Pediatric anesthesiologist Stephen Long, MD, discusses treating pain from long-term conditions, such as sickle cell disease. The best plans, he says, can minimize opioids’ well-known drawbacks by combining different drugs. Focusing on multimodal therapy, he breaks down the options and describes how low-dose ketamine infusions can mitigate pain and boost quality of life.
So my name is steve Long, I'm one of the pediatric anesthesiologists at Oakland. And um I I also do a lot of pain management, mostly chronic or complex pain and we started our our complex pain service at Oakland seven years ago and it actually started with with ketamine um introducing ketamine as an option for for acute um and complex pain management at the hospital. Um And it's it's really grown considerably over those seven years. And and so my talk is on ketamine, but I'm gonna focus on sickle cell disease. Um That being said we use ketamine for um all types of pain to be honest with you for somatic pain, neuropathic pain, this real pain. We use it in neo neyts all the way up to the oldest patient in the hospital. Um ketamine isn't an opioid. So so it's a nice alternative for patients who who have bad side effects to opioids or patients who have kind of reached the therapeutic ceiling with opioids. Um And I think, I mean especially in this day and age with with opioid um deaths rising both in adults and kids across the country. Covid has only accelerated that um uh epidemic um that that medications like ketamine should be looked at, you know more frequently. So, so my talk is on ketamine for acute pain management and sickle cell disease if you understand um this you you know it's it's it's a good way to to jump off and and look at other pain syndromes um here's my disclosures, I have none. Um So so we'll take we'll take a step back and just talk about sickle cell pain. Um So, you know, pain is like the first and only um you know, major symptom of sickle cell early on. Um you know, the patients start developing pain early and and by the time, you know, they're they're young adults, 30 or 40% of them have have pain every single day. Um And and the older they are, the more likely they are to have chronic pain. Um It spans their entire life from from the beginning, all the way to the end and and we really don't understand. Um it all that well, I mean, you know, viso exclusive crises cause it, but um but sometimes, you know, when when patients aren't in a crisis, they have severe pain. So it's not just that um yeah, it evolves. I mean, the pain syndrome does evolve and change over time and it gets more complicated. The older they are okay, three types of pain for sickle cell disease. You have, we have acute intermittent pain and that's the most common type. Um and um that would just be like a pain crisis that comes and goes chronic daily pain. Um We we see that in our older patients, um this is usually, I mean, to be honest with you, it's usually pain in the back or in their hips, those the two most common areas, sometimes arms, shoulders as well. Sometimes it's related to the crisis of the bones, but sometimes it's not. Um And then acute on chronic pain is is probably the worst. It's when patients who already have a chronic pain syndrome come in with acute pain. Yeah. Yeah. Um So so you know, we risk stratify patients for for difficult pain management. Um And here are the kind of the five categories that um that I use to put patients in high risk. Um So number one, if they've, you know, if they've already had pain that's difficult to manage and this can be applied to patients who don't have sickle cell too. Um patients who are already on opioids. So if a patient comes into the hospital in acute pain and they're on chronic opioid therapy, they're high risk if they have neuropathic pain or nerve injuries, they're high risk. Um patients who have a diagnosed chronic pain syndrome like fibromyalgia, for example, or high risk patients with anxiety. I should also put here or depression, anxiety and depression can amplify pain. We see it all the time. It's actually it's hard not to experience anxiety and depression if you have chronic pain, um they coexist and and each makes the other worse. Mhm. Um And when pain isn't managed adequately, patients there's this association with worse clinical outcomes, I mean, they're more likely to have uh thrombosis um m bliss. Um they don't breathe as well. Um They're more likely that maybe no suppression pTSD increased length of stay death. These are all associations that we see in patients who have poorly managed pain. I mean sometimes, you know, I'll get a consult on the pain service for a patient at the hospital who is experiencing new onset acute pain and I'll walk into the room to meet the patient for the first time. And really there, you know, there you know, the concert was placed because their heart rate is up and the respiratory rate is up. Um And it's it's it's like it's sepsis actually. Um Not not that's what's explaining the pain but it presents this pain. Um And sometimes it can masquerade like sepsis can look like pain. Um So that's an example patients who have poorly managed pain having worse clinical outcomes. So opioids are a very common modality, a very common way of managing acute pain in sickle cell disease and in many types of pain but they do have limitations and risks. And understanding the limitations and risks are important. They affect all different parts of the body, not just your nervous system. Um You know, the mu mu receptors. Delta receptors. Capital receptors are all over the place and and they are used for hormone regulation and neurotransmitter regulation. Um You know, they're they're all over um your gi system and if opioids do one thing consistently to most patients it is caused gi dysfunction. Uh you know I say you know every patient on opioids should be on a stool or bowel regimen because they do wreak havoc on your Gi system. And um and we can have patients who who don't respond to the therapeutic effects of opioids but who who get constipated. Um and usually you know as you go up on the dose of opioid, the side effect profile worsens. Um So you get more constipation, more nausea, more itching, um more sedation. At high doses of course respiratory depression. Um But as you go up on those opioid doses, even though the side effects are getting worse, the therapeutic effects are not necessarily getting better. And I tell my patients you know the first your first dose of an opioid is going to be your most effective dose and every subsequent doses probably going to be a little less effective than the one prior. Just because you build a tolerance um to them you just do. Um And and that's why we need to have alternatives. Um And just so you understand the physiology, just to review the physiology of of of respiratory depression. Opioid induced respiratory depression. What really happens with opioids is they blunt your your hyper kapnick ventilatory response. And so Um you know the partial pressure of carbon dioxide in your blood is triggering breaths and um you have a set point, it's usually 40 of mercury. The partial pressure of carbon dioxide in your blood normally is 40 of mercury um in your arterial blood and and um and then your brain stem senses that and and and and keeps it there by tricking you to breathe. But opioids will make your brain stem less sensitive to carbon dioxide. And so the partial pressure of carbon dioxide has to be higher in order to trigger a breath. And so you can see here um um We have two graphs. The blue graph is the minute ventilation of the subjects and the the yellow graph is their partial pressure of carbon dioxide after the morphine infusion was started. And so you can see the partial pressure of carbon dioxide goes up and the minute ventilation goes down. Um And and and that's what happens. And so um Patients who are on opioids who aren't used to them will have a really high co two And then the co two displaces oxygen in your lung and causes hypoxia. And the hypoglycemia is what's the most dangerous of course. Uh This is this is an old graph but it's still true. Um The this is a graph put out by the D. E. A. Which shows that the sales of opioids um correlates strongly with opioid related deaths and opioid related treatment. Um and this is you know the sales of opioids. This was just a measurement of the weight literally the sales per the same sales per kg per 10,000 people um in a given area around the country. Um So as as more opioids were sold and none other than the deaths went up. And the amount of treatment required for opioid use disorders also went up. Um So so because of the limitations of opioids, the amount of side effects they have. Um and um the risk that they have uh our approach is to use use many different types of pain medications, usually in smaller doses together uh to treat pain. So multi it's called multimodal analgesia, and I'm sure you've heard of that that concept. Um And so here are different pharmacologic modes of analgesia. There's opioids which we talked about. Um Local anesthetics. Um Local anesthetics are are good for for acute pain management um when just a part of your body is in pain like your arm or your leg or your foot or your hand. Um So we do a lot of nerve blocks at Benny of Children's hospital. And but it's usually for surgical pain. The patients who have who have chronic pain, in my opinion, the nerve blocks are not getting at the root of the problem and usually um they're just a temporary fix. Uh And they don't they don't give lasting benefit. Okay, but anyways, they can be extremely effective for acute traumatic pain or acute surgical pain. Um Another type of medication would be A. S. N. R. I, which is serotonin and norepinephrine reuptake inhibitor like DULoxetine or Venlo vaccine we used FLUoxetine usually. Um and and it's it works pretty well, especially for patients who have um you have like kind of abdominal pain or nerve pain. Um It can help and and if they're depressed um It's a nice medication to choose uh for for patients who have pain and depression, tricyclics are another type of of medication I use a lot. I like am a trip to lean but there are certainly others. Um tricyclics are quite effective for neuropathic pain. Um They're also they're also sedating. So if you have a patient who is having a difficult time going to sleep um and it also has neuropathic pain or or any type of pain for that matter. Using a tricyclic like amateur delaying at night might be a good treatment. Uh cox inhibitors cycle oxygen ace inhibitors. Um Our common, so that's that's those are all of your insets. And acetaminophen. Um There are a ton of n sets to use. Um We I mean ibuprofen of course is probably the most common when used in pediatrics. We also use naproxen a lot. It's nice but it is a little bit stronger than ibuprofen. Um It doesn't have to be dosed as frequently. Um So it's it's good for patients who don't like swallowing pills as much or or who have uh like constant pain um Of course insets have side effects. I you know, we we have tried the cyclo oxygenates two inhibitors. Um Like to as in the number two that are specific for that. Um cycle oxygen is so celecoxib CeleBREX is an example of it and I've had patients who don't respond to ibuprofen don't respond to naproxen but do respond to celecoxib. Um and and these cycle oxygen is two inhibitors um are marketed to have fewer side effects. Your gi side effects for example. Um And I you know in in my experience um that that that seems to be true. Um I've you know I've had patients who who do have like n said ulcers and yet they have chronic pain and then once they're ulcer resolves we put them on celecoxib and they don't get an ulcer again. So I've I've had some success with that but and I wouldn't say that I you know I've studied it closely enough to know how much safer the cox two inhibitors are versus um the cox 12 inhibitors and then acetaminophen is used a lot. Um We use it both centrally and potentially in the hospital. Um The I. V. Formulation of acetaminophen is great for patients who aren't taking anything by mouth or patients who You know our immediately post up um we don't we usually don't keep patients on CBS acetaminophen for more than 24 hours um if they can swallow and if they're eating. Um So the next category B NMDA antagonists. The NMDA receptor is the receptor that ketamine blocks. So ketamine is an NMDA antagonist. Um And so it's different than an opioid opioids work on the mu receptor, the kappa receptor, the delta receptor but the NMDA receptor is totally different um system and glutamate is the neurotransmitter that that often works or that agonizes and stimulates this receptor. So ketamine is an example of the medication that blocks the receptor. And um methadone also has that property. It's a it's a it's an opioid as well. Um But it's also an nd antagonist alpha two agonists like cloNIDine next minute Tommy dean. They certainly help with anxiety. They can be sedating. Um And I think given with a medication like Percocet um They can potentially eight the analgesic effect of an opioid by themselves. I use them more for management of agitation and anxiety. Um They also to be honest with you I mean planting can can be a pretty good sleep aid. So you can mix for example quantity being with um a trip clean and and that will certainly put someone to sleep. Um It's quite sedating. It works well you can mix cloNIDine with melatonin um You can meet mix cloNIDine with traZODone so you can add it to um your sleep aid and it will it will potentially eight. It steroids help with almost all different types of pain rarely do we start steroids for the indication of pain management by itself. Um But if patients need steroids for another reason and they have pain their pain usually improves gabapentin. Oid are like gabapentin and pregabalin. Uh They work on by blocking calcium um on nerves and uh so you know they're good for nerve pain neuropathic pain. They can be a little bit sedating. Um They're not super strong. Uh I do think that if the patient's going to respond to them you'll know pretty quickly after you start them. Um If a patient's pain does not improve um with initiation of gabapentin for example I might switch them to pregabalin if they still haven't don't show response and I would just stop it. Um And you'll know you'll know if they're a gabapentin really respond or not if it works great but a lot of times it just isn't strong enough. So like I said ketamine is an NMDA antagonist um It can be ministered all different ways. Um I ve um I am so inter nasal. I am as an intramuscular shot or orally. There is you know the oral so the the I. V. I. N. And I am formulations are all the same. You know you just draw it up out of the violin you give it one of those three ways um orally. Um It it can be compounded into an oral solution and almost all compounding pharmacies do this. There's one in Berkeley that I use but I'm sure that many can do it. Um And I've had some patients actually who responds so well to ketamine um on the in patient side the I. V. Formulation of ketamine and and they want to go home and they want to bring ketamine home with them. Um Just to help bridge them bridge their discharge. And so we will compound ketamine for them and they use it at home and it works pretty very well. So so ketamine um has this unique property. It's it's synergistic with opioids. Uh So so what that means this this this graph shows what it means. Um This was just an experiment looking at the pain threshold. Um They liked that there was like an electric shock um applied to uh subjects hands. And it was like the study was looking at what level of of shock the subjects could tolerate. And there were four more groups. One group only got saline that's that's the black dot one group got only academy. And that's the white dot fentaNYL was given to the black triangles. And both fentaNYL and ketamine were given to the white triangles. And so you can see that the sailing group was as you'd expect it had no effect. And then ketamine by itself and fentaNYL by itself um did improve the pain threshold in these patients. But when you put them together um it was powerful. Really really powerful. It's I mean it's more than them added together. They're multiplied together. Synergistic mm hmm. Um This is a study looking at patients who have cancer and who are who are on a lot of opioids a ton of opioids going into this study and um And they were given ketamine. And um one dose of ketamine and a pretty small dose. I mean at least this does the .25 mg per kilo um reduce their pain scores significantly significantly. You can see I mean the pain went from You know 6.6 to 1.4 after 30 minutes. Even after three hours it was still the pain score was still 3.8. And then when a bigger dose of ketamine was given, the pain went from 5.9 down to almost nothing At 30 minutes. And three hours later it was at two. The pain scores that too for these cancer patients, these are patients who are opioid tolerant. Um and who experienced high levels of pain every day. Um And ketamine was almost like a silver bullet for their pain. Yeah, ketamine also helps prevent this. This cruel side effect of opioids called opioid induced hyper analgesia. Um patients who take opioids over time become more sensitive to pain. And it can trick patients because they are on a medication to treat pain but that medication is also making them more sensitive to pain. Um And so when when you know the morphine or Dilaudid wears off their pain is sometimes worse than it was before they received that dose of morphine or Dilaudid. And that's called opioid induced hyper algae asia and we see it a lot a lot a lot a lot. And you'll see, you'll see it in patients who have chronic pain who are um on opioids and and during their mission or during their treatment as an outpatient. Their pain is not getting better on the opioids. It's almost like the opioids aren't um doing much at all. And then their pain, you know, they're they're opioid requirements going up and their pain isn't going down. And so that at least one thing that's going on there is opioid induced hyper algae Asia. It could also be opioid tolerance. Both of those things together can make opioids difficult in patients with chronic pain. So this was just a study looking at um this was an animal study. But I like I I haven't because I like the graphic. Um But this was kind of amount of pressure and animal could a mouse could handle on its paw. Um And fentaNYL was given. Um And and and the amount of pressure the animal could handle on day one was less. Um Then on day zero. Um when the fentaNYL was given before the final was given, this is where it was before. And then it took it actually took four days for the animal to to return to their baseline pressure that they could tolerate on their pop. And then the same experiment was repeated. But ketamine was given before the fence was given. And that effect that was seen when only Fenton was given disappeared. So you can see here, you know, day one the animal had the same pain threshold that they had on day zero. Whereas in the first experiment when only fentaNYL was given, the pain threshold was much lower. So what's going on here is something called opioid induced type analgesia. The opioid is making the animal more sensitive to pain. Yeah it can be really cruel and confusing for patients. So we give ketamine usually as an infusion um at at our hospital. And it's this is just a graph showing the context sensitive halftime for ketamine. Um context sensitive halftime is Is the amount of time it takes for the plasma concentration of the infusion to drop by 50% when the infusion is stopped. And um and so what you want is you want your context sensitive halftime graphic to be pretty flat. Um and so ketamine here is in purple and so you can see around eight hours into the infusion. The graph of the context sensitive halftime flattens Which means that you know at eight hours or beyond when you stop the infusion, it's predictable how long it's going to take For the plasma concentration of the drug to drop by 50%. And so here it at eight hours if you stopped the ketamine infusion It would take 45 minutes For the concentration of ketamine to drop by 50% in the patient's plasma which is good. And um and so four of those um Context sensitive half times would take you to three hours. And so after three hours, you know, the plasma concentration of the ketamine is less than five of what it was before the infusion was stopped. Um ketamine is an NMDA antagonist and there are oral antagonist as well. I mean other than oral academy that is um so my mom wanting this here it is, I'm I'm kind of circling it with my arrow Montaigne is an oral NMDA antagonist and it can be given um uh for treatment of pain in patients who who benefit from NMD antagonist and I've used it um it's not super strong but it does help. And this is just a study um kind of advocating for it. That showed that it helped. Um It's under it's it's the brand name is Namenda, I think it was originally designed to treat Alzheimer's disease um dementia. Um but it's also a pain medication. So I say here, so, so what sickle cell patients or really any any pain patients are good candidates for ketamine infusions. Uh 22 different categories. One is patients who do not tolerate opioids. So patients who have uh opioid induced hyper algae asia for side effect profiles, patients who are really nauseated or constipated on opioids um or patients who are who are too tolerant or who are just tolerant to opioids. So patients who have tacky feel axis in other words when higher doses of opioids are required with diminishing therapeutic effect. Um patients who they say, you know, the Dilaudid is like water, it feels like you're not giving me anything. Cancer patients who are on a lot of opioids like you saw in that study earlier, those patients who are highly tolerant to opioids seem to respond. Um Really? Well the academy. Mhm. This is um this is just our order set. Um I don't know how important these doses are but we run a very low dose in the hospital, we run ketamine on the floor, not most patients around the floor. I mean of course it can be run on the issue as well but these are four patients on med surge um receiving the ketamine. It's a low dose, it's not a sedating dose of ketamine. Um It's an analgesic dose of course. You know if you go high enough on your ketamine um Does it can be a general anesthetic but we're not even close to that for what I'm talking about. Um And the most common side effect that patients report is just feeling like a little bit woozy on it. Um Most patients don't feel that but there there is a minority of patients who do feel a little bit woozy. Um Some patients say you know they it's fine. I mean they feel a bit woozy, a little bit inebriated but they're they're pain has improved. So they're willing to tolerate that side effect. Other patients want us to go down on the dose and we do um And then some patients just don't like the way it makes them feel and we turn it off. Um We we we see almost no chemo dynamic changes, ketamine can cause like an increase in heart rate, increase in blood pressure one gift. And at high doses we don't see that at these doses in the hospital. Um So it's well tolerated. I mean I was joking. I mean I I have patients, older patients who who are on ketamine infusions doing their math homework in the hospital. I could do not. I had one patient who was 19 or 20 years old and she was zooming into her UC Berkeley calculus class while on a ketamine infusion and she was totally lucid and she didn't, she was able to attend class um Fine, there are no issues at all while being on this medication. So it's the psychotropic piece of ketamine that you may associate this drug with. Um that that's real but it's dose dependent and and we're giving it at a very low dose. Um but a low dose is all you need for the the analgesic properties. Um You know we we we are big on pain plans um at our hospital for patients who have chronic pain syndromes. And so this is an example of a pain plan for sickle cell, but we like to do individualized pain plan. So, so patients who have chronic pain who who for whatever reason come to the hospital for pain management. Um Almost all of them will be put on an individualized pain plan that can be used for future admissions. And we do that, you know for a lot of reasons, but mostly so so so the team that's taking care of them knows what to do because the patients can be complicated and and also so the patients feel like you know they're being they're being recognized, you know and not dismissed. Um And it gives the patients a sense of like security knowing that there's a pain plan. It also it also eliminates any conflict um that that sometimes happens with regard to opioids and I. V. Medications and patients and pain. So if we can get we agree on all the doses and the frequency of the doses and all the medications beforehand. Um And then we have a pain plan that that has different uh that kind of weans itself over a series of days. And so the pain plan starts with day one like you see here and then on day two it adjusts on day three it adjusts and it goes like that. Mhm. And we just scan these pain plants into the patient's medical chart and often will give the patients laminated copies of their pain plans and the pain plan will have an impatient component and an emergency department component and the pain plan can also have an outpatient component. So in conclusion almost done here. Uh multimodal pain therapy works better than opioids alone, for sure. And what I mean by that is if you use two or three pain medications in combination with each other um at lower doses um usually you'll have fewer side effects and better pain control than if you just relied on opioids or any any one medication. And I'm talking about for more moderate severe pain for mild pain. This I'm not talking about that kind of pain. I'm talking about moderate severe complex pain. Um ketamine may benefit a sickle cell patient or any any patient really who's tolerant or intolerant the effects of opioids. Um Yeah, I mean we we consider using low dose ketamine infusions for for all patients really who have sickle cell disease. And um and for a lot of patients who have other types of chronic pain syndromes, it's very well tolerated at the low doses that we use mm. Um This is this is my last slide. It's it's a referral slide for our hospitals