can afford it, be something that you'd be willing to try as long as the liver enzymes are not an issue, right?
00:42:02
Speaker
I agree. I think that, you know, I'm lucky to have Sandy as my in-house personal menopause expert. So we've had numerous cases that we've kind of used this kind of algorithm in this pattern and I do agree. I think it's a good strategy.
00:42:16
Speaker
Good, good. I'm glad that we think alike on this. And I just want to re-emphasize the efficacy of CBT and I'm preaching to the choir right here because that is something that I think CBT is probably good for everybody every single day, right? And I'm going to make that commitment to you guys here on the air, right? I'm going to look into that and see if I can get better at that.
00:42:39
Speaker
Well, thank you both. That's all for today's episode. We'd like to thank all of you for listening. If you enjoy this podcast and you found it useful to your clinical practice, really the best way you can support us is by sharing it with your colleagues, your friends.
00:42:55
Speaker
and even your patients. And we would also love to hear from you. So we invite you to share your experience, your thoughts, your questions about today's topic with us. And also, if you think there are topics that would be valuable for us to cover, please share those as well. You can reach out to us by email at whatstheproofpodcastatgmail.com or on X, formally known as Twitter, at The Proof Podcast. Until next time, this is What's The Proof?