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Freezing the Pain: A New Way to Treat Rib Fractures
This transcript has been edited for clarity.
Robert D. Glatter, MD: Hi. I’m Dr. Robert Glatter, medical advisor for Medscape Emergency Medicine. Joining me today to discuss a novel way to treat pain related to conditions such as rib fractures and burns is Dr. Sergey Motov, an emergency physician with expertise in pain management and research director in the Department of Emergency Medicine at Maimonides Medical Center in Brooklyn, New York.
Also joining me is Dr. Gary Schwartz, vice chair of pain and anesthesiology at Maimonides Medical Center. Dr. Schwartz is board certified in anesthesiology and interventional pain management.
Welcome, Sergey and Gary.
Sergey M. Motov, MD: Thank you, Robert.
Gary S. Schwartz, MD: Thank you, Robert.
Traditional Approaches to Pain Relief
Glatter: It’s a pleasure to have you both. Sergey, we were chatting earlier this week and you had mentioned a novel approach to treating a common condition we encounter in the emergency department — rib fractures.
As we all know, they’re very painful and can lead to pulmonary complications, including atelectasis, pneumonia due to splinting and lack of proper pain management, along with the use of incentive spirometry.
Sergey and Gary, can you describe traditional approaches to alleviating the pain associated with rib fractures? What do we typically use? Then we’ll get to some novel treatments that we’re here to discuss.
Motov: I’m going to use the emergency medicine approach to rib fractures. As you pointed out, pain relief is of utmost importance.
With the advent and acquiring of the amazing technique of interventional pain management, physicians, for the most part, are very astute about providing nerve blocks to alleviate pain, at least in immediate need. I’m talking about the relatively short term, 1-5 hours, in the emergency department.
Primarily, we focus on fascial plane blocks such as serratus anterior plane block. Traditionally, ED physicians don’t use much of the intercostal blocks. At times, we can direct the spinal block to cover the lateral aspect of the chest wall.
As part of the multimodal approach, we can use NSAIDs. If there’s a contraindication, we can use opioids. There are some data to support consideration of using topical formularies such as a lidocaine patch, but they are somewhat conflicting.
The question becomes what you’re going to send a patient home with. Again, traditional teaching is either opioids, immediate release with a short course, plus or minus NSAIDs, plus or minus acetaminophen.
The issue with rib fractures is that, while we can manage immediate and super-acute pain presentation in the ED and then discharge up to 24-72 hours, what happens afterwards is very challenging. Acute intercostal neuralgia related to traumatic rib fractures is semi-manageable, but if it’s inappropriately treated, it has a great tendency to transform into chronic intercostal neuralgia. It contributes a great deal of disability and morbidity.
Several years ago, I came across an entity called cryoneurolysis (cryo ─ cold temperature; neurolysis ─ freezing the nerve). I’m excited to be here today because Gary is the one who’s pioneering and championing this technique in our institution.
Cryoneurolysis: Mechanisms of Action and Benefits
Glatter: Gary, what do you see as the main role for this procedure at this time?
Schwartz: As Sergey alluded to, the traditional approach of opiates has side effects (ie, constipation, addiction, and tolerance). Unfortunately, many of these rib fractures occur in older patients. They come in anticoagulated, so they can’t have NSAIDs.
Sergey and his team in the ER have been pioneers in giving short-acting local anesthetic blocks that could last anywhere from 12 to 24 hours. There are long-acting local anesthetics that we can get out to 72 hours.
Unfortunately, these rib fractures and the pain associated with them, in addition to the intercostal neuralgia, could take weeks to heal. That’s where cryoneurolysis comes in. We’re all used to ice or cold temperature. For example, if your child gets an ear piercing, they put some ice on their earlobe beforehand, it numbs it up, and they don’t feel pain. It allows them to get their ears pierced without pain, but it’s short-acting.
What we have now are handheld devices with tips about as long as a pen, 3.5 inches, that allow you to go down precisely to these intercostal nerves that innervate the ribs and give a cold lesion that freezes these nerves.
The benefit of it is it’s not permanent like cryoablation, like we’ve seen for tumor necrosis, which destroys outside tissues. It’s really a small lesion, about 16 mm x 8 mm, which is enough to engulf the nerve and pretty much stun it.
It causes axonotmesis, but the epineurium, the endoneurium, and the perineurium — the inner workings of the nerve — stay intact, so it regrows. It just destroys the myelin sheath and the axon.
Glatter: You’re creating a scarring effect; is that what you’re saying? In other words, you’re doing a cold-temperature freeze and stunning the nerve. My question is, does it regrow? Is this a permanent type of injury?
Schwartz: With Wallerian degeneration, nerves do regrow after injuries.
Unfortunately, as you two probably see in the ER for big traumas, where the nerve is transected, those unfortunately do not grow back. This is considered a grade 2 lesion, so the Wallerian degeneration recurs. The nerves grow, depending on the literature you look at, about 0.5-2 mm per day.
This intervention gives us at least 3 months of relief for the patient, which is in the time frame where the rib fracture will heal, hopefully with no damage to the nerve from the fracture, and they go on living their life without having to take opiates or having to stop their anticoagulation.
Because prior to this, when I was a pain fellow, we used to put epidurals in many of these patients. The problem with that is patients can’t go home, and if they’re anticoagulated, you can’t place it because of the risk of a spinal hematoma.
Potential Use in Ventilation Weaning
Glatter: This is something we encounter daily, and certainly for those patients who have more numerous rib fractures or flail chest, this could be even more devastating, as well as for those who get intubated.
Do you see any role, in terms of ventilator weaning, in using this technique specifically in the ICU setting?
Schwartz: That’s an interesting concept. I’m not so sure about ventilator weaning, but we’ve used this in the hospital for rib fractures from traumas where patients had such severe fractures and had to go to the operating room for rib plating, and did necessitate an epidural. We’ve used this to discontinue their epidural and transition them to get the patient home.
I think that is part of the care, not only in the ER but in the hospital as well. We need to treat the patients, but we also have to have a transition plan to get them out of the hospital. Not that we don’t want to treat our patients, but we have to have a plan to get them home. I’m guessing that might be an interesting stage of research in the future if it does help with weaning from a ventilator.
Glatter: There are some studies out there suggesting that there can be some utility in terms of ventilator weaning using this technique. The ability of this to change how we manage pain is just incredible.
Sergey, do you feel that this is something that you could implement in your ED with your patients in the near future?
Motov: Definitely. I have personally been a very big proponent of it. I’m the theoreticist because I’ve covered a great deal of literature, and now having Gary and his team doing this in our institution, it’s a shame not to capitalize on it. I’m slowly moving toward figuring out the way of collaborative effort to have Gary and his team help my team and our colleagues, bring him on board, and maybe broaden the integration for pain management.
I believe, as Gary emphasized, that geriatric traumatic pain injuries are critically important due to the presence of comorbidities, potential drug interactions, and the challenges of managing these factors effectively.
There is one thing I want to bring up, and Gary, please support me on it. The procedure itself is fascinating because it provides long-term pain relief and reduces morbidity. I wouldn’t say mortality, just reduced morbidity. However, we need to be very conscious of the fact that this blockade, this ice-ball freezing of the nerve, can be detrimental to motor nerves. If your whole goal or idea of faster recovery after postoperative knee or hip replacements, or any traumatic lower- or upper-extremity surgery, includes blockade of motor nerves, it’s not going to be beneficial.
I believe the primary therapeutic application of this technology lies in targeting sensory nerves. For instance, intercostal nerves could be a focus in cases of rib fractures. Additionally, this approach shows promise for treating burns, particularly in the lower and upper extremities. Specifically, targeting nerves such as the lateral femoral cutaneous nerve or the anterior femoral cutaneous nerve could effectively neutralize pain and provide significant relief for weeks, if not months.
Based on additional predilection to what particular indications would be, maybe occipital headache with cervicalgia, occipital nerve block — it’s a sensory block — can benefit from it. Slowly but surely, there’s a slew of painful syndromes for which cryoneurolysis might have a great deal of use in the emergency department.
Cryoneurolysis for Other Pain Syndromes
Glatter: Gary, I’ll let you expand upon additional uses that you see. You did mention one on our chat earlier this week, which was postmastectomy pain syndrome with the intercostal brachial nerve. That’s a very compelling area of interest, certainly for the number of women that go through mastectomies or lumpectomies and that have axillary dissection or nerve injury.
Schwartz: Post-mastectomy is one way you could use this device and technology to attack painful syndromes, such as postmastectomy syndrome. Mastectomies are one of the most common surgeries performed in the United States, but I believe it’s a top three for post-op chronic pain, which we don’t normally think of.
There was a great study by a team in San Diego where they did intercostal brachial and intercostal nerve blocks on multiple nerves, and they decreased pain up to 3 months after the surgery and decreased opiates.
As Sergey alluded to, it’s approved for any peripheral nerve in the body. We’ve used it in our pain office for occipital neuralgia, postherpetic neuralgia, chronic rib pain after fractures, and surgery. Some of the most common uses are for superficial, sensory, genicular nerves, the lateral femoral cutaneous nerve, the anterior femoral cutaneous nerve, and the infrapatellar branch of the saphenous.
You could numb the skin preoperatively before a painful surgery, such as a total knee replacement — or as we like to call it, a total knee arthroplasty — to reduce opiates, improve function, and decrease length of stay. You could attack any sensory nerve.
We’ve utilized that already in our private practice. We’re trying to transition into the hospital to have everyone who gets a knee arthroplasty have this technology to decrease opiates, improve function, and recover faster.
This is quite interesting and motivating for me because when I first started, we had a femoral catheter to block the motor femoral nerve or an epidural. Patients were in the hospital for 3-5 days with the CPM [continuous passive motion] machine, which is like a medieval torture device that you might see in Mad Max — where you’re kind of moving the patient’s knee back and forth after surgery, and they were miserable, taking patient-controlled analgesia and high-dose opiates. Now, we’re freezing these nerves beforehand, doing our nerve blocks in the operating room with long-acting local anesthetic, and patients are going home the same day with minimal or even no opiates sometimes.
Implications for Patient Mobility and DVT Risk
Glatter: You’re getting up to 3 months of relief in that setting, doing it as you described?
Schwartz: Yes, up to 3 months of relief, which is huge, because most patients recovering from a knee arthroplasty, at about the 6- to 8-week mark, have improved range of motion, they have their 110° flexion, they have their extension, and they’re getting back to their normal life.
You cover the whole postoperative rehab, where patients don’t have to get recurring refills, they can participate in physical therapy. As you both know, part of the recovery process is to be able to interact with family and friends without being sleepy, angry, and in pain all day, so they can get back to their normal function.
Glatter: In terms of this procedure, would there be any increase in deep vein thrombosis (DVT) in relation to this, by chance?
Schwartz: Actually, there’s less of a risk of DVT because patients have less pain, so they can get up and move faster. Some of my surgical colleagues who have implemented this in their practice have gotten away from using the stronger anticoagulation like Xarelto (rivaroxaban) or Coumadin (warfarin), and they just give them baby aspirin postoperatively because their patients are going home the same day and walking. It’s probably safer for patients. There’s no research out there yet to show that, but we all know that the more you move and the more you’re not lying around, the lower the risk of having a DVT or a blood clot.
There are studies showing that there’s no damage to blood vessels, other than if you stick it with the needle, because the nitrogen gas in this that allows the ice ball to form does not get injected into the body. It’s all resorbed in the machine. The only thing the body sees is this ice ball, which would melt if you hit a blood vessel because we should be 98 °F and the ice ball is -88 °F. There’s no gas injected into the body either, so there’s no risk of a gas embolism.
Training and Implementation
Glatter: I was going to ask you about air emboli, and you perfectly led right into that.
In terms of training requirements, currently, what do you envision as a way we can train residents and fellows to do this? Is this currently something being considered in curriculum?
Schwartz: We are going to train our residents first. I’m training the attendings. Before you use this technology, you should have a basic understanding of ultrasound, how to use the device, the different settings, and what the risks are for each procedure you’re doing.
Let’s say, as Sergey alluded to, with an intercostal nerve block, you could have a pneumothorax. You have to be able to identify the rib, where the nerve should lie, the innermost intercostal muscle you could see on the newer ultrasounds, and where the pleura lies. People should start with just basic ultrasound training and then advance to a typical intercostal nerve block.
Once you master that, the procedure with the device is not much different than an intercostal nerve block, except you have a handheld device and the needle is just as long as a pen, 3.5 inches.
If you could do a nerve block with a spinal needle, you could do the procedure. Once people have the technical ultrasound skills, then they can advance to needle-based procedures, and once you have that training, you could use this procedure safely and efficaciously.
Glatter: Sergey, do you see this as requiring quite a bit of time and training in your program?
Motov: I mentioned earlier, before we started, that with the advent of ultrasound-guided nerve blocks, the vast majority of physicians are becoming very comfortable and fairly effective with maneuvering a needle and the ultrasound probe. The learning curve is essentially the same. The only difference is, as Gary pointed out, some of the nerves could be new to ED folks, but the technique, the understanding, the visualization, and the knowledge of anatomy are essentially the same.
As he pointed out, if you can use it with a spinal needle and local anesthetic, the procedure becomes exactly the same. It’s a slightly different drug and a different needle, and instead of local anesthetic, you’re using a gas at cold temperatures, and that’s pretty much it.
Glatter: Are there any other barriers to adoption in terms of cost, the device itself, or the companies that manufacture these handheld devices?
Schwartz: There’s always cost associated with the new device, needles, and the gas. Thankfully, they’re covered by Medicare, Medicaid, and most commercial insurances in the current framework, which I think is important. I think Congress is seeing the benefits of opiate sparing that Sergey helped lead in the ED.
At AABP Integrative Pain Care and Wellness and Maimonides, we’re doing this intraoperatively as well. I think the government is seeing that. There was a NOPAIN Act passed in 2023 that, starting January 1, 2025, will allow certain approved companies, devices, and medications to have to be repaid by CMS, Centers for Medicare & Medicaid Services, in the hospital setting and in the outpatient departments. In the inpatient surgical stays, we could have less opiates. I think that’s important. It is reimbursed now. Obviously, there is a cost associated.
The other benefit of this procedure and these techniques is, as Sergey alluded to, it’s done under ultrasound. The way we all learn procedures, whether it be central lines or chest tubes, is the blind technique. There is no good way to practice. In my interventional pain practice, many of our original techniques were done under fluoroscopy, and we don’t want to get extra radiation during practice.
The benefit of ultrasound and the advent of handheld ultrasound devices is that we can practice scanning and techniques on ourselves and on colleagues, without the fear of radiation. Other than the fact that we need to shower after the surgical lube is on from the scanning gel, you could practice your techniques in a safe way without harming a patient or yourself.
Future Directions in Pain Management Techniques
Glatter: Absolutely. Do you see any role for possibly stellate ganglion blocks, which are a bit riskier and have greater depth?
Schwartz: People are looking at different studies because, again, it’s a needle-based technology. We do many stellate ganglion blocks. I have not done it for this procedure yet, but that’s the next step of what I try. Under ultrasound, we could see the longus colli muscle and we could see the carotid artery. Obviously, we don’t see the ganglion per se, but anatomically, we know where it lies. You could drop a couple of lesions on there and give a theoretic prolonged sympathetic block, which might help with symptoms of complex regional pain syndrome.
I know there are some studies that have looked at stellate ganglion blocks for long-COVID symptoms. Unfortunately, it looks like we’re back in another wave right now. I think that’s the next step of the technology.
Glatter: Getting back to the emergency department, burns are something we see commonly — such painful conditions. This is something that could really provide significant relief, especially with burns that involve the chest wall, not just extremity burns.
Motov: I agree with you. Burns would be a very good indication to utilize this technique. Just listening to you and Gary, another thing that pops into my head, which may have actually some science behind it, would be any traumatic amputations done in a civilian environment or even in the military in a combat situation.
A person who has either an upper or lower extremity that is partially or completely severed or amputated, and the pain — God knows how bad it is — if not properly treated, it is going to be a very long recovery. That’s, I believe, another percutaneous condition where cryoneurolysis will be very beneficial to freeze those nerves, allowing patients to recover through rehab acute care, acute phases, rehabilitation, and move on with their lives.
Glatter: In the setting of a painful distal radius fracture, a femur fracture, and things of that nature, Gary, do you see this as a modality in conjunction with emergency medicine colleagues as being something that’s going to really become an important part of our armamentarium?
Schwartz: I do think it’s going to become more important in the future, as there are more studies to show what nerves you could block with cryoneurolysis in the longer term. I think you might see people start using these for fractures, especially for fractures that are not operable at the time or if a patient needs to be optimized prior to surgery.
As Sergey alluded to, it’s optimal in burns. People have been looking for relief of stump pain or postamputation pain. There’s a big researcher in Canada who’s been looking at pain with spasticity for people with cerebral palsy and poststroke issues, where they can’t move and they have pain moving an extremity after these conditions. We’re at just the tip of the iceberg as to where people are going to use this hand-held technology in the future.
Glatter: We use long-acting nerve blocks for hip fractures already in the emergency department. Why not employ this technique, which would have longer effects and limit opiate use?
Schwartz: It might even help a certain subset of the population, at least in Brooklyn, where we have a large elderly population. I believe it’s one of the oldest boroughs in the country, and definitely in New York.
There are some people that go on to surgery just because they might be bedbound, but it’s the pain that is dictating their surgical procedure, not that they’re ever going to walk again.
It’s maybe the next step to look for. If you could block this nerve for 3 months or longer, they’re still going to be bedbound, but maybe you could avoid a surgical procedure that carries its own morbidity and mortality, which I see a big interest in in the future.
Glatter: Absolutely. The idea behind treating spasticity is very important from an occupational therapy standpoint — eating, activities of daily living — just the basics.
Getting someone’s fingers released, being able to move their legs again, and getting them out of contracture states, I think, has a huge role.
Schwartz: Not only for the patient but also for the caregivers. For many of these patients, if they’re contracted fully and the pain from the spasticity is preventing their caregivers from moving them, it’s difficult to put on a shirt, pants, and so on.
One other point I’d like to make is that it’s reproducible. It’s not one-and-done. If the pain comes back from any of these conditions, you could treat again with another cryoneurolysis treatment. The current literature to date shows that it’s just as effective time and time again. I’ve seen clinically that you can repeat this procedure, whereas some of our other procedures that we do in medicine are not as reproducible, which is important for some of these chronic conditions.
Glatter: You had mentioned reimbursement earlier. Currently, this procedure is reimbursed under Medicare, Medicaid, and third-party payers, I assume?
Schwartz: Not all, but many commercial insurers. Yes for Medicare.
Final Takeaways
Glatter: Reimbursement has to be really universal because if this is shown to be more effective and limits opiate use, then there’s no question in my mind that this is such a groundbreaking procedure.
I’ll let you both give a few pearls for our audience to summarize our discussion.
Motov: I’d say it’s somewhat long overdue that this technique and pain-relieving modality should enter the emergency department, with the auspices and the beautiful collaborative effort between emergency department folks and interventional anesthesiologists, pain management specialists, collaborative training, and a collaborative goal of improving patients’ pain throughout the entire journey during the healthcare system.
That would be my only pearl. Just reach out to your colleagues within your respective institutions who you believe have aptitude, knowledge, and expertise. Reach out, get trained, and start passing down the knowledge to your faculty, and by virtue of extension, to your fellow residents and colleagues.
Schwartz: He took the words right out of my mouth. Communication and collaboration are the two most important things. There’s a shortage of physicians in this country. We can only each do so much, so we should each utilize and implement this technology to affect and help as many patients as possible.
We can decrease the amount of opiates, help our patients, help our family members in our community live with decreased pain, improve their function, and just get back to their lives and keep pushing the envelope of what’s the next step in treatment.
Again, like we went from giving opiates for this and that’s it — maybe an epidural, maybe a 5- to 6-hour intercostal nerve block — to fascial plane blocks like Sergey said, to more advanced procedures, to now we can give months of relief.
I think the communication, the collaboration, and the camaraderie among our different specialties are important to push the envelope to help our patients.
Glatter: That’s so well put. I completely agree.
I want to thank both of you for a very lively discussion. It was very informative. Your expertise is greatly appreciated and will certainly benefit our audience. Thank you both again.
Dr. Glatter is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. Dr. Motov is professor of emergency medicine and director of research in the Department of Emergency Medicine at Maimonides Medical Center in Brooklyn, New York. Dr. Schwartz is co-owner and primary clinic director at AABP Integrative Pain Care in Brooklyn, New York. Schwartz currently serves as the co-director of AABP Integrative Pain Care and Wellness and the vice chair of pain and anesthesiology for Maimonides Medical Center. Dr. Schwartz reported conflicts of interest with Pacira Biosciences and Dorsal Health; neither Dr. Glatter nor Dr. Motov reported relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Robert D. Glatter, MD: Hi. I’m Dr. Robert Glatter, medical advisor for Medscape Emergency Medicine. Joining me today to discuss a novel way to treat pain related to conditions such as rib fractures and burns is Dr. Sergey Motov, an emergency physician with expertise in pain management and research director in the Department of Emergency Medicine at Maimonides Medical Center in Brooklyn, New York.
Also joining me is Dr. Gary Schwartz, vice chair of pain and anesthesiology at Maimonides Medical Center. Dr. Schwartz is board certified in anesthesiology and interventional pain management.
Welcome, Sergey and Gary.
Sergey M. Motov, MD: Thank you, Robert.
Gary S. Schwartz, MD: Thank you, Robert.
Traditional Approaches to Pain Relief
Glatter: It’s a pleasure to have you both. Sergey, we were chatting earlier this week and you had mentioned a novel approach to treating a common condition we encounter in the emergency department — rib fractures.
As we all know, they’re very painful and can lead to pulmonary complications, including atelectasis, pneumonia due to splinting and lack of proper pain management, along with the use of incentive spirometry.
Sergey and Gary, can you describe traditional approaches to alleviating the pain associated with rib fractures? What do we typically use? Then we’ll get to some novel treatments that we’re here to discuss.
Motov: I’m going to use the emergency medicine approach to rib fractures. As you pointed out, pain relief is of utmost importance.
With the advent and acquiring of the amazing technique of interventional pain management, physicians, for the most part, are very astute about providing nerve blocks to alleviate pain, at least in immediate need. I’m talking about the relatively short term, 1-5 hours, in the emergency department.
Primarily, we focus on fascial plane blocks such as serratus anterior plane block. Traditionally, ED physicians don’t use much of the intercostal blocks. At times, we can direct the spinal block to cover the lateral aspect of the chest wall.
As part of the multimodal approach, we can use NSAIDs. If there’s a contraindication, we can use opioids. There are some data to support consideration of using topical formularies such as a lidocaine patch, but they are somewhat conflicting.
The question becomes what you’re going to send a patient home with. Again, traditional teaching is either opioids, immediate release with a short course, plus or minus NSAIDs, plus or minus acetaminophen.
The issue with rib fractures is that, while we can manage immediate and super-acute pain presentation in the ED and then discharge up to 24-72 hours, what happens afterwards is very challenging. Acute intercostal neuralgia related to traumatic rib fractures is semi-manageable, but if it’s inappropriately treated, it has a great tendency to transform into chronic intercostal neuralgia. It contributes a great deal of disability and morbidity.
Several years ago, I came across an entity called cryoneurolysis (cryo ─ cold temperature; neurolysis ─ freezing the nerve). I’m excited to be here today because Gary is the one who’s pioneering and championing this technique in our institution.
Cryoneurolysis: Mechanisms of Action and Benefits
Glatter: Gary, what do you see as the main role for this procedure at this time?
Schwartz: As Sergey alluded to, the traditional approach of opiates has side effects (ie, constipation, addiction, and tolerance). Unfortunately, many of these rib fractures occur in older patients. They come in anticoagulated, so they can’t have NSAIDs.
Sergey and his team in the ER have been pioneers in giving short-acting local anesthetic blocks that could last anywhere from 12 to 24 hours. There are long-acting local anesthetics that we can get out to 72 hours.
Unfortunately, these rib fractures and the pain associated with them, in addition to the intercostal neuralgia, could take weeks to heal. That’s where cryoneurolysis comes in. We’re all used to ice or cold temperature. For example, if your child gets an ear piercing, they put some ice on their earlobe beforehand, it numbs it up, and they don’t feel pain. It allows them to get their ears pierced without pain, but it’s short-acting.
What we have now are handheld devices with tips about as long as a pen, 3.5 inches, that allow you to go down precisely to these intercostal nerves that innervate the ribs and give a cold lesion that freezes these nerves.
The benefit of it is it’s not permanent like cryoablation, like we’ve seen for tumor necrosis, which destroys outside tissues. It’s really a small lesion, about 16 mm x 8 mm, which is enough to engulf the nerve and pretty much stun it.
It causes axonotmesis, but the epineurium, the endoneurium, and the perineurium — the inner workings of the nerve — stay intact, so it regrows. It just destroys the myelin sheath and the axon.
Glatter: You’re creating a scarring effect; is that what you’re saying? In other words, you’re doing a cold-temperature freeze and stunning the nerve. My question is, does it regrow? Is this a permanent type of injury?
Schwartz: With Wallerian degeneration, nerves do regrow after injuries.
Unfortunately, as you two probably see in the ER for big traumas, where the nerve is transected, those unfortunately do not grow back. This is considered a grade 2 lesion, so the Wallerian degeneration recurs. The nerves grow, depending on the literature you look at, about 0.5-2 mm per day.
This intervention gives us at least 3 months of relief for the patient, which is in the time frame where the rib fracture will heal, hopefully with no damage to the nerve from the fracture, and they go on living their life without having to take opiates or having to stop their anticoagulation.
Because prior to this, when I was a pain fellow, we used to put epidurals in many of these patients. The problem with that is patients can’t go home, and if they’re anticoagulated, you can’t place it because of the risk of a spinal hematoma.
Potential Use in Ventilation Weaning
Glatter: This is something we encounter daily, and certainly for those patients who have more numerous rib fractures or flail chest, this could be even more devastating, as well as for those who get intubated.
Do you see any role, in terms of ventilator weaning, in using this technique specifically in the ICU setting?
Schwartz: That’s an interesting concept. I’m not so sure about ventilator weaning, but we’ve used this in the hospital for rib fractures from traumas where patients had such severe fractures and had to go to the operating room for rib plating, and did necessitate an epidural. We’ve used this to discontinue their epidural and transition them to get the patient home.
I think that is part of the care, not only in the ER but in the hospital as well. We need to treat the patients, but we also have to have a transition plan to get them out of the hospital. Not that we don’t want to treat our patients, but we have to have a plan to get them home. I’m guessing that might be an interesting stage of research in the future if it does help with weaning from a ventilator.
Glatter: There are some studies out there suggesting that there can be some utility in terms of ventilator weaning using this technique. The ability of this to change how we manage pain is just incredible.
Sergey, do you feel that this is something that you could implement in your ED with your patients in the near future?
Motov: Definitely. I have personally been a very big proponent of it. I’m the theoreticist because I’ve covered a great deal of literature, and now having Gary and his team doing this in our institution, it’s a shame not to capitalize on it. I’m slowly moving toward figuring out the way of collaborative effort to have Gary and his team help my team and our colleagues, bring him on board, and maybe broaden the integration for pain management.
I believe, as Gary emphasized, that geriatric traumatic pain injuries are critically important due to the presence of comorbidities, potential drug interactions, and the challenges of managing these factors effectively.
There is one thing I want to bring up, and Gary, please support me on it. The procedure itself is fascinating because it provides long-term pain relief and reduces morbidity. I wouldn’t say mortality, just reduced morbidity. However, we need to be very conscious of the fact that this blockade, this ice-ball freezing of the nerve, can be detrimental to motor nerves. If your whole goal or idea of faster recovery after postoperative knee or hip replacements, or any traumatic lower- or upper-extremity surgery, includes blockade of motor nerves, it’s not going to be beneficial.
I believe the primary therapeutic application of this technology lies in targeting sensory nerves. For instance, intercostal nerves could be a focus in cases of rib fractures. Additionally, this approach shows promise for treating burns, particularly in the lower and upper extremities. Specifically, targeting nerves such as the lateral femoral cutaneous nerve or the anterior femoral cutaneous nerve could effectively neutralize pain and provide significant relief for weeks, if not months.
Based on additional predilection to what particular indications would be, maybe occipital headache with cervicalgia, occipital nerve block — it’s a sensory block — can benefit from it. Slowly but surely, there’s a slew of painful syndromes for which cryoneurolysis might have a great deal of use in the emergency department.
Cryoneurolysis for Other Pain Syndromes
Glatter: Gary, I’ll let you expand upon additional uses that you see. You did mention one on our chat earlier this week, which was postmastectomy pain syndrome with the intercostal brachial nerve. That’s a very compelling area of interest, certainly for the number of women that go through mastectomies or lumpectomies and that have axillary dissection or nerve injury.
Schwartz: Post-mastectomy is one way you could use this device and technology to attack painful syndromes, such as postmastectomy syndrome. Mastectomies are one of the most common surgeries performed in the United States, but I believe it’s a top three for post-op chronic pain, which we don’t normally think of.
There was a great study by a team in San Diego where they did intercostal brachial and intercostal nerve blocks on multiple nerves, and they decreased pain up to 3 months after the surgery and decreased opiates.
As Sergey alluded to, it’s approved for any peripheral nerve in the body. We’ve used it in our pain office for occipital neuralgia, postherpetic neuralgia, chronic rib pain after fractures, and surgery. Some of the most common uses are for superficial, sensory, genicular nerves, the lateral femoral cutaneous nerve, the anterior femoral cutaneous nerve, and the infrapatellar branch of the saphenous.
You could numb the skin preoperatively before a painful surgery, such as a total knee replacement — or as we like to call it, a total knee arthroplasty — to reduce opiates, improve function, and decrease length of stay. You could attack any sensory nerve.
We’ve utilized that already in our private practice. We’re trying to transition into the hospital to have everyone who gets a knee arthroplasty have this technology to decrease opiates, improve function, and recover faster.
This is quite interesting and motivating for me because when I first started, we had a femoral catheter to block the motor femoral nerve or an epidural. Patients were in the hospital for 3-5 days with the CPM [continuous passive motion] machine, which is like a medieval torture device that you might see in Mad Max — where you’re kind of moving the patient’s knee back and forth after surgery, and they were miserable, taking patient-controlled analgesia and high-dose opiates. Now, we’re freezing these nerves beforehand, doing our nerve blocks in the operating room with long-acting local anesthetic, and patients are going home the same day with minimal or even no opiates sometimes.
Implications for Patient Mobility and DVT Risk
Glatter: You’re getting up to 3 months of relief in that setting, doing it as you described?
Schwartz: Yes, up to 3 months of relief, which is huge, because most patients recovering from a knee arthroplasty, at about the 6- to 8-week mark, have improved range of motion, they have their 110° flexion, they have their extension, and they’re getting back to their normal life.
You cover the whole postoperative rehab, where patients don’t have to get recurring refills, they can participate in physical therapy. As you both know, part of the recovery process is to be able to interact with family and friends without being sleepy, angry, and in pain all day, so they can get back to their normal function.
Glatter: In terms of this procedure, would there be any increase in deep vein thrombosis (DVT) in relation to this, by chance?
Schwartz: Actually, there’s less of a risk of DVT because patients have less pain, so they can get up and move faster. Some of my surgical colleagues who have implemented this in their practice have gotten away from using the stronger anticoagulation like Xarelto (rivaroxaban) or Coumadin (warfarin), and they just give them baby aspirin postoperatively because their patients are going home the same day and walking. It’s probably safer for patients. There’s no research out there yet to show that, but we all know that the more you move and the more you’re not lying around, the lower the risk of having a DVT or a blood clot.
There are studies showing that there’s no damage to blood vessels, other than if you stick it with the needle, because the nitrogen gas in this that allows the ice ball to form does not get injected into the body. It’s all resorbed in the machine. The only thing the body sees is this ice ball, which would melt if you hit a blood vessel because we should be 98 °F and the ice ball is -88 °F. There’s no gas injected into the body either, so there’s no risk of a gas embolism.
Training and Implementation
Glatter: I was going to ask you about air emboli, and you perfectly led right into that.
In terms of training requirements, currently, what do you envision as a way we can train residents and fellows to do this? Is this currently something being considered in curriculum?
Schwartz: We are going to train our residents first. I’m training the attendings. Before you use this technology, you should have a basic understanding of ultrasound, how to use the device, the different settings, and what the risks are for each procedure you’re doing.
Let’s say, as Sergey alluded to, with an intercostal nerve block, you could have a pneumothorax. You have to be able to identify the rib, where the nerve should lie, the innermost intercostal muscle you could see on the newer ultrasounds, and where the pleura lies. People should start with just basic ultrasound training and then advance to a typical intercostal nerve block.
Once you master that, the procedure with the device is not much different than an intercostal nerve block, except you have a handheld device and the needle is just as long as a pen, 3.5 inches.
If you could do a nerve block with a spinal needle, you could do the procedure. Once people have the technical ultrasound skills, then they can advance to needle-based procedures, and once you have that training, you could use this procedure safely and efficaciously.
Glatter: Sergey, do you see this as requiring quite a bit of time and training in your program?
Motov: I mentioned earlier, before we started, that with the advent of ultrasound-guided nerve blocks, the vast majority of physicians are becoming very comfortable and fairly effective with maneuvering a needle and the ultrasound probe. The learning curve is essentially the same. The only difference is, as Gary pointed out, some of the nerves could be new to ED folks, but the technique, the understanding, the visualization, and the knowledge of anatomy are essentially the same.
As he pointed out, if you can use it with a spinal needle and local anesthetic, the procedure becomes exactly the same. It’s a slightly different drug and a different needle, and instead of local anesthetic, you’re using a gas at cold temperatures, and that’s pretty much it.
Glatter: Are there any other barriers to adoption in terms of cost, the device itself, or the companies that manufacture these handheld devices?
Schwartz: There’s always cost associated with the new device, needles, and the gas. Thankfully, they’re covered by Medicare, Medicaid, and most commercial insurances in the current framework, which I think is important. I think Congress is seeing the benefits of opiate sparing that Sergey helped lead in the ED.
At AABP Integrative Pain Care and Wellness and Maimonides, we’re doing this intraoperatively as well. I think the government is seeing that. There was a NOPAIN Act passed in 2023 that, starting January 1, 2025, will allow certain approved companies, devices, and medications to have to be repaid by CMS, Centers for Medicare & Medicaid Services, in the hospital setting and in the outpatient departments. In the inpatient surgical stays, we could have less opiates. I think that’s important. It is reimbursed now. Obviously, there is a cost associated.
The other benefit of this procedure and these techniques is, as Sergey alluded to, it’s done under ultrasound. The way we all learn procedures, whether it be central lines or chest tubes, is the blind technique. There is no good way to practice. In my interventional pain practice, many of our original techniques were done under fluoroscopy, and we don’t want to get extra radiation during practice.
The benefit of ultrasound and the advent of handheld ultrasound devices is that we can practice scanning and techniques on ourselves and on colleagues, without the fear of radiation. Other than the fact that we need to shower after the surgical lube is on from the scanning gel, you could practice your techniques in a safe way without harming a patient or yourself.
Future Directions in Pain Management Techniques
Glatter: Absolutely. Do you see any role for possibly stellate ganglion blocks, which are a bit riskier and have greater depth?
Schwartz: People are looking at different studies because, again, it’s a needle-based technology. We do many stellate ganglion blocks. I have not done it for this procedure yet, but that’s the next step of what I try. Under ultrasound, we could see the longus colli muscle and we could see the carotid artery. Obviously, we don’t see the ganglion per se, but anatomically, we know where it lies. You could drop a couple of lesions on there and give a theoretic prolonged sympathetic block, which might help with symptoms of complex regional pain syndrome.
I know there are some studies that have looked at stellate ganglion blocks for long-COVID symptoms. Unfortunately, it looks like we’re back in another wave right now. I think that’s the next step of the technology.
Glatter: Getting back to the emergency department, burns are something we see commonly — such painful conditions. This is something that could really provide significant relief, especially with burns that involve the chest wall, not just extremity burns.
Motov: I agree with you. Burns would be a very good indication to utilize this technique. Just listening to you and Gary, another thing that pops into my head, which may have actually some science behind it, would be any traumatic amputations done in a civilian environment or even in the military in a combat situation.
A person who has either an upper or lower extremity that is partially or completely severed or amputated, and the pain — God knows how bad it is — if not properly treated, it is going to be a very long recovery. That’s, I believe, another percutaneous condition where cryoneurolysis will be very beneficial to freeze those nerves, allowing patients to recover through rehab acute care, acute phases, rehabilitation, and move on with their lives.
Glatter: In the setting of a painful distal radius fracture, a femur fracture, and things of that nature, Gary, do you see this as a modality in conjunction with emergency medicine colleagues as being something that’s going to really become an important part of our armamentarium?
Schwartz: I do think it’s going to become more important in the future, as there are more studies to show what nerves you could block with cryoneurolysis in the longer term. I think you might see people start using these for fractures, especially for fractures that are not operable at the time or if a patient needs to be optimized prior to surgery.
As Sergey alluded to, it’s optimal in burns. People have been looking for relief of stump pain or postamputation pain. There’s a big researcher in Canada who’s been looking at pain with spasticity for people with cerebral palsy and poststroke issues, where they can’t move and they have pain moving an extremity after these conditions. We’re at just the tip of the iceberg as to where people are going to use this hand-held technology in the future.
Glatter: We use long-acting nerve blocks for hip fractures already in the emergency department. Why not employ this technique, which would have longer effects and limit opiate use?
Schwartz: It might even help a certain subset of the population, at least in Brooklyn, where we have a large elderly population. I believe it’s one of the oldest boroughs in the country, and definitely in New York.
There are some people that go on to surgery just because they might be bedbound, but it’s the pain that is dictating their surgical procedure, not that they’re ever going to walk again.
It’s maybe the next step to look for. If you could block this nerve for 3 months or longer, they’re still going to be bedbound, but maybe you could avoid a surgical procedure that carries its own morbidity and mortality, which I see a big interest in in the future.
Glatter: Absolutely. The idea behind treating spasticity is very important from an occupational therapy standpoint — eating, activities of daily living — just the basics.
Getting someone’s fingers released, being able to move their legs again, and getting them out of contracture states, I think, has a huge role.
Schwartz: Not only for the patient but also for the caregivers. For many of these patients, if they’re contracted fully and the pain from the spasticity is preventing their caregivers from moving them, it’s difficult to put on a shirt, pants, and so on.
One other point I’d like to make is that it’s reproducible. It’s not one-and-done. If the pain comes back from any of these conditions, you could treat again with another cryoneurolysis treatment. The current literature to date shows that it’s just as effective time and time again. I’ve seen clinically that you can repeat this procedure, whereas some of our other procedures that we do in medicine are not as reproducible, which is important for some of these chronic conditions.
Glatter: You had mentioned reimbursement earlier. Currently, this procedure is reimbursed under Medicare, Medicaid, and third-party payers, I assume?
Schwartz: Not all, but many commercial insurers. Yes for Medicare.
Final Takeaways
Glatter: Reimbursement has to be really universal because if this is shown to be more effective and limits opiate use, then there’s no question in my mind that this is such a groundbreaking procedure.
I’ll let you both give a few pearls for our audience to summarize our discussion.
Motov: I’d say it’s somewhat long overdue that this technique and pain-relieving modality should enter the emergency department, with the auspices and the beautiful collaborative effort between emergency department folks and interventional anesthesiologists, pain management specialists, collaborative training, and a collaborative goal of improving patients’ pain throughout the entire journey during the healthcare system.
That would be my only pearl. Just reach out to your colleagues within your respective institutions who you believe have aptitude, knowledge, and expertise. Reach out, get trained, and start passing down the knowledge to your faculty, and by virtue of extension, to your fellow residents and colleagues.
Schwartz: He took the words right out of my mouth. Communication and collaboration are the two most important things. There’s a shortage of physicians in this country. We can only each do so much, so we should each utilize and implement this technology to affect and help as many patients as possible.
We can decrease the amount of opiates, help our patients, help our family members in our community live with decreased pain, improve their function, and just get back to their lives and keep pushing the envelope of what’s the next step in treatment.
Again, like we went from giving opiates for this and that’s it — maybe an epidural, maybe a 5- to 6-hour intercostal nerve block — to fascial plane blocks like Sergey said, to more advanced procedures, to now we can give months of relief.
I think the communication, the collaboration, and the camaraderie among our different specialties are important to push the envelope to help our patients.
Glatter: That’s so well put. I completely agree.
I want to thank both of you for a very lively discussion. It was very informative. Your expertise is greatly appreciated and will certainly benefit our audience. Thank you both again.
Dr. Glatter is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. Dr. Motov is professor of emergency medicine and director of research in the Department of Emergency Medicine at Maimonides Medical Center in Brooklyn, New York. Dr. Schwartz is co-owner and primary clinic director at AABP Integrative Pain Care in Brooklyn, New York. Schwartz currently serves as the co-director of AABP Integrative Pain Care and Wellness and the vice chair of pain and anesthesiology for Maimonides Medical Center. Dr. Schwartz reported conflicts of interest with Pacira Biosciences and Dorsal Health; neither Dr. Glatter nor Dr. Motov reported relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Robert D. Glatter, MD: Hi. I’m Dr. Robert Glatter, medical advisor for Medscape Emergency Medicine. Joining me today to discuss a novel way to treat pain related to conditions such as rib fractures and burns is Dr. Sergey Motov, an emergency physician with expertise in pain management and research director in the Department of Emergency Medicine at Maimonides Medical Center in Brooklyn, New York.
Also joining me is Dr. Gary Schwartz, vice chair of pain and anesthesiology at Maimonides Medical Center. Dr. Schwartz is board certified in anesthesiology and interventional pain management.
Welcome, Sergey and Gary.
Sergey M. Motov, MD: Thank you, Robert.
Gary S. Schwartz, MD: Thank you, Robert.
Traditional Approaches to Pain Relief
Glatter: It’s a pleasure to have you both. Sergey, we were chatting earlier this week and you had mentioned a novel approach to treating a common condition we encounter in the emergency department — rib fractures.
As we all know, they’re very painful and can lead to pulmonary complications, including atelectasis, pneumonia due to splinting and lack of proper pain management, along with the use of incentive spirometry.
Sergey and Gary, can you describe traditional approaches to alleviating the pain associated with rib fractures? What do we typically use? Then we’ll get to some novel treatments that we’re here to discuss.
Motov: I’m going to use the emergency medicine approach to rib fractures. As you pointed out, pain relief is of utmost importance.
With the advent and acquiring of the amazing technique of interventional pain management, physicians, for the most part, are very astute about providing nerve blocks to alleviate pain, at least in immediate need. I’m talking about the relatively short term, 1-5 hours, in the emergency department.
Primarily, we focus on fascial plane blocks such as serratus anterior plane block. Traditionally, ED physicians don’t use much of the intercostal blocks. At times, we can direct the spinal block to cover the lateral aspect of the chest wall.
As part of the multimodal approach, we can use NSAIDs. If there’s a contraindication, we can use opioids. There are some data to support consideration of using topical formularies such as a lidocaine patch, but they are somewhat conflicting.
The question becomes what you’re going to send a patient home with. Again, traditional teaching is either opioids, immediate release with a short course, plus or minus NSAIDs, plus or minus acetaminophen.
The issue with rib fractures is that, while we can manage immediate and super-acute pain presentation in the ED and then discharge up to 24-72 hours, what happens afterwards is very challenging. Acute intercostal neuralgia related to traumatic rib fractures is semi-manageable, but if it’s inappropriately treated, it has a great tendency to transform into chronic intercostal neuralgia. It contributes a great deal of disability and morbidity.
Several years ago, I came across an entity called cryoneurolysis (cryo ─ cold temperature; neurolysis ─ freezing the nerve). I’m excited to be here today because Gary is the one who’s pioneering and championing this technique in our institution.
Cryoneurolysis: Mechanisms of Action and Benefits
Glatter: Gary, what do you see as the main role for this procedure at this time?
Schwartz: As Sergey alluded to, the traditional approach of opiates has side effects (ie, constipation, addiction, and tolerance). Unfortunately, many of these rib fractures occur in older patients. They come in anticoagulated, so they can’t have NSAIDs.
Sergey and his team in the ER have been pioneers in giving short-acting local anesthetic blocks that could last anywhere from 12 to 24 hours. There are long-acting local anesthetics that we can get out to 72 hours.
Unfortunately, these rib fractures and the pain associated with them, in addition to the intercostal neuralgia, could take weeks to heal. That’s where cryoneurolysis comes in. We’re all used to ice or cold temperature. For example, if your child gets an ear piercing, they put some ice on their earlobe beforehand, it numbs it up, and they don’t feel pain. It allows them to get their ears pierced without pain, but it’s short-acting.
What we have now are handheld devices with tips about as long as a pen, 3.5 inches, that allow you to go down precisely to these intercostal nerves that innervate the ribs and give a cold lesion that freezes these nerves.
The benefit of it is it’s not permanent like cryoablation, like we’ve seen for tumor necrosis, which destroys outside tissues. It’s really a small lesion, about 16 mm x 8 mm, which is enough to engulf the nerve and pretty much stun it.
It causes axonotmesis, but the epineurium, the endoneurium, and the perineurium — the inner workings of the nerve — stay intact, so it regrows. It just destroys the myelin sheath and the axon.
Glatter: You’re creating a scarring effect; is that what you’re saying? In other words, you’re doing a cold-temperature freeze and stunning the nerve. My question is, does it regrow? Is this a permanent type of injury?
Schwartz: With Wallerian degeneration, nerves do regrow after injuries.
Unfortunately, as you two probably see in the ER for big traumas, where the nerve is transected, those unfortunately do not grow back. This is considered a grade 2 lesion, so the Wallerian degeneration recurs. The nerves grow, depending on the literature you look at, about 0.5-2 mm per day.
This intervention gives us at least 3 months of relief for the patient, which is in the time frame where the rib fracture will heal, hopefully with no damage to the nerve from the fracture, and they go on living their life without having to take opiates or having to stop their anticoagulation.
Because prior to this, when I was a pain fellow, we used to put epidurals in many of these patients. The problem with that is patients can’t go home, and if they’re anticoagulated, you can’t place it because of the risk of a spinal hematoma.
Potential Use in Ventilation Weaning
Glatter: This is something we encounter daily, and certainly for those patients who have more numerous rib fractures or flail chest, this could be even more devastating, as well as for those who get intubated.
Do you see any role, in terms of ventilator weaning, in using this technique specifically in the ICU setting?
Schwartz: That’s an interesting concept. I’m not so sure about ventilator weaning, but we’ve used this in the hospital for rib fractures from traumas where patients had such severe fractures and had to go to the operating room for rib plating, and did necessitate an epidural. We’ve used this to discontinue their epidural and transition them to get the patient home.
I think that is part of the care, not only in the ER but in the hospital as well. We need to treat the patients, but we also have to have a transition plan to get them out of the hospital. Not that we don’t want to treat our patients, but we have to have a plan to get them home. I’m guessing that might be an interesting stage of research in the future if it does help with weaning from a ventilator.
Glatter: There are some studies out there suggesting that there can be some utility in terms of ventilator weaning using this technique. The ability of this to change how we manage pain is just incredible.
Sergey, do you feel that this is something that you could implement in your ED with your patients in the near future?
Motov: Definitely. I have personally been a very big proponent of it. I’m the theoreticist because I’ve covered a great deal of literature, and now having Gary and his team doing this in our institution, it’s a shame not to capitalize on it. I’m slowly moving toward figuring out the way of collaborative effort to have Gary and his team help my team and our colleagues, bring him on board, and maybe broaden the integration for pain management.
I believe, as Gary emphasized, that geriatric traumatic pain injuries are critically important due to the presence of comorbidities, potential drug interactions, and the challenges of managing these factors effectively.
There is one thing I want to bring up, and Gary, please support me on it. The procedure itself is fascinating because it provides long-term pain relief and reduces morbidity. I wouldn’t say mortality, just reduced morbidity. However, we need to be very conscious of the fact that this blockade, this ice-ball freezing of the nerve, can be detrimental to motor nerves. If your whole goal or idea of faster recovery after postoperative knee or hip replacements, or any traumatic lower- or upper-extremity surgery, includes blockade of motor nerves, it’s not going to be beneficial.
I believe the primary therapeutic application of this technology lies in targeting sensory nerves. For instance, intercostal nerves could be a focus in cases of rib fractures. Additionally, this approach shows promise for treating burns, particularly in the lower and upper extremities. Specifically, targeting nerves such as the lateral femoral cutaneous nerve or the anterior femoral cutaneous nerve could effectively neutralize pain and provide significant relief for weeks, if not months.
Based on additional predilection to what particular indications would be, maybe occipital headache with cervicalgia, occipital nerve block — it’s a sensory block — can benefit from it. Slowly but surely, there’s a slew of painful syndromes for which cryoneurolysis might have a great deal of use in the emergency department.
Cryoneurolysis for Other Pain Syndromes
Glatter: Gary, I’ll let you expand upon additional uses that you see. You did mention one on our chat earlier this week, which was postmastectomy pain syndrome with the intercostal brachial nerve. That’s a very compelling area of interest, certainly for the number of women that go through mastectomies or lumpectomies and that have axillary dissection or nerve injury.
Schwartz: Post-mastectomy is one way you could use this device and technology to attack painful syndromes, such as postmastectomy syndrome. Mastectomies are one of the most common surgeries performed in the United States, but I believe it’s a top three for post-op chronic pain, which we don’t normally think of.
There was a great study by a team in San Diego where they did intercostal brachial and intercostal nerve blocks on multiple nerves, and they decreased pain up to 3 months after the surgery and decreased opiates.
As Sergey alluded to, it’s approved for any peripheral nerve in the body. We’ve used it in our pain office for occipital neuralgia, postherpetic neuralgia, chronic rib pain after fractures, and surgery. Some of the most common uses are for superficial, sensory, genicular nerves, the lateral femoral cutaneous nerve, the anterior femoral cutaneous nerve, and the infrapatellar branch of the saphenous.
You could numb the skin preoperatively before a painful surgery, such as a total knee replacement — or as we like to call it, a total knee arthroplasty — to reduce opiates, improve function, and decrease length of stay. You could attack any sensory nerve.
We’ve utilized that already in our private practice. We’re trying to transition into the hospital to have everyone who gets a knee arthroplasty have this technology to decrease opiates, improve function, and recover faster.
This is quite interesting and motivating for me because when I first started, we had a femoral catheter to block the motor femoral nerve or an epidural. Patients were in the hospital for 3-5 days with the CPM [continuous passive motion] machine, which is like a medieval torture device that you might see in Mad Max — where you’re kind of moving the patient’s knee back and forth after surgery, and they were miserable, taking patient-controlled analgesia and high-dose opiates. Now, we’re freezing these nerves beforehand, doing our nerve blocks in the operating room with long-acting local anesthetic, and patients are going home the same day with minimal or even no opiates sometimes.
Implications for Patient Mobility and DVT Risk
Glatter: You’re getting up to 3 months of relief in that setting, doing it as you described?
Schwartz: Yes, up to 3 months of relief, which is huge, because most patients recovering from a knee arthroplasty, at about the 6- to 8-week mark, have improved range of motion, they have their 110° flexion, they have their extension, and they’re getting back to their normal life.
You cover the whole postoperative rehab, where patients don’t have to get recurring refills, they can participate in physical therapy. As you both know, part of the recovery process is to be able to interact with family and friends without being sleepy, angry, and in pain all day, so they can get back to their normal function.
Glatter: In terms of this procedure, would there be any increase in deep vein thrombosis (DVT) in relation to this, by chance?
Schwartz: Actually, there’s less of a risk of DVT because patients have less pain, so they can get up and move faster. Some of my surgical colleagues who have implemented this in their practice have gotten away from using the stronger anticoagulation like Xarelto (rivaroxaban) or Coumadin (warfarin), and they just give them baby aspirin postoperatively because their patients are going home the same day and walking. It’s probably safer for patients. There’s no research out there yet to show that, but we all know that the more you move and the more you’re not lying around, the lower the risk of having a DVT or a blood clot.
There are studies showing that there’s no damage to blood vessels, other than if you stick it with the needle, because the nitrogen gas in this that allows the ice ball to form does not get injected into the body. It’s all resorbed in the machine. The only thing the body sees is this ice ball, which would melt if you hit a blood vessel because we should be 98 °F and the ice ball is -88 °F. There’s no gas injected into the body either, so there’s no risk of a gas embolism.
Training and Implementation
Glatter: I was going to ask you about air emboli, and you perfectly led right into that.
In terms of training requirements, currently, what do you envision as a way we can train residents and fellows to do this? Is this currently something being considered in curriculum?
Schwartz: We are going to train our residents first. I’m training the attendings. Before you use this technology, you should have a basic understanding of ultrasound, how to use the device, the different settings, and what the risks are for each procedure you’re doing.
Let’s say, as Sergey alluded to, with an intercostal nerve block, you could have a pneumothorax. You have to be able to identify the rib, where the nerve should lie, the innermost intercostal muscle you could see on the newer ultrasounds, and where the pleura lies. People should start with just basic ultrasound training and then advance to a typical intercostal nerve block.
Once you master that, the procedure with the device is not much different than an intercostal nerve block, except you have a handheld device and the needle is just as long as a pen, 3.5 inches.
If you could do a nerve block with a spinal needle, you could do the procedure. Once people have the technical ultrasound skills, then they can advance to needle-based procedures, and once you have that training, you could use this procedure safely and efficaciously.
Glatter: Sergey, do you see this as requiring quite a bit of time and training in your program?
Motov: I mentioned earlier, before we started, that with the advent of ultrasound-guided nerve blocks, the vast majority of physicians are becoming very comfortable and fairly effective with maneuvering a needle and the ultrasound probe. The learning curve is essentially the same. The only difference is, as Gary pointed out, some of the nerves could be new to ED folks, but the technique, the understanding, the visualization, and the knowledge of anatomy are essentially the same.
As he pointed out, if you can use it with a spinal needle and local anesthetic, the procedure becomes exactly the same. It’s a slightly different drug and a different needle, and instead of local anesthetic, you’re using a gas at cold temperatures, and that’s pretty much it.
Glatter: Are there any other barriers to adoption in terms of cost, the device itself, or the companies that manufacture these handheld devices?
Schwartz: There’s always cost associated with the new device, needles, and the gas. Thankfully, they’re covered by Medicare, Medicaid, and most commercial insurances in the current framework, which I think is important. I think Congress is seeing the benefits of opiate sparing that Sergey helped lead in the ED.
At AABP Integrative Pain Care and Wellness and Maimonides, we’re doing this intraoperatively as well. I think the government is seeing that. There was a NOPAIN Act passed in 2023 that, starting January 1, 2025, will allow certain approved companies, devices, and medications to have to be repaid by CMS, Centers for Medicare & Medicaid Services, in the hospital setting and in the outpatient departments. In the inpatient surgical stays, we could have less opiates. I think that’s important. It is reimbursed now. Obviously, there is a cost associated.
The other benefit of this procedure and these techniques is, as Sergey alluded to, it’s done under ultrasound. The way we all learn procedures, whether it be central lines or chest tubes, is the blind technique. There is no good way to practice. In my interventional pain practice, many of our original techniques were done under fluoroscopy, and we don’t want to get extra radiation during practice.
The benefit of ultrasound and the advent of handheld ultrasound devices is that we can practice scanning and techniques on ourselves and on colleagues, without the fear of radiation. Other than the fact that we need to shower after the surgical lube is on from the scanning gel, you could practice your techniques in a safe way without harming a patient or yourself.
Future Directions in Pain Management Techniques
Glatter: Absolutely. Do you see any role for possibly stellate ganglion blocks, which are a bit riskier and have greater depth?
Schwartz: People are looking at different studies because, again, it’s a needle-based technology. We do many stellate ganglion blocks. I have not done it for this procedure yet, but that’s the next step of what I try. Under ultrasound, we could see the longus colli muscle and we could see the carotid artery. Obviously, we don’t see the ganglion per se, but anatomically, we know where it lies. You could drop a couple of lesions on there and give a theoretic prolonged sympathetic block, which might help with symptoms of complex regional pain syndrome.
I know there are some studies that have looked at stellate ganglion blocks for long-COVID symptoms. Unfortunately, it looks like we’re back in another wave right now. I think that’s the next step of the technology.
Glatter: Getting back to the emergency department, burns are something we see commonly — such painful conditions. This is something that could really provide significant relief, especially with burns that involve the chest wall, not just extremity burns.
Motov: I agree with you. Burns would be a very good indication to utilize this technique. Just listening to you and Gary, another thing that pops into my head, which may have actually some science behind it, would be any traumatic amputations done in a civilian environment or even in the military in a combat situation.
A person who has either an upper or lower extremity that is partially or completely severed or amputated, and the pain — God knows how bad it is — if not properly treated, it is going to be a very long recovery. That’s, I believe, another percutaneous condition where cryoneurolysis will be very beneficial to freeze those nerves, allowing patients to recover through rehab acute care, acute phases, rehabilitation, and move on with their lives.
Glatter: In the setting of a painful distal radius fracture, a femur fracture, and things of that nature, Gary, do you see this as a modality in conjunction with emergency medicine colleagues as being something that’s going to really become an important part of our armamentarium?
Schwartz: I do think it’s going to become more important in the future, as there are more studies to show what nerves you could block with cryoneurolysis in the longer term. I think you might see people start using these for fractures, especially for fractures that are not operable at the time or if a patient needs to be optimized prior to surgery.
As Sergey alluded to, it’s optimal in burns. People have been looking for relief of stump pain or postamputation pain. There’s a big researcher in Canada who’s been looking at pain with spasticity for people with cerebral palsy and poststroke issues, where they can’t move and they have pain moving an extremity after these conditions. We’re at just the tip of the iceberg as to where people are going to use this hand-held technology in the future.
Glatter: We use long-acting nerve blocks for hip fractures already in the emergency department. Why not employ this technique, which would have longer effects and limit opiate use?
Schwartz: It might even help a certain subset of the population, at least in Brooklyn, where we have a large elderly population. I believe it’s one of the oldest boroughs in the country, and definitely in New York.
There are some people that go on to surgery just because they might be bedbound, but it’s the pain that is dictating their surgical procedure, not that they’re ever going to walk again.
It’s maybe the next step to look for. If you could block this nerve for 3 months or longer, they’re still going to be bedbound, but maybe you could avoid a surgical procedure that carries its own morbidity and mortality, which I see a big interest in in the future.
Glatter: Absolutely. The idea behind treating spasticity is very important from an occupational therapy standpoint — eating, activities of daily living — just the basics.
Getting someone’s fingers released, being able to move their legs again, and getting them out of contracture states, I think, has a huge role.
Schwartz: Not only for the patient but also for the caregivers. For many of these patients, if they’re contracted fully and the pain from the spasticity is preventing their caregivers from moving them, it’s difficult to put on a shirt, pants, and so on.
One other point I’d like to make is that it’s reproducible. It’s not one-and-done. If the pain comes back from any of these conditions, you could treat again with another cryoneurolysis treatment. The current literature to date shows that it’s just as effective time and time again. I’ve seen clinically that you can repeat this procedure, whereas some of our other procedures that we do in medicine are not as reproducible, which is important for some of these chronic conditions.
Glatter: You had mentioned reimbursement earlier. Currently, this procedure is reimbursed under Medicare, Medicaid, and third-party payers, I assume?
Schwartz: Not all, but many commercial insurers. Yes for Medicare.
Final Takeaways
Glatter: Reimbursement has to be really universal because if this is shown to be more effective and limits opiate use, then there’s no question in my mind that this is such a groundbreaking procedure.
I’ll let you both give a few pearls for our audience to summarize our discussion.
Motov: I’d say it’s somewhat long overdue that this technique and pain-relieving modality should enter the emergency department, with the auspices and the beautiful collaborative effort between emergency department folks and interventional anesthesiologists, pain management specialists, collaborative training, and a collaborative goal of improving patients’ pain throughout the entire journey during the healthcare system.
That would be my only pearl. Just reach out to your colleagues within your respective institutions who you believe have aptitude, knowledge, and expertise. Reach out, get trained, and start passing down the knowledge to your faculty, and by virtue of extension, to your fellow residents and colleagues.
Schwartz: He took the words right out of my mouth. Communication and collaboration are the two most important things. There’s a shortage of physicians in this country. We can only each do so much, so we should each utilize and implement this technology to affect and help as many patients as possible.
We can decrease the amount of opiates, help our patients, help our family members in our community live with decreased pain, improve their function, and just get back to their lives and keep pushing the envelope of what’s the next step in treatment.
Again, like we went from giving opiates for this and that’s it — maybe an epidural, maybe a 5- to 6-hour intercostal nerve block — to fascial plane blocks like Sergey said, to more advanced procedures, to now we can give months of relief.
I think the communication, the collaboration, and the camaraderie among our different specialties are important to push the envelope to help our patients.
Glatter: That’s so well put. I completely agree.
I want to thank both of you for a very lively discussion. It was very informative. Your expertise is greatly appreciated and will certainly benefit our audience. Thank you both again.
Dr. Glatter is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. Dr. Motov is professor of emergency medicine and director of research in the Department of Emergency Medicine at Maimonides Medical Center in Brooklyn, New York. Dr. Schwartz is co-owner and primary clinic director at AABP Integrative Pain Care in Brooklyn, New York. Schwartz currently serves as the co-director of AABP Integrative Pain Care and Wellness and the vice chair of pain and anesthesiology for Maimonides Medical Center. Dr. Schwartz reported conflicts of interest with Pacira Biosciences and Dorsal Health; neither Dr. Glatter nor Dr. Motov reported relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
‘Green Whistle’ Provides Pain Relief -- But Not in the US
This discussion was recorded on March 29, 2024. The transcript has been edited for clarity.
Robert D. Glatter, MD: Joining me today to discuss the use of methoxyflurane (Penthrox), an inhaled nonopioid analgesic for the relief of acute pain, is Dr. William Kenneth (Ken) Milne, an emergency physician at Strathroy Middlesex General Hospital in Ontario, Canada, and the founder of the well-known podcast The Skeptics’ Guide to Emergency Medicine (SGEM).
Also joining me is Dr. Sergey Motov, an emergency physician and research director at Maimonides Medical Center in Brooklyn, New York, and an expert in pain management. I want to welcome both of you and thank you for joining me.
RAMPED Trial: Evaluating the Efficacy of Methoxyflurane
Dr. Glatter: Ken, your recent post on Twitter [now X] regarding the utility of Penthrox in the RAMPED trial really caught my attention. While the trial was from 2021, it really is relevant regarding the prehospital management of pain in the practice of emergency medicine, and certainly in-hospital practice. I was hoping you could review the study design but also get into the rationale behind the use of this novel agent.
William Kenneth (Ken) Milne, MD, MSc: Sure. I’d be happy to kick this episode off with talking about a study that was published in 2020 in Academic Emergency Medicine. It was an Australian study by Brichko et al., and they were doing a randomized controlled trial looking at methoxyflurane vs standard care.
They selected out a population of adults, which they defined as 18-75 years of age. They were in the prehospital setting and they had a pain score of greater than 8. They gave the participants methoxyflurane, which is also called the “green whistle.” They had the subjects take that for their prehospital pain, and they compared that with whatever your standard analgesic in the prehospital setting would be.
Their primary outcome was how many patients had at least 50% reduction in their pain score within 30 minutes. They recruited about 120 people, and they found that there was no statistical difference in the primary outcome between methoxyflurane and standard care. Again, that primary outcome was a reduction in pain score by greater than 50% at 30 minutes, and there wasn’t a statistical difference between the two.
There are obviously limits to any study, and it was a convenience sample. This was an unmasked trial, so people knew if they were getting this green whistle, which is popular in Australia. People would be familiar with this device, and they didn’t compare it with a sham or placebo group.
Pharmacology of Penthrox: Its Role and Mechanism of Action
Dr. Glatter: The primary outcome wasn’t met, but certainly secondary outcomes were. There was, again, a relatively small number of patients in this trial. That said, there was significant pain relief. I think there are issues with the trial, as with any trial limitations.
Getting to the pharmacology of Penthrox, can you describe this inhaled anesthetic and how we use it, specifically its role at the subanesthetic doses?
Sergey M. Motov, MD: Methoxyflurane is embedded in the green whistle package, and that whole contraption is called Penthrox. It’s an inhaled volatile fluorinated hydrocarbon anesthetic that was predominantly used, I’d say 40, 50 years ago, for general anesthesia and slowly but surely fell out of favor due to the fact that, when used for prolonged duration or in supratherapeutic doses, there were cases of severe or even fatal nephrotoxicity and hepatotoxicity.
In the late ‘70s and early ‘80s, all the fluranes came on board that are slightly different as general anesthetics, and methoxyflurane started slowly falling out of favor. Because of this paucity and then a subsequent slightly greater number of cases of nephrotoxicity and hepatotoxicity, [the US Food and Drug Administration] FDA made a decision to pull the drug off the market in 2005. FDA successfully accomplished its mission and since then has pretty much banned the use of inhaled methoxyflurane in any shape, form, or color in the United States.
Going back to the green whistle, it has been used in Australia probably for about 50-60 years, and has been used in Europe for probably 10-20 years. Ken can attest that it has been used in Canada for at least a decade and the track record is phenomenal.
We are using subanesthetic, even supratherapeutic doses that, based on available literature, has no incidence of this fatal hepatotoxicity or nephrotoxicity. We’re talking about 10 million doses administered worldwide, except in the United States. There are 40-plus randomized clinical trials with over 30,000 patients enrolled that prove efficacy and safety.
That’s where we are right now, in a conundrum. We have a great deal of data all over the world, except in the United States, that push for the use of this noninvasive, patient-controlled nonopioid inhaled anesthetic. We just don’t have the access in North America, with the exception of Canada.
Regulatory Hurdles: Challenges in FDA Approval
Dr. Glatter: Absolutely. The FDA wants to be cautious, but if you look at the evidence base of data on this, it really indicates otherwise. Do you think that these roadblocks can be somehow overcome?
Dr. Milne: In the 2000s and 2010s, everybody was focused on opioids and all the dangers and potential adverse events. Opioids are great drugs like many other drugs; it depends on dose and duration. If used properly, it’s an excellent drug. Well, here’s another excellent drug if it’s used properly, and the adverse events are dependent on their dose and duration. Penthrox, or methoxyflurane, is a subtherapeutic, small dose and there have been no reported cases of addiction or abuse related to these inhalers.
Dr. Glatter: That argues for the point — and I’ll turn this over to you, Sergey — of how can this not, in my mind, be an issue that the FDA can overcome.
Dr. Motov: I agree with you. It’s very hard for me to speak on behalf of the FDA, to allude to their thinking processes, but we need to be up to speed with the evidence. The first thing is, why don’t you study the drug in the United States? I’m not asking you to lift the ban, which you put in 2005, but why don’t you honor what has been done over two decades and at least open the door a little bit and let us do what we do best? Why don’t you allow us to do the research in a controlled setting with a carefully, properly selected group of patients without underlying renal or hepatic insufficiency and see where we’re at?
Let’s compare it against placebo. If that’s not ethical, let’s compare it against active comparators — God knows we have 15-20 drugs we can use — and let’s see where we’re at. Ken has been nothing short of superb when it comes to evidence. Let us put the evidence together.
Dr. Milne: If there were concerns decades ago, those need to be addressed. As science is iterative and as other information becomes available, the scientific method would say, Let’s reexamine this and let’s reexamine our position, and do that with evidence. To do that, it has to have validity within the US system. Someone like you doing the research, you are a pain research guru; you should be doing this research to say, “Does it work or not? Does this nonapproval still stand today in 2024?”
Dr. Motov: Thank you for the shout-out, and I agree with you. All of us, those who are interested, on the frontiers of emergency care — as present clinicians — we should be doing this. There is nothing that will convince the FDA more than properly and rightly conducted research, time to reassess the evidence, and time to be less rigid. I understand that you placed a ban 20 years ago, but let’s go with the science. We cannot be behind it.
Exploring the Ecological Footprint of Methoxyflurane
Dr. Milne: There was an Austrian study in 2022 and a very interesting study out of the UK looking at life-cycle impact assessment on the environment. If we’re not just concerned about patient care —obviously, we want to provide patients with a safe and effective product, compared with other products that are available that might not have as good a safety profile — this looks at the impact on the environment.
Dr. Glatter: Ken, can you tell me about some of your recent research regarding the environmental effects related to use of Penthrox, but also its utility pharmacologically and its mechanism of action?
Dr. Milne: There was a really interesting study published this year by Martindale in the Emergency Medicine Journal. It took a different approach to this question about could we be using this drug, and why should we be using this drug? Sergey and I have already talked about the potential benefits and the potential harms. I mentioned opioids and some of the concerns about that. For this drug, if we’re using it in the prehospital setting in this little green whistle, the potential benefits look really good, and we haven’t seen any of the potential harms come through in the literature.
This was another line of evidence of why this might be a good drug, because of the environmental impact of this low-dose methoxyflurane. They compared it with nitrous oxide and said, “Well, what about the life-cycle impact on the environment of using this and the overall cradle-to-grave environmental impacts?”
Obviously, Sergey and I are interested in patient care, and we treat patients one at a time. But we have a larger responsibility to social determinants of health, like our environment. If you look at the overall cradle-to-grave environmental impact of this drug, it was better than for nitrous oxide when looking specifically at climate-change impact. That might be another reason, another line of argument, that could be put forward in the United States to say, “We want to have a healthy environment and a healthy option for patients.”
I’ll let Sergey speak to mechanisms of action and those types of things.
Dr. Motov: As a general anesthetic and hydrocarbonated volatile ones, I’m just going to say that it causes this generalized diffuse cortical depression, and there are no particular channels, receptors, or enzymes we need to worry much about. In short, it’s an inhaled gas used to put patients or people to sleep.
Over the past 30 or 40 years — and I’ll go back to the past decade — there have been numerous studies in different countries (outside of the United States, of course), and with the recent study that Ken just cited, there were comparisons for managing predominantly acute traumatic injuries in pediatric and adult populations presenting to EDs in various regions of the world that compared Penthrox, or the green whistle, with either placebo or active comparators, which included parenteral opioids, oral opioids, and NSAIDs.
The recent systematic review by Fabbri, out of Italy, showed that for ultra–short-term pain — we’re talking about 5, 10, or 15 minutes — inhaled methoxyflurane was found to be equal or even superior to standard of care, primarily related to parenteral opioids, and safety was off the hook. Interestingly, with respect to analgesia, they found that geriatric patients seemed to be responding more, with respect to changing pain score, than younger adults — we’re talking about ages 18-64 vs 65 or older. Again, we need to make sure that we carefully select those elderly people without underlying renal or hepatic insufficiency.
To wrap this up, there is evidence clearly supporting its analgesic efficacy and safety, even in comparison to commonly used and traditionally accepted analgesic modalities that we use for managing acute pain.
US Military Use and Implications for Civilian Practice
Dr. Glatter: Do you think that methoxyflurane’s use in the military will help propel its use in clinical settings in the US, and possibly convince the FDA to look at this closer? The military is currently using it in deployed combat veterans in an ongoing fashion.
Dr. Motov: I’m excited that the Department of Defense in the United States has taken the lead, and they’re being very progressive. There are data that we’ve adapted to the civilian environment by use of intranasal opioids and intranasal ketamine with more doctors who came out of the military. In the military, it’s a kingdom within a kingdom. I don’t know their relationship with the FDA, but I support the military’s pharmacologic initiative by honoring and disseminating their research once it becomes available.
For us nonmilitary folks, we still need to work with the FDA. We need to convince the FDA to let us study the drug, and then we need to pile the evidence within the United States so that the FDA will start looking at this favorably. It wouldn’t hurt and it wouldn’t harm. Any piece of evidence will add to the existing body of literature that we need to allow this medication to be available to us.
Safety Considerations and Aerosolization Concerns
Dr. Glatter: Its safety in children is well established in Australia and throughout the world. I think it deserves a careful look, and the evidence that you’ve both presented argues for the use of this prehospital but also in hospital. I guess there was concern in the hospital with underventilation and healthcare workers being exposed to the fumes, and then getting headaches, dizziness, and so forth. I don’t know if that’s borne out, Ken, in any of your experience in Canada at all.
Dr. Milne: We currently don’t have it in our shop. It’s being used in British Columbia right now in the prehospital setting, and I’m not aware of anybody using it in their department. It’s used prehospital as far as I know.
Dr. Motov: I can attest to it, if I may, because I had familiarized myself with the device. I actually was able to hold it in my hands. I have not used it yet but I had the prototype. The way it’s set up, there is an activated charcoal chamber that sits right on top of the device, which serves as the scavenger for exhaled air that contains particles of methoxyflurane. In theory, but I’m telling how it is in practicality, it significantly reduces occupational exposure, based on data that lacks specifics.
Although most of the researchers did not measure the concentration of methoxyflurane in ambient air within the treatment room in the EDs, I believe the additional data sources clearly stating that it’s within or even below the detectable level that would cause any harm. Once again, we need to honor pathology. We need to make sure that pregnant women will not be exposed to it.
Dr. Milne: In 2024, we also need to be concerned about aerosolizing procedures and aerosolizing treatments, and just take that into account because we should be considering all the potential benefits and all the potential harms. Going through the COVID-19 pandemic, there was concern about transmission and whether or not it was droplet or aerosolized.
There was an observational study published in 2022 in Austria by Trimmel in BMC Emergency Medicine showing similar results. It seemed to work well and potential harms didn’t get picked up. They had to stop the study early because of COVID-19.
We need to always focus in on the potential benefits, the potential harms; where does the science land? Where do the data lie? Then we move forward from that and make informed decisions.
Final Thoughts
Dr. Glatter: Are there any key takeaways you’d like to share with our audience?
Dr. Milne: One of the takeaways from this whole conversation is that science is iterative and science changes. When new evidence becomes available, and we’ve seen it accumulate around the world, we as scientists, as a researcher, as somebody committed to great patient care should revisit our positions on this. Since there is a prohibition against this medication, I think it’s time to reassess that stance and move forward to see if it still is accurate today.
Dr. Motov: I wholeheartedly agree with this. Thank you, Ken, for bringing this up. Good point.
Dr. Glatter: This has been a really informative discussion. I think our audience will certainly embrace this. Thank you very much for your time; it’s much appreciated.
Dr. Glatter is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He is a medical adviser for Medscape and hosts the Hot Topics in EM series. Dr. Milne is an emergency physician at Strathroy Middlesex General Hospital in Ontario, Canada, and the founder of the well-known podcast The Skeptics’ Guide to Emergency Medicine (SGEM). Dr. Motov is professor of emergency medicine and director of research in the Department of Emergency Medicine at Maimonides Medical Center in Brooklyn, New York. He is passionate about safe and effective pain management in the emergency department, and has numerous publications on the subject of opioid alternatives in pain management. Dr. Glatter, Dr. Milne, and Dr. Motov had no conflicts of interest to disclose.
A version of this article appeared on Medscape.com.
This discussion was recorded on March 29, 2024. The transcript has been edited for clarity.
Robert D. Glatter, MD: Joining me today to discuss the use of methoxyflurane (Penthrox), an inhaled nonopioid analgesic for the relief of acute pain, is Dr. William Kenneth (Ken) Milne, an emergency physician at Strathroy Middlesex General Hospital in Ontario, Canada, and the founder of the well-known podcast The Skeptics’ Guide to Emergency Medicine (SGEM).
Also joining me is Dr. Sergey Motov, an emergency physician and research director at Maimonides Medical Center in Brooklyn, New York, and an expert in pain management. I want to welcome both of you and thank you for joining me.
RAMPED Trial: Evaluating the Efficacy of Methoxyflurane
Dr. Glatter: Ken, your recent post on Twitter [now X] regarding the utility of Penthrox in the RAMPED trial really caught my attention. While the trial was from 2021, it really is relevant regarding the prehospital management of pain in the practice of emergency medicine, and certainly in-hospital practice. I was hoping you could review the study design but also get into the rationale behind the use of this novel agent.
William Kenneth (Ken) Milne, MD, MSc: Sure. I’d be happy to kick this episode off with talking about a study that was published in 2020 in Academic Emergency Medicine. It was an Australian study by Brichko et al., and they were doing a randomized controlled trial looking at methoxyflurane vs standard care.
They selected out a population of adults, which they defined as 18-75 years of age. They were in the prehospital setting and they had a pain score of greater than 8. They gave the participants methoxyflurane, which is also called the “green whistle.” They had the subjects take that for their prehospital pain, and they compared that with whatever your standard analgesic in the prehospital setting would be.
Their primary outcome was how many patients had at least 50% reduction in their pain score within 30 minutes. They recruited about 120 people, and they found that there was no statistical difference in the primary outcome between methoxyflurane and standard care. Again, that primary outcome was a reduction in pain score by greater than 50% at 30 minutes, and there wasn’t a statistical difference between the two.
There are obviously limits to any study, and it was a convenience sample. This was an unmasked trial, so people knew if they were getting this green whistle, which is popular in Australia. People would be familiar with this device, and they didn’t compare it with a sham or placebo group.
Pharmacology of Penthrox: Its Role and Mechanism of Action
Dr. Glatter: The primary outcome wasn’t met, but certainly secondary outcomes were. There was, again, a relatively small number of patients in this trial. That said, there was significant pain relief. I think there are issues with the trial, as with any trial limitations.
Getting to the pharmacology of Penthrox, can you describe this inhaled anesthetic and how we use it, specifically its role at the subanesthetic doses?
Sergey M. Motov, MD: Methoxyflurane is embedded in the green whistle package, and that whole contraption is called Penthrox. It’s an inhaled volatile fluorinated hydrocarbon anesthetic that was predominantly used, I’d say 40, 50 years ago, for general anesthesia and slowly but surely fell out of favor due to the fact that, when used for prolonged duration or in supratherapeutic doses, there were cases of severe or even fatal nephrotoxicity and hepatotoxicity.
In the late ‘70s and early ‘80s, all the fluranes came on board that are slightly different as general anesthetics, and methoxyflurane started slowly falling out of favor. Because of this paucity and then a subsequent slightly greater number of cases of nephrotoxicity and hepatotoxicity, [the US Food and Drug Administration] FDA made a decision to pull the drug off the market in 2005. FDA successfully accomplished its mission and since then has pretty much banned the use of inhaled methoxyflurane in any shape, form, or color in the United States.
Going back to the green whistle, it has been used in Australia probably for about 50-60 years, and has been used in Europe for probably 10-20 years. Ken can attest that it has been used in Canada for at least a decade and the track record is phenomenal.
We are using subanesthetic, even supratherapeutic doses that, based on available literature, has no incidence of this fatal hepatotoxicity or nephrotoxicity. We’re talking about 10 million doses administered worldwide, except in the United States. There are 40-plus randomized clinical trials with over 30,000 patients enrolled that prove efficacy and safety.
That’s where we are right now, in a conundrum. We have a great deal of data all over the world, except in the United States, that push for the use of this noninvasive, patient-controlled nonopioid inhaled anesthetic. We just don’t have the access in North America, with the exception of Canada.
Regulatory Hurdles: Challenges in FDA Approval
Dr. Glatter: Absolutely. The FDA wants to be cautious, but if you look at the evidence base of data on this, it really indicates otherwise. Do you think that these roadblocks can be somehow overcome?
Dr. Milne: In the 2000s and 2010s, everybody was focused on opioids and all the dangers and potential adverse events. Opioids are great drugs like many other drugs; it depends on dose and duration. If used properly, it’s an excellent drug. Well, here’s another excellent drug if it’s used properly, and the adverse events are dependent on their dose and duration. Penthrox, or methoxyflurane, is a subtherapeutic, small dose and there have been no reported cases of addiction or abuse related to these inhalers.
Dr. Glatter: That argues for the point — and I’ll turn this over to you, Sergey — of how can this not, in my mind, be an issue that the FDA can overcome.
Dr. Motov: I agree with you. It’s very hard for me to speak on behalf of the FDA, to allude to their thinking processes, but we need to be up to speed with the evidence. The first thing is, why don’t you study the drug in the United States? I’m not asking you to lift the ban, which you put in 2005, but why don’t you honor what has been done over two decades and at least open the door a little bit and let us do what we do best? Why don’t you allow us to do the research in a controlled setting with a carefully, properly selected group of patients without underlying renal or hepatic insufficiency and see where we’re at?
Let’s compare it against placebo. If that’s not ethical, let’s compare it against active comparators — God knows we have 15-20 drugs we can use — and let’s see where we’re at. Ken has been nothing short of superb when it comes to evidence. Let us put the evidence together.
Dr. Milne: If there were concerns decades ago, those need to be addressed. As science is iterative and as other information becomes available, the scientific method would say, Let’s reexamine this and let’s reexamine our position, and do that with evidence. To do that, it has to have validity within the US system. Someone like you doing the research, you are a pain research guru; you should be doing this research to say, “Does it work or not? Does this nonapproval still stand today in 2024?”
Dr. Motov: Thank you for the shout-out, and I agree with you. All of us, those who are interested, on the frontiers of emergency care — as present clinicians — we should be doing this. There is nothing that will convince the FDA more than properly and rightly conducted research, time to reassess the evidence, and time to be less rigid. I understand that you placed a ban 20 years ago, but let’s go with the science. We cannot be behind it.
Exploring the Ecological Footprint of Methoxyflurane
Dr. Milne: There was an Austrian study in 2022 and a very interesting study out of the UK looking at life-cycle impact assessment on the environment. If we’re not just concerned about patient care —obviously, we want to provide patients with a safe and effective product, compared with other products that are available that might not have as good a safety profile — this looks at the impact on the environment.
Dr. Glatter: Ken, can you tell me about some of your recent research regarding the environmental effects related to use of Penthrox, but also its utility pharmacologically and its mechanism of action?
Dr. Milne: There was a really interesting study published this year by Martindale in the Emergency Medicine Journal. It took a different approach to this question about could we be using this drug, and why should we be using this drug? Sergey and I have already talked about the potential benefits and the potential harms. I mentioned opioids and some of the concerns about that. For this drug, if we’re using it in the prehospital setting in this little green whistle, the potential benefits look really good, and we haven’t seen any of the potential harms come through in the literature.
This was another line of evidence of why this might be a good drug, because of the environmental impact of this low-dose methoxyflurane. They compared it with nitrous oxide and said, “Well, what about the life-cycle impact on the environment of using this and the overall cradle-to-grave environmental impacts?”
Obviously, Sergey and I are interested in patient care, and we treat patients one at a time. But we have a larger responsibility to social determinants of health, like our environment. If you look at the overall cradle-to-grave environmental impact of this drug, it was better than for nitrous oxide when looking specifically at climate-change impact. That might be another reason, another line of argument, that could be put forward in the United States to say, “We want to have a healthy environment and a healthy option for patients.”
I’ll let Sergey speak to mechanisms of action and those types of things.
Dr. Motov: As a general anesthetic and hydrocarbonated volatile ones, I’m just going to say that it causes this generalized diffuse cortical depression, and there are no particular channels, receptors, or enzymes we need to worry much about. In short, it’s an inhaled gas used to put patients or people to sleep.
Over the past 30 or 40 years — and I’ll go back to the past decade — there have been numerous studies in different countries (outside of the United States, of course), and with the recent study that Ken just cited, there were comparisons for managing predominantly acute traumatic injuries in pediatric and adult populations presenting to EDs in various regions of the world that compared Penthrox, or the green whistle, with either placebo or active comparators, which included parenteral opioids, oral opioids, and NSAIDs.
The recent systematic review by Fabbri, out of Italy, showed that for ultra–short-term pain — we’re talking about 5, 10, or 15 minutes — inhaled methoxyflurane was found to be equal or even superior to standard of care, primarily related to parenteral opioids, and safety was off the hook. Interestingly, with respect to analgesia, they found that geriatric patients seemed to be responding more, with respect to changing pain score, than younger adults — we’re talking about ages 18-64 vs 65 or older. Again, we need to make sure that we carefully select those elderly people without underlying renal or hepatic insufficiency.
To wrap this up, there is evidence clearly supporting its analgesic efficacy and safety, even in comparison to commonly used and traditionally accepted analgesic modalities that we use for managing acute pain.
US Military Use and Implications for Civilian Practice
Dr. Glatter: Do you think that methoxyflurane’s use in the military will help propel its use in clinical settings in the US, and possibly convince the FDA to look at this closer? The military is currently using it in deployed combat veterans in an ongoing fashion.
Dr. Motov: I’m excited that the Department of Defense in the United States has taken the lead, and they’re being very progressive. There are data that we’ve adapted to the civilian environment by use of intranasal opioids and intranasal ketamine with more doctors who came out of the military. In the military, it’s a kingdom within a kingdom. I don’t know their relationship with the FDA, but I support the military’s pharmacologic initiative by honoring and disseminating their research once it becomes available.
For us nonmilitary folks, we still need to work with the FDA. We need to convince the FDA to let us study the drug, and then we need to pile the evidence within the United States so that the FDA will start looking at this favorably. It wouldn’t hurt and it wouldn’t harm. Any piece of evidence will add to the existing body of literature that we need to allow this medication to be available to us.
Safety Considerations and Aerosolization Concerns
Dr. Glatter: Its safety in children is well established in Australia and throughout the world. I think it deserves a careful look, and the evidence that you’ve both presented argues for the use of this prehospital but also in hospital. I guess there was concern in the hospital with underventilation and healthcare workers being exposed to the fumes, and then getting headaches, dizziness, and so forth. I don’t know if that’s borne out, Ken, in any of your experience in Canada at all.
Dr. Milne: We currently don’t have it in our shop. It’s being used in British Columbia right now in the prehospital setting, and I’m not aware of anybody using it in their department. It’s used prehospital as far as I know.
Dr. Motov: I can attest to it, if I may, because I had familiarized myself with the device. I actually was able to hold it in my hands. I have not used it yet but I had the prototype. The way it’s set up, there is an activated charcoal chamber that sits right on top of the device, which serves as the scavenger for exhaled air that contains particles of methoxyflurane. In theory, but I’m telling how it is in practicality, it significantly reduces occupational exposure, based on data that lacks specifics.
Although most of the researchers did not measure the concentration of methoxyflurane in ambient air within the treatment room in the EDs, I believe the additional data sources clearly stating that it’s within or even below the detectable level that would cause any harm. Once again, we need to honor pathology. We need to make sure that pregnant women will not be exposed to it.
Dr. Milne: In 2024, we also need to be concerned about aerosolizing procedures and aerosolizing treatments, and just take that into account because we should be considering all the potential benefits and all the potential harms. Going through the COVID-19 pandemic, there was concern about transmission and whether or not it was droplet or aerosolized.
There was an observational study published in 2022 in Austria by Trimmel in BMC Emergency Medicine showing similar results. It seemed to work well and potential harms didn’t get picked up. They had to stop the study early because of COVID-19.
We need to always focus in on the potential benefits, the potential harms; where does the science land? Where do the data lie? Then we move forward from that and make informed decisions.
Final Thoughts
Dr. Glatter: Are there any key takeaways you’d like to share with our audience?
Dr. Milne: One of the takeaways from this whole conversation is that science is iterative and science changes. When new evidence becomes available, and we’ve seen it accumulate around the world, we as scientists, as a researcher, as somebody committed to great patient care should revisit our positions on this. Since there is a prohibition against this medication, I think it’s time to reassess that stance and move forward to see if it still is accurate today.
Dr. Motov: I wholeheartedly agree with this. Thank you, Ken, for bringing this up. Good point.
Dr. Glatter: This has been a really informative discussion. I think our audience will certainly embrace this. Thank you very much for your time; it’s much appreciated.
Dr. Glatter is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He is a medical adviser for Medscape and hosts the Hot Topics in EM series. Dr. Milne is an emergency physician at Strathroy Middlesex General Hospital in Ontario, Canada, and the founder of the well-known podcast The Skeptics’ Guide to Emergency Medicine (SGEM). Dr. Motov is professor of emergency medicine and director of research in the Department of Emergency Medicine at Maimonides Medical Center in Brooklyn, New York. He is passionate about safe and effective pain management in the emergency department, and has numerous publications on the subject of opioid alternatives in pain management. Dr. Glatter, Dr. Milne, and Dr. Motov had no conflicts of interest to disclose.
A version of this article appeared on Medscape.com.
This discussion was recorded on March 29, 2024. The transcript has been edited for clarity.
Robert D. Glatter, MD: Joining me today to discuss the use of methoxyflurane (Penthrox), an inhaled nonopioid analgesic for the relief of acute pain, is Dr. William Kenneth (Ken) Milne, an emergency physician at Strathroy Middlesex General Hospital in Ontario, Canada, and the founder of the well-known podcast The Skeptics’ Guide to Emergency Medicine (SGEM).
Also joining me is Dr. Sergey Motov, an emergency physician and research director at Maimonides Medical Center in Brooklyn, New York, and an expert in pain management. I want to welcome both of you and thank you for joining me.
RAMPED Trial: Evaluating the Efficacy of Methoxyflurane
Dr. Glatter: Ken, your recent post on Twitter [now X] regarding the utility of Penthrox in the RAMPED trial really caught my attention. While the trial was from 2021, it really is relevant regarding the prehospital management of pain in the practice of emergency medicine, and certainly in-hospital practice. I was hoping you could review the study design but also get into the rationale behind the use of this novel agent.
William Kenneth (Ken) Milne, MD, MSc: Sure. I’d be happy to kick this episode off with talking about a study that was published in 2020 in Academic Emergency Medicine. It was an Australian study by Brichko et al., and they were doing a randomized controlled trial looking at methoxyflurane vs standard care.
They selected out a population of adults, which they defined as 18-75 years of age. They were in the prehospital setting and they had a pain score of greater than 8. They gave the participants methoxyflurane, which is also called the “green whistle.” They had the subjects take that for their prehospital pain, and they compared that with whatever your standard analgesic in the prehospital setting would be.
Their primary outcome was how many patients had at least 50% reduction in their pain score within 30 minutes. They recruited about 120 people, and they found that there was no statistical difference in the primary outcome between methoxyflurane and standard care. Again, that primary outcome was a reduction in pain score by greater than 50% at 30 minutes, and there wasn’t a statistical difference between the two.
There are obviously limits to any study, and it was a convenience sample. This was an unmasked trial, so people knew if they were getting this green whistle, which is popular in Australia. People would be familiar with this device, and they didn’t compare it with a sham or placebo group.
Pharmacology of Penthrox: Its Role and Mechanism of Action
Dr. Glatter: The primary outcome wasn’t met, but certainly secondary outcomes were. There was, again, a relatively small number of patients in this trial. That said, there was significant pain relief. I think there are issues with the trial, as with any trial limitations.
Getting to the pharmacology of Penthrox, can you describe this inhaled anesthetic and how we use it, specifically its role at the subanesthetic doses?
Sergey M. Motov, MD: Methoxyflurane is embedded in the green whistle package, and that whole contraption is called Penthrox. It’s an inhaled volatile fluorinated hydrocarbon anesthetic that was predominantly used, I’d say 40, 50 years ago, for general anesthesia and slowly but surely fell out of favor due to the fact that, when used for prolonged duration or in supratherapeutic doses, there were cases of severe or even fatal nephrotoxicity and hepatotoxicity.
In the late ‘70s and early ‘80s, all the fluranes came on board that are slightly different as general anesthetics, and methoxyflurane started slowly falling out of favor. Because of this paucity and then a subsequent slightly greater number of cases of nephrotoxicity and hepatotoxicity, [the US Food and Drug Administration] FDA made a decision to pull the drug off the market in 2005. FDA successfully accomplished its mission and since then has pretty much banned the use of inhaled methoxyflurane in any shape, form, or color in the United States.
Going back to the green whistle, it has been used in Australia probably for about 50-60 years, and has been used in Europe for probably 10-20 years. Ken can attest that it has been used in Canada for at least a decade and the track record is phenomenal.
We are using subanesthetic, even supratherapeutic doses that, based on available literature, has no incidence of this fatal hepatotoxicity or nephrotoxicity. We’re talking about 10 million doses administered worldwide, except in the United States. There are 40-plus randomized clinical trials with over 30,000 patients enrolled that prove efficacy and safety.
That’s where we are right now, in a conundrum. We have a great deal of data all over the world, except in the United States, that push for the use of this noninvasive, patient-controlled nonopioid inhaled anesthetic. We just don’t have the access in North America, with the exception of Canada.
Regulatory Hurdles: Challenges in FDA Approval
Dr. Glatter: Absolutely. The FDA wants to be cautious, but if you look at the evidence base of data on this, it really indicates otherwise. Do you think that these roadblocks can be somehow overcome?
Dr. Milne: In the 2000s and 2010s, everybody was focused on opioids and all the dangers and potential adverse events. Opioids are great drugs like many other drugs; it depends on dose and duration. If used properly, it’s an excellent drug. Well, here’s another excellent drug if it’s used properly, and the adverse events are dependent on their dose and duration. Penthrox, or methoxyflurane, is a subtherapeutic, small dose and there have been no reported cases of addiction or abuse related to these inhalers.
Dr. Glatter: That argues for the point — and I’ll turn this over to you, Sergey — of how can this not, in my mind, be an issue that the FDA can overcome.
Dr. Motov: I agree with you. It’s very hard for me to speak on behalf of the FDA, to allude to their thinking processes, but we need to be up to speed with the evidence. The first thing is, why don’t you study the drug in the United States? I’m not asking you to lift the ban, which you put in 2005, but why don’t you honor what has been done over two decades and at least open the door a little bit and let us do what we do best? Why don’t you allow us to do the research in a controlled setting with a carefully, properly selected group of patients without underlying renal or hepatic insufficiency and see where we’re at?
Let’s compare it against placebo. If that’s not ethical, let’s compare it against active comparators — God knows we have 15-20 drugs we can use — and let’s see where we’re at. Ken has been nothing short of superb when it comes to evidence. Let us put the evidence together.
Dr. Milne: If there were concerns decades ago, those need to be addressed. As science is iterative and as other information becomes available, the scientific method would say, Let’s reexamine this and let’s reexamine our position, and do that with evidence. To do that, it has to have validity within the US system. Someone like you doing the research, you are a pain research guru; you should be doing this research to say, “Does it work or not? Does this nonapproval still stand today in 2024?”
Dr. Motov: Thank you for the shout-out, and I agree with you. All of us, those who are interested, on the frontiers of emergency care — as present clinicians — we should be doing this. There is nothing that will convince the FDA more than properly and rightly conducted research, time to reassess the evidence, and time to be less rigid. I understand that you placed a ban 20 years ago, but let’s go with the science. We cannot be behind it.
Exploring the Ecological Footprint of Methoxyflurane
Dr. Milne: There was an Austrian study in 2022 and a very interesting study out of the UK looking at life-cycle impact assessment on the environment. If we’re not just concerned about patient care —obviously, we want to provide patients with a safe and effective product, compared with other products that are available that might not have as good a safety profile — this looks at the impact on the environment.
Dr. Glatter: Ken, can you tell me about some of your recent research regarding the environmental effects related to use of Penthrox, but also its utility pharmacologically and its mechanism of action?
Dr. Milne: There was a really interesting study published this year by Martindale in the Emergency Medicine Journal. It took a different approach to this question about could we be using this drug, and why should we be using this drug? Sergey and I have already talked about the potential benefits and the potential harms. I mentioned opioids and some of the concerns about that. For this drug, if we’re using it in the prehospital setting in this little green whistle, the potential benefits look really good, and we haven’t seen any of the potential harms come through in the literature.
This was another line of evidence of why this might be a good drug, because of the environmental impact of this low-dose methoxyflurane. They compared it with nitrous oxide and said, “Well, what about the life-cycle impact on the environment of using this and the overall cradle-to-grave environmental impacts?”
Obviously, Sergey and I are interested in patient care, and we treat patients one at a time. But we have a larger responsibility to social determinants of health, like our environment. If you look at the overall cradle-to-grave environmental impact of this drug, it was better than for nitrous oxide when looking specifically at climate-change impact. That might be another reason, another line of argument, that could be put forward in the United States to say, “We want to have a healthy environment and a healthy option for patients.”
I’ll let Sergey speak to mechanisms of action and those types of things.
Dr. Motov: As a general anesthetic and hydrocarbonated volatile ones, I’m just going to say that it causes this generalized diffuse cortical depression, and there are no particular channels, receptors, or enzymes we need to worry much about. In short, it’s an inhaled gas used to put patients or people to sleep.
Over the past 30 or 40 years — and I’ll go back to the past decade — there have been numerous studies in different countries (outside of the United States, of course), and with the recent study that Ken just cited, there were comparisons for managing predominantly acute traumatic injuries in pediatric and adult populations presenting to EDs in various regions of the world that compared Penthrox, or the green whistle, with either placebo or active comparators, which included parenteral opioids, oral opioids, and NSAIDs.
The recent systematic review by Fabbri, out of Italy, showed that for ultra–short-term pain — we’re talking about 5, 10, or 15 minutes — inhaled methoxyflurane was found to be equal or even superior to standard of care, primarily related to parenteral opioids, and safety was off the hook. Interestingly, with respect to analgesia, they found that geriatric patients seemed to be responding more, with respect to changing pain score, than younger adults — we’re talking about ages 18-64 vs 65 or older. Again, we need to make sure that we carefully select those elderly people without underlying renal or hepatic insufficiency.
To wrap this up, there is evidence clearly supporting its analgesic efficacy and safety, even in comparison to commonly used and traditionally accepted analgesic modalities that we use for managing acute pain.
US Military Use and Implications for Civilian Practice
Dr. Glatter: Do you think that methoxyflurane’s use in the military will help propel its use in clinical settings in the US, and possibly convince the FDA to look at this closer? The military is currently using it in deployed combat veterans in an ongoing fashion.
Dr. Motov: I’m excited that the Department of Defense in the United States has taken the lead, and they’re being very progressive. There are data that we’ve adapted to the civilian environment by use of intranasal opioids and intranasal ketamine with more doctors who came out of the military. In the military, it’s a kingdom within a kingdom. I don’t know their relationship with the FDA, but I support the military’s pharmacologic initiative by honoring and disseminating their research once it becomes available.
For us nonmilitary folks, we still need to work with the FDA. We need to convince the FDA to let us study the drug, and then we need to pile the evidence within the United States so that the FDA will start looking at this favorably. It wouldn’t hurt and it wouldn’t harm. Any piece of evidence will add to the existing body of literature that we need to allow this medication to be available to us.
Safety Considerations and Aerosolization Concerns
Dr. Glatter: Its safety in children is well established in Australia and throughout the world. I think it deserves a careful look, and the evidence that you’ve both presented argues for the use of this prehospital but also in hospital. I guess there was concern in the hospital with underventilation and healthcare workers being exposed to the fumes, and then getting headaches, dizziness, and so forth. I don’t know if that’s borne out, Ken, in any of your experience in Canada at all.
Dr. Milne: We currently don’t have it in our shop. It’s being used in British Columbia right now in the prehospital setting, and I’m not aware of anybody using it in their department. It’s used prehospital as far as I know.
Dr. Motov: I can attest to it, if I may, because I had familiarized myself with the device. I actually was able to hold it in my hands. I have not used it yet but I had the prototype. The way it’s set up, there is an activated charcoal chamber that sits right on top of the device, which serves as the scavenger for exhaled air that contains particles of methoxyflurane. In theory, but I’m telling how it is in practicality, it significantly reduces occupational exposure, based on data that lacks specifics.
Although most of the researchers did not measure the concentration of methoxyflurane in ambient air within the treatment room in the EDs, I believe the additional data sources clearly stating that it’s within or even below the detectable level that would cause any harm. Once again, we need to honor pathology. We need to make sure that pregnant women will not be exposed to it.
Dr. Milne: In 2024, we also need to be concerned about aerosolizing procedures and aerosolizing treatments, and just take that into account because we should be considering all the potential benefits and all the potential harms. Going through the COVID-19 pandemic, there was concern about transmission and whether or not it was droplet or aerosolized.
There was an observational study published in 2022 in Austria by Trimmel in BMC Emergency Medicine showing similar results. It seemed to work well and potential harms didn’t get picked up. They had to stop the study early because of COVID-19.
We need to always focus in on the potential benefits, the potential harms; where does the science land? Where do the data lie? Then we move forward from that and make informed decisions.
Final Thoughts
Dr. Glatter: Are there any key takeaways you’d like to share with our audience?
Dr. Milne: One of the takeaways from this whole conversation is that science is iterative and science changes. When new evidence becomes available, and we’ve seen it accumulate around the world, we as scientists, as a researcher, as somebody committed to great patient care should revisit our positions on this. Since there is a prohibition against this medication, I think it’s time to reassess that stance and move forward to see if it still is accurate today.
Dr. Motov: I wholeheartedly agree with this. Thank you, Ken, for bringing this up. Good point.
Dr. Glatter: This has been a really informative discussion. I think our audience will certainly embrace this. Thank you very much for your time; it’s much appreciated.
Dr. Glatter is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He is a medical adviser for Medscape and hosts the Hot Topics in EM series. Dr. Milne is an emergency physician at Strathroy Middlesex General Hospital in Ontario, Canada, and the founder of the well-known podcast The Skeptics’ Guide to Emergency Medicine (SGEM). Dr. Motov is professor of emergency medicine and director of research in the Department of Emergency Medicine at Maimonides Medical Center in Brooklyn, New York. He is passionate about safe and effective pain management in the emergency department, and has numerous publications on the subject of opioid alternatives in pain management. Dr. Glatter, Dr. Milne, and Dr. Motov had no conflicts of interest to disclose.
A version of this article appeared on Medscape.com.