Hello, my name is Julie Kmik, and I'm an addiction psychiatrist within the Department of Psychiatry here at University of Pittsburgh. I work primarily in our outpatient clinics for addiction, working at our buprenorphine and methadone clinics, as well as our outpatient bridge program and ambulatory detox program. I also spend some time at Mercy Hospital on our inpatient detoxification unit, too. Today I'm going to be talking to you about prescribing naloxone to patients for overdose reversal. So I have no financial disclosures or conflicts of interest. I just want to say that I'm going to be talking about intranasal use of naloxone solution 1mg per 1mL, which is an off-label use of this product. So the objectives for today's lecture are to discuss how the opioid prescribing epidemic is associated with the overdose epidemic, discuss opioid overdose risk factors, describe the basic pharmacology of naloxone, describe studies demonstrating the efficacy of naloxone in bystander overdose, and to name the four different forms of naloxone that are available for bystander reversal of overdose, and to discuss how to prescribe naloxone. So this is just another overview here of how this lecture is going to be going. First we're going to talk about the opioid epidemic. So from 1999 to 2008, the number of opioids prescribed in the United States quadrupled. And this was kind of a perfect storm. There were all these different things that were happening at the same time that resulted in this quadrupling of the opioid prescriptions. First was there was a consensus statement from the American Pain Society and the American Academy of Pain Medicine in 1997. And what they said in this consensus statement is that there's little risk of addiction and overdose in pain patients. And what they based this on was this letter to the editor in the New England Journal. And what it said was fewer than 1% of patients become addicted to opioids. And so this is just like a very short letter to the editor. And we're going to look at it in one of the coming slides. But this was recited several times that people who have pain don't get addicted to opioids. And the other thing that was happening at that time was that there was a greater emphasis in assessing and treating pain. So the Joint Commission said that you need to assess pain and treat pain adequately. And the American Pain Society and the VA said pain should be thought of as the fifth vital sign. At the same time, Purdue Pharma introduced OxyContin. And they said it was a safe and effective medication. And they funded greater than 20,000 educational programs on pain for physicians. And they encouraged long-term opioids for pain. And they supported professional societies, the Federation of State Medical Boards, and the Joint Commission. And so you can see this conflict of interest there. And you might have heard about these lawsuits against Purdue as far as their part in the opioid epidemic. OK, what you can see here is that letter to the editor by Porter and Chip. And you can see that it's very short, probably less than 100 words. And what they did is they talked about patients who were admitted to the hospital and if they received one narcotic preparation during their time in the hospital. And of those 11,882, there were only four cases of reasonably well-documented addiction in patients who had no history of addiction. And then they said that the addiction was considered major in only one instance. And so they put on the last sentence there, the development of addiction is rare in medical patients with no history of addiction. So this was a study that was published in the New England Journal in 2017. And what they looked at were how many times the Porter and Chip editorial were cited after it was published. And on this graph, you have other are the white in the bars, negational mentions and studies were in the kind of light blue-green, and then affirmational mentions are in the darker green. And so in the 1980s, there were a lot more affirmational, same with the 1990s. And then it started downtrending in the early 2000s. And there were a total of 608 citations and 72% of 439 cited addiction as rare when they were citing the article. And almost 81% did not cite that the patients were hospitalized and given opiates, so that they didn't have control of the opiates on their own outside of the hospital. So let's talk about people who are prescribed opioids and how many misuse them or develop an opioid use disorder. So roughly 21% to 29% of patients prescribed opioids for chronic pain misuse them. And then between 8% and 12% develop an opioid use disorder. So you could still misuse pain pills, but not actually develop an opioid use disorder. And an estimated 4% to 6% who misuse prescription opioids transition to heroin. And about 80% of people who use heroin first misuse prescription opioids. Now that is changing a bit nowadays, since the prescriptions of opioids have gone down. There are more people who are starting out using heroin or fentanyl. So this is an interesting slide here showing the opioid of first use, basically. So what you can see, looking back to 2005, is that oxycodone and hydrocodone were the most frequently used opioids to start off with. And back then, heroin, only about 10% started using opiates with heroin, or other prescription opiates with less than 10%. And over the years, you see that heroin started creeping up. It looks like that ascent starts around 2010, and then it slowly creeps up. And then there's a really big upswing from 2014 to 2015. At the same time, the number of people who were starting using opiates using oxycodone or hydrocodone was going down. And you see that heroin crossed those two lines. And more people in 2015 started using heroin as their first opiate versus oxycodone or hydrocodone. Now, the significance on this graph shows that there was a significant change for heroin, hydrocodone, and other prescription opioids, but not oxycodone, even though it did go down a little bit there. So let's shift gears and talk about the overdose epidemic. From 2000 to 2014, there was a 200% increase in deaths involving opioids. And opioid overdoses increased 30% from July 2016 through September 2017 in 52 areas and 45 states. So that's a pretty big increase. So let's look at the national drug overdose deaths. These data are from NIDA and the CDC. And what you see here is from 1999 till 2018, the number of drug overdose deaths. And they increased substantially from 1999 up until 2017. And you see in 2017, that's when we had the most drug overdose deaths, more than 70,000 in one year. And this could be an overdose from any substance. So it could have been from heroin, fentanyl. It could have been from cocaine, methamphetamine, benzodiazepines, et cetera. So these were all the drug-involved poisonings. Luckily, or thankfully, we had this decrease of almost 3,000 deaths in 2018. And that could have been from some of the measures that we've been taking to enhance treatment and make treatment more widely available, as well as harm reduction approaches, such as distributing naloxone to people who are at risk or may know somebody who's at risk for having an overdose. So these, again, are data from the CDC and NIDA. And what you're finding here are the national drug overdose deaths involving any opioid. So looking from 1999 till 2018. And you can see that they steadily increased, and there was a kind of sharp spike there from 2015 up till 2017-18. And that's attributed to fentanyl being in the drug supply. One of the other interesting things here is to look at the gender. Females, there are fewer overdose deaths involving women versus men. You can see the spike in deaths of males. However, the number of women who are dying from overdose has been steadily increasing over the years. And this is looking at the drug overdose deaths involving prescription opioids. So you can see here that it was kind of a steady climb in the 2000s. And then we've been around the same, or within 3,000 deaths, from 2010 until 2018. And if you remember that last slide where it was looking at any opioid, there were about 47,000 deaths from opioids. And on this graph, in 2017, there were 17,000 deaths from prescription opioids. So that accounts for a smaller proportion of the deaths. And this is where you're going to see a big change. So looking back at 1999 up until around 2010, we had a pretty steady number of people who were dying from overdoses with heroin. And then it starts climbing. And you see it's kind of peaking around 2016-17. And it went down a little bit in 2018. The two lines within these bars show heroin without other synthetic narcotics, for the light yellow, and heroin with other synthetic narcotics. So what they're talking about is fentanyl. And so you can see this spike happening. The number of deaths involving synthetic narcotics starts rising in 2014, 15, 16, 17. And so a lot of the heroin supply was adulterated with fentanyl or replaced with fentanyl. And so you can see those number of deaths increasing there. And then the number of deaths that didn't involve any kind of synthetic narcotics started decreasing in 2016. So let's talk about overdose risk factors. So there's a lot of different data out there. But generally, it seems that using more than 50 milligrams of oral morphine equivalents daily puts one at an increased risk of having an overdose. There are some data out there that says greater than 20, 25, and then some that says greater than 100. The other factors would be recent release from a controlled environment. So that could be from being incarcerated. So if somebody gets out of the Allegheny County Jail, hasn't been using for weeks or months, and then they get out and then they start using again, especially if they're using the same amount, that puts them at an increased risk of having an overdose. The other thing you can think about is a treatment environment. So somebody might go to a 28-day residential rehab facility and they go through a detoxification process and then leave the facility and then start using shortly thereafter. That's an increased overdose risk. Or it might be patients that go into the hospital for whatever reason. Maybe they go to a psychiatric hospital for depression and they get a withdrawal management protocol there. Or maybe they go to the medical floor because they have endocarditis and so they're in treatment for a good amount of time getting IV antibiotics and then they get discharged and they're at increased risk because their tolerance went down. Other risk factors include mixing opioids with benzos, so benzodiazepines, alcohol and other drugs, so cocaine, methamphetamine. Those all would be other risk factors. Medical conditions, so if somebody has any kind of kidney problems, hepatic problems, pulmonary disease, HIV, cardiac disease, all of these things put somebody at an increased risk of having an overdose. So how does an overdose happen? First we have to understand a little bit more about respiration. So respiration is principally controlled by the medullary respiratory center with peripheral input from the chemoreceptors. And so your respiration is controlled from the dorsal respiratory group, which probably produces breathing rhythm and has an influence on the ventral respiratory group, which has efferent fibers that innervate the muscles of respiration. So respiration involves both phasic activation, so you're going to have your excitatory amino acids like glutamate involved, as well as there's some inhibition, so GABA-mediated inhibition. And GABA receptors, both A and B, have high density in the dorsal respiratory group as well as the ventral respiratory group. And those chemoreceptors I mentioned earlier are located in the carotid and aortic bodies and they respond to changes in blood gases, they're stimulated by decreases in oxygen, and also, but to a lesser extent, by increase in CO2 and a decrease in pH. So what happens when somebody uses an opioid is that opioids can modulate respiration, depress respiration through the reduction of glutamate-induced excitation. And the agonist activity at the medullary, mu, or delta receptors causes respiratory depression. So you're getting respiratory depression through both the reduction in the glutamate-induced excitation as well as agonist activity at the medullary, mu, and delta receptors. So the agonist activity at the kappa receptor, and this is also an opioid receptor, has either no effect on respiration or could stimulate respiration slightly. So that's not as much of a factor. And then you have those chemoreceptors at the carotid and aortic bodies. And remember that inhibition is mediated by mu opioid receptor binding and it results in a decreased sensitivity to changes in oxygenation and CO2. Particularly, they respond to increased CO2. So remember I had mentioned that both glutamate and GABA can be involved in overdoses? Well, glutamate and GABA mediate the control of respiration, and that can explain the contribution of benzodiazepines and alcohol to overdoses. So benzodiazepine and alcohol facilitate the inhibitory effect of GABA at the GABA-A receptors, and alcohol decreases the excitatory effect of glutamate at the NMDA-A receptors. In addition, there could be individual differences based on the individual's metabolism. So how well they're able to perform glucuronidation or their levels of cytochrome P453A4 and 2D6, because a lot of opioids go through these two isoenzymes. Overdose may occur when there's a loss of tolerance at either the cellular and or the pharmacokinetic level. And somebody who has a high tolerance could increase their risk of having an overdose because they have to use higher doses in order to get an effect. And at some level, you use higher and higher amounts, and you're going to have more and more respiratory suppression. The other thing to remember is that pulmonary edema could be a consequence of overdose, and that could contribute to the death as well. So during an overdose, there's decreased oxygenation of the brain and the heart, and the person becomes unresponsive. They may appear anoxic and cyanotic, and then eventually they die if they don't have any kind of intervention. Respiratory depression can last for one to three hours, but it is reversible with naloxone. So let's go over some possible complications of nonfatal overdoses. Some people who were down for a long period of time may have anoxic brain injury, pulmonary edema, acute respiratory distress syndrome, hypothermia, renal failure, compartment syndrome, liver failure, and some people have a seizure. So let's talk about how naloxone works. Naloxone is an opioid antagonist, and it has a very high affinity for the mu opioid receptor, and it's going to displace found agonist and prevent other agonists from binding. It can work within minutes, and its effects last 20 to 90 minutes. It has been FDA approved for intravenous, subcutaneous, intramuscular, and intranasal use. And it's been used for opioid reversal for 40 years or more in hospitals, and it's been used for overdoses in the emergency department and by paramedics for years. And since the mid-1990s, it's been provided outside of medical settings for people who are at risk of having an overdose or know somebody who's at risk of having an overdose. So here are some of the possible adverse effects of naloxone. The most important thing is that if it's administered in its usual dose to somebody who wasn't using opioids, so say you found somebody down on the street and you thought, oh, maybe this person is having an overdose, they're not breathing very much, their lips are blue, I'm going to give them some naloxone, and it wasn't, they weren't down from an overdose, it's not going to cause them any harm. It is often used to rule out an opioid overdose. So if you do find somebody down and you give them naloxone and they don't respond, then you know, okay, well, it probably wasn't an opioid overdose at that time. The other kind of adverse effects that somebody might have are tachycardia, hypertension, hypotension, seizure, that could be due to being anoxic, nausea and vomiting, diaphoresis. They could have other opioid withdrawal symptoms. A lot of those things that I mentioned there, the nausea and vomiting and the diaphoresis, those are symptoms of opioid withdrawal. And there were some severe symptoms that were listed in the prescribing information that were seen post-operatively, and they haven't been seen in the field when people are using this for overdose reversal. So I'd like to talk about some data for the efficacy of naloxone. And this first study that I'm going to talk about is looking at naloxone intramuscularly versus intranasal naloxone. And this study was published back in 2009, and they used concentrated naloxone, so it was 2 milligrams per 1 ml, either intramuscularly or intranasally, and it was a randomized controlled open-label trial. So the paramedics were administering this to people that they found down, and they did this in a randomized fashion. And they had 172 patients who had a suspected overdose that were treated by EMS, and 83 of them received 1 milligram per 0.5 ml of naloxone in each nostril, and 89% received 2 milligrams per 1 ml intramuscularly. And so 129 of those people who got the naloxone had an adequate response within 10 minutes, and there wasn't a difference between the groups. You see that 72% in the intranasal group had that response within 10 minutes. And there wasn't a difference between the groups. You see that 72% in the intranasal group had that response within 10 minutes and 77.5% in the intramuscular group had a response within 10 minutes. The adverse events were similar between the groups and the mean response time was similar between the groups. It was about eight minutes after they were administered the naloxone. So I just wanna go over this table and point out a few things from these studies that are listed. So this first study, Merlin et al, it was an urban setting and they had 277 patients who received naloxone by paramedics. And it was a retrospective study. They reviewed the charts and they wanted to determine if intranasal naloxone was non-inferior to intravenous naloxone. And what they did find was that intranasal naloxone was non-inferior to the intravenous route at reversing the effects of an opioid overdose in terms of the Glasgow Coma Scale and the respiratory rate. But 42% of the intranasal naloxone recipients required redosing compared with 20% of those who received it intravenously. And this Barton study published in 2005, done in Denver, Colorado, they had 95 participants and they were adult patients in the pre-hospital setting, so out in the field, who had a suspected opioid overdose. They were found down with or with altered mental status and they received intranasal naloxone. So this was a prospective cohort study. And they wanted to see if intranasal naloxone was effective for suspected overdose in pre-hospital settings. And they found that 83% of the patients who responded to naloxone responded to the intranasal and didn't require intravenous. And then this last study here was done in Oslo, Norway, published in 2004, and there were almost 1,200 patients. And the patients received naloxone by paramedics for heroin overdose. And this was a prospective observational study. And what they wanted to do was determine the frequencies and characteristics of adverse events related to out-of-hospital administration of naloxone by paramedics. And they conducted the study over a one-year period. And what they looked at here were some adverse events, and people are often concerned about this. 32% had some confusion, 22% had headache, 9% had nausea and vomiting, 8% with aggressiveness, 6% with tachycardia. And there were only three cases, or 0.3%, who had serious adverse events from naloxone that required a hospitalization. And this table is a compilation of some studies that talk about administration of naloxone in a community setting by a non-medical personnel. And so what you can see here are some studies where they had police officers who were trained to administer naloxone. And in this first study, this Rando and colleagues, you see that the number of overdose deaths decreased by 4.1 individuals per quarter in contrast to their pre-programmed quarterly increase by 1.5 deaths. So getting police officers involved to respond to overdoses was helpful. It looked helpful in this study. And in the Rho and colleagues study, the second one listed, these are for people who were given naloxone at a harm reduction program. And when they asked them, when they came to get a refill, what happened in terms of the overdose or how they used the naloxone, and then did the person survive, greater than 90% reported that they used heroin. And that was what resulted in the overdose. And they called EMS in about 27% of the cases. In this Quannister and colleagues study, they had people who were given naloxone in the community. And then they asked them about that experience. And they had 30 administrations and 100% were successful, meaning they reversed the overdose and 40% of the overdose responded within two minutes and another 40% within two to five minutes. So that's a lot faster than what was in that curve study that we talked about a couple of slides back. And four treated individuals were reportedly angry due to withdrawal, but there weren't any other issues. And then two thirds of the people who witnessed overdose called EMS. And lastly, we'll talk about this last study here. They gave 0.4 milliliters in each nostril via an atomizer, and then they repeated times one. So the total dose was two milligrams per one ml. And they had 277 administrations. And out of that 265 of those individuals survived. So that's 96%. And the doses were titrated and 24% of participants reported using all of the doses available. 73% used two doses or fewer, while 27% used the whole two milliliters and one used four milliliters. So and then it listed, you know, what kind of symptoms they had. And so the most common was confusion with 27%, 11% were angry. Then you have the nausea, vomiting, feeling tired, shock. And then there were some other adverse symptoms. And looking at how many called EMS, well, about two thirds called EMS when they witnessed an overdose. And they found that 84% of the naloxone were used for heroin overdoses. So we talked a lot about heroin and naloxone and overdoses, but what about fentanyl? Fentanyl has a really strong binding affinity to the mu opioid receptor than other opioids and naloxone. So when we look at the inhibitory constant, which is a proxy for the binding affinity, what you find is that fentanyl is 0.7 to 1.9, whereas naloxone is one to three. And so there's a little bit of overlap there, but you might have fentanyl that has a stronger binding affinity than naloxone. And that could be dangerous when you want to reverse an overdose. The other thing is that fentanyl is very highly lipophilic and it'll rapidly equilibrate between the plasma and the CSF. And so that results in a fast onset of analgesia, but it's also respiratory depression. And it can be extensively redistributed to less highly perfused tissues. And so typically it's considered very short acting when it's given IV. And, or if somebody had some other formulation that's pharmaceutical grade fentanyl, if they were given a patch, for example, the fentanyl patch, once they take it off, it's gonna leave their system pretty quickly, but the fentanyl that's illicitly manufactured and distributed in the street seems to not follow these kind of pharmacokinetics that pharmaceutical grade does. The other thing to keep in mind is that large doses of fentanyl can prolong the duration of action due to being highly distributed into the tissue. So this leads to the question, do you need to administer more naloxone with somebody who's overdosing on fentanyl? Well, this one review article talked about a study that was done. And in 2015, almost one fifth of patients receiving naloxone from EMS required more than one dose. And that was higher than in 2011, where only one in six required more than one dose of naloxone. And that coincides with the increase of fentanyl in the U.S. heroin supply. And I just wanted to show you on this graph about the number of overdose deaths and what they contained. And you might recall from those earlier graphs that we looked at that the spike in synthetic narcotics, mainly fentanyl, started out around 2013, 14, and then goes up very rapidly. So that study that they were talking about, they looked at 2012, and then they looked at 2015. So that was how it coincided. In 2012, it was mostly heroin overdoses, prescription opioid overdoses. Whereas in 2015, you have people, more and more overdoses from fentanyl. Okay, so some researchers at Columbia wanted to answer this question too. Do you need more naloxone with fentanyl exposure? So what they did is they looked at data from their other studies that they'd been doing. And in these studies, they usually want people who are using heroin or fentanyl, any kind of opioid, to enroll in their studies. And often what they do in these studies is they have to administer a naloxone challenge to determine if the person is physically dependent on opioids. And so they have these data that they reviewed. And they had 29 intramuscular naloxone challenges that they analyzed. What a naloxone challenge is, is you have somebody come into the clinic or to the research lab, and you assess them for withdrawal at 0.1. And they did this using the CAWS scale, which is the Clinical Opioid Withdrawal Scale. And so you can see on this graph here that they didn't really have much withdrawal at the beginning when they got assessed. And then what they did is they gave both groups an injection of 0.2 milligrams of naloxone intramuscularly. In their subjects, they had divided into these two groups. One group was a group of people who were using fentanyl, and they determined that based on their urine drug testing. So their urine drug test said specifically that they used fentanyl, whereas the other group didn't have fentanyl-positive urines. They had opiate-positive urine, so they used heroin. But they didn't have any fentanyl mixed into their heroin. So they wanted to do these challenges for each group, and then see how severe their withdrawal was. And so they had 15 people in the group that was using fentanyl, and 14 in the group that was using heroin. And then at 10 minutes, they measured them for withdrawal again using that CAWS scale. And if needed, they would give them another 0.2 milligrams of naloxone if they didn't have any kind of withdrawal. But you can see on this graph here that from before they got naloxone, they went from less than five here to a withdrawal scale of around 10 or more for both groups. And there wasn't a significant difference between the two groups here. And then at 20 minutes, what they did is they assessed them for withdrawal again. And then if they still had that high withdrawal, they would do what was called a morphine rescue. And what that is is giving them a dose of morphine to treat the withdrawal. Because if you're in opioid withdrawal, to suppress it, you give somebody an opioid. And in this study, their protocol was to use morphine. Now that's not something that you can do for treatment on an outpatient basis or in the hospital trying to suppress withdrawal using an opiate other than buprenorphine or methadone. And that'll be a topic for other lectures. So what happens if somebody refuses medical treatment after they're given naloxone? So say somebody's at home, they have an overdose, and then their friend or relative gives them naloxone and calls 911, paramedics come, the patient says, no, I don't wanna go to the hospital, I'm fine now. There's no need to go. So what happens to those individuals? Well, there was a retrospective review of data from the San Diego EMS system, as well as the medical examiner's database in San Diego. And so they looked at the paramedic data and they found who received naloxone and signed an AMA form. So they signed a form saying, no, I'm not going to the hospital. And there were close to 1,000 people. And then they looked at the medical examiner's data and they asked who died of a heroin overdose, and there were 601 people. And they cross-referenced those lists and nobody who was released AMA died of an overdose within that 12 hours. So it seems like it is, in that case, people did okay after they received naloxone and even if they didn't go to the hospital. That's not to say that people shouldn't go and get an evaluation, because sometimes if you're using a long-acting opioid, once the naloxone wears off, remember it was only 20 to 90 minutes, then they could have another overdose event. A number of other studies have wondered, okay, well, how long should somebody be observed in the emergency department? And this retrospective study, which was conducted looking at data from 2009 to 2014, looked at people who presented to the ED for a heroin overdose after they received naloxone. And they wanted to determine the safety of a two-hour observation period. And of the 806 patients who were seen in the ED, after two hours, almost 4% received additional naloxone and 2% received oxygen. The intervention rates at two hours was 4.6, three hours was 1.9, four hours was 0.9. So you see with longer hospital stay or emergency department stay, the intervention rate decreased. And the authors favored a three-hour observation period, especially if the patient was using multiple substances. They found some differences with the people who were using more than one substance and having these kind of need for supplemental O2 or additional doses of naloxone. So this study is a prospective study of St. Paul's early discharge rule. And what that rule says is that you can discharge somebody who had an opiate overdose and received naloxone one hour later if they have a normal O2 saturation, normal respiratory rate, temperature, heart rate, and Glasgow Coma Scale. And in the study, they had 538 patients who received at least one dose of pre-hospital naloxone. And of those 538, 82 or 15.4% had adverse events. And what they defined as an adverse event were repeat naloxone, supplemental oxygen, assisted ventilation, et cetera. They also considered death an adverse event, but there were no deaths within the 48 hours of them coming to the ED. The rule failed to predict adverse events in 13 of the people, so that was 2.4%. And only one patient with a normal one-hour evaluation received additional naloxone. So what the authors concluded in this study was that applying the rule when there's low suspicion of adverse events is reasonable. And they say that you should be cautious in the case of somebody who's using oral opioids or a mixed overdose, so people who are using several substances at once. And the reason they said oral opioids is because it's going to have a long, the onset of action is longer, and the oral opioids may outlast the naloxone that somebody is given. Now I wanna shift gears a little bit and talk about something that I frequently am asked, and it is, does providing naloxone result in increased or more risky substance use? So sometimes people in the community are afraid of naloxone being distributed to people who use drugs because they're afraid that it's gonna encourage them to use more. They feel like, oh, I have a safety net, so now I can engage in more risky drug use behavior. I could use more fentanyl than I would normally because I got this naloxone. I know that some lawmakers were against naloxone as a harm reduction strategy because of these kind of beliefs. And some patients too worry about that, or their family members worry that, okay, if they have this naloxone at home, are they just gonna use more? So this study wanted to answer that question, and it compared the quantity of heroin use, and so often people tell you how many bags per day they're using. The frequency of polysubstance use, and this is the number of days, the mean number of days in the past 30 days. And then also this Addiction Severity Index drug composite score. And what the ASI is, is an indicator of impairment from drug use. And they looked at these measures at baseline, one in three months after providing overdose education and naloxone. And so when somebody gets overdose education, they're educated about the risk factors of overdose, and they're taught how to administer naloxone, they're taught what else to do when somebody is overdosing, like call the paramedics, perform rescue breathing, and stay with the person. And then they're given a take-home kit of naloxone. So here are the results from that study. We have the three outcome measures in graph form. And the first one is the number of bags of heroin use per day. Now they put on here two groups of individuals. The black circles are people who are using heroin. And then those black squares are people who are on an opiate maintenance program, meaning buprenorphine or methadone. And so just to start off, looking at the number of bags per day that people were using, they were significantly different when somebody was on an opioid maintenance program, so methadone or buprenorphine, compared to people who were not in treatment at one of these programs and using solely heroin. But what you see over time is that there wasn't an increase in the number of bags per day. In fact, it decreased a little bit. And you can see that there's a significant difference from a baseline to three months in the heroin group. And then the next outcome measure was previous 30-day poly drug use. So using more than one substance, because that does put people at an increased risk of having an overdose. And you can see here that all three groups, they went down from baseline to three months, so that high-risk or higher-risk behavior decreased over time after they had their naloxone training. And then this addiction severity index drug composite score, so the severity of their impairment from addiction, it stayed about the same for the people who were on opioid maintenance treatments, so people on methadone or buprenorphine, those black boxes. And for people who were on using heroin, it went down slightly from baseline to three months. And you can see there was a significant difference there. So if anything, providing naloxone in the overdose education did not increase people's substance use or make them engage in more risky substance use behaviors. So let's talk about overdose prevention programs. Opioid overdose prevention programs were started in 1996. The first one was a harm reduction program in Chicago. And what they do is they train people who are at risk for having an overdose in how to prevent overdose, as well as how to recognize and respond to an overdose. So the participants are trained to seek help, so they call 911, they do rescue breathing, they administer the naloxone, and they stay with the person who's overdosed until help has arrived. So these are some data looking at the number of overdose prevention programs and how they've grown from 2010 to 2014. So you see the number of sites providing naloxone, there was a 243% increase in the number of sites. Number of persons provided kits, that increased by 187% over those four years. Number of reversals reported, that increased by 160%, and the number of states with an overdose prevention program increased by 94%. So let's talk about this study that was done in Massachusetts. And what they did is they started overdose prevention programs, and they looked at the data between 2006 and 2009. And overall, there were 4,857 people who were enrolled in opioid overdose prevention programs, and 545 naloxone rescue attempts were reported. When they looked at certain communities out of this study, they wanted to look at the data a little bit more closely. And so they had 2,912 that were enrolled and 327 rescue attempts that were made. And so we're gonna be looking at these data more specifically here. Those 327 rescue attempts that were made were made by 212 individuals. So what that means is that some people made more than one rescue attempt. And 87% were by people who used opioids themselves. And most rescue attempts occurred in private settings, so people's homes. And rescuer and the person who overdosed were usually friends, so it wasn't somebody rescuing a stranger. And looking at the data even further, they had a question on there if the overdose was successfully reversed. And they had that data for 153 of those rescue attempts. And they found that naloxone was successful in 98%. And the remaining three people received care in the hospital and they survived the overdose, so there weren't deaths. And what they found overall is that there were reduced death rates in communities that implemented an opioid overdose prevention program. So even low implementers, so only having one to 100 enrollments per 100,000 people in the community, had a 27% decrease in the death rate. And in communities that were considered high implementers, so greater than 100 enrollments per 100,000 had a 46% decrease. So getting that naloxone out there widespread was important and likely important and likely involved in reducing the death rate. So this figure is looking at the number of states and territories that had a naloxone access law. And this is looking at 2011, and you can see the blue states are the ones that had naloxone access laws, and there were six at that time. And then 45 of the states and territories didn't have a naloxone access law. Contrast that to 2017, and that's when we're in the height of the overdose epidemic, and all states had a naloxone access law. So there can be lots of different components to a naloxone access law. And I selected four of the things that Pennsylvania's law entails. And what we have is civil liability, liability immunity, as well as criminal prosecution immunity for prescribing, dispensing, and distributing naloxone. So prescribers don't have to worry about getting sued, or they don't have to worry about being arrested for prescribing naloxone to a lay person. The other component is that naloxone is authorized to be given to third parties. So the way that that's helpful is that often people can't administer naloxone to themselves. And so maybe somebody comes into your clinic and says, my son is using heroin, and I'm afraid he's gonna overdose. Can I get some naloxone? And that's okay. You can prescribe to the mom or the dad that's concerned about their son. And then they could use that naloxone on their son if he were to overdose. They could even use that naloxone on somebody else that they found that was overdosing. And in our state too, the pharmacists are allowed to dispense or distribute naloxone without a patient-specific prescription from another medical professional. And we'll talk a little bit more about this, the specifics of this, but what that does is that somebody can go to their local pharmacy, and right now there's a state standing order in place that allows for naloxone to be given to anybody who requests it at the pharmacy. The pharmacist would follow the standing order that the state put out. The other thing is that there's collaborative pharmacy agreements where pharmacists can initiate treatment if they're collaborating with a physician. So that's similar to how pharmacists can give flu shots and shingle shots and things like that. They can also distribute the naloxone to somebody. And then the last couple of components are, is a lay person immune from criminal and civil liabilities when administering naloxone to somebody they think is overdosing? Yes. They're not gonna get in trouble if they do this in good faith. So if they think that somebody is overdosing and they're going to try to save them by giving naloxone, they're not gonna get arrested and they're not gonna get sued for it. So I have here a picture of the different formulations of naloxone. We have naloxone in vials with syringes that you draw the naloxone into. And then we have this other formulation, which is naloxone and you put this vial here inside the syringe here. And you're gonna remove the yellow caps, you're gonna remove the red cap and then put it into here. And then you're gonna screw this mucosal atomizing device onto the end of the cap. So that was being used, this formulation was being used quite a bit before this new branded formulation came out and I think it was around 2016. And so I remember writing a lot of prescriptions for this with this mucosal atomizing device because this would reduce the risk of having a needle stick injury for somebody who is drawing up the naloxone or administering the naloxone using a syringe. The other thing that's available is this MCL branded naloxone auto-injector basically. So this one talks, you take the top off and then it'll talk and tell you what to do. And so that's convenient because it just gives you instructions if you're really anxious or nervous and because you're witnessing an overdose, this can help you through that. And you can administer it, you administer this injection in the thigh area and it can be administered through like jeans or pants. So the intramuscular formulations are the vials here with the syringes or this abzeal auto-injector. And then the intranasal formulations are gonna be this naloxone here with the mucosal atomizing device, that little white cone. And that's off-label use of that kind of naloxone there that comes that one milligram per ml formulation. Or you can use this branded Narcan nasal spray, which is one, all you've got to do is take it out of the package and spray it up once one nostril of the person who's overdosing. So how to prescribe naloxone to patients. The first thing to do when you want to prescribe naloxone to a person is to talk to them about overdose. Ask them if they've ever overdosed, ask them what the circumstances were, what happened, how did they survive? And also, a lot of times people have witnessed overdoses, so what did they do in that circumstance? This is a good opportunity to teach people how to respond to an overdose, because sometimes the knowledge out there is not accurate. People are putting people in bathtubs or punching them, things like that, to try to get them to be aroused and stop overdosing, and that doesn't work. You can ask patients, what did they do to protect themselves from overdose? Sometimes what they'll say is they don't use a loan, they might use test shots, so a smaller dose of heroin or fentanyl if they're not familiar with the product, to make sure that it's not stronger than it usually is. What are some risk factors for overdose? So asking them to see if they know what kind of things put them at risk for having an overdose, such as using more than one substance, drinking, using benzos plus opioids, using cocaine, methamphetamine plus opioids. Then ask them if they know about naloxone for reversal of overdose. In this day and age now, most people do, but when I first started, I'm gonna say probably like six, seven years ago, people weren't all that familiar with naloxone. Okay, so who's a good patient for naloxone? Well, somebody who's had a history of having an overdose, somebody who's gone for emergency treatment of opioid overdose or intoxication, somebody who you suspect or know to be using heroin or non-medical prescription opioids, or somebody has a prescription for opioids and they're misusing them, they would be good candidates. People who are buprenorphine and methadone maintenance programs too, even though they're in treatment and they're receiving buprenorphine or methadone, they still could be at risk for having an overdose, especially if they use on top of the buprenorphine or the methadone. People who are receiving anywhere from 50 to 100 milligrams or greater morphine equivalents of opioids per day. Remember in the beginning, I was talking about, there's these different risk factors and different data about what's a risk for an overdose. So basically, if somebody is getting more than 50 milligram morphine equivalents of opioids per day, they would be a good candidate. The other thing is, if somebody is changing from one opioid to another, so they have incomplete cross-tolerance when they change from one opioid to another, so it's good to give them naloxone at that point. Somebody who lives in a remote location or has difficulty accessing EMS, so if you're seeing somebody who lives in a rural area, they would be good candidates for that. Now, if the patient requests naloxone, that's a good person to give it to as well as a concerned significant other. So if somebody is receiving an opioid prescription, so say you have somebody that you see in the emergency department and they have a fracture and they're gonna get sent home and you're gonna give them some opioids for that, here are some additional considerations. So somebody who gets this opioid prescription and they're a smoker, they have COPD, asthma, sleep apnea, respiratory infection, other kind of respiratory illness, they would be a good candidate. Somebody with renal disease, liver disease, cardiac disease, HIV or AIDS. Somebody who's known or you suspect to be using alcohol heavily. Somebody who's using benzodiazepines or other sedatives and you're giving them a prescription. Somebody who's on an antidepressant or they have a psychiatric diagnosis. And then people who are recently released from incarceration, detoxification, some kind of mandatory abstinence program. So there are some educational videos out there for patients to look at on the internet or for you to view with them to do education. Some good ones are available at prescribedtoprevent.org. And when they've looked at how much education does somebody need to receive to be able to administer naloxone successfully, this study looked at people who received naloxone and received a five to 10 minute education on overdose education and how to use naloxone, demonstrated a high level of knowledge on this brief overdose recognition and response assessment inventory. So you don't have to spend that much time doing the education, only five to 10 minutes. And here's how you would write a prescription for intramuscular naloxone. So this is when you're gonna be prescribing one or two vials of naloxone for them to use. And it's all written out right here. So if you're gonna use naloxone 0.4 milligrams per ml, you want to do, it depends on how big the vial is. So there is a vial that is up to 10 milligrams. And so they would receive one of those because they're just going to, each injection is going to be one milliliter. And if they're going to get single dose vials, then you would write for two of them. So then that way they can give a second dose if needed. So, and then you can write for refills. I'll usually write so they can have six refills, 11 refills, et cetera. And you'll also need to write for the syringe. And so they have a 23 gauge, three CCs, one inch syringe, and then the quantity. So you want to make sure if you're giving them two, two syringes, one for each vial, and then refills, you can write for refills on that. And then what you'd write for the SIG is for suspected overdose, inject one ml intramuscularly in the shoulder or thigh. Repeat after three minutes if minimal or no response. And to write this for the naloxone that comes with the mucosal atomizing device. So you'd write naloxone one milligram per ml. So it's a, you'd give them two, two milliliter pre-filled Luerloch needleless syringes. Okay, I know that's a mouthful here. And then I would give refills on that. So you want to make sure to give a quantity of two. So if the first doesn't work, then you can do another atomization. And you want to give them two mucosal atomizing devices and then refill. So this mucosal atomizing device is that little white cone that you put on the end of this needleless syringe that the naloxone comes in. And then what you're going to write on the prescription is similar to the other one. For suspected overdose, spray one ml in each nostril. So in this case, you're going to want to put one milliliter, so about half of that syringe in each nostril and repeat after three minutes if minimal or no response. This auto-injector, and this is that one that talks to you. So you can just write naloxone auto-injector two milligrams per four mls and dispense one twin pack. And then you're going to write on there, use one auto-injector upon signs of opioid overdose. Repeat after three minutes if minimal or no response. So once they open it up, that auto-injector is going to talk to them and tell them what to do. It's going to say, you know, put it next, put it on the thigh and then press down. So it's going to give all the instructions when they open it up. And then I would put some refills on there. And one thing I wanted to point out here is that the dose was changed in 2016. So they gave a higher dose. It used to be 0.4 milligrams per 0.4 mls, but now it's two milligrams per 0.4 mls. So these are the instructions for writing for that naloxone nasal spray. So this is the one that comes in one piece. You don't have to put it together. You can just open up the package and squirt it up one side of the nose. So this is that newer one that came out in like 2016. So you'll write naloxone nasal spray, four milligrams per 0.1 mls. And then you can give them one box, which is a pack of two. And what you'll write on there is for suspected overdose, spray in one nostril. May repeat in three minutes if minimal or no response. So the difference between this naloxone, this nasal spray and that naloxone with the mucosal atomizing device is that you just spray it up one nostril. And you should tell the patient not to prime the pump or anything like that. They can just take it out and squirt it up the nose because if they squirt it a little bit, the medication's gonna be lost into the air. And when they spray it up one side of the nose, they can, and the person doesn't respond in three minutes, they can give it up the other side of the nose too. But they don't have to divide half in one nostril and half in the other one like you do with the naloxone that comes with the mucosal atomizing device. And then I would put refills on that as well. So some common issues regarding naloxone. Well, good news is that it's covered by commercial insurance, Medicaid, Medicare. The cost of naloxone has gone up in recent years due to increased demand. That mucosal atomizing device may not be covered. It typically costs $4 to $8 each. I don't know anybody who's really writing for that version of the prescription anymore. And a lot of pharmacies aren't carrying that kind of naloxone. They don't carry the mucosal atomizing devices. So I probably wouldn't even bother writing for that anymore. I just wanted you to know about it in case that's all the community has or in case you hear of somebody else doing it that way. Now that branded naloxone nasal spray that comes all in one piece, it could cost about $130 cash, but it is covered by insurance, including Medicaid, Medicare. That auto injector, the one that talks to you, that one's really expensive. It could cost over $3,000. It is covered by some insurances and by Medicaid, but you have to do a prior auth. And I don't know of the reasons that Medicaid would really authorize this because I've put in for a prior auth in the past and they didn't want to pay for it. And the naloxone is regularly stocked, and you can see that pharmacies, now most of them are stocking that branded naloxone nasal spray. And if they don't carry it, you can see if the pharmacist will order it. And naloxone has a shelf life of 12 to 24 months. It should be cupped in like room temperature. It doesn't need to be in the refrigerator. At the same time, you shouldn't keep it in a hot car. And so it needs to be at a normal kind of room temperature. And this is looking at standing orders. So how are pharmacists allowed to dispense or distribute naloxone without a patient-specific prescription from a medical professional? So this is showing how many states had the standing order as of July 2017, and you see Pennsylvania has that. So we have the state physician general wrote a standing order for naloxone. So that's good at any pharmacy in the state of PA. And for example, I've written a standing order for our methadone program. And so that's good for the patients, for us to be able to distribute naloxone to the patients at the methadone program without getting a specific prescription for each patient. The other way that naloxone can be distributed is through these collaborative pharmacy practice agreements. So this permits pharmacists to work in collaboration with the prescriber on drug therapy management. So this is when I was mentioning about how pharmacists can give flu shots, shingle shots, and stuff like that. So 48 states allow collaborative pharmacy practice agreements to manage pharmaceutical care under agreement, and 21 states permit pharmacists to initiate medication under the agreement. So it's not in every state, but I know around here there's certain pharmacies, the chain pharmacies, that have these collaborative pharmacy practice agreements, and they can initiate naloxone that way. Now this would be the time normally where I'd ask for any questions or comments, or throughout the lecture we would have done that. However, since this is recorded, we don't have the opportunity to do that. So what I'm gonna do is ask you if you have any questions, comments, concerns, you can always email me. My email is listed below. Thank you very much for your attention during this lecture, and good luck with the rest of your course and your first year. These are the references for the studies that I mentioned and the figures in these slides.

lecture

Dr. Julie Kmik

opioid epidemic

naloxone

overdose reversal

opioid prescriptions

risk factors

pharmacology

forms of naloxone

efficacy