Episode 2: Special K

Sarah Dabagh: 0:01

Hi, this is Sarah,

Daniel Eison: 0:03

and this is Dan.

Sarah Dabagh: 0:04

And we'd like to welcome you to PediPal!

Daniel Eison: 0:07

a new podcast about all things pediatric palliative care.

Sarah Dabagh: 0:12

The views in this podcast are ours alone and not representative of our respective organizations, and do not constitute medical advice.

Daniel Eison: 0:20

If you are interested in learning about cereal, you may be listening to the wrong podcast.

Sarah Dabagh: 0:27

And why is that, Dan?

Daniel Eison: 0:28

Well, just like you can't fake the deliciousness of real fruit, nuts, and whole grains, there's no substitute for the analgesia, amnesia, and sedation provided by the other

Special K: 0:39

ketamine, although it's not crunchy, flaky or full of vitamins.

Sarah Dabagh: 0:45

But is it good for you?

Daniel Eison: 0:47

It is my favorite anti NMDA antagonist, and part of a well balanced breakfast

Sarah Dabagh: 0:52

So more than methodone, your're saying? You rank it above methadone.

Daniel Eison: 0:54

Uh... Um, well...

Sarah Dabagh: 1:00

Hard to say. Yeah. Well, to learn more about this drug that's shrouded in mystery--

Daniel Eison: 1:06

--and shrouded in the party scene of the 1980s--

Sarah Dabagh: 1:09

--we thought we'd bring in two guests who, as far as we can tell, are absolute ketamine experts.

Stephen Long: 1:15

Hello, my name is Steve Long. I'm a pediatric anesthesiologist and Medical Director of the Pain Service at UCSF Benioff Children's Hospital Oakland.

Anu Agarwal: 1:23

Hello, my name is Anu Agarwal. I'm Associate Professor of Pediatrics in the Division of Hematology Oncology BMT at UCSF Benioff Children's Hospital Oakland.

Stephen Long: 1:32

Ketamine is an old drug that's been around for more than 50 years. And in anaesthesia we've used it that whole time, actually, we always joke that if we were on an island, and there's only one drug that we could use, it would be ketamine because it can be an anesthetic, it can be an analgesic, it can be an amnestic. It has all these different properties. And, of course, all those are dose-dependent. But when the pain service at Oakland was started-- or expanded in 2015, Anu and I were talking about alternatives to opioids. And we have a large number of patients who have kind of constant severe pain that isn't responsive to opioids or they're very sensitive to the side effects of opioids. So ketamine is a solution. Actually, we've been infusing ketamine continuously at Oakland, 24 hours a day, seven days a week, 365 days a year, for five years in a row. Every single minute of the day, over the last five years and counting, we've had at least one patient on ketamine.

Sarah Dabagh: 2:31

So maybe we go back in time a little bit, because it sounds very successful now, but talk a little bit about when this idea first came, how it was received and how the program started.

Anu Agarwal: 2:42

it was clearly recognized that we had a group of patients that were not getting better with opioids. We have a large sickle cell population, and we had a lot of patients that were coming in frequently, and they were getting opioids, and they weren't really getting better. And then we had patients with refractory cancer pain. And so thinking about non-opioid modalities was was becoming more and more important. And fortunately, the, in general, the Heme/Onc staff, talking about staff nursing, etc, is pretty open to trying new modalities. So I think that was really helpful. So in terms of a place in the hospital where we could try to pilot something, it was much more feasible, although it took a lot of effort and many, many steps to get buy-in. And so we started with the standard process within our hospital, which is going to a Committee of Pharmacy and Therapeutics to get this approved. Steve and I wrote a protocol. And, and then the biggest step really, honestly was getting nursing to be agreeable. That was really the biggest hurdle. And, and Steve did a great job, he came up and did so much inspirational teaching to nursing each shift, to really explain to them the logic behind it. And to reassure them that low-dose ketamine was safe, because from a nursing standpoint, you know, you hear about ketamine, you're like,"Oh, this patient's gonna have respiratory depression and etc." So that was that was really the key. Actually getting it through the pharmacy and therapeutics committee was easier than I expected. But getting the nursing buy-in, took a little bit of time. But once they bought in and they saw the benefits, and they-- and the nurses are there, right, 24/7, and they could subjectively see that ketamine was helping these patients where we didn't have previous modalities that were. And the nurses then became the advocates for the patients. They would-- initially, it was-- there was resistance, but once they saw it working, and more and more the nurses were pushing to say, "Hey, this, this patient should get ketamine," and I think that's really been a big part of it, too.

Daniel Eison: 4:37

What were the main things that people were worried about?

Stephen Long: 4:40

Ketamine is seen as a very strong drug. And the reason is because it's usually given at a higher dose. The key in implementing something like this is we're not talking about a ketamine infusion protocol. In general, we're talking about a low-dose infusion protocol, and so always seen it as a low-dose protocol is key. It has to be sold that way: that we're giving like a sub-anesthetic dose of ketamine, that's non sedating. The side effects that you read about with ketamine, like nystagmus, for example, or even, I mean, even the psychotropic side effects where patients go into a K-hole are not present when the dose is low. But like any any drug, side effects are dose-dependent. And so we're always trying to find the lowest therapeutic dose, because that, you know, has the fewest side effects. And so our ketamine infusion protocol, it started off maxing out at five micrograms per kilogram per minute, which to be honest with you, I mean, I've had patients who are on that dose doing calculus homework at UC Berkeley(remotely). So it's not sedating for most patients. But that was the-- that was the concern. And that, you know, that patients were going to be like, given anesthesia on the floor.

Anu Agarwal: 5:49

When we initially started the protocol, I was definitely worried with the first couple patients are we going to see dysphoria, and then that's going to be the end of the whole thing. But we definitely started at the low end of our low range. So we initially started more in the 1-2 mic per kilo minute, whereas now we move up pretty rapidly from that dose.

Sarah Dabagh: 6:05

So I was gonna ask about that, and maybe slightly selfishly, because we just wrote our protocol and we max at five. Where have you felt comfortable going? And where have you really started to see adverse effects?

Stephen Long: 6:16

I mean, you can go up to, and we've gone up to 10 on the floor. You know, the thing with ketamine is, as you increase the dose incrementally, you will get more therapy, but less, it's not a linear response, the difference between one mic and two mics is much bigger than two to three, which is bigger than three to four, and four to five. And so you know, as you move up that range by increments of one mic per kilo per minute, the therapeutic benefit will diminish. Now, that being said, some patients need doses that are higher than five. We usually don't do that for patients who are coming in for a short hospitalization. For example, sickle cell pain crisis. One group that does benefit from that is like a sickle cell BMT patient, or patients who have advanced cancer, who aren't responding, you know when we've run out of options,

Anu Agarwal: 7:07

We made the initial protocol up to five and I would say the vast majority of patients do fine with up to five. And then if we need to move above that now, we updated our protocol to include going up from five to 10. But that requires involvement of the Pain Team for that level. But I would say it's rare that we need to go to that dose for those indications that Steve mentioned.

Stephen Long: 7:27

I mean, you don't think about it as your primary modality for treating pain. You think of it as-- like salt that you're adding to the dish to like, enhance, you know. I mean, you want to enhance the opioids, you want to reduce the dose of opioids and keep them as strong as they were before you started ketamine, you know, enhance the COX inhibitors and all these other things. So it is like a kind of a soup that you're putting together and the ketamine kind of brings everything together, it makes, yeah, the flavors come out more effectively, or the therapies come out more effectively. So, so a low dose ketamine is often all you need. Because it's it's a synergistic medication, it's, it's making the other medications do their job better, really. And you know, there are some patients who do fine, you know, just on a little bit of ketamine, but they're not the patients with severe pain. The ones who come in with really severe pain, need ketamine plus opioids, plus acetaminophen, plus all these other things.

Anu Agarwal: 8:25

We're working on publishing our use of ketamine bolus in the emergency department. And we were able to show benefit and decrease opioid utilization in the ED too, but the dysphoria was a little bit more, not a lot, but I think part of it too is when you're on a continuous infusion, it becomes very tolerable and so it's pretty easy to titrate dose and now we've started adding bolus dosing in, too, for inpatients which has been a new thing that I think has been very helpful.

Stephen Long: 8:50

Again, I recommend low bolus dose so we do 100 mics or 0.1 milligrams per kilo as a bolus every two hours as needed. And like Anu said, I mean if patients are already on the infusion, the bolus dose doesn't seem to have side effects. Versus if a patient comes in, in the emergency department and they get a bolus of ketamine having not been on an infusion for the last couple days, they are more likely to be dysphoric, go into a K-hole, that kind of experience. One thing I've learned is I don't I don't like the emergency department to give a big bolus of ketamine to any patient because then they have a negative experience with ketamine and they're not willing to try a low-dose infusion on the floor and we've lost them. There is a huge difference between a ketamine bolus and a ketamine infusion. And if a bolus is given, then it needs to be low. I mean very low. And you can repeat the bolus if needed but start low because you don't know if you're going to send someone kind of onto some trip. And then all sudden you know the dysphoria is worse than the pain and that's what they remember. So my recommendation for bolus is a small... I mean, I think that like 0.1 milligrams per kilo is a good place to start, to be honest with you, not 0.2, not 0.3, like some emergency departments use.

Daniel Eison: 10:05

In a lot of ways, it sounds like ketamine dosing is very similar in philosophy to opioid dosing: Start low, go slow, you can repeat it if necessary. And I know when we introduce opioids to a family, especially if they're skeptical or nervous, we'll often tell them it's safe, here are the side effects you can expect... When you're introducing ketamine to someone, and you want to get that buy-in, and they haven't had the k-hole experience in the ED yet, how do you introduce it?

Stephen Long: 10:36

I mean, I talk about side effects. I say it has different side effects. Usually we're walking in because the opioids aren't working, or they're itchy or constipated, or, you know, something like that. I sell it by saying this is a pain medication that has different side effects than the pain medication you're already on. And that's beneficial because you don't like the side effects of the opioids. You're constipated. Or I say this is a pain medication that is synergistic with the opioids that you're on, that aren't sufficient to treat your pain. And usually one of those two explanations does it. If patients are more trepidatious, then, you know, I emphasize the fact that we start at a really low dose, we go slow, they have control over the-- I honestly I give them kind of full rein over titrating. I usually start at three mics per kilo per minute. I say, you know, we can go up or down by increments of one. So you can make the change every three hours. And I try to give them a lot of control. And you can with ketamine, because it's such a safe drug, you know. It's not like opioids. You know, it's hard to mess it up. From a safety perspective, it really is so safe at these doses. And so I feel comfortable giving patients a lot of autonomy.

Anu Agarwal: 11:48

The other thing too, is that it has such a rapid half-life. So it's not like opioid that's gonna stay in your system for a while, you know, once you turn off the infusion, it's going to be out very quickly. So we didn't have to have, in our patients that we studied, we didn't have to use a benzo for any single patient for the side effects.

Stephen Long: 12:05

If you're going to be a prescriber for a ketamine infusion, you have to be familiar with the concept of context-sensitive halftime. Every infusion that's given in the hospital has a context-sensitive halftime and what that term means is when you turn the infusion off, how many minutes does it take for the plasma concentration of the drug to drop by 50%. And that number of minutes is your context-sensitive halftime. I don't care about how much drug is in your body, I care about how much drug is in your plasma, all the drug that's built up in your fat or something's kind of inactive, it's not really at the receptors where it's doing its job. So the context-sensitive halftime of ketamine is 45 minutes, which means that if you turn the infusion off, in three hours, it's more than 90% of it is out of your plasma. So it is pretty quick.

Sarah Dabagh: 12:50

It's funny to hear both of you talk about how safe it is. I'm hearing "on the floor," I'm hearing "no Pain consult necessary," until you're getting into that greater-than-five dose zone, in the context of some hospitals who don't use it at all. And some people who feel really afraid of this medication.

Stephen Long: 13:08

Yeah, we do have pain consults for all patients on ketamine, with the exception of Oncology, I would say. Not because ketamine can't be prescribed by non-pain specialists. But because patients who end up on ketamine usually are complicated pain patients. Our experience with ketamine from a safety standpoint has been rock solid. I mean, we have not had one serious adverse event. The most common side effects that we see with low dose ketamine is like feeling a little bit inebriated or woozy. That's the most common complaint. And maybe that occurs on 10% of patients, in which case, we either turn it off or we just lower the dose. And usually, actually, if we just lower the dose, the side effect goes away. And then the next day, we can bring the dose back to where it was, and then they don't have that feeling of fuzziness or inebriation, so...

Anu Agarwal: 13:57

I think a lot of it is just exposure and experience. Once you get over the hump of trying it, and it goes well, then it becomes much easier. And that's why again, I think for us having started it on the Heme/Onc floor, it was kind of the ideal place to do it. Because one, we had multiple advocates at the physician level, but it was also easy to get nursing buy in, because our nurses are so attuned to our patients' pain. And for them, that's a really problematic symptom. And so we have a novel therapy that's going to potentially benefit the patients, they're willing to try something new. And I think that combination of things allowed us to get over that hump, and it's much easier and then you just use it more and more because because the opioids aren't working and you know, eventually we're going to get to a point where we're trying to use all of these other modalities and use opioids less and less. I think we'll continue to use opioids, we have to, but I think the goal really is to find effective pain control and minimize opioids.

Stephen Long: 14:53

You know, I'll say, you know the thing about ketamine, it has in my mind, it has two really beneficial qualities. The first is that it's synergistic with opioids, which means that you can lower the dose of opioids, you can lower the opioid exposure when the patient's on ketamine. And then the second thing about ketamine, like I said, it has a different side effect profile, but it treats an opioid side effects that can be really cruel, which is opioid-induced hyperalgesia. The first dose of opioid is always your most effective one, and every subsequent dose is gonna be less effective. And then you know, as time goes on, patients actually may become more sensitive to pain, which is like the phenomenon of hyperalgesia. And ketamine can help treat that. Opioids will cause these neuroplastic changes to the nervous system. Ketamine is an NMDA antagonist. Glutamate is the neurotransmitter that works on the NMDA receptor. And glutamate seems to be the neurotransmitter that's implicated in hyperalgesia in some of these pain pathways. By blocking that neurotransmitter at that receptor, you really can mitigate the hyperalgesia. And so a lot of patients who are on high doses of opioids, they have it. I mean, they, they just do! I mean, most people have had an opioid. When you take an opioid, you probably are a little more aware of sensations. I almost would do this experiment, if you have to take an opioid kind of ask yourself, like, "Gosh, does my skin feel the same? Do my clothes feel the same?" They probably don't. If you keep taking opioids, that phenomenon, that kind of sensation, that changes when you're on the drug just becomes stronger, and then it becomes hyperalgesic. Ketamine helps treat that. So that's a huge benefit of it. We should say in this podcast that ketamine is a derivative of PCP. And it's a drug that is used recreationally that causes-- it's a dissociative medication. You know, if you crank up the dose enough, you do kind of get high in a sense, and that can be a very pleasant experience for some patients and for others, it can be a really negative experience, depending on your reaction to the medication. We're advocating for a low-dose ketamine infusion, not a high dissociative dose. But even at that lower dose, some patients can feel a little bit woozy, a little bit inebriated, or some patients can feel just a little bit elated. And that usually is a good thing when you're dealing with pain.

Anu Agarwal: 17:24

But you described it to me before as a clean drug, not only, as you describe, there's not really much of a need for tapering, but also there's not really dependency with ketamine. So it's not that patients, similar to opioids, want the medication. They may ask for it when they come back into the hospital with pain, but it's not in the same terms as an opioid where there's any component of dependency, which is also really important.

Stephen Long: 17:47

Yeah, we have not seen dependency, and I've been using it so much. I never have a conflict with a patient over ketamine infusion. I never have a conflict about the dose. I never have a conflict about the day that I turn it off. It's like a no-drama drug. There aren't those issues that we see those social or emotional issues that we see with opioids, they, they just don't exist at these doses.

Sarah Dabagh: 18:10

I think selling it as a no-drama drug goes a long way.

Anu Agarwal: 18:14

Yeah. And that's I mean, that's part of the reason probably we're using it more is because it's not like the opioids in that regard. I think it's a really good contrast, actually.

Stephen Long: 18:21

One of the things that I'd like the podcast listeners to hear is that they may be asking themselves, "Gosh, so if a patient's been on ketamine for days or weeks, does it need to be weaned? Is there a withdrawal syndrome the patients go through when they've been on ketamine for a long period of time?" In my clinical experience? No, not at these doses. I've had some patients, not many, but some patients on ketamine for more than eight weeks in a row continuously. Oncology patients or BMT patients, those two groups, and I've seen no withdrawal from ketamine when it's turned off. And to be honest with you, we were on, you know, like, let's say five mics per kilo per minute for the first seven and a half weeks and then the next day we go on to four, then three, then two, then one, and then it's off within, you know, four days, and even then there's no withdrawal. So what that says to me is that it's not like an opioid. I mean, opioid withdrawal is pretty miserable to go through. Ketamine doesn't seem, in my experience, to have that issue. Now, I don't wean opioids off before I take ketamine off, I don't do it in that order, but I will decrease the dose of the opioids and then kind of decrease the ketamine and then decrease the opioids again. Usually though, the ketamine comes off before the PRN opioid comes off. So a ketamine infusion, it's not just about the therapy that it's giving. It's also-- the other consideration is, you know, this is an IV infusion. What is it compatible with, what is it not compatible with? And one challenge is that you know, ketamine is not compatible with lipids, it's not compatible with TPN. So you need to have a second line, and there gets to be a point where it's like, okay, is it worth maintaining the second line just for the sake of ketamine? And sometimes it's not. So we just remove the peripheral IV, we stop the ketamine and, you know, manage the patient with you know methadone and they do just fine.

Daniel Eison: 20:17

So, ketamine sounds great. I work on an oncology floor. I want ketamine for all my patients now, I want ketamine for me, I want ketamine for my friends, right? Like it sounds like a fantastic drug. Are there patients for whom ketamine doesn't really work? For whom you would say I wouldn't even try ketamine for this kind of a patient?

Stephen Long: 20:35

Okay, so if patients have severe pulmonary hypertension, I would be cautious because ketamine can increase pulmonary vascular resistance. Another group would be severely like premature babies. I just don't give it in really small infants. I usually wait until they're three months old, unless they're a really exceptional case. And I-- and the reason why I do that is because ketamine, like a lot of-- and this is not true for opioids, but the ketamine like a lot of other sedatives have been shown in animal studies to have neurodevelopmental consequences in really young children. But so does uncontrolled pain. So it's-- if I'm in the NICU, and I can't control a baby's pain, then I will move to ketamine. But I'm a little more cautious in that age group. You know, we do actually have a ketamine infusion protocol now for our neonatal patients. And we have one patient a month basically, who requires it and benefits from it. They're usually patients who have had in utero exposure to you know, opioids and multiple medications, multiple drugs, and then they come out, they're so irritable, and then they require some major surgery. And then there's no way that any opioid or Tylenol is going to help them out after that surgery and then they're put on ketamine, it actually really helps these babies stay comfortable and calm. And we don't use high doses in the babies, it's the same, it's the same dose: one to five mics per kilo per minute seems to work. So that's what those are the two groups I would say. You could also say patients with a history of schizophrenia may not be the best candidate for ketamine. Although, you know, low-dose ketamine is probably safe in that group, I would say those are the three groups that come to mind.

Anu Agarwal: 22:14

Are you still stepwise utilizing other medications and then, if they're not well controlled, then moving to ketamine as kind of the adjuvant after opioids?

Stephen Long: 22:26

You know, I do the same, I mean, I do the exact same pain approach for almost every single patient. So, you know, the first thing is like,"Can we manage this pain without any drugs?" And then if the answer's no, then the question is, "Can we manage this pain with non-opioids, orally?" And if the answer is no, then it's like okay, "Now, can we manage this pain with oral opioids and oral non-opioids?" And then if the answer is no, then it ends up being IV opioids plus or minus ketamine.

Anu Agarwal: 22:55

And I think with time maybe that will change, as our experience with ketamine grows, but I think that's really how the oncologists are doing it as well.

Stephen Long: 23:01

Yeah, I mean, I'm, I'm not here to like say opioids are bad. I mean, they're not going away; for some types of pain, they really are the standard of care. If you can manage their pain with oral medications, there's no reason to put an IV in and start ketamine. Absolutely not. I mean, the second that they can-- their pain is managed on oral opioids, we usually stop the ketamine.

Anu Agarwal: 23:19

I would say generally, on our unit, it's been these patients with chronic pain and those with refractory pain, I think those are really the two groups. And again, I mean, like Steve said, we don't have to consult Pain, but the reality is, those are the complex patients where we want Steve's or Pain's input.

Stephen Long: 23:35

Yeah, you don't need to be a pain specialist to start ketamine. It's safe. But the patients are complicated who require ketamine.

Anu Agarwal: 23:42

I think I was thinking a little bit more about your question, Sarah, about why institutions aren't necessary implementing ketamine. I think one of the challenges with pain research and implementation of new drugs is you have this group of incredibly complex patients, very variable, very heterogeneous group. And it's it's hard to show objective measures. So even in our group that we're working on getting published, there's no difference in pain scores, there's no difference in opioid utilization. But all you can really go on is the subjective benefit. And I would say that, once we introduced it, there is a large group of patients who want it, who've had it, who feel like it benefits them, and you're not going to see those objective changes. But we have seen subjectively that the patients feel better. I can see that as a criticism in places trying to implement and say, well, the literature doesn't necessarily in consensus support it, in terms of opioid sparing or objectively incremental improvement, but I think it is there. It's just so hard to really objectively show it. I think, for me, the way I measure in these kinds of situations, a medication or an intervention that's beneficial is how much people start advocating for it over time. So we saw the same with the Pain Service. And same with ketamine. It's another example and now we're seeing it with our integrative modalities. We introduced massage and acu-therapy, and now it's just everybody wants it, the nurses are advocating it. So I think for these softer-- and softer is probably not the better word but, you know-- softer things like pain, yes, it's now a vital sign, but it's so variable that it's not something you can maybe have such an objective measurement of. But I really look at that as the most important way to say that it's efficacious.

Sarah Dabagh: 25:29

So where were you last year when I was working on a ketamine protocol at our hospital?

Daniel Eison: 25:34

Actually, that was going to be my last quick question, was, aside from Sara here who has used this podcast as an excuse to pick your brains, have there been people who have kind of approached you to franchise this ketamine success story? And like do it at their own hospital? Has it spread from Oakland across to San Francisco? Like, are other people sort of following your model?

Stephen Long: 25:55

San Francisco uses it and their protocol is just like ours, and they've had a lot of success with it. And one of Anu's colleagues went out to Wisconsin, and she reached out to us and now she's starting a low-dose ketamine infusion protocol there. It's just not that hard to do. Once you have like the protocol from another institution that's been using it for a while, and you can bring that to your institution and say, "Look, you know, this is been very successful at Oakland or wherever." And Anu and I, and to be honest with you, a lot of the nurse managers, would be happy to help anyone out there who is interested in doing this at their institution.

Anu Agarwal: 26:31

This manuscript that hopefully will get published soon will also include our ketamine protocol as a supplement. So it'll allow easy access. But it's relatively straightforward. Honestly, the protocol it's, it's partly too being, you know, able to do a continuous infusion on the floor, which hopefully most institutions would allow.

Stephen Long: 26:48

Yeah, I'll tell you this: If your institution allows opioid infusion on the floor, they definitely should allow ketamine infusion on the floor. Opioid infusions are less safe. So you can start with that logic, if there's any resistance.

Sarah Dabagh: 27:01

So I almost feel like if there is a summary statement for this episode, it would be just like a ketamine infusion, if you're an institution, "Start low, go slow, but you're gonna see a lot of benefit."

Stephen Long: 27:13

Yeah, I would say the summary statement would be:"Start low. Go slow. It's safe."

Sarah Dabagh: 27:21

Okay, that's better. I like that. That was great.

Daniel Eison: 27:27

I'm so glad that we had them on the podcast.

Sarah Dabagh: 27:29

I'd like to propose a subtitle for our

Special K episode: 27:32

"How I Learned to Stop Worrying and Love the Ketamine."

Daniel Eison: 27:38

I like it, I like it. It's a good reference. And if anyone else is interested in learning to love the ketamine the way we now do, I have good news for you: Our guests are willing to share their protocol for low dose ketamine infusion, and we're gonna post it on our website PediPal.org, in our Show Notes for this episode.

Sarah Dabagh: 28:00

We'd like to thank all our guests for joining us on this episode of PediPal, and thank you for listening. Our theme song was created by Kevin McLeod. You can follow us on twitter where our username is@Pedipal, that's p-e-d-i-p-a-l. You can find the notes for this podcast and all our episodes on PediPal.org. If you'd like to submit thoughts, objections, or ideas for future episodes, please reach out via the email on our website. This has been PediPal. See you next time.