This talk is going to cover some of the topics that we have not gone into in depth in the presentation. We're going to give you more information on extended-release naltrexone, talk briefly about methadone, and then about naloxone. So beginning with naltrexone, naltrexone is a long-acting, high affinity, competitive opioid receptor antagonist. It has an active metabolite, which gives us a longer half-life. In sufficient concentrations, it's going to block all opioid effects and will prevent the individual from experiencing opiate high. The extended-release formulation is the main focus of today's discussion. It's been approved for prevention of relapse and opiate use, and it's an appealing choice for patients who want to completely withdraw from all opioids and see that as the first stage in their treatment. We still don't totally understand the mechanisms behind the effect of naltrexone. We know that you have a blocking effect from the behavioral mechanisms. Because you don't get any reinforcement when you use opiates, you get a gradual extinction of drug-seeking and craving behavior. And patients who use opiates while they're on naltrexone have no effect, so they will eventually stop using. There's also probably a pharmacological mechanism, and this is less understood, but naltrexone decreases reactivity of drug-conditioned cues and decreases craving, therefore it minimizes pathological responses that contribute to reslap. What we do know in this case is that there appear to be reduced urges to use in most of the patients who are on naltrexone. There are some limitations, however, to this treatment. Probably the most complicated issue is the logistics of beginning the treatment. Patients need to be fully withdrawn from all other opiates, and the FDA requires a 7-10 day wait from their last use of opiates before their first dose of naltrexone. And this is a major barrier for some patients. They often find it extremely difficult to avoid opiate use during this period. Another difficulty is the fact that if the patient has used opiates or you start too quickly after their last use, you may precipitate withdrawal or develop protracted withdrawal, and that this can be quite uncomfortable for the patient. And thirdly, there are concerns because we have limited research. This is the newest treatment for opiate use disorder. There are many unknowns. We don't know the ideal duration of treatment. We don't know the best frequency of dosing. We don't know its effect on other substances, and we really don't know who the optimal patients are for naltrexone, particularly in comparison to buprenorphine and methadone. This is another version of the graph that we showed you earlier, here comparing the effects of agonists and antagonists, and I won't go through this in great detail at this point, but you can see that the antagonist really has minimal effects. It does not cause dependence. It is compatible with other substances. There's no interaction with other drugs. There's no potential for tolerance. However, you may understand that it may alter the use of other drugs. The duration of treatment is not well understood, and there clearly is no long-term experience on what's the ideal length of time for someone to remain on injectable naltrexone. There are cultural barriers to the use of agonists that do not occur with naltrexone, and the public and patients seem to be in opposition more likely to buprenorphine or methadone, and that's less of a problem with naltrexone. Work with naltrexone began in 1984 with the development of the oral formulation. From the very beginning, it was clear that the drug worked pharmacologically, but the clinical reality was that it was not particularly effective. There was low patient acceptability, and most critically, there was poor compliance. Patients simply would not stay on the oral medication unless they were really being observed and it was forced that they take the drug. The reviews concluded that there was really no evidence that naltrexone was effective beyond a very highly selected and very highly motivated group of patients. Often these were physicians who were in monitoring programs. Various behavioral therapies were developed to try and improve patient compliance and improve the therapy response, but none of these resolved the problems of the compliance issue. Finally, the development of the injectable long-acting formulation really resolved the compliance issue or at least guaranteed effective medication for approximately three weeks and that patients could have opportunities for stable recovery. This slide gives you some understanding of why this injectable medication is much more effective than the oral medication. What you can see in the bottom of the row of repeated spikes are the blood levels of naltrexone following the oral dose. You can see here that every day there's a spike, but it drops very rapidly so that much of the day there's relatively low levels of naltrexone available in the patient's system. Compare that to the red line. You can see that within a day or two of the shot, you have a very high coverage and high levels and very therapeutic levels of serum naltrexone and that this gradually reduces over the rest of the month and is probably clinically effective for 28 days. The area under the curve in terms of the efficacy of the injectable naltrexone compared to the oral naltrexone is four times greater with the injectable formulation. Naltrexone, as I mentioned before, can only be started in individuals who have been fully withdrawn from opiates. If you give it to patients who are physically dependent and have a short-acting opioid in their system, it's going to displace that opioid from the receptor and will precipitate severe opioid withdrawal. The severity of the withdrawal is lower depending on the length of time from their last opioid use and the initiation of the naltrexone and is also lower if the amount of opioid they used last was lower. Generally the requirement is at least five to seven days after the last opioid dose and at that point it's possible for most patients that you can give naltrexone without precipitating opiate withdrawal. But one needs to understand that that five to seven day period is a period of high risk for relapse. Every day that the patient is not on naltrexone is a day that they are not receiving any blockade and that they may well use opioids and trigger a relapse to opiate use. So you need to sort of complete the medication withdrawal treatment either with a buprenorphine taper or with a combined clonidine benzodiazepine protocol. The FDA recommends seven to eight washout period between the last dose of the opioid and the first dose of naltrexone. Another option for approaching this, and this is the way to guarantee that there's no active opioid in the system, is to give a naloxone challenge test before you give the first dose of naltrexone and we'll explain that in more detail in the next slide. But there are really two ways to approach this. You can begin after the washout period with oral naltrexone at low doses, 25 to 50 milligrams on day one. And if they tolerate that dose with no difficulty, then you can begin with the injection that day or the second day. The other alternative is to use the naloxone challenge test and then if they successfully pass the challenge test, give the first injection. So how do you prepare for the naloxone challenge? You first want to obtain urine screens to confirm the absence of any opioids, buprenorphine, methadone in their system. You want to measure baseline vital signs. You want to verbally confirm with the patient that they have not used methadone or buprenorphine and how long it's been since they used anything and there should be no use reported within the past seven days. You need to remind the patient if they have not been truthful about this and they receive the first dose of naltrexone, they will precipitate severe opioid withdrawal. So you need to have this negative urine screen and the confirmation of no use from the patient before you proceed. So how do you actually do the naloxone challenge test? Naloxone can be administered sub-Q, IM or IV. It's effective either way so it depends on the patient's preference or the physician's preference. You would give an initial test dose of .1 milligrams or .2 milligrams. If there's no subjective discomfort or objective withdrawal after that test, wait a few minutes and then give a repeat of that dose. So you want to get up to a total dose of .4 milligrams. Again you want to wait and see if there's any subjective response or signs of withdrawal. After a few minutes, if everything is clear and appropriate, you want to give them additional naloxone to bring the total dose up to .8 milligrams. That's your target dose to achieve the test result. You then want to wait for 45 minutes to be absolutely sure there are no signs of withdrawal or no discomfort. If you get through that 45 minutes without any symptoms, then you have successfully passed the naloxone challenge test and you can then proceed with administering the injectable naltrexone. Now once naltrexone is in the patient's system, it is very common that patients will try and test the blockade. They want to know whether the naloxone or rather the naltrexone is really working. It's common that once or twice within the next few weeks the patients will try opiates to see what happens. As the blood level may be very low in the first 24 hours, if they try that they may get some opioid effect. After the first day or two, if they try to test the blockade, it's very likely they will get no effect whatsoever. There are a few patients who continue to do these tests over the next few weeks, but almost all patients will stop once they realize that they can't overcome the blockade and that the naltrexone is working effectively. So this continuous blockade will prevent the patient from relapsing to physical dependence. And once this happens, many patients are going to prefer to maintain the medication long term. But it's important to understand that relapse can happen at any time if the patient misses or forgets to get their next shot. So they need to be scheduled to get their repeated doses and it needs to be stressed that long term treatment is critical and they have to take the responsibility to make sure they get their next injection. It's been noticed that some patients will have increased craving and may use in weeks three or four when they have the lowest serum level of naltrexone. This can be managed by giving the shots every three weeks instead of every four weeks. Or in some cases, physicians have supplemented the injection with oral medication for the last week. So that's an effective alternative. However, the most common sign for relapse is that patients simply don't return for their next scheduled injection. Within a week or two, the blockade really is completely absent and they are able to use other opiates without getting any blockade effect. It's important that once people are in treatment, they be given additional therapy to help them comply with treatment. If patients don't do well and they don't continue with the shots, inpatient stabilization should be considered and then perhaps another attempt at antagonist treatment or perhaps referral to residential treatment or a sober house. And if none of that works, it should be considered that the patient would be a better candidate for agonist treatment with methadone or buprenorphine. What about managing severe pain? Patients on naltrexone will experience pain. You cannot give them opiates in a simple way to manage that and override the blockade. So you first want to try NSAIDs. If that doesn't work, if the pain is persistent or intolerable, you may need to go to a regional nerve block. If that fails, you can override the blockade with very high-potency opioids such as fentanyl or buprenorphine. But this should be done in the hospital and it should be done under the supervision of anesthesiology. All patients should also wear a medical bracelet or carry a wallet card that indicates that they are on naltrexone and gives 24-hour contact numbers. Now how do you manage the concerns for overdose? As I mentioned before, as the effect of the drug wears off at the end of those three to four weeks, the patients may be at higher risk for overdose. And you need to try to do everything possible to make sure they return for their next injection. You need to make sure in the informed consent that patients understand that they are at risk for relapse at this point, that they will have lost their tolerance for opioids and that they may have a fatal overdose if they use opiates at a point when they have no tolerance. However, this risk is true for any medication-assisted treatment. So patients who stop methadone or stop buprenorphine, as with patients who stop naltrexone, are at much higher risk for overdose with opioids. Now we want to look at using medications to handle this problem. Again, warning the patients about the risk for overdose with any of the medication-assisted treatments and staying on those treatments reduces mortality significantly more effectively compared to drug-free treatment. The risk for overdose is present with all three of the medication-assisted treatments. There is some difference in mortality rates between the different treatments. The mortality rate is higher on patients treated with oral naltrexone as compared to patients treated with methadone. It's higher in patients treated with oral naltrexone as compared to patients with extended release naltrexone. It's comparable in patients with extended release naltrexone and methadone. The long tail of the serum naltrexone may give them some added protection and give them the opportunity to develop a drugs-free lifestyle, but it will wear off and at this point there is risk for extended and elevated mortality. Now we'll talk about methadone. There have been numerous studies about methadone that have demonstrated its efficacy. What does it do? It stabilizes lifestyle. It improves health and nutrition. It will reduce criminal behavior, increase employment, reduce the use of injection drugs and needles. Regulations require that to get into long-term methadone treatment you need to demonstrate a one-year history of opiate use disorder. This is not required for buprenorphine, so patients with a shorter history are eligible for buprenorphine, but they have to have a one-year history to be eligible for methadone. The target methadone dose is 80 to 100 milligrams daily. Methadone appears to be a better choice for individuals with higher levels of drug dependence or specifically for those individuals with more psychological pathology or individuals who require really intensive support services. Doses over 100 milligrams may induce prolonged QTC intervals in susceptible individuals. Methadone is metabolized with the CYP3A4 system and I'll show you a slide with the numerous drug interactions with methadone. Patients on methadone who take it regularly do experience pain and they may need additional opioids if they have pain and if they require analgesia. And it's also been noted that high doses of methadone seem to reduce serum testosterone. So again, how do you induce people on the maintenance with methadone? You need to document that 12-month history of opiate use disorder using DSM-5 criteria. The individual has to be 18 years old or older. This is in contrast to buprenorphine where you can be treated if you are 16 years or older. There can be no active dependence on other substances, so if you have an individual who is alcohol-dependent or benzo-dependent or cocaine-dependent, you may need to hospitalize them for medication withdrawal treatment before starting them on methadone. It's required that you check the state physician prescription drug monitoring program to make sure they're not receiving methadone or other opiates from another source. You want to get a urine toxicology to be sure what medications they're using. And finally, you want to do screening liver tests, check for TB, hepatitis, and HIV. The initial dose of methadone on an outpatient basis should be 30 milligrams or less. The final 10 milligrams can be given two or three hours later after a physician assessment, but the maximum dose is really going to be 40 milligrams on the first day. You want to observe the patient in the clinic for at least another hour to make sure you're not seeing excessive sedation or any adverse drug effects. From that point on, doses will be 5 to 10 milligrams at a time, and these are usually given every 2 to 5 days. You're aiming to a total daily dose of 50 milligrams, but it's very dangerous to increase the dose every day. Methadone can accumulate rapidly, and there have been reported deaths from toxicity if patients' dose have been increased every day in patients who did not have significant tolerance. Once you reach the target dose of 50 milligrams, you still need to go more slowly, usually four or five days before there are any further dose increases. You really need to wait and see how the patient adjusts to that dose and to not rapidly increase because of the risks of toxicity. In our clinic, we usually increase doses once a week once people have reached this level. You want to target the dose here of 80 to 100 milligrams. At that point, you should expect elimination of withdrawal symptoms, elimination of craving. There should be no evidence of sedation or toxicity, and if you see patients who appear to be toxic, it's highly likely that they may be adding other doses or drugs such as alcohol or benzodiazepines on top of their methadone. If the dose goes over 100 milligrams, you need to monitor for prolonged QTC in susceptible individuals. What are the side effects of methadone? There's minimum sedation once withdrawal is achieved. Constipation unfortunately does not go away, so patients need to be on a good bowel program. They may have increased appetite and weight gain, so they need to be encouraged to get exercise and watch their diet. There may be reduced libido, so you may be watching for a decrease in gonadal hormone levels. We mentioned before rare increases in the QTC interview, but there does not appear to be harm to any other major organ system. How do you monitor for QTC problems? This does not occur in all patients. In fact, it's relatively rare, only about 2% of the patients. You need to get an EKG before starting methadone in patients with risk factors, and those are individuals with a familial long QT, people with a history of unexplained syncopal episodes, people with a history of heart disease, people on any medications that may interact with methadone or medications that may increase the QTC, and there are a number of psychiatric drugs that may do that. You need to determine if there was a pre-existing prolonged QT interval. If that's the case, you want to repeat the ECG after 30 days on methadone and compare that to baseline. If you notice that the QTC is 500 milligrams or greater, then you're going to need to reduce the methadone dose to bring that down. This is a list of the medications, at the top of the list are the medications that decrease methadone concentrations, Phantoin, carbamazepine, rifampin, which is used for TB, a number of HIV drugs. All of this makes it more complicated to manage a number of patients on methadone. There are also drugs that will increase methadone levels, and here there's some of the SSRIs, other drugs that we use in psychiatry may increase methadone levels. You need to be careful watching for cognitive impairment or a respiratory depression or prolonged QTC on any drug that's going to increase your methadone levels. What are your treatment recommendations for methadone maintenance? Long-term treatment, if not indefinite treatment, is the most effective approach. You want to conduct random urine toxicology examinations, federal regulations say this must be done at least eight times a year. It's important that individuals receive skilled individual or group counseling. They should be encouraged to attend AA and NA, and you want to periodically check with the state prescription drug monitoring program to make sure they're not receiving opiates from another source. After 90 days of treatment, stable patients may begin to get take-home medication. If they continue to do very well, within two years or so, patients may achieve up to one month's supply of take-home medications. It's highly unlikely for patients to do that that effectively, and our experience, it's often five to 10 years before patients achieve that level of stability. During treatment, it's useful to have medication callbacks to monitor for diversion and to get random urine checks. Now talk a little bit about the neurobiology of opiate withdrawal. Opiate withdrawal can be thought of as occurring in two ways. There's hyperactivity of noradrenergic neurons in the locus coeruleus. This is responsible for the physiologic aspects of opiate withdrawal, increased blood pressure, respiration, sweating, et cetera. Clonidine and opiates will reverse these physical effects. However, there's another aspect of opiate withdrawal that are primarily GABA effects caused by reduced dopamine in the nucleus accumbens. This causes dysphoria, depression, and craving. This is often what's most uncomfortable for the patient. Only opioids such as methadone or buprenorphine will reverse these effects. What this is basically saying is that the primary treatment for opiate withdrawal should be a full agonist like methadone or buprenorphine, and that clonidine is an inadequate treatment for the full range of symptoms for opiate withdrawal. If you are going to treat withdrawal, you should not give the first dose until you've actually observed withdrawal symptoms to make sure the patient was truly physically dependent. Federal recommendations say don't exceed more than 20 milligrams methadone for the first dose, and for very young patients, only 10 milligrams. You can repeat that dose in two hours. Most inpatients don't require more than about 40 milligrams in 24 hours to control withdrawal symptoms. From that point on, you're going to adjust the dose to avoid either too much, that is intoxication, or excessive withdrawal. We recommend that for the withdrawal taper, you cut the dose by 10 milligrams a day until you get to 20 milligrams, and from 20 milligrams on, you cut the dose by 5 milligrams a day down to zero. Now the final section of this talk, I want to briefly cover naloxone and the management of opioid overdoses. Naloxone is a full antagonist of the mu opioid receptor. It reduces opioids by blocking opioid receptors and prevents opioids from reaching the brain. These are the symptoms for, or the situations that are likely to cause risk for opioids. Change in opioid tolerance, mixing opioids with other sedative hypnotic drugs such as alcohol or benzodiazepines. Change in physical health, variations in the strength or content of medications that have been taken, individuals who switch from snorting a medication to smoking or injecting the medication. As we've mentioned several times in this talk, there's a higher risk post-withdrawal treatment, and individuals who use alone are at high risk for fatal overdoses because there's no one to call the police or initiate rescue interventions. What are the symptoms of an opioid overdose? How do you recognize it? The skin will be pale, cold, and blue. Mainly lips and fingertips show these symptoms first. There may be a coma or slow, irregular breathing. Pinpoint pupils, the body may be very limp, the face very pale. The pulse will be slow, erratic, or may be undetectable. There may be vomiting, difficulty breathing, choking sounds, gurgling, noisy breaths. The patient may be awake but may be unable to respond to commands. So how do you treat? The number of overdose deaths has increased dramatically in the United States in the last few years. This was driven by the abuse of opiate pharmaceuticals, but in the last year, the abuse of fentanyl and carfentanil has been driving up the overdose death rates around the country. So what is the treatment? Naloxone is the drug of choice. You're going to give 0.4 milligrams either IV or sub-Q every four minutes, and you will repeat that dose if you don't get an immediate response. If there's no response after a number of repeated doses, you should assume that what you're seeing is a sedative-hypnotic overdose, not an opioid overdose, and you may need to initiate another type of treatment. If patients have overdosed on methadone or any long-acting opioid, they need to be treated with naloxone for 24 to 48 hours until their body has completely metabolized the long-acting opioid. That means they need to be admitted to an ICU and placed on a naloxone drip for the next 48 hours. A single dose of naloxone usually lasts from one to no more than four hours. Because fentanyl is much more potent than the usual drugs on the street, patients may need multiple doses of naloxone to reverse a fentanyl overdose. There's been major public health initiatives around the country to make naloxone rescue formulations available to patients, to their families, to EMTs, and to the general public. Naloxone activity is usually from 30 to 90 minutes. It's going to wear off often before the full effects of the opioid have worn off, and the patient is at high risk for relapsing and going back into an overdose state. This is going to depend on several factors, the individual's metabolism, the amount of drugs that they originally ingested, whether they have normal or impaired hepatic function, and whether they ingest further sedating drugs. Often individuals, when they're treated with naloxone, if they're physically dependent, will have precipitated alcohol withdrawal, and they may actually leave the hospital setting and go out and seek more opiates to reverse those withdrawal symptoms, and this is a highly dangerous reaction. Naloxone blocks the receptors in the brain and, as we've said several times, will cause withdrawal symptoms if the person is physically dependent. If the person was simply using opioids, was not physically dependent and overdosed, you will be able to reverse the overdose but will not cause precipitated withdrawal. Such an individual who has withdrawal is going to experience severe symptoms and may want immediately to use again. They need to be told that they're at very high risk for a repeat overdose and that that overdose could be fatal. It's also extremely important that anyone who overdoses be referred for counseling or addiction treatment. This is clearly a sign of a very serious medical problem, an opiate use disorder, and treatment is obviously necessary. These are the various formulations of naloxone that are now available. There are injectable naloxone, there's intranasal formulations. If you have used intranasal formulations or the injectable formulation, those vials should be discarded after six hours and not used again. The more recent developments have been a formulation of self-injection, self-injectors of naloxone, and also a nasal spray, which is shown here. So putting this all together, how should you respond to an opioid overdose? The first thing to do is call 911. The next thing is to initiate mouth-to-mouth breathing if the person is not breathing on their own. Next, you want to administer a dose of naloxone. If they don't respond after two to five minutes, administer a second dose. And in the interim, you may need to administer more breaths if the patient is not breathing at the rate of 10 to 12 breaths per minute. Once the patient wakes up, you need to warn the patient that the naloxone will wear off and that they could overdose again. And perhaps very important or most important, the patient needs to be referred for counseling or addiction treatment. This last slide gives you some dramatic evidence of how effective naloxone rescue preparations are. This is data from San Francisco. It tracks the number of deaths that were occurring related to heroin overdose in San Francisco from 1993 on. And you can see in 2003, the city introduced the availability of intranasal naloxone as a rescue preparation. And from that point on, you see a dramatic drop in the overdose deaths. So it's important to understand patients will die from opioid overdoses, that we have extremely effective treatment, that patients need to be educated about what these risks are, and all clinicians need ready access to naloxone rescue preparations because you never know when the situation will occur that you may be able to save a patient's life. Thank you.

opioid addiction

treatment

extended-release naltrexone

opiate use

methadone

naloxone

overdose