Episode 7 Production:

Podcast Guest:
•Dr. Jennifer McEntee, MD, MPH, MA.Ed
Dr. McEntee’s Bio Link

Podcast Host:
•Dr. Justin Brooten, MD
•Dr. Daniel Markwalter, MD
Dr. Markwalter’s Bio-Links:
Palliative Care
Emergency Medicine

Transcription Editing
•Michelle C. Brooten-Brooks

Educational Resource
The Role of Ketamine for Acute Pain
UNC Lineberger Cancer Network
Lecture recorded: April 24, 2019
Lecture Link for Dr. Jennifer McEntee

The PalliEM Podcast:  Episode 7: It’s All About The Ketamine – with Jennifer McEntee MD, MPH, MA.Ed and Daniel Markwalter, MD

Total Time: 38:30

SPEAKERS

• Justin Brooten, MD
• Daniel Markwalter, MD
• Jennifer McEntee, MD, MPH, MA.Ed

Justin Brooten, MD:  00:01

This is the PalliEM podcast, a production of palliEM.org at the intersection of palliative and emergency medicine. I’m your host, Justin Brooten. Today on the PalliEM podcast, I’m joined by Jennifer McEntee and Daniel Markwalter. Jennifer McEntee is an associate professor in the Department of Medicine and Pediatrics and serves as a clinician educator, academic hospitalist and palliative care and hospice provider. Dr. McEntee also serves as the Associate Program Director for the internal medicine residency program for the inpatient rotations. In addition to degrees in education and public health, she completed her residency in Internal Medicine and Pediatrics at the University of North Carolina Chapel Hill and fellowship training in hospice and palliative medicine at Duke University. Dr. McEntee is extremely interested in improving medical provider patient communication, medical provider resiliency, international health, public health, quality improvement, resident and medical student education, and in promoting competent, compassionate patient-oriented care. Daniel Markwalter received his emergency medicine residency training at the University of North Carolina, where he served as education chief resident, and completed fellowship training and palliative care. He is currently an assistant professor in the Department of Emergency Medicine, and the UNC Palliative Care program. His scholarly interests include ED-based advanced care planning, transitions to hospice from the ED, and Palliative Care Education for emergency medicine physicians. Dr. Markwalter is also a contributor to content at PalliEM.org. Thank you both for joining us today.

01:34

Daniel Markwalter, MD:

Thanks for having us.

Jennifer McEntee, MD:
Thank you.

Daniel Markwalter, MD:

I appreciate you letting me be a guest interviewer on today’s episode. Today we’re talking about a subject that I think is near and dear to both emergency medicine and out of care these days. And that’s ketamine. Many of us are familiar with the use of ketamine for sedation and agitation in the emergency department and a lot of newer protocols for analgesic dosing. There seems to be an explosion of routes of administration, these days, intranasal options, looking at topical and nebulized ketamine, recent studies on the use of ketamine for depression. It really is a big ketamine world out there. So, we want to pivot a little bit to the use of ketamine in the overlap between palliative care and the emergency department. There was some interest in this at the recent 2022 annual assembly. And so we’re excited to have one of our experts from the University North Carolina here, Dr. McEntee and she was the palliative care driver behind the ketamine policy at UNC. And so we’re glad to have you here. But I know in particular, you have a story that sort of sparked your interest in the subject. Would you mind sharing that with us?

02:42

Jennifer McEntee, MD:
Thank you so much again for having me to also help spread the word of how ketamine can really help most of our patients, or many of our patients. So, this patient was a beautiful 40-year-old woman, mother of three, who was diagnosed with de novo metastatic breast cancer in 2017. And we have seen her numerous times throughout her hospitalizations. Many of those times were for pain crisis, secondary to refractory pain. The most memorable one related to ketamine, was she presented with 10 out of 10 refractory pain. At home, she was on methadone 30 milligrams TID, she was also on a Dilaudid pca, 1.5 milligrams q/ 15 minutes, and she was also on dexamethasone. We continued to kind of ramp that pain medicine up through her hospitalization and we were getting nowhere, her pain still was 10 out of 10. At which point, at that point, we decided to transfer her to the ICU because we had to, because that was the ketamine policy at UNC at that point in time all of our patients had to be treated in the ICU, subsequently that is no longer the case, which I’m really excited for. We can now treat these patients on the floor. And we transitioned her, we started her on a chronic ketamine dose on let’s just say June 2nd 0.1 mg/kg/hr And we were able to slowly titrate that up to 0.25 mg/kg/hr over the next couple of days. When I saw her three days later, I approached her and she told me she was in zero out of 10 pain, which I had ¾ I was in utter disbelief. I told her I didn’t believe her because I’d never seen her without pain, without 10 out of 10 pain. For four and a half years she was unable to climb a flight of stairs. She was unable to play, and to play with her kids, and to do any physical activity with her kids because of the pain. And so she said, “I’ll prove this to you, Doc.” And she stood up and like danced with me in the room. And so, she was really adamant that she needed to get out in a couple of days because she needed to go see her daughter graduate, and we knew time was limited because of her de novo metastatic breast cancer. So, we got her out of the hospital on the fifth day of ketamine. We quickly transitioned her to po ketamine so she was discharged on 20 milligrams of po ketamine TID. She was also transitioned to methadone, 40 milligrams po TID,  and a Dilaudid pca. At that day she was discharged, she walked into her daughter’s graduation. That weekend, she played tennis, and she walked up a flight of stairs to be able to sleep with her husband. And then seven days after discharge, she was transitioned off of her pca, just to oral Dilaudid, and continued on the oral ketamine, and the oral methadone. So quite a remarkable story. And when I asked her if I could share her story, she said, “Oh, my gosh, please tell everyone about ketamine. And please tell my story.” So, it was it was a remarkable story for all of us.

05:30

Daniel Markwalter, MD:

That’s awesome. Really seems like one of those practice-changing cases and something that I think we all hope with the right patient selection is something we can replicate in other patients as well. But taking a step back from that specific example, to kind of the larger scope, in your mind, why should emergency medicine and palliative care physicians care about ketamine beyond its use and sedation where it was, you know, traditionally been used? And then in particular, why is the palliative care world really excited about it right now?

05:58

Jennifer McEntee, MD:
Well, I think two major things about ketamine that I want to share is number one, it’s a relatively safe medicine is probably a safer medicine than any of the medicines we prescribe. It has a safety profile. Let me just say since it was FDA approved in 1970, there was only one lethal case that has ever been administered, or has been associated with ketamine, and that was unfortunately the Elijah McLean incident in 2018, in Aurora, Colorado. Where he got a seven, probably mgs per kg dose of ketamine times two. And we give, just as a reminder, what sub-anesthetic dosing is, so analgesic dosing for ketamine is 0.1 mgs per kg. And I know we’ll talk a little bit more about that. But that is a significant difference between seven mgs per kg, and 0.1 mgs per kg. So, it’s a relatively safe medicine. And then number two, what we don’t have anything in our arsenals for opioid refractory pain other than sometimes sedation and other pain adjuvants and so what do we do when we get to the point where we have these patients, and many of us see these patients in the emergency room and internal medicine as a hospitalist. I see these patients and in palliative care I see these patients who have life-limiting illness and have refractory pain to opioids. And I think ketamine can be a really good adjuvant therapy.

07:08
Daniel Markwalter, MD:

Excellent. So let’s dig into into the details a little bit. So we’re all on the same page. Can you provide us an overview of some of the ketamine pharmacology and how it works to provide analgesia?

07:18

Jennifer McEntee, MD:
Yeah, so ketamine acts and one of my favorite, one of my new favorite receptors, the NMDA receptor, and so at its resting state, magnesium blocks the NMDA receptor, and when the NMDA receptor gets activated, it releases potassium or sorry, releases sodium and calcium into the neuronal channel. And as you remember, going back to your first, second years of medical school, sodium and potassium, sodium and calcium are very important ions in the pain pathway. The NMDA receptor mirrors the opioid receptors in the neuronal membrane, and calcium activates, if I can remember this right, protein kinase C, which diffuses to the neuronal membrane, and then causes hyperalgesia and opioid tolerance. And so the hope is, is that if we can decrease the calcium influx, decrease protein kinase C, we can actually decrease opioid tolerance, which we think, maybe resets our opioid receptors. The other important aspects that many of us kind of forget about is that it also decreases interleukin six, which is a really important cytokine that causes inflammation. And so, if we can also decrease inflammation by decreasing interleukin six, we could also potentially decrease pain. So, I think ketamine has multi, hits different receptors and different mechanisms of actions for its pain. Lastly, I’ll comment that it also hits the muscarinic dopamine norepinephrine and serotonin receptors, which I’m sure, Daniel, you can talk a lot more about that, and how it relates as an antidepressant. And I think many of our patients who have been in pain and have severe pain are probably have a component of depression, anxiety and existential suffering, which I think ketamine may help in regards to the kind of euphoria that you get with ketamine. And it can help with the depression and anxiety. So, I think that should not be forgotten when we talk about the other mechanisms and actions for ketamine.

09:06
Daniel Markwalter, MD:

I think absolutely right. And from an anecdotal standpoint, from patients, I’ve used analgesic ketamine on, you know, frequently it’s with conditions with significant overlap with psychiatric disease, or even in the setting of chronic life-limiting illness such as cancer, or significant overlying components of anxiety or depression. And you know, I agree with your assessment that there’s likely benefit from the other receptor actions as well. And so, thinking about the different routes of administration, you know, we talked a little bit about the IV infusion in the case that you gave us converting over to oral ketamine. Tell us a little bit about how it can be administered and what you know about its use in these different forms. And myself and Justin can chime in a little bit about some of the other options that we see in the ED, intranasal use, or recent trials on nebulized ketamine, and even topical or mucosal ketamine.

10:06

Jennifer McEntee, MD:
That’s awesome. Great. So I’ll talk a little bit about the formulation demonstration that we use for sub anesthetic, or sub anesthetic dosing for pain or analgesic pain, or analgesic administration for ketamine. So, it’s simply just the IV solution that’s actually administered in all these different routes. And so it’s the IV solution, through the IV, through the subcutaneous route. If you give ketamine IV, or subcutaneous in IV, it’s active within seconds, we think subcutaneously it maybe takes 15 to 20 minutes. The oral bioavailability of ketamine is tricky, and we think it’s probably anywhere between 1 to 17% of the bioavailability for oral ketamine, the important thing to remember is that it’s metabolized by C3A4 to norketamine  and norketamine is bioavailable. It is bioactive in our system. And so we think norketamine does play a significant role in the oral version of ketamine and its actions. And so, I think the administration is nice with ketamine because it can be administered IV subcutaneous, there’s topical preparations, you talked about intranasal, it can also be supplied it through a suppository, rectally. So, I think there’s lots of different variations on how we can administer ketamine, if you can find the pharmacy to compound it, or to actually provide the patient with the medication.

11:26

Daniel Markwalter, MD:
Yeah, and frequently I’ve seen that for some patients in the palliative care world and we’re talking about outpatient use with finding the appropriate pharmacy to for the preparation, certainly, In the emergency departments, I think probably outside of IV dosing or intramuscular dosing and the setting of agitation. I think inter-nasal use would be the one that you providers are next most familiar with. Often, add dosing around probably like one mg per kg there. Of interest, there was a trial published in the Annals of Emergency Medicine in December of last year that looked at three different dosing regimens of nebulized ketamine for pain in the ER, they looked at .75 mgs per kg, 1 mg per kg, 1.5 mg per kg in  nebulized forms, and saw a reduction in pain scores for all three dosing regimens of a similar magnitude. And then, there are options available for topical ketamine looking at use in complex regional pain syndromes or neuropathic pain, reducing allodynia, and then even use for oral solution for mucositis pain. I’m going to flip it over to Justin, I know he’s had some experience with this as well. Justin, what’s your experience been?

12:43

Justin Brooten, MD  

Well, it’s interesting, actually. Recently, I’ve had several trauma patients who have been hemodynamically unstable, and we’re needing to start chest tubes and do other things. So that’s been really helpful to have something in the arsenal that you can give when you really don’t want to give them opiates, and you’re trying to resuscitate them, kind of very different from the palliative care world. Certainly burns, we have a burn center. So many times, I’ve used it for burns to as an adjuvant along with when we’re having escalating doses of opiates. And then in the palliative care, in addition, I haven’t actually used it as much in palliative care in the IV form. I have had some experience with that with dealing with patients. Our current protocols have it limited to our inpatient pain service so we use it a lot in the ED, but our inpatient Pain Service has access to that. Where I’ve personally used it some and palliative medicine. Fortunately, we do have local compounding pharmacies. It’s actually for refractory neuropathic pain. So topical preparations, I found to be helpful. I’ve had patients really get some benefit from that.

Daniel Markwalter, MD:
Yeah. Excellent.

Jennifer McEntee, MD:

Yeah, that’s great.

13:46

Daniel Markwalter, MD:
And so I think you we got a couple examples, Justin, maybe some patient populations where this could be helpful. But let’s be a little more specific so that our listeners can get a sense of who they might identify as, as great candidates for ketamine. So, you know, the two broad categories might be patients requiring palliation in the ED for some acute incident or maybe acute on chronic pain, and then there’s sort of the broader palliative care population. And so, in your opinion, on records, what patients should we be thinking of and considering for analgesic ketamine?

14:22

Jennifer McEntee, MD:

So I think as you, Daniel, and Justin, commented, really refractory neuropathic pain is something that we don’t have a lot of tools in our arsenal for. And so, I think that is something that we should think about ketamine. So refractory neuropathic pain, again, pain that’s refractory to opioids that we are just not touching it with opioids were escalating rather quickly. I think the other patient population, or that we need to talk about is our patients with sickle cell disease. There has been lots of there have been many, many case reports about the benefit of using ketamine in our patients with sickle cell disease by decreasing their opioid tolerance, and maybe resetting their opioid receptors and decreased seeing the amount of opioids that these patients experienced throughout their lifetime. And I think that is something that I would love to see us start using more at UNC and at other tertiary quaternary care academic centers. And then lastly, patients who cannot tolerate the side effects of opioids. So, if they have severe constipation, if they have severe nausea, vomiting, sedation, or like you said Justin, are hypotensive and or their clinical status, their clinical status is tenuous. Ketamine generally doesn’t have a hypotensive side effect, right. The side effects of ketamine generally are the opposite, and will cause hypertension or type of cardio. And so, I think, probably those four patient populations, again, refractory neuropathic pain, opioid refractory pain, patients with sickle cell disease, even patients who are really having a hard time tolerating the side effects of opioids.

15:49
Daniel Markwalter, MD:

Excellent. I think Justin mentioned a few populations that we may think of specifically in the ED and yes, there’s some overlap those who are on chronic opioids, and we may be looking for opioid-sparing options or ways to dose reduce. But, in the acute setting, pulling control pain in the setting of burns is very common. And trauma is a great one, especially for a short-acting agent, where you need to do some procedures such as chest tubes, even conditions that lead to severe respiratory distress in which you can provide some analgesia, but in the ED, if it’s consistent with patient’s goals of care, it can also give a chance to then provide maybe some dissociated dose ketamine to then provide some respiratory support. And so, it’s a very flexible agent in that regard.

16:34
Jennifer McEntee, MD:

And then, can I add something, Daniel?

Daniel Markwalter, MD:  

Yeah

Jennifer McEntee, MD:

I think the other as I think about this more, I think, another patient population that would benefit as his patients who have somatic pain, so physical nociceptive neuropathic pain, and also have this component of existential suffering, anxiety, depression, where we know ketamine has an important role, specifically with depression. I think if those, all three or four or five of those things coexist in the same patient, which happens in many of our palliative care patients, specifically our young palliative care patients, I think ketamine may also play an important role there for sure.

17:09
Daniel Markwalter, MD:
For sure. Excellent. So, we’ve identified different routes of administration, some patients that may benefit from ketamine, but we also need to be thinking about who it’s not appropriate for. So, Dr. McEntee, tell us a little bit about the contraindications to ketamine use and are there any studies or things we need to look at before trying ketamine in a patient?

17:30

Jennifer McEntee, MD:

Yeah, so there’s, you know, I’ll talk about the second first. The latter, there are no great randomized control studies in regards to ketamine. There are no randomized control trials in regards to sickle cell patients, which I really love our patients, excuse me, with sickle cell disease, which I would really love to get off the ground at, and use a multiset, have a multicenter study for that for that specific patient population. And let me, the caveat of everything that I’m about to say, is that all of the side effects and contraindications regarding ketamine have been all based on anesthetic dosing, which again, is 10 times higher than the dosing we use for analgesic dosing. So, the side effects that we see predominantly for ketamine, again are the psycho mimetic effects. So those emergence phenomenon of having some hallucinations, auditory-visual hallucinations, some cognitive effects that all go away once ketamine has stopped. The cardiovascular side effects we also see are like increased heart rate, increased systolic blood pressure. From a GI perspective, we see nausea, we can see nausea, we can see anorexia and some hypersalivation. There are relatively no contraindications to ketamine. We at UNC have the have a policy that says there’s a grade B, so moderate contraindication regards regarding psychosis, so we generally with our patients who are psychotic, we don’t give ketamine to because that will, again, increase the risk of ongoing psychosis, and pregnancy. The other relative kind of moderate contraindications are severe cardiovascular disease, increased intracranial pressure, increased intraocular pressure cirrhosis, and moderate liver disease. Again, those contraindications are all based on 10-times dosing at the anesthetic dosing, versus the 1/10 of that dosing, which is analgesic dosing.

19:18
Daniel Markwalter, MD:
Excellent. I think many listeners will be interested in how the policy developed here at UNC, and many places. The Anesthesia Pain Service is sort of in charge, or has traditionally been in charge, of ketamine infusions, certainly in the ED we are equipped and comfortable and capable of using ketamine in the ED, but once a patient maybe is admitted, how’s this palliative care service take over that? Or specifically at UNC how did that policy come about? And to give the palliative care team and the consult service the opportunity to manage that medication?

19:56

Jennifer McEntee, MD:

Yeah, so that’s all really relatively exciting new news. When I first joined faculty back to UNC in 2016, it was a really barren landscape of ketamine. In fact, we lost the patient early on that probably would have benefited from ketamine and may have prevented her death, which was then highlighted to me, is the need that I need to do something about ketamine at UNC. And so, I did some research and found, as a new faculty member, that there’s another faculty member, who actually did residency with, Dr. Andrew LeBlanc, who’s in anesthesia who was a help leading and spearheading the ketamine policy at UNC. And so, then the two of us joined forces and did Grand Rounds once we got the ketamine policy approved for internal medicine, Grand Rounds, and anesthesia Grand Rounds, and continue to kind of do ongoing work. And we continue to push for palliative care providers to be able to write for ketamine. And Dr. LeBlanc really wanted the ketamine policy just to be successful at UNC. And so, we were very conservative at the very beginning, and only letting anesthesia pain write for ketamine. And when we saw the success and how safe this medicine really is, we continued to train our palliative care faculty and fellows, and advanced practice providers on the use of ketamine and how to write for ketamine and look at the order set and reevaluate the order set. And in January of 2022, six years after I joined faculty, we were able to finally have our palliative care providers write for ketamine, which is a huge step in the landscape of ketamine at UNC, it really broadens our scope as providers, as well as providing, I would argue, better patient care at UNC.

21:38
Daniel Markwalter, MD:  

That’s great. And so, I think it might be helpful to even hear a little bit about what the policy at UNC looks like, so that others can think about maybe an appropriate dosing regimen, or how to create a protocol at their institution. So, based on what’s been developed at UNC, what are your recommendations for dosing and initiation?

22:00

Jennifer McEntee, MD:

Yeah, so at UNC because of the conservative nature of our policy, we don’t do any bolus dosing, or a trial dose of ketamine. So for a patient who comes in and needs ketamine for refractory pain, and we want to use it in the IV form, we generally start patients off on a 0.1 mg per kg per hour infusion of ketamine. And we will go to a max dose of 0.5 mg/kg/hr. In the literature, you’ll see a max dose of 1 mg per kg per hour, for again at sub-anesthetic dosing of analgesia dosing. But we maxed ours out at 0.5, which again is very conservative, we realize that, but we wanted to prove that this is a safe kind of a successful medication. We’ve had success with that max dosing, and we will titrate that up maybe every 8 to 12 hours, so maybe twice a day, and double it’s like 0.1, and we’ll only go by 0.05 microgram per mg per kg per hour increments. And we’ll use it over five to seven days. It’s kind of the length of the IV infusion that we’ll use. At that point, we think we’ll see the benefit and hopefully the opioid receptors have reset. If we decide to stop the infusion, palliative care will recommend maybe transitioning to oral ketamine if we’ve seen some benefit. Oral ketamine, generally I would start off despite what your dose was from an IV infusion 10 to 25 milligrams Q8 hours and you can titrate that up over every 48 hours by about 25% and you can titrate that up to the max dose which is 200 milligrams Q6 hours which I have never seen, or 0.5 mgs per kg, which would be your max dose. The oral ketamine is tricky because there’s, we don’t think there’s any randomized controlled trials, large randomized controlled trials for IV ketamine. There’s hardly anything for oral ketamine. And so, I would say probably the length of duration for oral ketamine would be maybe one month, three to four weeks. At that point, the major side effect that you’re looking out for, for oral ketamine is ulcerative cystitis. So maybe getting weekly urine dipsticks just to make sure that you’re not developing ulcerative cystitis this is something that I would be concerned about from a long term side effect of ketamine. This is what we see in patients who have substance use disorder or abuse ketamine on the streets. So that so generally again, start at 0.1, and titrate up to 0.5 mg/kg/hr over five to seven days; for IV ketamine infusion and for po I would generally start 10 to 25 milligrams Q eight hours and increased by 25% every 48 hours. If that makes sense.

24:34

Daniel Markwalter, MD:  

Yeah, absolutely does and you know, you call that conservative, but I think for ED physicians who have been using bolus dosing for pain in the ER, is going to sound very familiar. So, the ER here typical dosing will be 0.1 to 0.3 mg/kg, if you’re just going to do a bolus for pain. Having done that for chest tubes, orthopedic injuries. No, I actually think that aligns really nicely probably with what a lot of people’s experiences, and so certainly then hearing about how that you know gets translated into an infusion, and then kind of what that transition to oral ketamine like that, as you said, is it kind of a data free zone. There’s much to be desired with understanding exactly, probably what the best dosing regimen is. But it sounds like you’ve had success with that.

25:19

Jennifer McEntee, MD:

We’ve had success with numerous patients in regards to oral ketamine and some even patients where IV ketamine didn’t work. Oral ketamine has worked, I can’t explain that. But that has been our patients experience. And then I think the other thing that I should probably mention is because of the hypersalivation that you can get with IV ketamine, generally we provide, write for an order for glycopyrrolate. Just PRN for the side effect prophylaxis, even if they do have hallucinations, and they can tolerate the hallucinations, and they’re not super bothered by it, sometimes we just let that continue to happen. For example, my patient that I mentioned at the very beginning of this podcast, she was definitely having some auditory hallucinations where she was hearing that the nurses were talking about sex on the beach. And she said that was she said that was fine. She really appreciated, she knew that it wasn’t real, and she kind of appreciated having that experience. And so, if it does bother the patients, but they we think we’re having benefit from the ketamine, we will try benzodiazepines, low dose benzodiazepines, or low dose held off to kind of help with that, no side effect of that medication.

26:20

Daniel Markwalter, MD:  

Yeah. I think you touched on this briefly before, but just to kind of drive home the point, what sort of ongoing monitoring, or you mentioned, but what sort of ongoing monitoring do you need for these folks whether you know, or they always are on a monitor, are you getting daily lab draws? What sort of monitoring do these folks get?

26:42

Jennifer McEntee, MD:

Yeah, so that is, again, our policy at UNC, highlights that they want a baseline EKG, there’s no indication for that. But that is what our policy says, a baseline EKG, a basic metabolic panel, making sure they’re not pregnant, so, a urine pregnancy test. Ongoing monitoring while they’re on ketamine, because of the tachycardia that it can definitely cause. And so those patients generally are on a telemetry monitoring. They don’t have to be in a telemetry monitored unit, just a unit that can have, they can have a remote-tele is fine. And then as we start the infusion, we get vital signs more frequently like Q4 hours for the first maybe for the first 24 hours. But then after that, if their vital signs are stable, we just continue to have regular vital signs tech, or they’ll assign checks. The other thing that I didn’t mention before is that as we titrate up the ketamine, we generally decrease the opioids by half. So as we start ketamine, we cut their opioids in half, and then we continue. As we’re seeing good pain relief, we will continue to kind of cut the opioids and decrease the opioids as we’re seeing increased benefit from the ketamine.

27:45

Daniel Markwalter, MD:  

Yeah, I think that’s a really important point to drive home that, for me, these patients does not necessitate a reduction in their opioid dosing. But, you know, while they’re on the infusion, but hopefully for maintenance afterwards, and so, you know, the question was there sort of you said, you know, five to seven days is kind of typical max length. What in point, are you looking for therapy, you started somebody on an infusion, what sort of your endpoint where you say, All right, I think we’re where we need to be, you know, let’s work on getting off of the infusion.

28:14

Jennifer McEntee, MD:

Definitely, what I look for is decreasing their pain, whatever that is a pain where they can function, hopefully, or at least function better than they were functioning before. And if we reach that pain, then if we reach that threshold, I keep them on the infusion for maybe 24/48 hours to kind of make sure make sure we maintain, maintain that effect, and then we’ll slowly transition them off. And on to oral ketamine. If we’ve seen the effect. If we don’t see the effect within three to five days, then ketamine may not be the drug of choice for them, it may not be a drug that works for them. And then we can just stop the ketamine infusion and continue the opioids and think about novel therapies, or interventional procedures. So, I think we’re looking for the effects that we want on their pain and on their daily life and their function. And if we can get that then we can stop the ketamine infusion and transition to oral ketamine and continue their opioids and hopefully follow up with their palliative care providers and outpatient so we can continue to titrate down their opioids.

29:08

Daniel Markwalter, MD:  

Perfect. And I think for our listeners, it’s really interesting because, you know, we have some, you know, palliative care providers, maybe some are more in the ED world, some who are straddling both, and obviously, the protocol that you’ve described is for an inpatient infusion.

Jennifer McEntee, MD:

That’s true.

Daniel Markwalter, MD:  

But maybe in the future, we’ll have enough data to back up and tell us more about converting people from maybe they got some IV ketamine in the ER and getting them on oral ketamine and getting them discharged, maybe some options for even more abbreviated regimen. So, I think you mentioned this before, but just to sort of drive home the point and get people thinking about it. It’s not like they’re ketamine pills sitting around. So, when you’re getting somebody on oral ketamine, how do you prescribe it?

29:50

Jennifer McEntee, MD:

I think the best piece of advice is check with your pharmacy to make sure they have it before you even think about prescribing it. Because if they don’t have it, and if they can’t get it, it’s a moot point. It is relatively cheap is a World Health Organization essential drugs are so it’s a WHO list of essential drugs. And so at UNC, for example, I think it’s $17 to get it filled for a two-week supply. And the important thing to remember about oral ketamine is that it only will last for two weeks. After two weeks, it’s no longer in acceptable form. I don’t know if it biodegrades at that point in time is no longer effective, or are safe to administer. So after two weeks, we can only use the oral ketamine for two weeks. So after two weeks, we have to discard it. And so, you have to number one, have a pharmacy who can prescribe or who can fill it, have an insurance or a patient be able to afford the copay, or afford the $17. And then be able to have a provider who’s going to be willing to kind of, prescribe it ongoingly. And so generally, the dose that I would start at again, it’s just it’s just the IV form in the liquid solution that people drink. And you can find compounding pharmacy that will make it into a pill and, in certain areas of North Carolina at least. And we generally start off at 10 to 25 milligrams Q8 hours is generally the starting dose. If they’ve gotten an IV dose in the emergency room, and they tolerated that well and you want to transition to oral ketamine, you could probably do 20 to 25 Q8 hours and be safe, and then have an ongoing provider continue to monitor them. Does that answer your question?

31:21

Daniel Markwalter, MD:  

Yeah, absolutely. And some of this is obviously going to be dependent on as you said, local pharmacies. And so that’s, that’s the importance of checking with pharmacies, but also when it comes to follow up, that’s going to depend on the structure and network, and what your local resources are. And so, give us a sense of what you know, who’s following up these patients for the pallative care team at UNC?

31:45

Jennifer McEntee, MD:

Yeah, so many of times, our UNC palliative care outpatient providers will follow these patients up, whether it is a palliative care provider that’s embedded in our cancer clinic with UNC or embedded in our internal medicine clinic. And so, if the patient doesn’t have cancer, the patient can go to our palliative care provider in our general internal medicine clinic. And so generally, their palliative care providers who are following them up, if the patient’s going home on hospice, hospice will also follow them up and hopefully continue to provide ketamine if it’s on their formulary. And then I think my hope is, is that as we get more and more, and more of our residents and internal medicine physicians comfortable with this drug, again, I would like to highlight that it’s safer than many of the drugs that we prescribe them, that they will be able to and feel comfortable helping meet this need for our patients, if this is shown to be really beneficial.

32:32

Daniel Markwalter, MD:  

Yeah, and I’m really glad you brought up the piece about hospice as well, because for many hospice agencies, this is on their formulary and many inpatient hospice units will and do use ketamine as an adjunct or as an independent analgesic outside of opioids. And so knowing that, especially from an ED standpoint, if you have a patient who is, who is dying, and you’re having trouble with pain control, but you feel like they’re stable enough, and it’s in line with their goals, to get them to inpatient hospice unit, you may actually find inpatient hospice units who are okay with you starting them on ketamine and getting them to the inpatient unit where they will continue the ketamine. And so it’s not just for folks who were thinking about plugging into clinics scenario and maybe someone you see in the ED who ultimately will go, excuse me will go to hospice.

Jennifer McEntee, MD:

Right.

Daniel Markwalter, MD:  

Much about ketamine is either a data freezone or a data limited zone, whether it’s oral ketamine, topical, nebulized, ketamine, we’re just looking for more data, we aren’t great at identifying, you know, which patients will benefit exactly what the optimal protocols are. Where do you see ketamine going in the future? And what are your hopes for research and its use?

33:49

Jennifer McEntee, MD:

Yeah, so I really would love to partner with anybody who’s out there who wants to do a multicenter trial in regards to ketamine, with our sickle with our patients with sickle cell disease, as well as with our palliative care patients who have opioid refractory pain. I think that’s where the data needs to come from. It’s really hard and why I’m focusing on patients with sickle cell disease is because it’s really hard to get patients in our palliative care population to conduct research. It’s really hard for me to deny a medicine that I think could help them. If they’re randomized to a medicine that may not be helpful to them as like a placebo in regards to opioid refractory pain. I would give them ketamine, if that was my patients. And so it’s really hard for me to deny them ketamine if they only have days, two days to live in there and refractory pain, it’s really hard to conduct research on that patient population. And it’s really hard for them to come in for research. And so that’s why I really would like to focus on the patients with sickle cell disease because I think that is a much more readily studied patient population and could really benefit from the use of ketamine in their lives. I think the hope is, is that we can when we can’t get randomized control trials, you have to go to the Cochrane Review. There’s the Cochrane review said there’s not enough evidence and then where do you go, you go to the guidelines. And I think this is where palliative care needs to kind of step up to the plate in my mind and really started developing palliative care guidelines in the use of ketamine, around the use of ketamine. Anesthesia as we were writing our policy for UNC anesthesia had just come out with their own guidelines about the use of ketamine, oral and IV for chronic and acute pain. And so, I think we as maybe departments of medicine departments of Emergency Medicine, palliative care, anesthesia need to come together to form kind of universal guidelines if we can’t get randomized control trials started and initiated. So that’s where I’d really love to see kind of these uniform guidelines for these, for this patient population specifically. And then again, like I said, I would love to partner with anybody who’s interested in our patients with sickle cell disease, because I think they would really benefit. And then I’d love to see kind of how ketamine can also be used for patients with existential suffering or this deep sense of anxiety and depression around their pain and around their suffering. Because I think there is use of maybe potential use for ketamine in that specific patient population, because I think that is why many, some of my patients have had benefit from ketamine. And so, I think there’s a lot of hope around ketamine. I am not naive enough to think that it’s going to be the end all be all drug for everybody. It definitely isn’t. And it’s definitely not for many patients. But if it does work for some patients, it’s really nice to find out those patients that it works for, and to give them some pain-free days are some pain less days, for sure.

36:39

Daniel Markwalter, MD:  

Yeah. And kind of to bring it home. Is there anything we haven’t touched on that you think our listeners should hear?

36:46

Jennifer McEntee, MD:

I think the goal of all physicians, specifically palliative care physicians, is to make every day as good as we can for our patients and to help them live as well as they can. And I think if ketamine can help that, and can provide wellbeing for our patients, and help them live the best life that they can live with whatever time they may have left, I think it needs to be in our arsenal. And so I think, in our arsenal of tools to kind of help treat these patients. And I’d love to be an advocate for that and also help other institutions, other providers in regards to the use of ketamine. And I think we just need to think outside the box at times for many of our patients with when the traditional therapies don’t work. And I think this may be one of those times that we can think outside the box.

37:35

Daniel Markwalter, MD:  

Absolutely. And we’re really excited to see kind of what the future ketamine is. Yeah, I

37:40

Jennifer McEntee, MD:

I hope to be on this podcast again and in a year or so, so that we can recap with the advances of ketamine event.

37:46

Daniel Markwalter, MD:  

I love it. Thank you very much.

37:47

Jennifer McEntee, MD:

Thanks so much for having me. You bet.

Justin Brooten, MD  37:49

Thank you so much Dr. McEntee that was extremely informative. And as somebody who appreciates having this tool in my arsenal, in practice, you’ve given me some more ideas about how it can be utilized. And Dr. Markwalter, thank you for being your guest interviewer for this episode, and also for your contributions to our content on PalliEM.org. Thank you very happy to be part of it. For more information on current topics in the fields of palliative emergency medicine, please visit PalliEM.org.