Welcome to the American Osteopathic Academy of Addiction Medicine's Essentials and Addiction Medicine Learning System. This topic is on Alcohol Use Problems, Recommendations for Medical Management. There are no ethical or financial disclosures to be made, but at this point I would like to credit Dr. Marla Kushner for the preparation of these slides. My name is Dr. Gregory Landy, and I will be the narrator for this presentation. Thank you for your interest, and let's go ahead and get started. There are three objectives for this particular presentation, to have a better understanding of the origin of the comorbid illness, to understand some of the more common presentations, and finally, to understand the basic principles of the treatment of the comorbid patient. As a result of your participation in this learning module, the AOAAM hopes that you as an attendee will have a better understanding of the developmental components of alcohol use problems, the commonly used medication-assisted withdrawal techniques, and understanding the importance of monitoring and encouraging ongoing treatment at the appropriate level of care for these complicated patients. So let's take a deeper dive into what this particular presentation will cover. This is your introduction. We're going to look at the epidemiology of comorbid conditions and medical morbidity and mortality. We're going to conduct what is a review of the neurobiology of alcohol, both from its behavioral and pharmacokinetic aspects. We'll look at patterns of drinking, and we'll spend a little bit of time looking at screening for alcohol use disorders. Then we're going to turn our attention to treatment, motivational enhancement therapies, the steps, relapse prevention, and the various pharmacological interventions that you can consider. And finally, we'll look at treatment in a chronic illness paradigm. One of the principal reasons the AOAAM prepared this lecture on comorbid alcohol problems and their subsequent management is the rather interesting notion that comorbid alcohol problems constitute the third leading cause of death in the United States, lagging behind only tobacco, poor diet, and physical inactivity, which of course, in turn, leads to being overweight. Comorbid alcohol problems are the second leading cause of disability and disease burden in the United States, and it probably comes as no surprise that alcohol problems are associated with at least 41% of traffic-related deaths. Alcohol is also associated with 29% of suicides, which in turn constitutes the leading cause of death among persons aged 15 to 35 years of age. All in all, comorbid alcohol problems are worthy of our attention as physicians. The health risks associated with excessive alcohol consumption cannot be underestimated. Excessive alcohol consumption is associated with a variety of cancers, including cancer of the pancreas, the mouth, pharynx, larynx, esophagus, breast cancer, and of course, hepatic cancer. Excessive alcohol consumption is also one of the leading causes of pancreatitis and is associated with sudden death in people with preexisting cardiovascular disease. Various neurologic conditions such as stroke, brain atrophy, are also related to heavy alcohol use. Of course, cirrhosis of the liver, miscarriages, fetal alcohol syndrome, injuries, of course, very commonly related to alcohol consumption, not the least of which are impaired motor skills that will lead to all sorts of accidents, including motor vehicle accidents. And as we just mentioned, suicide and heart muscle damage, such as alcoholic cardiomyopathy. So let's take a further moment and drill down into this epidemiologic data a bit more. 13.5% of the U.S. population has experienced an alcoholic disorder during their lifetime. A third of those people have had at least one other psychiatric diagnosis, a number that is even higher among women. And keep in mind that 22% of mood disorder patients have an alcohol use disorder, nearly 18% of anxiety patients, and 74% of antisocial patients, all of which goes to the absolute impurity of need to screen for alcohol problems among your patients. Humans, of course, have been consuming alcohol as long as their recorded history. And of course, not everyone that consumes alcohol develops physical or emotional problems as a consequence. And researchers have, over the years, conducted a number of studies which seem to suggest that moderate consumption of alcohol may actually confer some health benefits, such as reducing your risk of developing heart disease, peripheral vascular disease, and intermittent claudication. And the same may be said of reducing your risk of dying of a heart attack. Moderate alcohol consumption may also possibly reduce your risk of strokes, particularly ischemic strokes. Lower your risk of developing gallstones, and possibly reduce the risk of diabetes. In all these areas, pay attention to the clinical literature and see how it develops as new information is developed through research. When you begin discussing problem drinking with your patients, it seems quite natural that they're going to ask, well, how much is too much? And there are answers to this question. How much is too much? Causes or elevates the risk for alcohol-related problems, or complicates the management of other problems. There are increased risks for alcohol-related problems for men who drink more than four standard drinks in a day, or more than 14 in a week. And for women who drink more than three standard drinks in a day, or more than seven per week. So here we have both qualitative and quantitative answers to that question. So just how significant is problem drinking? About three in 10 adults drink at levels that elevate their health risks. Among heavy drinkers, one in four, or 25%, and using DSM-5 terminology, have an alcohol use disorder. And it probably goes without saying that all heavy drinkers have a greater risk of developing hypertension, GI bleeding, naturally their sleep will be severely disturbed, it will certainly complicate major depression, hemorrhagic stroke, cirrhosis of liver, and as we mentioned in previous slides, the possibility of developing a variety of different cancers. Adding to the difficulties associated with problem drinking is the fact that it often goes undetected. Of course, a number of factors are involved in that. The individual themselves will often go to great lengths to minimize or hide their drinking, and of course, loved ones may also be involved in that process. But it's important to remember that patients with alcohol use disorders receive the quality of care that they need in only about 10% of the cases, which again goes to the importance of screening all your patients for the risks of developing problems with the use of alcohol. Unfortunately, part of the problem in identifying individuals who may be at risk of being a problem drinker can be found in the medical professions themselves. There seems to be at times a reluctance to screen for alcohol use disorders. Perhaps, again, a number of factors are involved, not the least of which may be a fear of confrontation when factual data exists that may suggest your patient has an alcohol use disorder. But in terms of screening and brief intervention, it's important to remember that your patients are likely to be more receptive and ready to change than you may be expecting. Most patients don't object to being screened for alcohol use by clinicians, and many are open to hearing advice afterwards, particularly if it's factual and evidence-based. Most primary care patients who screened positive for heavy drinking or alcohol use disorders are probably implicitly aware of the problem, which gives some credence to the fact that they may be more ready to change and adopt suggestions for treatment than you might think. And those who have the most severe symptoms are often the most ready to change. As we delve deeper into our ongoing discussion of screening and brief interventions as a clinical tool, let me underline that brief interventions can promote significant lasting reductions in drinking levels in at-risk drinkers who are non-alcohol dependent. As we proceed through these slides, keep that in mind. Screening for at-risk drinking imagines an echelon approach, a tiered approach, using increasing levels of scrutiny depending on your patient's responses. You begin with asking, do you sometimes drink beer, wine, or other alcoholic beverages? Now there are patients who will adamantly declare that they do not drink at all, and there are people who do abstain from all alcoholic beverages. But people that answer that question affirmatively, saying, yes, I sometimes drink beer, wine, or other alcoholic beverages, you want to probe a little bit deeper and ask, how many times in the past month have you had, for men, five, or for women, four drinks in a day? Now keep in mind that what we're after here is a standard drink, which envisions 14 grams of alcohol, typically contained in a 12-ounce beer, five ounces of wine, and an ounce and a half of liquor. So you will need to probably clarify this with your patients so that you can more accurately quantify your patient's alcohol consumption. Now as I mentioned, the screening of at-risk drinking involves an echelon approach. Your patient indicated that they were consuming a daily amount of alcohol that exceeded the limits we just discussed. Your patient was a man, and he's drinking more than five drinks in a single day. At this point, you will invite your patient to complete the audit, the Alcohol Use Disorders Identification Test, which is a self-reporting instrument of alcohol consumption. The audit involves 10 questions. And of course, it's used to obtain more information about your patient's use of alcohol. There's been a tremendous amount of research conducted with the audit. So it's a reliable instrument, and it's valid. And it's most useful in populations including women, minorities, adolescents, and young adults. The audit includes questions about the quantity of alcohol consumed, the frequency of its use, the presence of binge drinking, dependent symptoms, and the consequences of the individual's drinking measured in terms of alcohol-related problems. There are different ways to score the audit. In this particular example, the audit is scored using a gender-based model, where individuals that score 8 or above for men or 4 or greater for women would be considered at-risk drinking. So let's move on to the next section of this presentation. And let's take a few moments to review the neurobiology of alcohol intoxication. Now this model is fairly well understood through research, but it's also at the same time incredibly complicated. Alcohol involves numerous neurobiological systems, including the GABA aminobutyric acid system, GABA, the glutamate system, opioid receptors, cannabinoid receptors, dopamine, and serotonin. This slide visually depicts the complicated relationships that alcohol has from a neurobiological perspective. If you look on the left, you can see that alcohol is interacting at the GABA receptor sites, at the opioid peptides, and at the glutamate inputs. Alcohol has actions both in the ventral tegmental area and in the nucleus accumbens. So let's spend a moment looking at each of these in turn. GABA A is intimately involved in the intoxicating effects of alcohol and is involved in the motor impairment and anxiolytic effects. GABA B is involved in the craving and withdrawal effects of alcohol. The opioid system, of course, is involved in the desire to drink and repeated self-administrations. The cannabinoid 1 receptors result in decreased alcohol preference. And dopamine, of course, is involved in alcohol reinforcement, the reward system. Repeated administration increases dopamine in the nucleus accumbens and involved in the behavioral clues. And serotonin reuptake blockade can decrease alcohol intake. So with that ever so brief review of the complicated aspects of the neurobiology of alcohol use, let's turn our attention to the treatment of alcohol-related problems. The humor in this slide captures an important and real factor that patients and clinicians and family and loved ones all struggle with. Patients with an alcohol use disorder, on the one hand, want to change, but on the other hand, they do not. It's a very difficult to and fro process. And sometimes when backed into a corner, I can change. I swear I can change. For purposes of this presentation, treatment will consist of and be reviewed in terms of motivational enhancement therapy, the steps, relapse prevention, family therapy, and social support. In the next few slides, we're going to look at the behavioral aspects of alcohol use. This slide is somewhat of a summary of what we'll be looking at in terms of the behavioral reinforcing aspects of alcohol use. And that can occur when alcohol is present or absent. It's always important to keep in mind that genetics play a role in this. We won't be discussing that in this presentation. But there's a well-developed and continuing trend to examining human genetics and its role in the development of many substance use disorders, and particularly alcohol use disorders. But of course, when alcohol is present, it can produce a positive reinforcement through its rewarding effects. Or when it's absent, it produces punishing effects, both of which, in their own ways, can lead to problem drinking. In classical conditioning and relapse theory, we begin with an unconditioned stimulus, which of course is the presence of alcohol in the brain, which produces the response that the individual finds pleasurable. This reward then produces alterations in neurotransmission that causes the subsequent relaxation, euphoria, stress reduction that, again, the individual finds pleasurable, or at least beneficial or positive. There are associated stimuli, the interoceptive. There are mood states that precipitate drinking, such as, of course, being anxious. And there are extero-receptive factors, such as the environment, the sight of alcohol in alcoholic drinks, the smell and the taste of alcohol, or paired behaviors, such as smoking. Repetition makes the associated stimuli become conditioned stimuli that are by themselves then capable of eliciting the anticipation of the reward. In other words, they've become positively reinforcing and potential causes of relapse. Now let's take a look at negative reinforcement in terms of abstinence. We have the same unconditioned stimulus, but here we have a different response in terms of adaptation. We have the same associated stimuli. But in alcohol use disorders, the conditioned stimuli elicit a central nervous system adaptation alcohol generating what is referred to as condition tolerance, if alcohol is taken, and pseudo-withdrawal if it's not, so that they are now negatively reinforcing and become potential causes of relapse. Other factors in this model can then be thought of in terms of cues and priming. We have the conditioned stimuli, epic and stress, mood states that precipitate drinking, and of course the environment, sight of alcoholic drinks, smell and taste of alcohol, and paired behaviors, such as smoking and drinking. So at the end of the day, the causes of relapse are many. Relapse can perhaps be caused by genetic factors that make individuals more susceptible. Boredom, of course, peer pressure can never be minimized. Or even just memories of drinking. Now, in these particular cases, there's not much that drug treatment can do about these. Now, areas where drug treatment may be potentially effective involve areas that are stress-related causes of relapse, such as anxiety or depression, and possibly cues and priming. So now let's look at some medical issues involving alcohol withdrawal treatment. When faced with the possibility of seizures in a patient in alcohol withdrawal, of course, it's important to take into account, as part of your history, any past seizure disorders. Any history of prior withdrawal seizures, be they alcohol or other drug-related. It's also important to keep in mind combination alcohol and benzodiazepine withdrawal, which, of course, is a more complicated scenario. Alcohol-related seizures, it's been suggested that they are grand mal in 15% to 23% of the cases. Those alcohol-related seizures typically occur in the first 48 hours, but they may be seen up to 10 days later. They may be multiple. They're rarely of the status epilepticus type, and they may require diazepam, 10 milligrams slow IVP. The first episode or atypical seizure, of course, needs an evaluation for other potential causes, and is a general rule. Of course, every case being evaluated on its own merits, but in general situations, ongoing pharmacotherapy is not indicated for strictly withdrawal seizures. A common clinical presentation of alcohol withdrawal will include hallucinations. These are primarily auditory in nature, but may include tactile or visual hallucinations. And again, the typical alcohol withdrawal examples unfold with an intact sensorium. Alcohol withdrawal may proceed to what is more commonly known as delirium tremens, a more severe clinical presentation. Delirium tremens are acute but reversible organic psychoses, but are accompanied by significant morbidity and mortality. Delirium tremens usually begins within 72 hours and may last two to six days, and in some cases, even longer. Here we have a situation of severe alcohol withdrawal symptoms with a clouded sensorium. And whereas before the hallucinations were present with an intact sensorium and delirium tremens, the hallucinations do not have any insight or recognition. And that, in turn, produces panic and the resulting agitation. Mortality increases with delayed diagnosis and inadequate treatment, and of course, with any concurrent, complicating medical conditions. In the broadest terms, alcohol withdrawal treatment involves four areas. There needs to be supportive treatment, a quiet, well-lit room, particularly to aid clouded sensoriums. There are behavioral components, nutritional elements, and of course, medication-assisted treatment. An important tool that helps guide treatment in alcohol withdrawal is the Clinical Institute Withdrawal Assessment, otherwise known as CWA. This particular instrument is subjective in terms of the assessment scoring that both the patient or nurse may employ. The CWA is a 10-item scale, quickly administered, easily scored with 10 signs that can be scored on a scale from 0 to 7, which can produce an ultimate score ranging between 0 to 67. The instrument does require that the patient be able to communicate. So here we have the revised CWA scale. So let's take a moment just to briefly look at this. And you can see the various domains that are covered. And again, the seven items that can be scored under each element. So we have either you or a nurse or other health care professional evaluating in cooperation with the patient elements involving nausea and vomiting, tremor, presence of paroxysmal sweats, anxiety, agitation, tactile disturbances, auditory disturbances, visual disturbances, headache or fullness in the head, and orientation and clouding of the sensorium. Again, fairly easy instrument to administer, but important in helping guide treatment. Two other factors that are important in your clinical management of an individual with potential alcohol withdrawal are the vital signs, particularly looking at the pulse, a resting pulse greater than 90 beats per minute, or a systolic blood pressure greater than 140. In those cases, you'll want to be thinking about beginning treatment. The treatment of alcohol withdrawal can be thought of as a gateway to the longer term treatment of an alcohol use disorder. The goals of alcohol withdrawal treatment then should be and should lead to the individual's recovery in a program immediately following their stabilization. With that in mind, the goals of alcohol withdrawal treatment include the smooth, efficient course, no seizures, of course, minimal agitation and discomfort, a smooth glide path that will allow the individual with your encouragement and your team support to continue on to the next and even more important phase of their recovery treatment. In terms of detoxification from alcohol, there are situations where you will need to consider the use of a short half-life sedative. This list is by no means conclusive or all involved, but it does give you some factors to consider. For example, liver disease if the patient is jaundiced. If the patient is intoxicated and agitated. If multiple drugs are being used. Or if you are uncertain whether your patient has early delirium tremens or early portal systemic encephalopathy. Clinicians have different options in terms of the way they want to medically manage alcohol withdrawal. Each has their own pros and cons. On this slide, we see a clinical example of how to administer a fixed dose regimen. Use of a fixed dose regimen, as you can see on the slide, is straightforward and simple. And if not complicated by the emergence of any problems, it can be well-calculated to occupy only a few days' time. A different management technique for alcohol withdrawal is referred to as symptom trigger detoxification. This clinical method requires familiarity with and use of the previously discussed CWA. So in this clinical example, chloridized epoxide, 50 milligrams, would be administered for a CWA score greater than 9. The CWA would then be administered hourly. And the medication could be administered every two hours if the CWA score, again, is greater than 9. No more than 300 milligrams should be administered in a 24-hour period. Now, we previously discussed the use of short half-life sedatives for detoxification. But it's important to keep in mind that lorazepam for detoxification should be reserved for those patients with significant liver disease or another specific indication as we identified previously. But in this example, symptom trigger detoxification with lorazepam can be used in combination with the CWA. So 1 milligram could be administered in CWA scores greater than 9. Again, the CWA would be administered hourly. And every two hours, the lorazepam could be repeated when the CWA score is greater than 9. But no more than 10 milligrams of lorazepam should be used in any 24-hour period. So you and your patient have successfully navigated an alcohol withdrawal period. And the discussion now turns to considering maintenance medications that may be helpful in preventing relapse in your patients. And these should be discussed with all patients. And there are four that can be considered. The first is disulfiram, naltrexone, which is available in both oral and injectable forms, acamprosate, and topiramate that does not currently have FDA approval. In terms of longevity, disulfiram, otherwise known as Anabuse, certainly has the record. Disulfiram dates to the 1940s. And it works by inhibiting the breakdown of acetaldehyde, which leads to an increase of acetone in the body, which carries with it the noxious side effects associated with the disulfiram alcohol combination. So when an individual consumes alcohol in the presence of disulfiram, they will feel sick, flushed, and have a pounding headache. Those are the mildest symptoms. Should you consider using disulfiram with your patients, it's very important that there be an informed consent discussion that looks into the pros and cons of the use of this medication and clearly explains to your patients all the hidden sources of alcohol that they must also avoid. This discussion would need to be carefully noted in the record and the patient in future visits. Queried as to any side effects that may occur from even incidental exposure to alcohol. So disulfiram may be helpful in light of what we just said in promoting abstinence for highly motivated patients who are monitored to make sure they take their medication. These need to be, in the ideal world, very reliable patients. It's a reasonable choice when abstinence is the desired and necessary goal. The standard clinical dose is 250 milligrams a day. There are variations on this theme and consult the literature for those. Disulfiram is contraindicated in the presence of psychosis, significant liver disease, esophageal varices, pregnancy, and impulsivity, particularly when measured in terms of an individual's adherence to the treatment regimen. Another medication you can consider for alcohol cravings and relapse is naltrexone, either in its generic form or as Revia, or in the injectable form as Vivitrol. Naltrexone is a relatively new selective competitive antagonist. It inhibits endogenous opioid transmitters released by alcohol. As a consequence of which, it reduces the rewarding effects of alcohol and the conditioned anticipation of alcohol, meaning it targets positive reinforcement. Now, long-term compliance with oral naltrexone is generally not good. It may produce some anhedonia. And this gave rise, at least in part, to the initiation of the injectable form. So what does the evidence say about the use of naltrexone? Well, meta-analysis looking at short-term studies of oral naltrexone demonstrated that its use reduced the rate of relapse to heavy drinking by about 38%. In a study of the extended release injectable form of naltrexone, also known as Vivitrol, reductions in heavy drinking plus counseling were on average 25% greater than reductions with placebo injections plus counseling. Here we have the results from a study that was published in the Journal of Clinical Psychopharmacology. The results are from a six-month, multi-centered, double-blind, placebo-controlled clinical trial among individuals with an alcohol use disorder. And you can see that the median drinking days per month declined precipitously from the number of drinking days prior to treatment to the number of drinking days with psychosocial treatment plus the use of the injectable form of naltrexone. As with all medications, there are certain things to keep in mind when using naltrexone. It's certainly contraindicated if the patient is on opioid pain medications. Now, there are common adverse events associated with naltrexone, such as nausea, headache, and an injection site reaction, such as hardening, itching, or swelling that can occur with the Vivitrol. It can cause hepatocellular injury in very high doses or five to 10 times higher than the normal doses. Naltrexone is contraindicated in acute hepatitis or liver failure. You do need to check liver function before every month for three months, and then every three months while continuing to use naltrexone. The black box warning regarding risk of liver injury was removed from Vivitrol in July of 2013. Just a few remaining notes in terms of dosing. In terms of the oral naltrexone, the FDA-approved dose is 50 milligrams per day. And in terms of the long-acting injectable naltrexone, it's a monthly IM injection of 380 milligrams. The third medication that clinicians can consider in terms of maintenance is acamprosate or Campro. Acamprosate indirectly inhibits the N-methyl-D-aspartate receptors for glutamate that in turn reduces withdrawal weakly and reduces conditioned pseudo-withdrawal. And it may target negative reinforcement and conditioning. Long-term compliance is pretty good with acamprosate. Side effects are minimal. It can cause diarrhea. It does require dosing three times a day. Some other notes about acamprosate. It appears to stabilize glutamatergic neurotransmission, which has been altered during withdrawal. It's anti-craving, reduces protected withdrawal states, appears to have no abuse liability, muscle relaxant or anxiolytic properties. Again, the dose is 2 grams daily, which can be two 333 milligram pills three times a day, which can be, for some patients, a factor leading to adherence issues. Acamprosate is contraindicated among those individuals that have severe renal disease, as suggested by creatinine clearance less than 70. In determining whether or not acamprosate may be beneficial for your patients, it may be particularly helpful for those who feel irritable, anxious, and restless, and those who have sleep difficulties. It may relieve protracted withdrawal symptoms and reduce negatively reinforcing alcohol cravings. In a meta-analysis, maintenance of abstinence was significantly improved with acamprosate. Now, although acamprosate and atrexone work through different mechanisms, it remains unclear whether they produce additive or synergistic benefits when used in combination. In terms of very general guidance, although, of course, always keeping in mind that any medication selection is a process of a discussion with your patients, their preferences, and their unique medical circumstances. But again, in very general terms, disulfiram may be suggested when the patient is committed to no further drinking and there are significant consequences of relapse. Now, atrexone may be indicated for the patient who wants to come back or get help for craving. And acamprosate may be considered when atrexone didn't work. The patient needs opioid analgesia or disulfiram is simply not an option. So in summary, the treatment of alcohol use disorders is a dynamic field undergoing a great deal of research. And with this in mind, watch for new research. For members of the American Osteopathic Academy of Addiction Medicine, you have a free subscription to the Journal of Addictive Diseases, which is your portal to the latest research in this area. Medications can be an important part of treatment. Patients experience powerful conditioned responses, positive and negatives, resulting in a powerless feeling. Medications, social treatments, environmental assistance, family therapies, the treatment of alcohol use disorders is a multi-modal intervention. As this presentation comes to a conclusion, let me thank you on behalf of the American Osteopathic Academy of Addiction Medicine for participating in our learning management system. Again, my name is Dr. Gregory Landy. And we look forward to your participating in our other learning management systems. And our other topics in addiction medicine.

Alcohol Use Disorders

Comorbidity

Neurobiology

Treatment Strategies

Pharmacological Interventions

Withdrawal Management

Motivational Enhancement

Behavioral Therapies