<v ->Hello, everyone, my name is Larissa Mooney.</v> I am a Professor of Psychiatry at UCLA. Really happy to be here today to present on pharmacotherapy management for alcohol use disorder. I have no relevant disclosures, financial disclosures or other disclosures today. The target audience for PCSS is listed here. The educational objectives of my talk include explaining how to establish a diagnosis for alcohol use disorder, explain the rationale for using pharmacotherapy in the treatment for alcohol use disorder and to describe the dosing and mechanism of action for the following medications, three of which are FDA approved, naltrexone, acamprosate and disulfiram, actually, two formulations of naltrexone, and two that are off-label that I will talk about today include topiramate and gabapentin. And also, we will be identifying alcohol use disorder pharmacotherapy options through use of a case vignette. And the focus today will be on outpatient management of alcohol use disorder, not inpatient withdrawal management, though I will touch on that topic. We know that alcohol use disorder is one of only three substance use disorders for which we have FDA approved medications. The others are tobacco and opioid use disorder. We also have some non-approved pharmacotherapy options that I'll be discussing today with some efficacy, not all of which, but two that have some signals and are more commonly used. In 2019, 14.5 million adults in the United States had a diagnosis of alcohol use disorder. But we know that in general, these medications are underutilized. Only about 7% of individuals with alcohol use disorder receive formal treatment that includes medication treatment. I like to think about using medications in a broader context. We know that addiction is a chronic relapsing disease of the brain. That's how the scientific and medical communities often describe addiction in comparison to other chronic illnesses. The hallmark of addiction is use with loss of control, even in the face of harmful consequences. Medications I view as a tool. It's one of many tools that we have to aid in the treatment of alcohol use disorder, and they are ideally used in a broader comprehensive treatment plan in combination, when possible, with behavioral interventions, social support and other lifestyle changes. So this is one tool that we have, and medications can help with the biological component of alcohol use disorder and target some of the symptoms that contribute to return to use, but, in combination with other treatment modalities, is optimal when possible. So, I'll only have one glass. I include this slide because we know that when taking an initial history, an assessment of someone for whom we are assessing alcohol use disorder, it's sometimes hard to quantify how much is someone drinking? What is their pattern of use? And are we really speaking the same language when a patient mentions how much they're drinking? The NIAAA, which is the National Institute on Alcohol Abuse and Alcoholism, has put forth standard drink equivalents that are helpful to use and refer to when taking a history from a patient. One standard drink is 12 ounces of beer, five ounces of wine or 1-1/2 ounces of hard liquor. And five ounces of wine is a smaller glass of wine. Often in a restaurant or when someone may be pouring it themselves, they're pouring more than five ounces. So it's also useful to ask how much of a bottle of wine do they drink? That's another way to capture and quantify the total amount of wine consumed. For example, in a bottle there's about five glasses total. So someone drinking half a bottle or three quarters of a bottle, that can help to distinguish the total quantity. The most recent US Dietary Guidelines have defined moderate drinking cutoffs as follows. For men, no more than two drinks in a day. For women, no more than one drink per day. And we know that for women, there is a higher risk of alcohol-related health consequences. This has to do with alcohol being primarily stored in the water component of the body. Women have a different water to adipose tissue ratio than men and therefore absorb alcohol differently. Men have different levels of enzymes in the GI tract that metabolize alcohol such as alcohol dehydrogenase, which ends up metabolizing alcohol, some of the alcohol before it's absorbed. So women are essentially absorbing more alcohol from the GI tract, and it is acting more quickly in the body and less dilute given the differences in water to adipose ratios. NIAAA has defined heavy drinking as use above certain cutoffs. For men, it would be more than four drinks on any given day or more than 14 drinks in a week. For women, greater than three drinks in a day or seven total drinks in a week. And when quantifying alcohol and use patterns, individuals who are consuming greater than these cutoffs warrant more screening, more thorough assessment for alcohol use disorder. Not everyone drinking at these levels has an alcohol use disorder. Approximately one in four who exceed these levels will ultimately have an alcohol use disorder. And any consumption above these levels is associated with greater risk of alcohol-associated harms and health consequences such as injuries. NIAAA has also defined binge drinking as for men, five or more drinks in one sitting approximately two hours or four or more drinks for women in approximately two hours. And these levels will typically bring blood alcohol concentrations above .08. So that would be a binge episode. So as I mentioned, one of the early steps in assessing utility of medications to treat alcohol use disorder is establishing a diagnosis. Our approved medications are indicated for alcohol use disorder, and we use the DSM-5 substance use disorder criteria to establish that diagnosis. There are 11 criteria assessed over the past 12 months, and as you can see here, these criteria really describe what I mentioned earlier around use disorder being loss of control over use even in the face of harmful consequences. So the criteria include using larger amounts or for longer periods than intended, difficulty cutting down, excess time spent using or recovering from use. Cravings are another criteria. And then some of the consequences, failure to fulfill role obligations during the day, giving up of certain activities, recurrent use in physically hazardous situations. And then also continuing to use despite knowledge of either medical or psychological consequences or social or interpersonal problems. Tolerance and withdrawal are the physical dependence criteria, and tolerance indicates that the individual is using at higher levels in order to achieve the same effect or that the same level of drinking no longer produces the same effect. Withdrawal indicates withdrawal syndrome or symptoms upon reduction or cessation of use. If somebody endorses two to three criteria, that's categorized as a mild use disorder. Moderate is four to five, and the severe use disorder is six or more. This slide captures some of the effects of alcohol in the brain on neurotransmitters. Alcohol actually acts on many different neurotransmitter systems in the brain. Here are described four of the primary neurotransmitter effects. And these also link to some of the mechanisms of action of the medications that I'll be describing. In short, alcohol is increasing endogenous opioids and dopamine, which cause the pleasure sensation and the reinforcement after drinking. Alcohol is also acting on GABA receptors. GABA is our inhibitory neurotransmitter causing calming effect or even sleepiness. And glutamate is the excitatory neurotransmitter, and the brain is trying to maintain balance between glutamate and GABA. So we'll talk about how that works. When somebody takes a drink, again, this is a simplified version, but just to talk through it, after alcohol is consumed, endogenous opioids are released, and that indirectly causes the release of dopamine, again, our brain's pleasure chemical that causes reinforcement and reward. Dopamine causes feelings of pleasure. So this is how alcohol makes somebody feel happy or euphoric through this mechanism. And then again, as I mentioned, alcohol's acting on GABA receptors. That slows the brain down, causing some of the more sedating or at least initially, anxiety-reducing effects of alcohol. But when alcohol is consumed chronically or heavily over periods of time, the brain is upregulating glutamate receptors to counteract the activation of GABA. So that's happening simultaneously to maintain that homeostasis. And as a result, an individual who has abruptly stopped drinking, who was previously drinking at heavy chronic levels, if they abruptly stop or if they more dramatically reduce their quantity of drinking, withdrawal symptoms can emerge. And these can range from tremulousness, anxiety, insomnia, irritability, also elevations in vital signs, higher pulse rate, blood pressure and in more severe cases, risk of seizures or delirium tremens. And those are the the withdrawal symptoms that can be potentially fatal. We want to pay attention to protecting against the emergence of those. So I'm going to shift now to talk about a case vignette, a brief case vignette that highlights some of the clinical factors that might shape how you would think about approaching selection of pharmacotherapy for alcohol use disorder in an outpatient setting, in this case in a primary care setting, but it could be adapted to other settings as well. We will talk about the case and some options for pharmacotherapy, then describe each medication and come back to the case at the end to pull it all together and talk through why you might or might not select certain medications in this case. So in summary, this is a 52-year-old man with a long history of heavy drinking who comes in reporting consumption of two bottles of wine. He denies other substance use and endorses symptoms of depression and insomnia. He, on assessment, meets criteria for alcohol use disorder, moderate severity. And on questioning, he endorses cravings for alcohol. That is one of the criteria he meets. His liver function enzymes on lab evaluation are elevated two times above upper limit of normal, and you also note macrocytosis as the only other lab abnormality. He, upon questioning, denies any symptoms of alcohol withdrawal and denies a history of complicated withdrawal. He has never previously received treatment for alcohol use disorder or a psychiatric disorder. However, on further evaluation, he does have a history of chronic lower back pain for which he takes low-dose oxycodone one to two times per month during flareups. So question one, that again we will get back to at the end to tie it all together, which medication would you consider for the treatment of alcohol use disorder in this patient? Acamprosate, disulfiram, naltrexone, PO, oral, or intramuscular, gabapentin or topiramate? And you might think about what would be your first choice and what other medications might you consider and are there any you definitely wouldn't consider? As a first step when thinking about pharmacotherapy on that initial visit, we do want to triage and assess whether an individual should be referred for medically assisted withdrawal management, also known as detox. So the term detox is falling out of favor. It's less accurate and potentially a more stigmatizing term. So this is the use of medications to facilitate reduction or stopping of alcohol use. Most commonly, benzodiazepines are used. They are given either in a symptom-triggered fashion, meaning based on symptom severity, you administer doses of benzodiazepines, or they can be prescribed as a standing taper with as-needed doses for breakthrough withdrawal. And the safest setting to conduct withdrawal management is on an inpatient setting with monitoring of vital signs and progress and decisions made each day about dose reduction of the benzodiazepines as tolerated. Also as part of withdrawal management, we administer thiamine, folate, multivitamin to supplement some of the expected deficiencies associated with chronic drinking. There are other approaches for withdrawal management, use of barbiturates, for example, but again, outside the scope of this talk today. To review withdrawal symptoms which we'll link with some of the initial assessment questions in an intake visit, minor withdrawal symptoms typically emerge within 36 hours of either reducing or stopping drinking. Those might be tremor, sweating, anxiety, insomnia, nausea or vomiting. And certainly, one question you might ask is at what time of the day does your patient start drinking? If somebody, for example, endorses waking up at 3 a.m. feeling shaky and needing a drink to fall back asleep, that's an indicator of higher tolerance and greater severity, meaning they are experiencing some withdrawal for which they are alleviating the withdrawal by drinking. Seizures, if they occur, typically occur within one to two days after reducing or stopping drinking. They are usually singular, generalized tonic clonic. They can progress to status epilepticus, and that's what we're concerned about. And they're treated and managed with benzodiazepines and other seizure medications. Alcohol hallucinosis, hallucinosis can occur in association with drinking, and they can be independent of delirium tremens. Hallucinosis will emerge typically within one to two days after reducing or stopping drinking. They're associated with otherwise normal mental status, meaning oriented to surroundings and expected vital signs, maybe some elevation associated with withdrawal, but not out of proportion. They're usually visual but may be auditory or tactile. In the case of delirium tremens, which is a very severe consequence of alcohol withdrawal, is a very severe indicator, these may emerge one to four days after the onset of withdrawal. And they're marked by disorientation, agitation and hallucinations, also autonomic instability and a mortality risk, which is even higher if left untreated. Delirium tremens are managed in a intense medically monitored setting, ICU-type setting, and we ideally want to treat withdrawal before the emergence of DTs. There are some risk factors for delirium tremens, including chronicity of drinking, how many years has the patient been consuming alcohol, more severe, higher levels of drinking, also over 30 years of age and any prior history of DTs is a predictor of higher risk of future DTs during withdrawal. I include the CIWA scale here. We won't, again, go through this in depth, but this is one scale that can be used to assess the severity of withdrawal symptoms. And in the case of symptom-triggered withdrawal management with benzodiazepines, the total score on the CIWA scale can be used to indicate whether additional doses of benzodiazepines are indicated. But as you can see here, the CIWA scale covers various symptoms of withdrawal ranging from anxiety, headaches, sweating, nausea, vomiting or perceptual disturbances and tremor. So based on the severity scores of approximately eight or above would indicate a need for administration of benzos. Scores 15 or above are in the more severe range. And over 20, 25 would warrant more intense monitoring and management in an ICU setting. As I mentioned before, medications are optimally administered in combination with behavioral treatment. We certainly want to meet people where they're at and give them a range of options, give them our best recommendations, but also see what are they willing to accept, what is feasible for them. And in some cases individuals may say, "I'm only willing to try behavioral treatment right now," or "I'm only willing to try pharmacotherapy." Ambivalence is certainly common in the process of treating addiction and substance use disorders, so really exploring what's feasible and what would be of interest, but just giving our range of options and trying to come up with a comprehensive plan. We do have some evidence-based behavioral treatments that have been studied in the treatment of alcohol use disorder and shown to be beneficial. Cognitive behavioral therapy for relapse prevention is one. This is use of cognitive and behavioral skills to identify potential triggers for return to use and skills to manage and cope with cravings and risky situations. Motivational enhancement therapy, MET, is used to really address the common ambivalence around treatment or change and help facilitate that progress through change and using patient-centered motivational interviewing approach to facilitate that. 12-step facilitation is a manualized treatment that helps people link with mutual support groups such as AA meetings, and it's delivered in a group setting. And the process of linkage to mutual support groups is discussed and encouraged. And then, of course, family-based therapy involving the family in the treatment and recovery process can be very useful. So ideally, best practices should include a combination of these approaches, available behavioral treatment with medication, and that's been demonstrated in recent meta-analysis by Dr. Lara Ray and colleagues and other prior literature. Linkage with social support and peer support can be beneficial and really round out that comprehensive approach . And mutual support meetings are free, peer-led, available now via virtual platforms or in-person meetings and can really be a complementary approach. Disulfiram is the first medication that we will discuss in a little bit more depth. One of the FDA approved medications that's been around since the 1950s, this is a medication that can be useful for individuals who are motivated to have an external source of almost enforced abstinence, meaning this is a medication that when somebody consumes alcohol in combination with the medication, they feel physically ill, it's aversive. And for some people, they don't want that kind of approach. Others find it very helpful to have that external motivator when they are in potentially risky situations. This is a medication that is generally low-cost and on formularies. The dosing is standardly 250 milligrams by mouth per day. It can be raised to 500 milligrams, but higher doses might be associated with greater chance of side effects. Because of that aversive reaction in combination with alcohol, it needs to be initiated after alcohol is completely out of the system, typically at least 12 hours, and it stays in the system a long time. It's metabolized slowly. So we caution individuals that the reaction could be triggered up to one to two weeks after the last dose of disulfiram. It is common for individuals to test this out. If they start on disulfiram, they drink and may see what their reaction is. And of course, it varies across individuals, but the symptoms are usually going to start within 10 to 30 minutes after alcohol is consumed. Metallic taste is a more common side effect, but there are some other serious, even if rare side effects like optic neuritis, peripheral neuropathy and hepatotoxicity is a particular warning with this medication. When it happens, again it's rare, it can be very serious. It can be associated with fulminant liver failure. So I do recommend before starting disulfiram, check baseline LFTs and then check them again within the first month before the first refill is even issued because when it happens, it happens early in most cases. And you would recheck the liver function around three to four weeks after starting the medication and ensure that you have that before issuing the next refill. Then recheck them a few months later, within three months, then move to six months and that more standard monitoring of LFTs would be appropriate at that time. This slide shows the normal metabolism of alcohol into harmless byproducts, H2O and CO2, and the mechanism of disulfiram, which is to irreversibly block aldehyde dehydrogenase, which is one of the steps in this breakdown process. When aldehyde dehydrogenase is blocked, there's a buildup of toxic acetaldehyde causing flushing, sweating and other physical symptoms that are unpleasant. This slide shows a long list of potential effects in the disulfiram-alcohol reaction. There are many, but most commonly, again, people will experience flushing, headache, nausea, vomiting and sweating. They may end up needing supportive treatment in an ED such as IV fluids, though most commonly after they start to feel these unpleasant symptoms, they stop drinking. In the most severe cases, there is a risk if someone's on high dose disulfiram and really continues to drink at high levels throughout, that they could have more serious outcomes like cardiovascular collapse and potentially seizures or death. So we do want to warn individuals about this range of effects. Some people carry a wallet card. The more serious adverse effects would be rare and again, associated with ongoing drinking. More commonly, I would say these are not a reason not to use the medication, but instead to have an informed consent discussion. The reaction itself can last for 30 to 60 minutes most typically. And we do want to caution people about alcohol-containing products like hand sanitizers and certain mouth washes that have alcohol, most do not, some foods that are cooked with alcohol, these typically would cause a milder reaction, but alcohol can be absorbed through the skin. So colognes, hand sanitizers, you might experience some milder symptoms. Disulfiram is a medication that has been shown to be most effective in highly motivated individuals. I've had some patients who use it really just in risky situations, like if they view traveling by plane to be high-risk or going to a wedding because alcohol is served, they might take the disulfiram just as needed. Others take it daily, and in prior studies it's been shown to have effects on short-term abstinence and reduction in drinking days, time to return to drinking relative to placebo. However, it's a challenging medication to study because if you randomize someone to disulfiram versus placebo and the participant tests it out and drinks, they will quickly learn whether they are on the active medication, the study medication or the placebo. So it does limit our ability to draw some conclusions about this medication. But in general, supervised dosing can be very helpful because it is long-lasting and slow to metabolize in the system. In situation where someone can observe the dose, maybe three times a week, that could be effective, or in highly motivated individuals who maybe are at risk of losing a professional license, this could be populations for whom it might be more effective. Moving along to discuss acamprosate, this is a medication approved in 2004 with a somewhat challenging or more cumbersome dosing regimen. The dose is two 333 milligram tablets by mouth three times a day. That's a lot of medication, a lot of pills. So adherence becomes an issue, similar to disulfiram, but for different reasons. For disulfiram, adherence can be a challenge because if someone wants to drink, they just stop their disulfiram. With acamprosate, it's remembering to take so many pills in a day. The dose can be pretty quickly titrated up to the full dose. It's usually a very well-tolerated medication, easily tolerated. The most common adverse effects are GI upset such as diarrhea. And so usually within a couple of days individuals can just titrate up to the full dose, if they're tolerating it, of 666 milligrams three times a day. This is a medication that's indicated for the maintenance of abstinence from alcohol in individuals with alcohol use disorder, ideally started and initiated when somebody is already abstinent at treatment initiation, such as someone who has just gone through a course of medically assisted withdrawal management or detox, And it can help to reduce post-acute withdrawal symptoms. We'll talk about the mechanism in a moment. The advantage of this medication is that it is renally cleared. It's not metabolized by the liver, so dose adjustment is required in renal impairment, but it's a safer medication in somebody with significant hepatic compromise. The mechanism of action is linked to modulation of the glutamate receptor. It helps to restore that GABA glutamate balance that can be dysregulated in the case of someone who has recently quit drinking. In general, as I mentioned, when someone is entering early abstinence, there's an excess of glutamate, and that can be associated with post-acute withdrawal symptoms, anxiety, irritability, insomnia, and those are unpleasant symptoms that are associated with risk of return to drinking. It's a riskier period to get through and to maintain abstinence. So this medication is reducing the amount of glutamate released, reducing the activity of the glutamate receptors, helping to restore that balance. In terms of prior research, this is a medication that's been demonstrated to help people maintain complete abstinence more frequently than those randomized to placebo in the studies that led to its approval. Caveat is that not all of the randomized clinical trials on acamprosate have been been positive. There had been some mixed findings, but there were enough statistically significant findings and studies that led to its FDA approval. It has also been shown to prolong the time to the first drink relative to placebo and greater reduction in number of drinking days. And in those who did start to drink after starting the medication in clinical trials, they were more likely to regain complete abstinence if they had been randomized to acamprosate. Moving along now to discuss naltrexone. Naltrexone is a medication approved for both opioid use disorder and alcohol use disorder. And it's available in two formulations, oral and monthly injectable. It is an opioid receptor antagonist. As such, it blocks the opioid receptors. So it's intuitive why it can be helpful for opioid use disorder. When it's on board, it's going to block or prevent the effects of exogenously-administered opioids. In the case of its use in alcohol use disorder, if you recall, we discussed the neurotransmitter effects when alcohol is consumed, andogenous opioids are released, which then lead to a release of dopamine, the brain's pleasure chemical. So this medication is going to help blunt the effects of those endogenous opioids and then indirectly help reduce the release of dopamine. So it can help to make the alcohol itself less rewarding, less reinforcing, less pleasurable. Unlike disulfiram, it doesn't cause a physically aversive reaction when the two are used together, but instead reducing the pleasure and rewarding effects of drinking. And that's what patients will describe when it works. It does not work for everyone, but individuals will come back and say, "Oh, you know, I drank but I didn't lose control. One or two drinks didn't turn into eight or 10 drinks. I could take it or leave it more readily." Oral naltrexone is dosed standardly at one 50 milligram tablet per day. To minimize potential side effect of nausea and vomiting, when that happens, the nausea is a fairly common side effect that can happen early in treatment. It's typically transient. It typically resolves after a few days. But to minimize that potential side effect, I will often advise starting at 25 milligrams per day, half a tablet for the first three days and just take it with food, take it in the morning after you have some food in your stomach. As long as you're tolerating the half tablet per day, you can go up to the full tablet. And there are different approaches to this, that's just how I approach it. And then if they are having nausea, we can extend the half tablet for five days or seven days until they're comfortable going up to the full dose. As I mentioned, this is approved for alcohol use disorder and opioid use disorder, and it's important to assess and verify that there are no opioids in the system. If somebody is using opioids, administering naltrexone, which is an opioid receptor antagonist, it can kick the other opioids off the receptor and precipitate withdrawal. We definitely want to avoid that. So when in doubt, you can check a urine drug screen and take other measures, check prescription drug monitoring database, and really do a thorough history and informed consent process around that risk. Back to dosing, 50 milligrams per day is standard. Off-label and some research supports sometimes increasing the dose higher than 50. I've sometimes gone to 75 or 100. Some studies have even looked at 150 milligrams per day. But when you start to get into higher than standard dosing, the increase of elevated liver function enzymes goes up. There is a caution about this medication and the risk of elevated liver function tests, but more and more research is showing that at standard dosing, increasing liver function enzymes is very uncommon, meaning it's unlikely to cause liver function enzyme elevation. In fact, continuing to drink, particularly at high levels, would be a much greater risk factor for toxicity to the liver. So if someone comes in and their liver function enzymes are mildly elevated, that would not be a contraindication to naltrexone. In fact, you would just follow them more closely and observe the trends. And if they're reducing their drinking, the LFT should trend down. It is contracated in severe end stage liver disease such as Child-Pugh Class C. And as I mentioned, we want to verify that they are opioid-free and somebody who's using opioids regularly, we'd want to see that they have no opioids in their system and have avoided opioids for at least seven to 10 days, depending on how long-acting the opioid is. In terms of prior research, I mentioned acamprosate is associated with prolonged abstinence. Naltrexone, the strongest signal has been in comparison to placebo in reduction of quantity of drinking and frequency of drinking. So naltrexone is more consistently associated with reduction in quantity consumed, total drinking days and return to drinking. Extended release injectable naltrexone was developed to address adherence and improve adherence to daily oral naltrexone. This is a medication that is also approved for opioid use disorder and alcohol use disorder. It's given as a 380 milligram injection in the deep gluteal muscle every four weeks, on alternating sides each month to minimize injection site reactions. This medication can cause redness, swelling or induration at the injection site. In more rare cases, some of the injection site reactions have required debridement, and that's typically if it's not actually administered in the muscle. But this is a medication that will block the opioid receptors for a month. And so you might wonder what happens if someone actually needs opioids during that time? Again, sometimes individuals will carry this information on a wallet card in case of emergency. But if they need surgery, they've been in an accident, they need emergent surgery for any reason, the naltrexone can be overridden by high-potency opioids in a medically monitored setting. So using something like fentanyl to override the naltrexone, by all means they can receive their treatment and their opioids. Otherwise pretty well-tolerated medication, again, nausea, vomiting can occur, and we definitely want to avoid the risk of precipitated opioid withdrawal by confirming opioid-free status. Could even give a test dose, well, a naloxone challenge and or a test dose of PO naltrexone or a lead-in period with PO naltrexone. There are various approaches to inducting someone onto extended-release naltrexone to minimize, in the case of the injectable, a very protracted and more severe opioid withdrawal risk. We also monitor for mood. Depression can be, it's a reported potential adverse effect, though in clinical practice I don't typically see it. We've covered what the research shows. One other point to make is that studies have shown individuals who have maintained abstinence for at least four days before initiating extended-release naltrexone have, it's associated with improved outcomes, so whether that's partly due to patient motivation that they're starting this medication after a period of withdrawal management and now they're abstinent, that could be a factor, but we don't know all of the factors. However, it's not contraindicated to start naltrexone while drinking. Want to mention now the two off-label medication options. Gabapentin is a medication with some early signals in benefit in the management of alcohol use disorder. This is a medication that we use a lot off-label to help reduce anxiety or improve sleep, really used for many different off-label symptoms and conditions. And in the case of alcohol use disorder, it's intuitive that this might help with post-acute withdrawal symptoms, again, the anxiety, insomnia that can occur when somebody is trying to reduce or quit their drinking. And so in one early study conducted by Mason and colleagues, they demonstrated improved rates of abstinence in heavy drinking when titrated to a target dose of 1800 milligrams per day in divided doses, that the medication was associated with these improved alcohol use disorder outcomes relative to placebo. So a titration schedule might be 300 milligrams three times a day titrated up to a dose that's tolerated and or effective. There's wide variability in how that's done. Sometimes it's helpful to start at even a lower dose, like 100 or 200 milligram capsules, working up to higher doses and really stopping and targeting the dose that is effective and or tolerated by the patients, even if you don't get up to that full target dose. And then in the study, improved symptoms of insomnia, dysphoria and craving were noted. In another study, combining gabapentin with naltrexone post-drinking cessation improved outcomes in the first six weeks. So again, that's that post-acute withdrawal period. Comparing naltrexone plus gabapentin versus just naltrexone, improved outcomes were demonstrated in the first six weeks after drinking cessation in the combination medication group. So that's another approach to consider, particularly if someone is endorsing insomnia, irritability, anxiety, and that could be risky for return to drinking. More recently, a study has demonstrated improved drinking outcomes in individuals who endorsed higher alcohol withdrawal symptoms at baseline. So that subgroup who actually endorsed some degree of withdrawal symptoms did better when gabapentin was administered at a target dose of 1200 milligrams per day. And those outcomes included heavy drinking days and total abstinence, which we're not seeing in the subgroup with low withdrawal symptoms, which is also intuitive based on how this medication works and the symptoms it targets. Gabapentin is usually well-tolerated, but again, starting at too high of a dose, sometimes individuals will endorse dizziness, fatigue, GI symptoms, headache, impaired coordination. Also important to note the misuse potential of this medication, there are reports of misuse, which can be mitigated through closer follow-up, monitoring, checking of prescription drug monitoring databases to at least assess what other essential nervous system depressants the person may be taking. And lastly, topiramate, it's an important medication option that we have, one of our more robust tools, even though it's off-label, it's not FDA approved. This is a generic medication that probably won't be on track to get FDA approved. But there have been some well-done, robust randomized clinical trials demonstrating its benefit for alcohol use disorder treatment in comparison to placebo. This is a medication that is approved as an anticonvulsant and for migraine prophylaxis. And in the case of alcohol use disorder, it's been shown to be associated with reduction in heavy drinking days and other drinking outcomes. It works by facilitating GABA neurotransmission and inhibiting glutamate, so again, helping to restore that balance. And it may help with post-withdrawal dysphoria, cravings and impulsivity. In the prior randomized clinical trials, doses have been titrated slowly up to a target dose of 300 milligrams per day. In my clinical experience, many cannot tolerate that dose. You might target 200 milligrams per day or really, the dose that works and or is tolerated by the individual and stop at that threshold. Potential adverse effects, and there are many, adverse effects are fairly common with this medication, unfortunately, despite its good evidence, are cognitive effects, paresthesias, dizziness, altered taste, weight loss, and some less common effects include kidney stones, metabolic acidosis and narrow-angle glaucoma. So back to our case vignette, pulling this all together, we've just reviewed dosing mechanisms of action of these medications that you might consider for initiation in somebody with alcohol use disorder. To recap, we have a 52-year-old man, meets criteria for alcohol use disorder, has elevated liver function enzymes, two times above normal. We know that he occasionally uses opioids for back pain flareups and has no prior treatment history. So really you can start from scratch with an approach that might incorporate medications, might also incorporate behavioral treatment and, of course, in a patient-centered approach, really assessing what he's willing to do, interested, where is he at with his own treatment goals? Does he even want to receive help to reduce drinking? So is naltrexone contraindicated in this patient? The answer is no. Elevated two times above normal would not be a contraindication. Most likely explanation is consumption of two bottles of wine per night. I would consider naltrexone with a caveat about the opioid use, if we can resolve that issue and follow liver function enzymes more closely to ensure that they are trending down, if he is indeed successful in reducing his drinking. Under what circumstance would you consider disulfiram? If he's highly motivated, requests it. Ideally in patients who have tried something else or tried other approaches, or if they know that it's already working for them, meaning a brand new to treatment individual, I don't often turn to disulfiram as my first choice, but I certainly inform them about that option in the discussion. Back to the liver function issue and in combination with the opioids for back pain flareups, we certainly don't want to start naltrexone if we learn that he really needs these opioids and he's anticipated to need them, that that's the only way that he can manage that pain. So that might involve more investigation, coordination of care with whatever doctor is prescribing them, checking of the prescription drug monitoring database and really asking him, are there other approaches that work, and is he willing to abstain from opioids and avoid opioids? So if we can establish that his back pain could be managed without opioids and he's willing and motivated to do so, naltrexone is a reasonable option. And again, we would then follow the liver function enzymes. Number three, under what circumstance would you consider combining medications? As I mentioned, there is a study demonstrating benefitof combining naltrexone with gabapentin. This is someone who endorsed cravings. That's another reason I'm thinking of naltrexone. He also endorsed some other symptoms like insomnia. If you were to learn that he's really very anxious, irritable, and we think that the gabapentin could reduce some of those symptoms, we want to give him the best chance of success. So I don't automatically combine medications from day one. It's a more thoughtful process. I might also start one medication, assess the result and the outcome, and then consider combining medications down the line. And as I mentioned earlier, in addition to medications, number four, we do want to suggest, recommend and describe evidence-based behavioral treatment that can be helpful in the process of learning skills around use reduction, relapse prevention or motivational enhancement therapy. Other approaches that can be combined with medication, depending on what is available in your clinic, healthcare facility or in the community, therapists or groups that administer those evidence-based behavioral treatment approaches, and what is he willing and able to do? Thank you very much.

pharmacotherapy management

alcohol use disorder

FDA-approved medications

off-label options

withdrawal management

case vignette

individualized treatment

behavioral treatments