Good day. My name is Christopher Winfrey. I'm going to be speaking with you today about an introduction to opioid pharmacology. My hope is that this talk is appropriate for neurosurgeons and gives you the information that you need to safely begin to use opioids in your neurosurgical practice. I have no disclosures and I'm past president of the AANS and CNS joint section on pain. Let's begin with a little bit of terminology so that we can share a common vocabulary when discussing the topic of opioids. So opiates are actually natural substances that are derived from opium, which is a substance that comes from the poppy. Opioids are any drug that interact with the opioid receptor within the human body. These include the naturally occurring opiates, includes the synthetic drugs, which are made in a lab, or the semi-synthetic ones, which are natural substances that are modified chemically, the enkephalins, and any receptor blockers, think naloxone, that can bind the opioid receptor and inhibit its function. To understand opioid pharmacology, we really need to understand the endogenous opioid receptor system. It's a diverse network of pathways throughout the nervous system and human body. It's very complex. Basically what you need to understand is that there are endogenous opioid ligands. These are the dynorphins, the enkephalins, the endorphins, and these bind to receptors within the opioid system. The receptors, the mu, the delta, the kappa, et cetera, these are inhibitory G-protein coupled receptors. They're all over the place. They're in the brain, the spinal cord, the peripheral nervous system, the digestive tract. When the opioids, whether it's the opiates or the synthetic opioids, when they bind to these receptors, they mimic the endogenous opioid activities. Your body produces ligands that interact with these receptors, and then you can be administered drugs, morphine, or any other drug that interacts with these receptors and that can mimic their function. Generally speaking, these ligands tend to be potent analgesics, and given the diversity of the connections of the endogenous system, there are a lot of side effects, GI effects, psychological effects, potential for abuse, which we'll discuss here shortly. Opioid receptors tend to reside on the presynaptic terminals at the location of a synapse. You can see here in the diagram. They tend to be inhibitory in nature, and activation of the opioid receptors tends to inhibit synaptic transmission. Some of the different opioid subtypes, the mu, the delta, and kappa, and the nociceptin receptors, each has a slightly different function. All of them can be related or can contribute to some analgesic effects. Bees tend to see that most with the mu receptor, and that can contribute to the euphoric side effects of the opioids. Delta tends to be analgesic. Kappa receptors tend to have a role in substance use disorders, and the nociceptin receptors tend to be relevant in the development and persistence of emotional behaviors. But again, these are generalizations, and these receptors tend to have far more complicated interactions than these simplified summaries here. These receptors are widely distorted throughout the body, and again, can have complex roles in pain, relaxation, social interactions, and many other roles as well. Let's now discuss the opioid receptor in a little bit of detail. It's fairly complicated, but keeping it simple for illustrative purposes, a ligand such as morphine will bind to the opioid receptor. This will then activate an intracellular G-protein, which will release some of its G-protein subunits. These then diffuse throughout the cell and exert different effects. One protein subunit will bind to the voltage-gated calcium channel. What this does is it inhibits that channel, and it lessens the amount of calcium influx into the presynaptic terminal. What calcium does is it enables the synaptic vesicle to bind and release their contents. So if the calcium influx is inhibited, it reduces synaptic transmission. Another G-protein subunit will bind to the rectifying potassium channel. This actually actively pumps potassium outside of the cell, thus hyperpolarizing the cell. So the cellular hyperpolarization, coupled with the reduction of calcium influx, has a net result of reducing synaptic transmission, thus exerting its inhibitory effect on the system. So the endogenous opioid system is pretty complicated, but a helpful way to think about it is to focus on one of the anti-pain pathways. The best way to think about this is you have the opioid pathways originating in the periaqueductal gray and the rostral pons areas. These project to the raphe nucleus, which is an adrenergic system. When the raphe nucleus is activated, it sends descending excitatory pathways, which will synapse onto inhibitory interneurons in the dorsal horn of the spinal cord. So a descending activating pathway will trigger a response in interneurons in the spinal cord that are inhibitory. So these inhibitory neurons will then converge on a portion of the dorsal horn, which represents an area that afferent sensory information, say pain information from the peripheral nerves, converges on the dorsal horn, and there's descending inhibitory influence from this opioid pathway. And then the net effect determines how much ascending pain information goes up. The more opioid activity there is, the less ascending nociceptive or painful information reaches the brain. And the net effect is as the opioid pathways activity goes up, the subjective experience of pain goes down, and the reverse is also true. So that's a sort of a simplified but fairly accurate model for at least how nociception or antinoception activity by opioids occurs in the brain and spinal cord. And again, here is a blown up view of the dorsal horn of the spinal cord demonstrating the primary afferent fiber coming into the dorsal horn. There's a synapse in the dorsal horn, and there's a descending presynaptic influence on that primary afferent fiber that's opioid mediated, and that decreases the amount of painful input that reaches the summation centers of the dorsal horn, which then sends up the afferent information or the painful information to the brain. So again, as opioid activity goes up, pain levels go down. It's important to keep in mind, though, that this fairly simplified model is just that it's a model for how the opioid system works. It's not the whole story. And if you look, there's a lot more effects that occur in the human body with opioid activity. And so you've got to understand, so from a neurosurgical standpoint, you can use these medications to treat pain, but there are a lot of other effects that occur in the human body. It's important to be mindful of that. So now that we have some sense of endogenous opioid systems and how they work, we can start to manipulate these with medications. So to understand opioid medications, you need to understand a little bit about where opioids and opiates come from. So the opium is a substance derived from the poppy, the plant of joy, something that's been known to humans for thousands and thousands of years. Humans have been deriving pain relief from this plant for millennia, and these substances are alkaloid toxins. And with processing, you can derive morphine from opium from the poppy. And morphine is the prototypical pain medication, which has, again, been around for basically the duration of human civilization. Morphine is an important pain medication, still in use today. It can be administered orally, intravenously, subcu, intramuscular, epidural, intrathecal. Basically almost any way you can give a drug, you can give morphine. Its peak plasma levels occur about 60 minutes after oral administration. It's important to note that it's liver metabolized, and if you do administer it orally, understand that there's first pass effects with oral dosing. Patients who have liver disease, got to worry about reducing the dose appropriately. And for neurosurgeons, it's good to understand that there's rapid CSF distribution, especially if you're giving intrathecal injections of morphine. It easily crosses the blood-brain barrier, and it can be a really effective pain medication for almost any neurosurgical need for pain relief in severe pain states. Morphine is incredibly effective. It's been around a long time. This is a picture of a Surrette, which are these little self-injectable syringes that soldiers could use in combat in World War II. And morphine's still in use today. Any complex, severe injuries or pain problems in hospitals and clinics today, morphine is one of the frontline medications used to treat any severe pain state. It's thought to be best for nociceptive pain or musculoskeletal pain, but it can still be used for neuropathic pain, especially when neuropathic pain is so severe that traditional neuropathic pain medications, such as the anticonvulsants and antidepressants, aren't working so well. Morphine is available in both short-acting and long-acting formulations, and it's pretty much readily available in every hospital and clinic as needed. So when morphine is administered, it has a number of different treatment effects, and these generally hold true for most of the opioids in use today. So when administered, the drugs produce pain relief. They alter function in both the medial and lateral pain pathways. If you recall, the lateral pain pathway involves the metatarsophageal cortex, and this is sort of the ability to localize the type of pain and the severity of pain. The medial pain pathway, in contrast though, mediates the affective component of pain. So not necessarily how severe the pain is, but how the pain affects one's emotional state. Not the fact that there's pain there, but how much does the pain bother a person. So the opioids not only reduce actual pain levels, but they can reduce a person's ability to be bothered by the pain. Morphine and other opioids tend to have no sealing effect. This is not true for all the opioids, as we'll see later. But basically what this means is you can keep giving more or higher doses of morphine, and you keep getting additional effects on top of it. There's no maximal effect that morphine has. The more you give, the more of a response you get. Some of the side effects include euphoria, dizziness, nausea, vomiting, sedation, constipation. And at the higher doses, you can actually get respiratory depression and even death. So these are clearly powerful medications, and it helps to have some sense of how to incorporate them into one's practice. So there's a framework for dosing opioids that was developed in the 1980s called the World Health Organization Treatment Ladder. It basically describes a clinical scenario where you gradually escalate up the potency and the dosing of your medications from weaker medications to stronger medications to address severe or worsening pain states. So basically, at the bottom rungs, you use non-opioid medications to treat pain that's not particularly severe. And as the patient has either worsening pain or has pain that's just worse, that's not responding to the less powerful medications, you increase the potency of the medications and the dosing of the medications, say, to a mild opioid to address pain in the intermediate levels. And if that's ineffective, you escalate up to higher doses of even stronger, more potent opioids. And you do that and escalate up as high as you need to get adequate pain control or until you reach undesirable side effects. And this is generally true for treating acute pain. It's been generalized to treat chronic pain. But basically, it's a strategy where you start with the weak medications and you escalate up to the stronger medications as needed to achieve the desired analgesic effect. So from a practical standpoint, the bottom rungs of the opioids, at least, will include the weak opioids such as codeine or Tylenol-3, tramadol, and hydrocodone such as Norco or Vicodin. The middle rungs will include things like morphine. And there's the short and long-acting versions of that. Oxycodone is an example of an intermediate sort of opioid, not quite as strong as morphine. In the top rung, you have the strongest synthetic and semi-synthetic opioids such as hydromorphone or Dilaudid and fentanyl. So we discussed some of the side effects of acute administration of opioids. Opioids can have a lot of long-term effects too, which is important to keep in mind if you're going to be utilizing these medications in practice. Opioids are associated with dependence. Dependence is the need for increasing levels of drug to achieve the same therapeutic response. So if you take a single dose of an opioid for a number of weeks or months for a particular type of pain, your patient may find that they need to take more and more of the drug to get the same pain relief the longer they take the medication. And this is a physiologic adaptation to dosing of the medication. You have an alteration of the regulation of the receptors such that to get the same pharmacologic response, you need more drug. You can also see with chronic administration of opioids, decreased libido, change in hormones. You can add high doses of medication for a very long period of time, generally seen with chronic pain patients, something called opioid-induced hyperalgesia. This is an unfortunate circumstance where patients, despite increasing doses of very high levels of opioid medication, their pain just gets worse and worse and worse. And that's a tough situation to be in, and that's not something you really want to find yourselves in as neurosurgeons. And generally, with short-term administration of the drugs, it's not really something that happens. And then lastly, be mindful that these drugs can cause addiction, also known as a substance use disorder. This is different than dependence. Dependence is just a physiologic need for more medication. Addiction is actually a psychological or psychiatric disorder where a person craves the medication and where the person uses different sort of drug-seeking behaviors to acquire the medication, lying, cheating, stealing, that sort of thing. And that's in the realm of the psychiatrist, but it's something to be aware of, and it's something you definitely don't want to mess around with as a neurosurgeon. If you suspect your patient has any sort of addiction or substance use disorders, you really need to involve a mental health professional at that point. That's not something you should be managing yourselves as neurosurgeons. So one of the key things to know about opioids is they can get you high. And so it's nice to understand a little bit about the physiology of that. And so basically, a really basic sort of model for this is that when you inject morphine, for example, that morphine binds the mu opioid receptors in the nucleus accumbens in the brain. This decreases GABA release in that nucleus. That decrease will then increase dopamine release. It's the dopamine that then results in a euphoric feeling. Dopamine is what happens when you get a text message or an email or some response from another human being. It triggers this pleasure-reward kind of response in your brain. That's dopamine-mediated. And so what morphine does is it triggers the release of a lot more dopamine than you'll ever get from a text message. But it's that same kind of euphoria, just a thousand-fold greater. And it's that euphoria which patients crave. And over time, they will do anything to get that euphoria again and again and again. And that's the physiologic basis of getting high. The potency of a medication refers to the amount of medication required to produce an effect. In the case of pain, maybe reducing pain by three points on the visual-analog scale, for example. Different opioids have different potencies. Morphine is the standard by which all other opioids are measured. Heroin, for example, is twice as potent as morphine. Fentanyl, on the other hand, a synthetic opioid, way more powerful. It's 100 times more potent than morphine. It's important to keep this in mind, especially when viewing, not only dosing these medications as a physician, but looking at this in terms of the opioid crisis, where patients are basically dying, overdosing, using these synthetic, very powerful medications where only tiny amounts, milligrams of these medications can actually kill people. So it's important to be aware that different opioid medications have different potencies, and they can vary dramatically in their potency. The potency of fentanyl in particular was made painfully obvious in recent years with the opioid crisis. If you look at the first graph, you see a steady increase in opioid overdose deaths in the U.S., largely attributable to heroin. And as soon as fentanyl, or synthetic fentanyl, hit the market in the mid-2000s, you see this ramping up, this rapid escalation of opioid deaths directly as a result of that. And if you break down these opioid overdose deaths into deaths from each particular type of substance, that's in the second graph. The black line shows the deaths from the synthetic opioids, which again held pretty level for the first few years, and then mid-2000s just skyrocketed as those drugs hit the street. So again, these increased deaths are really due to the dramatic increase in the potency of the available drug to these people taking them on the street. Let's talk a little bit now about opioid antagonists. These are powerful tools which you may come across as a neurosurgeon, and it's helpful to have a little bit of an understanding of them. Naloxone is the first one you should know about. It's a competitive opioid receptor antagonist, which means it reversibly binds to the opioid receptors. It typically binds mu-receptors, and it displaces whatever opioid is at the receptor. So if you think about this, if a person has a morphine or heroin overdose, that drug is binding to the mu-receptors. You can give naloxone, and you bounce out those opioids from the receptors, and it reverses the effects of the opioid pretty much immediately. This is a way of effectively treating opioid overdoses, and it can save lives. Naloxone is typically effective within two minutes when given intravenously, so it's quick, and it's effective within five minutes when given intramuscularly, which is typically how you'd give it to someone emergently on the street, say a first responder or a bystander seeing someone with an opioid overdose. You can save their life. Note, however, that naloxone has a fairly short half-life, and when you dose it, it's only effective for anywhere from 30 to 60 minutes, whereas most opioids, especially ones you'd take on the street, can last longer than that. So naloxone may need to be re-administered to prevent opioid re-overdose. So again, if you're in a situation either in the clinic, the hospital, or on the street where you're able to give naloxone to reverse someone's opioid overdose, that person's got to be monitored because they can easily relapse. Also note that if you give naloxone to an opioid-dependent person who's been on opioids for weeks or months or years, you can immediately precipitate withdrawal symptoms because that naloxone will displace the opioid that's at their endogenous receptors and put them right into withdrawal. So that's a very cruel thing to do if you don't have to give them naloxone. Buprenorphine is an interesting medication. It's an opioid agonist and an antagonist. It's a semi-synthetic opioid. It binds to the opioid receptors. It has a little bit different effects than a simple blocker like naloxone. It's FDA-approved as both a pain medication and as a treatment for opioid dependence and addiction. So what's interesting is it actually binds to the mu receptor and it activates it. So it's an agonist. But it only works to a certain point. There's a sealing effect. Unlike morphine, which has no sealing effect, the more morphine you take, the more of an effect it has, buprenorphine is limited in how much effect it has on the mu receptor. It also antagonizes the kappa and delta receptors. So you get this sort of competing sort of anti-opioid effect as well. And this is an interesting set of properties because you can use buprenorphine as a substitution treatment for people who are either addicted or dependent on opioids. So when administered, the mu effect, the mu agonism, helps treat pain and it prevents opioid withdrawal. But since there's a limit to how potent this medication is, you don't get the intense high associated with stronger opioids and you don't get an additional effect by breaking the medication down and injecting it intravenously, which some people do when they try to abuse a medication. So if you utilize buprenorphine, especially if you mix it with naloxone, which again will provide this inhibition of the opioid system so that if you inject it or try to abuse it, you get a counterbalancing of the opioid effect. So you get this opioid effect which can treat the pain and you also have this anti-opioid blocking effect which really limits how much of an opioid effect you get from the medication. It can be a great treatment that's basically abuse-proof to the extent that anything can be abuse-proof, that you can put patients on, it gives them some pain relief, it prevents them from going to withdrawal, it allows you to stop the other opioid medication, it allows you to taper the buprenorphine down gradually and actually get them off of opioids over a period of time and you can do it fairly safely. Sounds like a great medication and it is in certain settings. The problem is if you have a patient of yours that you're going to operate on who is also on buprenorphine, that can be a real problem if you're trying to manage their pain postoperatively. Because remember, buprenorphine, and if they're on suboxone with the naloxone, they've got these opioid receptor blockers on board. And so if you then operate on that patient and you need to treat their pain postoperatively, you're going to have a really difficult time doing that because if the patient wakes up from, say, a spinal operation and they have pain and you try to treat that with morphine or Percocet or whatever else, that medication is not going to have the same effect as it would if they were not on buprenorphine because those opioids that you're giving to treat their pain are going to get blocked. So the recommendation is if you can for elective surgery, you try to get them off the buprenorphine before you operate on them. And if in an emergency setting there's nothing you can do about it, then there's nothing you can do about it. But these patients can be a real problem to treat and they can go through a lot of suffering if they're taking buprenorphine and they have a new postoperative pain to deal with. So be mindful of that. And our recommendation generally is involve your pain colleagues when managing these patients because it can get real complicated really fast if you try to do this yourself as a neurosurgeon. So in summary, we reviewed a number of different elements of opioid pharmacology. We discussed the endogenous opioid system. We talked about some of the natural opiates such as morphine, some of the synthetic opioids and the differences in their relative potencies. We talked about indications for opioid administration, some of the side effects, some of the short-term and long-term side effects, and we discussed the role of opioid blockers in clinical use. And so some of our subsequent talks will then discuss in greater detail how to incorporate opioids into your neurosurgical practice and some of the regulatory framework around their use in the United States today. So thank you for your attention and good luck.

opioid pharmacology

neurosurgeons

morphine administration

synthetic opioids

risks

naloxone