Suzetrigine aims to deliver non-addictive, non-opioid pain relief

Host Amber Smith: Upstate Medical University in Syracuse, New York, invites you to be The Informed Patient, with the podcast that features experts from Central New York's only academic medical center. I'm your host, Amber Smith.

Lots of people with short-term pain are concerned about becoming addicted to opioid pain medications.

The Food and Drug Administration recently approved a new non-opioid prescription pill called  suzetrigine that is said to be non-addictive. Here to tell us about it is Dr. Vandana Sharma. She's an anesthesiologist and the director of pain management services at Upstate.

Welcome back to "The Informed Patient," Dr. Sharma.

Vandana Sharma, MD: Thank you, Amber. Thank you for having me for this talk show. It's really a pleasure to be here.

Host Amber Smith: Well, if I understand correctly, suzetrigine is the first in a new class of analgesics.

So what type of pain is it designed to treat?

Vandana Sharma, MD: You are very correct. For a very long time, actually, the acute pain world has been missing a new addition to our armory of medications that we use for acute pain, so this comes as a very nice change for us. Long time ago, World Health Organization revealed the WHO "Ladder" (for pain treatement), which most physicians are aware of, and that includes, starting with the least addictive drugs, and then moving up the ladder to treat patients' acute pain.

And for almost decades now, we have been using acetaminophen, in other words, Tylenol, ibuprofen. We have been using weak opioids and adding some adjuvants (secondary treatments) to them, like gabapentin and nortriptyline are antidepressants.

But each one of these comes with its own side effects or sometimes inefficacy or not being able to work alone. So we did need another drug, in this continuum of medications that we have, that could one, give us another option to treat pain, and two, could work along with all other medications and help better to increase the potency of pain control.

As an acute pain specialist and chronic pain specialist, I'm very excited to know that finally we have one more breakthrough in this realm of acute pain management, where we could help our patients with another class of medications.

Host Amber Smith: So it's another tool that you can use?

Vandana Sharma, MD: Absolutely.

Host Amber Smith: Would you use it more for chronic pain or acute pain?

Vandana Sharma, MD: At this point of time, it's only approved for acute pain and for a short period of time. So based on the limited studies that we have available, it's marketed by a pharmaceutical company, and they have studied it on over a thousand-plus patients. And this is studied only for acute pain patients. It has not yet been studied for chronic pain patients. And they have been cleared to use it only for a two-week period maximum. So 14 days would be the maximum time period that we could use it, but it definitely gives us the option when the patients need it the most.

Where I'm looking at it is, like, patients who have acute postoperative pain, where we do not want to quickly go over to opioids right away. This would be another thing that we could use before we put our hands on the big guns.

Host Amber Smith: So after surgery, this might be something they get in the hospital, or they get sent home with?

Vandana Sharma, MD: We don't know yet, but I'm working on it, to put it there. This was very recently cleared by FDA, and typically, in academic institutions like Upstate, we usually do not quickly rush over to something that just comes out. We want to foresee the results, and again, sometimes looking for the results takes a long time as well.

So we did our own research, we did our own studies and talked to the company reps as well. So far it's looking promising, but I wouldn't know for sure till I use it, and that's why we are trying to be as familiar with the drug as possible.

For now, just as you said, I think we could start using it in acute postoperative period. But also there is a limitation that this is an oral drug, so a lot of times people are not ready to take orally as soon as they come out of surgery, so I don't see that I could use it in PACU (post-anesthesia care unit) right away.

But I do see that this is something we could start once the patients are able to take orally at all our outpatient surgery centers, where the patients could be sent home the same day, so they're ready to take orally after a couple hours, after anesthesia wears off.

Host Amber Smith: Well, let me ask you a little bit more about some basic questions. Can you explain for us how pain works in the body? How does the brain receive pain signals?

Vandana Sharma, MD: That's an interesting question. I'll try to simplify it as much as possible.

I know it's a complicated phenomenon, but let's try to make it simple. I'll start with the concept of nociceptors, or in simple words, these are pain receptors. Now, these pain receptors are everywhere in the body. They're present on the skin, in the tissue, in muscle tissue, in joints, in the coverings of the brain, which is called dura.

In other words, they're present everywhere. These pain receptors, they sense pain, and then their job is to, once they have sensed an injury ... so, going back again, pain is like a response of the body to protect itself from the injury. So that's how the pain initially evolved, as a protective response. And typically it starts with an injury or an inflammation, something that the body senses as not a pleasant experience to it. It can be a chemical injury. It can be a mechanical injury, like a surgery, or it can be an inflammatory injury, any kind of injury sensed by these pain receptors.

And then they transmit this pain signal through the specialized nerves to the spinal cord. And in the spinal cord, the conjunction of these nerves are what we call first-order neurons, or first-order nerves. They hand over the signal to the second-order nerves, and then these nerves from spinal cord take the signals over to the brain.

So this is like a pathway that starts in the periphery. And periphery could be anywhere in the body. And from the periphery, they transmit this signal to the center, which is first the spinal cord, and then spinal cord to the brain.

When we talk about the pain pathways, we have targets at all these different sites where the pain pathway can be blocked. And in other words, those are the places that we use as pain physicians to help our patients. The most promising thing that we were using so far to treat acute pain or acute postsurgical pain was nerve blocks, which is to numb up the nerves that are sensing this pain. And they obviously have to be injected near a nerve, so it's a procedure.

Suzetrigine, which is a new drug, is doing this similar thing. It's working on the same receptors that the nerve-blocking agents work on, such as lidocaine works on, but in a different manner. And it's highly specific for the specialized nerve receptors, or the channels that activate these nerves, which are called sodium channels.

Another good thing about suzetrigine is that it works in the periphery, which means right where the pain begins. That's where it dampens the nerve signals as they're carrying the nerve sensation, the pain sensation, from the periphery over to the spinal cord, so it's a novel mechanism of action.

But unlike the nerve-block agents like lidocaine or bupivacaine, the commonly used local anesthetics in practice, which may or may not be feasible to be used in all sorts of patients, suzetrigine, most likely being an oral agent, can be used in the periphery for variety of pain syndromes.

Host Amber Smith: And it's again, an oral medicine that you take, you swallow, as opposed to the injections with the nerve blocks.

Vandana Sharma, MD: That is correct. It's an oral pain medication. By no means I want to sound like this would replace the nerve blocks, because nerve blocks are still, I feel, the most potent way for us to control pain, to stop pain. Regional anesthesia still is, I should say, the best tool that we have available to control acute pain in whatever circumstances we can use it. Like, for example, in orthopedic surgeries or major abdominal surgeries or major thoracic surgeries, regional anesthesia, in whatever form, either in the form of central blocks or peripheral blocks, it helps the best, as the topmost site of controlling pain. And then after that, we use all the other adjuvants, and I see suzetrigine as being an adjuvant, where we could use it in addition to everything else.

Host Amber Smith: This is Upstate's "The Informed Patient" podcast. I'm your host, Amber Smith.

I'm talking with Dr. Vandana Sharma about a new non-opioid pain medication called  suzetrigine.

So if suzetrigine and nerve blocks work on nerves, is that how opioids and acetaminophen and ibuprofen work? Do they also work on the nerves?

Vandana Sharma, MD: They do not work directly on the nerves, but they do work in the whole pathway, as I talked about, from periphery to the spinal cord and from spinal cord to the brain.

So, as I said, there are several areas of pain modulation in this whole pathway where these drugs work at different steps. So let's first talk about Tylenol, for example. Tylenol and NSAIDs (nonsteroidal anti-inflammatory drugs) both. So they are both anti-inflammatory agents, which means they stop the inflammation. The NSAIDs like ibuprofen or meloxicam or Celebrex, they all work in the periphery, where the inflammation is happening.

So as I first alluded to the pain receptors, or nociceptors, they usually get activated by inflammatory markers that rise in our blood as a result of inflammation injury and whatever. So these anti-inflammatory drugs like ibuprofen and other NSAIDs, they stop the inflammation in the periphery, and that's how they stop the pain signals from going forward.

Tylenol, on the other hand, is more of a central inflammatory agent, so it doesn't work as much in periphery as it works in the central nervous system. So that's how it causes a reduction in fever as well as in pain.

Now, talking about the other agents, like opioids, which work on separate kinds of receptors, these are immune receptors that are present, again, everywhere, but they are more concentrated in the spinal cord as well as in the brain. And they can be used as an IV (intravenous) agent or as oral agents or even in the form of an adjuvant to the epidural infusion sometimes, where they can work directly on the spinal cord receptors.

So they are very potent. But then, at the same time, they do carry the risk of dependence and addiction. And that's why, if you would know that we are trying to find ways to minimize the use of opioids in the perioperative period, what we have noticed over last few decades is that the acute perioperative period is the time when the patients could for the first time get exposed to opioids, even though it's for a short period of time. But it can sensitize them to a different pathway in their lives towards pain sensitivity and also is a crucial time when people could develop opioid dependence and, in worse forms, could develop opioid addiction.

And believe it or not, perioperative period is a very critical time when all these things can happen, and especially in "opioid-naive" individuals. So we are always, as I said, trying to find out ways to minimize the use of opioids. To say we can do opioid-free anesthesia or opioid-free analgesia (pain relief) in the perioperative period would be a long shot, at least at this point. It's not impossible, but it's difficult. And that's why we depend upon many medications that work on different mechanisms to stop the progression of pain, in addition to opioids.

So, going back to how these other drugs work, I just briefly talked to you about how opioids work, how NSAIDs work, how Tylenol works, and how nerve blocks work as well, which is like numbing up these nerves from carrying the pain. And then we have several other adjuvants, like gabapentin or pregabalin or Lyrica, that all have shown a little bit of promise. We have gotten some studies that have shown they're wonderful, and then there's some studies that have shown that the side-effect profile is not as good. So they cannot be used on every patient with the same efficacy.

And I think that's true for all other medications, too. You have to be very selective for which patients, what kind of pain that you're treating and what combination can you use, several interactions that they could have with other medications.

And same thing is true for suzetrigine, as well, and even though we don't know a whole lot yet, because of the lack of real world data. All we are getting is from these randomized control trials that the drug company did. But again, the way I look at it is, it's a promising avenue, at least for the first time someone is looking at sodium channels, highly selective sodium channels, blocking them and trying something that is not addictive, that does not work on, these other receptors, does not interact a whole lot with other medications and could help through a different pathway.

Host Amber Smith: Now, you used the phrase "opioid naive." is that someone who hasn't taken opioids before?

Vandana Sharma, MD: Yes. CDC (Centers for Disease Control and Prevention) defines opioid-naive individuals, who have had minimal exposure to opioids, for less than two weeks.

Host Amber Smith: Well, how do we know that suzetrigine is not addictive?

Vandana Sharma, MD: That's a great question actually.

First of all, the best evidence that I can tell you is that it does not work on the receptors that addictive drugs work; for example, it does not work on new receptors.

Secondly, in all of these studies, there was nothing so far to prove that the patients who took it had any withdrawal reactions after it was stopped, or there were any difficulties with stopping the medication after 14 days. So it's probably safe to assume at this point that suzetrigine is not an addictive agent and also based on the available data that includes its mechanism of action, the preclinical data, and the clinical adverse event data. All of these have not so far shown an addictive potential for this drug.

Host Amber Smith: Are there people that would not be candidates for taking the drug? Does it have interactions with other medications, for instance?

Vandana Sharma, MD: The answer is yes. we first have to look at how this drug is metabolized in our body.

This is metabolized by the liver enzymes. These are specialized. Liver has a multitude of enzymes, but what we are talking about is a particular subset, which is called cytochrome P450 system. This enzyme is responsible for the majority of metabolism of this drug, so in patients who have liver dysfunction, and especially advanced liver dysfunction, where we would expect that this enzyme would not be fully functional, we expect that suzetrigine may not get metabolized easily. So the pharmaceutical company recommends that there should be dose reduction in patients who have mild to moderate liver dysfunction and should be altogether avoided in patients who have severe liver dysfunction. So definitely that would be one class of patients where I would be hesitant on using this drug.

Anytime we are taking any medications that could inhibit this enzyme, could potentially increase the amount of drug in the system. The company recommends that patients who are using grapefruit, in any form, shouldn't be using that because with enzyme inhibition, there could be potential interactions or increase in the drug levels.

Some other drugs, like some antibiotics, like clarithromycin or erythromycin, could also inhibit the enzyme and could be problematic. Several other medications could cause interactions as well. So it's very important that patients do reveal their medication list to the physicians if they're interested in using this drug.

What we are looking at at this point is at least start using it in inpatients, and then, seeing whether the patients can be sent home with this for a short period of time, like, as I said, 14 days is the maximum. And in most of these studies it was used for a minimum of seven to 10 days.

And for myself, I would want to see how much dose reduction can, be seen in the opioid use, and whether this is worthwhile being used among other medications or not.

If we see that patients have a meaningful improvement in their pain scores, a meaningful reduction in the use of opioids, then I would certainly consider this as a successful endeavor as an acute pain physician.

Secondly, patients with end-stage kidney diseases, where they have kidney insufficiency to severe degree or to the point of requiring dialysis, we wouldn't be using that. It has not been studied in pregnant patients or in children, so again, that is one population where we are still restricted.

We don't know what's next to come, though. I think those are the common ones. And then anytime we are talking about restricting in which populations, we think about elderly population as well. So as long as the liver function and kidney functions are pretty good, so far it has been proven safe in elderly individuals as well.

Host Amber Smith: Well, let's talk about the side effects, because opioids come with a lot of side effects. What about suzetrigine? Are there side effects to be aware of?

Vandana Sharma, MD: As I was telling, they have studied this in more than a thousand patients at this point, and the amount of side effects that they found were not very serious.

Based on the data that I looked at, I think the common side effects that they found were muscle spasms, incidents of rash, some patients had a mild increase in a certain chemical in our body that's called creatine phosphokinase, or CPK. And we do not know what caused this because less than 1% of patients or close to 1% of patients got these side effects.

What was the mechanism behind these? It's hard to say. They also checked on nausea, vomiting, and there was a very mild increase, I believe, in patients who were taking suzetrigine, but nothing was clinically significant for not being able to prescribe. Like, for example, among a thousand patients, I think there were 10 who developed rash, and itching, and some people developed muscle spasms, but nothing was clinically significant to stop the medication.

But I think overall, maybe less than 1% of patients actually stopped the medication for several reasons, not necessarily because of any life-threatening or bigger adverse events.

Host Amber Smith: You didn't mention constipation, and I know that's a big one with opioids. Is that not seen in suzetrigine?

Vandana Sharma, MD: So far they have not mentioned that constipation was seen, and that's one of the big points that causes patient dissatisfaction in the acute perioperative period, not being able to move their bowels. So nothing that has been noticed so far or has been pointed out yet.

Host Amber Smith: Well, it is exciting to have a new class of analgesic. Do you have patients asking you for this?

Vandana Sharma, MD: Yes. I think it was beginning of March, or maybe February, sometime the same day when the news broke out that FDA has cleared this new drug for use in acute pain. At least a few patients in the clinic in my pain clinic, same day, started asking about that.

I do have some colleagues up in the OR (operating room) asking about this as well. So yes, I see the level of excitement among, the general population as well as among the physicians about being able to use this drug.

And I shared the same enthusiasm as well. And that's why I reached out to the pharmaceutical company to see, like, if they could give us more information, whether we could attend some of their webinars to get more information about the drug and if there were safer ways to start using it among highly selective patient groups in the hospital, for inpatients, to get more familiarity with the medication and seeing the safety profile for ourselves.

But at least based on the preliminary data that we have available from a lot of these studies that have been done, I feel confident that I could start using it without worrying too much about the side effects or safety profile of the drug.

Host Amber Smith: Now, suzetrigine is what it's called, but are there brand names available yet?

What else might people hear it called?

Vandana Sharma, MD: The brand name for the drug is Journavx, and I just came to know about this, that what they meant by this was your "nav." Nav is the voltage-gated sodium channel. So they put NAV in there, so it kind of puts the mechanism of action in there, too. So Journavx is what we are seeing right now.

Host Amber Smith: Well, Dr. Sharma, thank you so much for making time to tell us about this. I appreciate it.

Vandana Sharma, MD: Thank you very much for having me.

Host Amber Smith: My guest has been Dr. Vandana Sharma. She's an anesthesiologist and the director of pain management services at Upstate.

"The Informed Patient" is a podcast covering health, science and medicine, brought to you by Upstate Medical University in Syracuse, New York, and produced by Jim Howe, with sound engineering by Bill Broeckel and graphic design by Dan Cameron.

Host Amber Smith: Find our archive of previous episodes at upstate.edu/informed.

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