There have been drastic changes made in the regulation of opioids for medical treatment in the past few decades. However, with advent of fentanyl and carfentanil addiction, overdose-related death continues to increase. In this episode, our guests discuss continued regulation of opioids, use of naloxone and when it may not counteract an overdose, the case for limiting the use of opiates in elderly populations who have existing co-morbidities, and how the use of opioids in certain populations continues to be appropriate.
There have been drastic changes made in the regulation of opioids for medical treatment in the past few decades. However, with advent of fentanyl and carfentanil addiction, overdose-related death continues to increase. In this episode, our guests discuss continued regulation of opioids, use of naloxone and when it may not counteract an overdose, the case for limiting the use of opiates in elderly populations who have existing co-morbidities, and how the use of opioids in certain populations continues to be appropriate.
Opiates and Respiratory Toxicity
Raed Dweik, MD:
Hello, and welcome to the Respiratory Exchange Podcast. I'm Raed Dweik, Chairman of the Respiratory Institute at Cleveland Clinic.
This podcast series of short, digestible episodes is intended for healthcare providers and covers topics related to respiratory health and disease. My colleagues and I will be interviewing experts about timely and timeless topics in the areas of pulmonary, critical care, sleep, infectious disease and related disciplines. We will share information that will help you take better care of your patients today as well as the patients of tomorrow.
I hope you enjoy today's episode.
Eduardo Mireles-Cabodevila, MD:
Hello everyone, and welcome to the Respiratory Exchange Podcast. I'm your guest host, Eduardo Mireles-Cabodevila, MD. I currently serve as the Director of the Medical Intensive Care Unit at the Cleveland Clinic Main Campus.
My guests today are Dr. Deborah Rathz and Dr. Philippe Haouzi. Dr. Rathz is a Critical Care and Emergency Medicine Specialist. She serves as the Medical Director of the Intensive Care Unit at the Cleveland Clinic Hillcrest Hospital. Dr. Philippe Haouzi is a Pulmonary and Critical Care Specialist who serves as the Director of the Pulmonary Function Laboratory for the Department of Pulmonary and Critical Care of the Integrated Hospital Care Institute at the Cleveland Clinic.
Today, we'll be talking about opiates and respiratory toxicity. Welcome to the podcast. Deb, in your role as an Emergency Medicine and Critical Care Specialist, I would like to start with you discussing what is the magnitude of the problem.
Deborah Rathz, MD:
Well, thanks for having me today, Eduardo. The magnitude of the problem I think is summed up in how it's referred to out there in the community as an opioid epidemic. It's a very large problem and it's growing. Depending on how far back in time you go, you'll see that it's doubled, tripled, quadrupled in the number of deaths that we're seeing in the community.
Key things that have happened over time, we saw a rise in prescription opioids in the 1990s, then we started to see increased deaths due to heroin in the early 2000s, and now the big problem is synthetics. And so now what we're seeing in the community is the result of synthetic contamination of heroin products that are out there.
The problem is fentanyl is 50 times more potent and carfentanil is 5,000 more potent than heroin alone. So, using your standard dose of heroin, you can very easily overdose and have respiratory compromise.
Eduardo Mireles-Cabodevila, MD:
So, hearing about this potency of all these opiates and what we're seeing in the community, Philippe you have done a lot of research into control of, of breathing. Can you explain the basic mechanism by which opiates impact the respiratory system, and particularly in relationship with respiratory depression?
Philippe Haouzi, MD:
Oh, thank you Eduardo for inviting me to this podcast. So, of course it's a very important question because the main toxicity of opioids and the new generation of opioids like fentanyl, carfentanil, you know, can stop your breathing activity. In most cases they would depress the breathing activity, but they will eventually stop it when the drug's injected intravenously.
So, what are these compounds doing? They are, without getting into too much details, creating certain group of neurons in your brain and hyperpolarization of neuron. What does it mean? That the neurons cannot work anymore. Not every neuron is affected, only neurons and group of neurons which have opioid receptors. Those encode for pain, that's why we use them. Those also, like, encoding for the level of vigilance. In other words we can use this drug for sedation and anesthesia, but also and unfortunately against neurons which are controlling breathing. They are locating above the spinal cord, and these neurons are exquisitely sensitive to the effect of opioid. They will therefore be depressed rapidly by the drugs, causing within seconds sometimes, complete cessation of breathing movement and affecting, when they are taken chronically, breathing during sleep. So that's how opioids are toxic for the respiratory control system.
Eduardo Mireles-Cabodevila, MD:
Is there a relationship with the dose and which ones get affected first in terms of those receptors in the respiratory control, the pain control, and the consciousness control or is it homogenous?
Philippe Haouzi, MD:
It's a very good question. So, at low dose, analgesic dose which are commonly used to treat pain, the other side effects are not as large as, of course, as when we increase the dose, yet even at low dose, breathing is affected. Typically, it starts with sleep, and you have abnormality of breathing during sleep even at low dose. As the dose is increased and more importantly when the dose is injected rapidly, like following an opioid overdose with IV users, you immediately get the other, or the additional affect, or opioid which will be a coma.
People are sedated, associated all the time with depression, a significant depression in breathing that can be life threatening. But indeed, at low dose, the aberrational breathing, is more subtle, occurring mostly during sleep.
Eduardo Mireles-Cabodevila, MD:
Deb, let's talk a little bit about the specific things that you're seeing in your ICU, and the emergency room. Is this common that you're seeing them, this group of patients coming in or patients that see the effects of opiates in general? Are you seeing this?
Deborah Rathz, MD:
Yes, we're definitely seeing it in the emergency departments and in critical care. I think the hardest thing that we see is when a young person has come in and overdosed and required resuscitation and oftentimes then have hypoxic brain injury, if not brain death. So we are definitely seeing it.
Eduardo Mireles-Cabodevila, MD:
So tell me a little bit about this naloxone and the role it, I mean, how in that group of patients that we're seeing coming first what is the role, and number two are you seeing the using the community of naloxone to treat this group of patients?
Deborah Rathz, MD:
So, naloxone is referred to as the antidote for opioids. It's an anti-opioid. It displaces it from receptors to which the opioid has turned on a signaling system.
It's used in the community, there is a specific project in Ohio called the DAWN Project and it's coordinated through the Ohio Department of Health where users or their family and friends can get free naloxone, and it comes intra-nasally or intermuscular.
So, I think oftentimes when it's used out on the community by the community, sometimes those patients aren't making it to the emergency department. If EMS is bringing a patient in then they're usually establishing IV access or IO access and giving that IV which is gonna act much quicker, 'cause there is a difference in how you administer this. If you're giving it IV, it's working within one to two minutes, and sometimes even faster, we see them wake up quickly. If you're giving it IM or Sub-Q it's still on the order of minutes but it's a little bit longer between two and five minutes, and then if it's given intra-nasally it's gonna take longer, more like 10 to 15 minutes.
So, when you're talking about not breathing, though, that's a significant amount of time and if you don't have normal lungs to begin with, then you're gonna suffer hypoxia much sooner.
Eduardo Mireles-Cabodevila, MD:
That is a very important point. So you're making actually, you reminded me about when we talk about the magnitude of the problem, is that I went to have my ACLS the other day and part of the training that we received during the ACLS was related to the administration of intra-nasal naloxone for this group of patients.
Deborah Rathz, MD:
Mm-hmm.
Eduardo Mireles-Cabodevila, MD:
So, I think that when you start seeing it at that, in a systematic way in the courses that we get to do, CPR for our practice, now we're being trained on naloxone talks to you about the magnitude of the problem.
So, let me move a little bit within this environment. There's an issue that I have heard a couple of times in our patients which is, you know, "I came to the hospital with acute pain," or, "I was admitted to the Intensive Care Unit," or, "I was there for X, Y, or Z." Does the use of opiates in the hospital lead to a higher incidence of addiction afterwards?
Deborah Rathz, MD:
I think one of the key things that leads to addiction is the duration for which you're using the medication.
Eduardo Mireles-Cabodevila, MD:
Mm-hmm.
Deborah Rathz, MD:
So if you come in with an acute injury, and you get an appropriate dose of a narcotic to control the pain until we can help remedy the underlying cause of that pain, that is not gonna lead you to increase of addiction. What we have noticed over time is that when people go home with prescriptions for opioid medications for longer periods of time, then that can lead to dependence and then in the right person in the right circumstance, addiction. But if it's acutely used for a short duration, it’s unlikely that you're gonna become addicted.
Eduardo Mireles-Cabodevila, MD:
So when used appropriately within the amount of time that you need it, we think that's okay. There’s been a lot of changes recently in the way that we prescribe opiates.
Deborah Rathz, MD:
Yes.
Eduardo Mireles-Cabodevila, MD:
So that these large doses that we used to give are limited.
Deborah Rathz, MD:
Yeah.
Eduardo Mireles-Cabodevila, MD:
Can you talk a little bit about that?
Deborah Rathz, MD:
Sure, yeah. Large doses and large volumes. That's drastically changed over the years. The recommendations now usually are limiting a short course of opioids if you think they're necessary for no more than three or five days, and then using alternatives as well. We know that non-narcotic medications, simple things like acetaminophen, ibuprofen, those are actually very helpful in pain management as well.
Another example of pain management that I've gone through with patients multiple times is treatment of a headache, and we give them a cocktail of medications, none of it's a narcotic, but the point is that they all work differently. They all act on different pathways in pain management and sometimes it's combinations of things that work better, but they don't have to include opioids necessarily.
Eduardo Mireles-Cabodevila, MD:
That's fabulous to hear, it actually, that takes me to another topic or related topic which is combining the opiates with other medications and so there's two pathways here, Philippe, and I would like to hear your thoughts on two items.
The first one is the combination of opiates with prescribed or other substances that we have available at home, and the second one is the substances that may be combined with the illegal administration of other opiates too. Do you want to talk about this a little bit more?
Philippe Haouzi, MD:
So any medication that will decrease the level of activity or that would be a sedative, who have sedative property, including benzyl, barbiturates, sedative drug will, combined with an opiate, would magnify the effect of the opioid. Not only on the level of sedation, people will be more sleepy obviously, but on the depression of breathing. So that's a non-specific effect, but it any drug used commonly, sleeping pills, whatever.
So that's well established of course. The combination of drugs, of other, other drugs in the street, that's a major issue. As you probably have heard, there is a recent document released by the CDC, the White House, a lot of organizations do this, bringing the attention of the medical community to the use of xylazine combined with fentanyl.
Fentanyl is now one of the most commonly used drug in the street, I think there's about, you know, 60,000 death by fentanyl every year in the US, and the association with cocaine or other drugs has been going on for many, many years, but a new trend started a couple of years ago is to associate xylazine. Now so xylazine is not well known by the medical community because it's used by veterinarians. It's the equivalent of precede. It's the same family, it's an [unclear] agonist. It's the same cousin of precede, but not using humans. It's not FDA approved because it had some [unclear] affect, however, it's easy to find.
It has an additional sedative effect so people somehow like to use it, and it's a very cheap way to cut fentanyl for those selling it. So, it has become a dramatic problem to the point that it has been called even a, a new emergency, a medical emergency for the US population now, so this association. It produce higher toxicity and we have actually looked in [inaudible} study if you combine low dose of xylazine which are not depressing your breathing so much with non-lethal dose of fentanyl the cocktail is lethal.
So the combination of the two drugs seems to be extremely toxic, plus it creates local necrosis and other side effect which has become a real, real problem. So yes, this association is causing major public health issues and then very little strategy in place to try to prevent that.
Eduardo Mireles-Cabodevila, MD:
In those cases does naloxone become less effective for this group of patients?
Philippe Haouzi, MD:
So it's a very, yes it's a very important question. So naloxone will of course overcome the effect of the fentanyl-
Eduardo Mireles-Cabodevila, MD:
Mm-hmm.
Philippe Haouzi, MD:
... or opioid. I use fentanyl as a generic term because it's now the vast majority of overdose is right to fentanyl IV, but will not counteract the effect of xylazine nor the effect of other sedative agent, of course. So, there is actually an initiative by different institution when, or by different organizations like the NIH to try to develop research program to understand what is the best antidote that could be used against this association, but the, certainly the, the naloxone would never have the same effect than if, if it were used on fentanyl alone, and we don't exactly know for the moment what to do.
Eduardo Mireles-Cabodevila, MD:
Oh-
Philippe Haouzi, MD:
And what the best antidote to use.
Eduardo Mireles-Cabodevila, MD:
Very concerning know that, thank you for sharing that.
I wonder, Deb, if you can talk to us a little bit, and especially in the emergency environment when, w- when these, when these patients arrive to us. When do you stop with the naloxone? How high do you go and how, what's the pathway there?
I know that once that they reach us we can secure the airway and institute mechanical ventilation and, and essentially respiratory support, but there is always a, an issue of, "Oh, I already gave this amount of, of naloxone," what's your recommendation there, what's your practice?
Deborah Rathz, MD:
I think it depends on how the patient presents.
Eduardo Mireles-Cabodevila, MD:
Mm-hmm.
Deborah Rathz, MD:
There's a spectrum. So if they've received some naloxone in route already and they're showing some response, then we're titrating it to respirations. What you want to avoid doing is completely waking the patient up in those situations, 'cause you can overshoot and then precipitate withdrawal, they'll get a catecholamine surge, they become angry, violent, so you don't want to titrate it to consciousness per se, but titrate it to their respirations and then eventually as the narcotic wears off then you won't need naloxone anymore.
Now, what's unique about naloxone compared to the opiates is that it's shorter acting than most of these opiates and so naloxone wears off usually in about two hours, and so you most likely will have an opiate that's there that's gonna last longer, so you may have to re-dose those patients.
Now if they've already come in and they're, they're intubated, that's a different scenario and they're already supported with their respirations, there's nothing that you can do at that point to help eliminate the drug that's there, so I don't know that I would continue with naloxone at that point if the airway was already secured and I would allow them to wake up on their own.
Eduardo Mireles-Cabodevila, MD:
Let, let it wear off on-
Deborah Rathz, MD:
Yes.
Eduardo Mireles-Cabodevila, MD:
... and come back to earth.
Deborah Rathz, MD:
There's plenty of stories where providers have been injured because they've overshot.
Eduardo Mireles-Cabodevila, MD:
Yeah, you don't, we don't want that. So that, this is a very good point of titrating to respiratory rate. Philippe?
Philippe Haouzi, MD:
Yeah, so the challenge in an environment where there is no capacity to monitor breathing-
Eduardo Mireles-Cabodevila, MD:
Mm-hmm.
Philippe Haouzi, MD:
... like first responders, or even, you know, lay public, family members who have a naloxone and have to inject when they witness one of the loved ones, you know, on the floor not breathing is, is indeed a big issue. In an environment where we can monitor breathing, we can actually monitor the level of naloxone but in the, in the street, it's a big, it's a big problem and in- indeed, family members or responders, first responder, experience withdrawal. Because there is no middle ground, there is no place for tailoring the dosed breathing so they have to resuscitate the patient and act very rapidly.
So in this situation I'm not sure what are the current recommendation but we are - the problem is still present. The risk of dying, 'cause you can die very quickly actually by hypoxia if you're not breathing-
Eduardo Mireles-Cabodevila, MD:
Mm-hmm.
Philippe Haouzi, MD:
... for obvious reason, by ventricular fibrillation, asystole, and even [unclear] circle where the level of hypoxia actually prevent naloxone to work by inhibiting the receptor neurons. So all we think why hypoxia estimated breathing, it is true up to a certain point where PO2 is too low and breathing doesn't start so these patients do not respond even to naloxone until you restore a little bit the PO2, the partial pressure of oxygen above a certain level.
So for the big challenge outside the hospital setting is to know what to do. The risk of having a withdrawal in an ambulance and someone jumping to your throat and trying to kill everyone is a big risk and sometime people are under using lower dose of naloxone to prevent that, risking a fatal outcome.
So it's a very difficult question outside the hospital setting how to monitor, so I'm not sure if there is a new recommendation or new-
Eduardo Mireles-Cabodevila, MD:
Yeah, that's a great point because actually when we were being trained for this overdose in the, is, les- what the paramedic made specific recommendations regarding that, saying after you give the dose, he would recommend, at that time, he was saying to stand by the door, be ready to move out of the environment where you are once that the patient wakes up.
So, thank you very much for highlighting that Philippe. Now, let me ask, is there, there are specific populations out there, patients with preexisting pulmonary conditions, elderly, and others that may be at higher risk of respiratory complications. What would be the recommendation that you would give in terms of opiates, chronic opiates, or starting opiate therapy for this group of patients in respect to the toxicity and in this group of population?
Philippe Haouzi, MD:
So any patient who have already some kind of, some degree of a deterioration of their respiratory control. What I mean by that, a patient with, for example, obesity hyperventilation syndrome.
Eduardo Mireles-Cabodevila, MD:
Mm-hmm.
Philippe Haouzi, MD:
Patient who have chronic CO2 retained, COPD. The young and the elderly population certainly are more exposed to the toxicity of CO2. So, if you have a patient who is overweight, have sleep apnea, the best ways to try to avoid completely the prescription of opioid if possible. As you mentioned earlier Deb, they are a new strategy to treat pain, and we should really [unclear] in this population more than any other population with this kind of approach.
CO2 retainer, we see a patient with COPD, emphysema, all the problems including neurological problems. In this population we should avoid as much as possible the prescription of opioid. I know that opioid was even suggested to be prescribed to treat [unclear] at some point, this was fashionable at some point. People have changed their strategies so for this population we should avoid prescription as much as possible.
If we, if we can't then we have to monitor their breathing at night, and some of these patient may b- may need to be supported by CPAP or BiPAP at night, simply because of the prescription of CRIC opioid but in this population chronic CO2 retainer, obviously hyperventilation, we should try to avoid prescription of opioid at any cost.
Eduardo Mireles-Cabodevila, MD:
Is there any testing that we can do in the lab to detect a group of patients that may be at higher risk under control of CO2?
Philippe Haouzi, MD:
So, I think that it's well established in the literature. So, of course we could tailor to a given patient, you know, by measuring, I don't know, the CO2 sensitivity or do sleep studies systematically if we want to prescribe opioid, but we do know now by experience that the vast majority of these patients will have sleep disordered breathing, and may experience during daytime an increase an increase hypercapnia.
Eduardo Mireles-Cabodevila, MD:
Okay.
Philippe Haouzi, MD:
So, as a general rule, we should avoid using opioid in this population as a general rule.
Eduardo Mireles-Cabodevila, MD:
Fantastic. So without a doubt therein we, we have heard the issues with respiratory toxicity but we do know that there are certain populations that definitely benefit from opiates, and we have to balance the good and the bad of the opiates.
Deb, can you talk to us a little bit more about that? What populations... It's obviously, the toxicity of the respiratory centers may be something that we can tolerate because of we are trying to treat the pain or other issues.
Deborah Rathz, MD:
You raise a really good point,Eduardo. There are certain populations that do benefit from opioids, even though we're in general trying to reduce the amount that we have out there in the community. One population that we end up dealing with a lot, especially in critical care, but it also exists outside of critical care elsewhere in the hospital and sometimes out there in the community as well, are patients who are at the end of life. And so in those circumstances, we do accept the respiratory depression that goes along with it because they're having pain and anxiety and that opioid can actually be very helpful for them and give them peace.
Eduardo Mireles-Cabodevila, MD:
Thank you very much. Philippe?
Philippe Haouzi, MD:
Of course, the new approach is to try to avoid as much as possible the use of opiates for all the reasons we discussed but this is true also that a patient with cancer, for example, could benefit and some of them do benefit from the prescription of opioid.
Eduardo Mireles-Cabodevila, MD:
Mm-hmm.
Philippe Haouzi, MD:
End of life situations are also critical and opioids can bring a lot of comfort to the patient and the family. So, we have to remember that these are potent agents, with still some indication in some of our patients.
Eduardo Mireles-Cabodevila, MD:
Yeah, absolutely. I mean there's no doubt that it's a very efficient pain control mechanism for acute pain or chronic pain in certain populations. Perhaps the key message here is that they have certain side effects and we have to be aware of them, and this respiratory toxicity that we're talking about right now is something that we as a medical group have to be aware of how do we treat it? How do we go about it? So, thank you for highlighting that.
So we have gone through a lot of items and I really, really appreciate you highlighting this respiratory toxicity from opiates and how it applies, one, in the acute setting and also in the chronic setting. I mean, this is something that we have to be aware of as respiratory practitioners in general for our patients.
Any closing comments, Deb, that you would like our audience to know?
Deborah Rathz, MD:
As we talked about earlier, there's been a big shift in how we prescribe opiates and we're using them for short durations and trying to limit doses. But I think another takeaway is that chronic pain probably is not best managed with an opioid. There might be patients out there that have been on them for long periods of time, but there are programs to wean them off and use alternative therapies and so I think we really need to push for that in the community.
Eduardo Mireles-Cabodevila, MD:
I practiced in another country for some time in which opiates were not prescribed at all, and I believe Philippe, it was probably zero.
Philippe Haouzi, MD:
Europe is the last prescribed as much as in the US.
Eduardo Mireles-Cabodevila, MD:
And I mean, we have chronic pain, and, in both countries, and in other places and this just highlights the potential, I mean, that there has to be a balance between obviously under treating chronic pain, but over treating chronic pain with opiates. So thank you for highlighting that.
Philippe, any closing comments?
Philippe Haouzi, MD:
No, I think for chronic usage I think Deb has made the right point. Eventually we may resolve this problem by avoiding as much as possible the prescription of opioid and hopefully a next generation of analog education will be valuable in the new future which do not have the same effect. But even with the cure and medication we have by combining them we can certainly avoid as much as possible the use of opioid after a few days.
The, for an acute problem which is a very different issue, the use in the street, the 60,000 people dying from fentanyl and other opioid overdose, of course the problem may be more complex. Political issues, social issues, economical issues are involved, but for us, as physicians, we have also to remember that there are very little options beside naloxone at this point to treat someone who is unconscious with a life-threatening depression of breathing.
Eduardo Mireles-Cabodevila, MD:
Fantastic, so I want to thank you, Deb, and Philip, and thank you everyone for listening to our podcast today. Today we heard from Dr. Deborah Rathz and Dr. Philippe Howse. Doctor Rathz is a Critical Care and Emergency Medicine Specialist, she serves as the Director of the Medical Intensive Care Unit at Cleveland Clinic Hillcrest Hospital, and Doctor Philippe Haouzi is a Pulmonary and Critical Care Specialist who serves as the Director of the Pulmonary Function Laboratory for the Department of Pulmonary and Critical Care of the Integrated Hospital Care Institute at the Cleveland Clinic.
I'm your guest host Eduardo Mireles and I want to thank you both, and all the audience for listening to us on this fabulous topic. Thank you.
Raed Dweik:
Thank you for listening to this episode of the Respiratory Exchange Podcast. For more stories and information from the Cleveland Clinic Respiratory Institute you can follow me on Twitter at radeddweikmd.