Jill Cottel, MD - LDN for Alcohol Use Disorder (2017 Conference) (LDN, low dose naltrexone)


Jill Cottel, MD - LDN for Alcohol Use Disorder (2017 Conference) (LDN, low dose naltrexone)

Dr Jill Cottel: Hello everyone. This is Dr Jill Cottell. I'm an internal medicine doctor from Poway in California. As always, it is my pleasure and privilege to work with the LDN Research Trust.

All our speakers for this conference are discussing topics that relate to low dose naltrexone or LDN, which I could talk about forever, but for the purposes of this presentation, we are going to be looking at a different way of using naltrexone, not in low dose form, but in standard dosing, which is 50 to 100 milligrams per day rather than the couple of milligrams per day we dose with when we use LDN. Specifically, today I will be talking about something called targeted dose naltrexone used for the treatment of alcohol use disorder. At our LDN conferences, we generally have a large number of nonmedical people, such as patients watching our presentations. So I have tried to design this talk to meet the requirements for the conference and at the same time be at a place for someone who is not a medical provider, who is perhaps a patient or a family member of someone with alcohol use disorder where that person can follow along, understand what we're talking about, and get something out of this.

Also, if you are a patient listening and are only interested in getting right down to the nitty-gritty on targeted dosing and not the background information leading up to it, you can skip forward to about halfway through this presentation to where we start dealing with that specifically. Now you're going to notice that the slides that I'm using are not overflowing with information.

They really have just a few words on them, just enough to keep us on track as we move through different topics. The slides are beautiful pictures that my kids have taken, so I'd like to think some, the reason that there isn't much text on the slides is that I need you listening to me. Me, I'm going to be talking for about an hour.

You can't see me talking or watch my hand movements, and I need you to be listening to me carefully in order to hold your attention, and I don't want to lose you while you're reading slides while I'm talking. There will be a few slides that will have references for them. You could feel free to pause the video at that point and take notes.

Just don't start reading and quit listening, or you'll miss some good stuff. So today we're talking about alcohol use disorder, but before we begin, I want to ask you a question, and I want you to consider it carefully. But before I do, I need you to do something for me. I need you to forget everything you have ever been told about alcoholism.

Forget everything you have ever heard about different alcohol treatments. Forget everything you think you already know and stay with me for just a moment. The question is, what if there was a cure for alcohol use disorder? Think about it for a moment. What if there was a cure? Not a treatment, but actually a cure.

And I'm not saying there is one. Not right now anyway, but I'm just asking you if there work here, how would that change the way you think about alcohol use disorder? And I want you to really think about it. Who do you know that could be helped? Are you thinking of a patient? Are you thinking about someone who is a patient right now?

Or are you thinking of one of your patients who may be died of an alcohol-related medical problem? So stay with me. Are you thinking about someone else? Is there a family member you know? A distant relative, maybe a close to a relative. What if alcohol craving could be fixed and done away with no longer in someone's life?

What if it was the same way we treat strep throat or an ear infection? The patient comes into the office, we make the diagnosis, and then we prescribe treatment. They take the medicine, and the problem is gone. It's not something they live with all their life, constantly enduring pain and suffering, experiencing it, not just themselves, but affecting everyone they care about.

We don't expect people with ear infections to live their life with an ear infection. We address it, we treat it, and then they no longer have an ear infection. What if alcohol use could be treated the same way? I just want you to think about that today as we go through some slides.

So I've been in practice a long time, long enough to know that I don't know everything.

And that's a difference from when I first started practising about 20 years ago because at that point I thought I knew at all. That's the system we're trained as doctors. I was trained to ditch traditionally as an allopathic medical doctor.

Many of you listening were trained in other traditions, maybe osteopathic medicine or holistic medicine, and maybe your training does it like that. I don't know. And maybe the training that I went through is different now. Maybe it's changed in the past 20 years, and doctors come out of training now with a different spirit. I don't know. All I can tell you is what it was like for me, but putting years on your life and your career changes you, it humbles you, or at least it should, and it has enabled me to think about things a little bit differently than I did back then.

I'm going to tell you about two patients of mine. They are or were both very dear to me and their families as well for that matter. The first patient I want to tell you about is Larry. That's not his real name, of course. I met Larry when I was only 33 years old, just getting started in private practice.

Larry was 53 years old and a great guy. He enjoyed hanging out with his family. He had a good job and was able to provide for everyone, but he had a problem, and that was that he drank too much, and by that, I mean too much alcohol. It had been hard liquor for many years, and then he cut back to wine. Larry eventually ended up developing cirrhosis, and then he developed liver failure.

He became jaundiced and had terrible abdominal swelling from ascites. He was getting regular paracentesis. That's a procedure to remove fluid from the inside of the abdomen. The problem is that it just recollects. It's a temporary fix. He finally got into the transplant clinic at the local university, but he wasn't a candidate for transplant because he was still drinking.

At that point, he was finally able to achieve sobriety, but he had to remain sober for six months before he could go on the list. I think it must've been the worst six months ever, both for him and for his family. During this time, his jaundice and swelling kept getting worse, and he had to see multiple specialists and take more medication.

He had something called a TIPS procedure done, which stands for transjugular intrahepatic portosystemic shunt, to relieve the pressure on the circulation through and around the liver. It seemed to help, but then he developed hepatic encephalopathy, which is where jaundice just starts affecting cognition.

Eventually, he made it onto the transplant list. Towards the end of the year, he was cleared by cardiology for the surgery, and just a little month later when the liver became available, he went for the transplant, but he didn't survive. He was 62 years old when he passed away, leaving behind a wife and two daughters.

This was six years ago. Now I'm going to tell you about a different patient. His name is Carl. That's not his real name, of course. He also started seeing me when I was fairly early in my career. He was 70 or 47 years old when I met him. Carl is a great guy, works hard, has a great family, a great wife. He's a big guy, six foot five inches tall, and so he can put away a lot of alcohol and not feel it at all.

The problem is that his heart feels it. He started developing episodes of heart arrhythmias. He had been to the ER a few times and had visited the cardiologist who had a conversation with him about how alcohol affects the heart, and when I saw him, we would talk about his alcohol intake. I would tell him to drink less, and he'd come back in, and somehow he'd still be drinking the next time I saw him. You know how it goes. So this went on for six years. Well, there's a twist on this story because, in 2014, I was at a conference put on by the LDN Research Trust, where we're all learning about low dose naltrexone. There was someone there by the name of Claudia Christian, and she gave a talk on how naltrexone given in a targeted way, one hour before drinking, had helped her to stop drinking. It was a really good presentation, and she was very passionate, so I looked over what I found out about it, and it seems safe and certainly worth trying. When I got back into town, I called up Carl and had him come into the office. I told him about everything I had learned about this method of treating alcohol use, and he was up for trying it.

As it happened, it worked very well over the course of two months. Instead of drinking one to two 12 packs of beer, plus however many shots of liquor, he was down to a few drinks a night, and that's now three years ago. He's still doing well and has been able to maintain it, and not only that, he's much healthier, and his heart is happy, and his cardiologist is happy, and that makes me happy.

So I'm going to ask you. If you have a patient who is consuming more alcohol than his or her body can handle, how do you want their story to end? Are you planning on telling him or her at every single visit that they need to drink less cut back or stop drinking? Or would you like to have the opportunity to offer them a treatment that could change their life? So maybe prevent cirrhosis or heart disease? It's really a pretty easy question.

So what exactly is alcohol use disorder? How do you define it? Alcohol use disorder (AUD) is a new terminology that was introduced in 2013 in the DSM five. It is defined in the following way. There is a list of 11 criteria, and the presence of at least two of the criteria qualifies for alcohol use disorder or AUD. The severity is defined by how many criteria the patient has. Mild is two to three, moderate, four to five and severe is the presence of six or more symptoms. Here's the list:
1.    Alcohol is taken in larger amounts or over a longer period than intended
2.    Persistent desire or unsuccessful efforts to cut down or control alcohol use
3.    A great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or recover from its effects
4.    Craving or strong desire. Urge to use alcohol
5.    Recurrent alcohol use resulting in a failure to suffer fill major role obligations at work, school, or home
6.    Continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol
7.    Important social, occupational, or recreational activities are given up or curtailed because of alcohol use.
8.    Recurrent alcohol use in situations in which it is physically hazardous
9.    Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol. And note here that this number nine is pretty easy for us to inform our patients of once we know that alcohol is affecting their health
10.    Is tolerant as divided, defined by either of the following:
a.    a need for markedly increased amounts of alcohol to achieve intoxication, or the desired effect or
b.    a markedly diminished effect with continued use of the same amount of alcohol
11.    Withdrawal as man manifested by either of the following:
a.    the characteristic withdrawal syndrome for alcohol or
b.    alcohol or a closely related substance such as a benzodiazepine is taken to relieve or avoid withdrawal symptoms

So this brings us to the problem of how to identify patients with AUD so we can get them treated. We need to realize that only a very small minority of people who have the problem are coming to us.

One report I read said that if you look at people who have had AUD in the past 12 months, only 7.7% of them are seeking help, and only 3%, 3.6% of them received treatment from a healthcare practitioner. And the population of people with a lifetime AUD, only 8.7% of them have received treatment from a healthcare practitioner.

We can do better. US preventive services task force recommend screening all adults age 18 years and older. There are very simple three questions screening test for AUD that only takes one to two minutes to give. It is called the AUDIT. It was developed as part of a world health organization collaborative project for identifying and managing alcohol-related problems in primary care.

The original AUDIT screen, which was ten questions long, was developed and evaluated over a period of two decades, and it has been found to provide an accurate measure of risk across gender, age, and cultures. It was the first screening test designed specifically for use in primary care settings, and it is the only screening test that was specifically designed for international use.

The screen identifies hazardous and harmful alcohol use as well as possible dependence. It is fast and easy and focuses most on recent alcohol use. The AUDIT-C, which is the abbreviated three-question version, has similarly been validated now, and it is used by the VA clinics here in the U S.

As to who is qualified to screen the patient, the VA says specifically, “Any trained person who is willing to ask the questions verbatim in a private setting, in a non-judgmental fashion.” AUDIT-C is scored on a scale of zero to 12. The questionnaire goes like this:
1.    How often do you have a drink containing alcohol?
2.    How many standard drinks containing alcohol do you have on a typical day?
3.    How often do you have six or more drinks on one occasion?
You can see from the slide the options for the answers. Each answer has the value of zero, one, two, three, or four points, then you add them all up. A positive score for women is three or more points, and a positive score for men is four more points.

This works very well for identifying patients who are at risk for developing problems related to their alcohol use, and for catching people who are already there. If you look at the statistics, the sensitivity and specificity are very good for hazardous drinking and all active alcohol use disorder. Interestingly, the sensitivity is higher in men, but the specificity is higher in women.

So, moving on. Now that we know how to identify someone who may need help, we need to understand why it's important to find these people. And in order to do that, we need to look at the burden that alcohol use and abuse puts on our world. The world health organization lists AUD as among the highest disease, morbidity and mortality burden worldwide with an estimated 2.5 million deaths per year. And the US AUD is the third leading cause of preventable deaths, killing an estimated 85,000 people per year and costing the country over $220 billion annually.

Motor vehicle crashes are the leading cause of death for adolescents in this country. 37% of traffic deaths among youth age 16 to 20 years of age involve alcohol. And these deaths frequently involve alcohol-impaired drivers with lower blood alcohol levels than other age groups. In 2009 about 4% of 16-year-olds and 9% of 17-year-olds drove under the influence of alcohol at least once during the previous year.

Alcohol use disorders caused threefold to fourfold increased risk of early mortality. AUD is associated with hypertension, heart disease, stroke, cancer, including specifically of the mouth, throat, oesophagus, colon, liver, and breasts. It's associated with cirrhosis of the liver, cognitive impairment, peripheral neuropathy, gastritis and gastric ulcers, pancreatitis, decreased bone density, anaemia, depression, insomnia, and anxiety.

Alcohol use in pregnancy is linked to a pattern of developmental abnormalities known as fetal alcohol syndrome, which occurs in about 0.2 to 1.5 per 1000 live births in the United States. Alcohol is often involved in injuries and violence, fires, drownings, falls, homicide, suicide, child maltreatment and domestic abuse, pedestrian injuries, and as mentioned above, motor vehicle crashes.

Now I'd like to turn your attention to a publication by the Substance Abuse and Mental Health Services Administration, a division within our Department of Health and Human Services. This is a 64-page report on results from the 2014 national survey on drug use and health. For the report, they interviewed almost 68,000 people who are 12 years of age and older and residing in households and non-institutionalized residences such as boarding homes, college dorms and shelters. The survey was conducted in such a way as to be representative of the country as a whole and of each of the 50 States. The targeted sample size was distributed across three age groups with 25% allocated to adolescents age 12 to 17, 25% allocated to young adults age 18 to 25 and 50% allocated to an adult age 26 or older.

Here's what the data shows. There were 139.7 million past month alcohol users age 12 or older, including 60.9 million who are binge alcohol users and 16.3 million who were heavy alcohol users. Binge alcohol use is defined as drinking five or more drinks on the same occasion on at least one day in the past 30 days.

Heavy alcohol use is defined as having this number of drinks on the same occasion on five or more days in the past 30 days. In 2014 to present you to people aged 12 or older who are past month alcohol users. With 52.7 of people surveyed, and this was similar to the percentages found in 2009 through 2013.

The percentage of past-month binge drinking in the same group was 23%. This number had not changed over a 12 year period from 2002 to 2014. The percentage of people in the same group who are past month heavy alcohol users with 6.2% and this was similar to the percentages in 2011 to 2013. If you look at these numbers in the circle diagram, you can see the percentage in another way. Of the 139.7 million drinkers,

43.6% were binge drinkers. And of the binge drinkers, 26.8% of them were heavy drinkers. Another thing you can see is that the heavy drinkers are making up 11.7 of all drinkers. So when you think about the numbers, some studies are estimating that eight to 9 million people in the US are affected by AUD.

But if you look at this survey, we're actually looking at what could be more like 16 million people with a problem. That's a lot of people. And so maybe at this point, you're just thinking, well, these are adults. We don't feel sorry for them. They've made their bed, let them live with the consequences, why I'm about to show you another slide that might make you feel differently about that.

Let's look at a different group. These are people between the ages of 12 and 20 these are teenagers. These are our kids. In 2014 22.8 of underage people, recurrent alcohol users. That's 8.7 million teens, 13.8% were binge alcohol users. That's 5.3 million teens. And 3.4% or already heavy alcohol users.

That's 1.3 million teens. We have 1 million teens in this country drinking heavily, and just like the last slide, we can see these percentages and another way. Of the 8.7 million teenage drinkers, 60% of them are binge drinkers of the binge drinkers, 24.8% of them are heavy drinkers. Of all teenage drinkers, 15% of them are heavy drinkers.

Looking at the young adult group aged 18 to 25 more than one-third of young adults in 2014 were binge alcohol users at 37.7%, and one in 10 were heavy alcohol users at 10.8% again, the takeaway point is that a lot of our kids are in trouble. Here's another interesting slide. The large yellow circle shows a group of 17 million people who have an alcohol use disorder.

The smaller red circle shows a group of 7.1 million people who have an illicit drug use disorder. The middle orange area shows the overlap between people who had an alcohol use disorder and people who had another substance use disorder. The overlap is smaller than you might think. There were 2.6 million people who had both an alcohol use disorder and an illicit drug disorder.

This is only 12% of all patients who have an alcohol use disorder. So 79%, almost 80% of people with AUD do not also have a problem with illicit drugs. So the great majority of people with AUD are only having trouble with alcohol and not with other drug use. This has implications for treatment, especially in primary care where doctors might be worried that patients with AUD are too complicated to manage and need to be referred out.

So at this point, you should be sufficiently convinced that we have a problem and we need to do something about it. But what? It's just telling them to stop drinking enough. The US preventative health task force says it's worth a try.

If you catch someone with a positive screening test, a brief behavioural counselling intervention lasting somewhere between six and 15 minutes could be all it takes.  Brief, multi-contact behavioural counselling has the best evidence of effectiveness. The counselling can include action plans, drinking diaries, stress management, or problem-solving. And there are some people who are capable of just stopping drinking with no further treatment. There are some studies suggesting that 20 to 30% of people with AUD can achieve long-term remission without any formal treatment.

Many of us know that. Many of us know these people, and of course, they don't get why other people can't just do the same thing. According to the next publication that we will be looking at. There are other studies indicating that less than 10% of people with AUD are able to achieve long periods of non-problematic drinking.

Because of that, the goal of treatment in the US has traditionally been complete abstinence because of the belief that it is unlikely that those with alcohol use disorders can return to controlled healthy alcohol use. However, controlled drinking and harm reduction are often goals of treatment in parts of Europe.

Over the past 15 to 20 years, awareness has grown that treatment may still be beneficial even if complete abstinence is not achieved. Measures such as significant increases in abstinence days, decrease in heavy drinking episode, improved physical health and improvements in psychosocial functioning are used to look at results.

Research using these outcomes have provided evidence for the effectiveness of treatment for alcohol dependence, medications are currently FDA approved in the US for the treatment of alcohol dependence. These disulfiram, acamprosate, and oral naltrexone and long-acting injectable naltrexone.

Until the 1990s, we only had the one medication disulfiram available for use. Disulfiram is an aversive deterrent that basically makes you sick when you drink. It works by causing the buildup of acid aldehyde, drain alcohol consumption. This produces a variety of nasty side effects, which can include nausea, dizziness, flushing and changes in heart rate and blood pressure.

The second medication, acamprosate is thought to work on the NMDA receptors in the brain and modulate their activity. All of these medications have shown evidence for efficacy, enhancing abstinence, reducing relapse to heavy drinking and reducing overall drinking behaviour. For the purposes of this talk, we are going to focus exclusively on naltrexone.

This is a medication that has a very interesting history. Back in the 1980s, researchers were looking for a way to treat opioid addiction. Naltrexone as a compound that almost exactly matches an endorphin that our body makes naturally called metencephalon. Endorphins are happy hormones, kind of like natural opiates.

They were released when we are doing something that makes us feel good like jogging or eating chocolate. Well, naltrexone matches this endorphin so closely that it actually binds to one class at the endorphin receptors. It doesn't turn them on. You can't get higher or anything, but rather it locks them up.

You can have a patient who was addicted to opiates take their opiate drug of choice, and they couldn't get high because their endorphin receptors were locked up and blocked. Naltrexone was approved by the FDA for the treatment of opiate addiction in 1984, and it worked quite well for that. After that Naltrexone began getting attention for possible use in the treatment of alcohol addiction. In 1992 there were two studies published in the Archives of general psychiatry, one by Volpicelli at al, and one by O'Malley at al. Both of these studies showed naltrexone to be superior to placebo in reducing the rate of relapse to heavy drinking and alcohol-dependent individuals.

Based on these two studies, the FDA approved naltrexone for the treatment of alcohol dependence in 1994; this was closely followed by approval by similar boards than many other countries. In 1996 the World Health Organization concluded that naltrexone was a safe and effective treatment for alcohol dependence.

In 1999 the Agency for Healthcare Policy and Research, a division of the Department of Health and Human Services also came out with support. Currently, the VA guidelines recommend that oral naltrexone and or acomprosate routinely be considered for patients with alcohol dependence. So let's look at the data for naltrexone.

In 2005 the largest meta-analysis to that day looked at 24 randomized controlled trials. It showed that daily treatment with oral naltrexone decreases the risk of relapse to heavy drinking by about 36%. In 2014 and meta-analysis published in the journal of the American medical Association looked at 53 studies involving over 9,000 subjects.

It concluded that naltrexone was associated with a reduction in return to drinking. On this site, you can see that the different boxes of diamonds shifted to the left, or all the studies shown favouring treatment, and there are many more of them on the left than on the right. A clinician research summary published by the Agency for Healthcare Research and Quality concluded that there was moderate strength evidence for oral naltrexone.

Within the summary is a table looking at the studies, and I want you to just focus on the oral naltrexone. The oral naltrexone is outlined here in the bold blue in the middle of the slide. They show a number needed to treat of 12 to prevent a return to heavy drinking. This value is very good. We prescribe a whole lot of medications with a number needed to treat a much higher than that.

In summary, as stated by Dr John Davidson Claire, in his review article written in 2001, quote, the use of naltrexone in the treatment of alcoholism is well supported by the scientific evidence and accepted by many regulatory agencies. Indeed, there probably is stronger scientific evidence supporting the use of naltrexone than for any other medication and probably more conclusive scientific evidence for it than any other alcoholism treatment of any kind.

So we go from there to this. This is a 447-page document by the agency for Healthcare Research and Quality published in May of 2014. It is a review of all different types of medications used to treat alcohol use disorder in outpatient settings. The technical expert panel consisted of prominent people from the Medical University of South Carolina, Yale University, John Hopkins University, New York University, The National Institutes of Health, and SAMHSA, The Substance Abuse and Mental Health Services Administration. There were 44 trials that met their criteria for inclusion in their review. The majority of the trials were conducted in the United States. 27 trials. Eight trials were conducted in Europe, three in Australia. Two in Brazil. One was multinational involved with the United States, France and the Netherlands, and there was one each in Singapore, Iran, and Taiwan.

Here's what they found in regards to naltrexone, 4% fewer subjects treated with naltrexone returned to any level of drinking. 7% fewer subjects returned to heavy drinking. Substance subjects treated with naltrexone had 4.6% fewer drinking days than those treated with placebo. 3.8% fewer heavy drinking days and 0.5% fewer drinks per drinking day than those treated with placebo.

Looking at health outcomes, none of the studies showed a significant difference between those treated with naltrexone versus placebo. Either in quality of life scores or overall physical or mental health scores. One study measured the drinker inventory of consequences at 16 weeks. More patients in the placebo group reported alcohol-related consequences then in the naltrexone group as measured, 76% versus 45%. Based on the results, the experts concluded that naltrexone was indeed effective for improving alcohol consumption outcomes for patients with AUD, but at least with the question of why are the numbers so unimpressive? And why are there so many contradictory studies?

It makes you wonder if there is another factor involved. Something that could explain why naltrexone sometimes works very well and other times not so well. Could it have anything to do with how it is being dosed? Well, there's actually a very easy way to look at that. When you use injectable naltrexone, it produces a steady-state level of the medicine, whereas always in the patient system, if there's truly no difference in results with dosing methods, we should see the injectable formwork exactly the same as the oral naltrexone. Now it happens that the same people who wrote that the 474-page document reviewed four trials on injectable naltrexone involving about 1,300 subjects.

There was no significant difference in return to any drinking or returned to heavy drinking. There was a slight decrease in heavy drinking days at 4.6%. So what does this tell us? It means that there's something important about how naltrexone is dose. This takes us back to the person I mentioned earlier, Dr John Davidson Claire. He had been doing research with animals for decades and looking at how animals respond to alcohol based on the specific timing of naltrexone dosing. He thought that naltrexone worked the different way, actually changing the wiring, if you will, in the brain. So now I'm going to back up a bit.

It is thought that for many people, when alcohol is consumed, it causes a release of the person's natural endorphins. These endorphins then act on the dopamine system of the brain, which in turn affects how behaviours are developed and reinforced. It has been hypothesized that if naltrexone could block the endorphin receptors when alcohol was consumed, it could change the way the brain reacts when people drink.

This idea is something called pharmacological extinction. It happens when the brain finally learned that certain behaviour, in this case, the consumption of alcohol no longer leads to the release of endorphin. When it does, it will actually shut down the pathway that drives the brain to crave the behaviour.

In this case, the craving for alcohol. This is similar to Pavlov's effect in reverse. Yvonne Pavlov was the Russian physiologist who won the Nobel prize in 1904 for his work on how behaviours are learned and extinguished. In his famous experiments, when dogs were fed at the bell was ringing. So the dogs began associating the bell ringing with food coming, and they began to drool as soon as the bell was run. If you only rang the bell, the dogs would drill because of the positive reinforcement of food. Eventually, the dogs began to drool, just drool just when the bell rang, even before they were fed. But if you stopped feeding them when the bell rang—thereby removing the reinforcement, eventually, they stopped drooling because their brains learned that the bell no longer equalled food. This is called extinction of behaviour. So these experiments were with dogs and dr Davidson Claire's work had been done in rats, and we all know that people are much more complicated than rats or dogs, but there are some primitive pathways in the brain that work pretty much the same way.

The question was, could naltrexone block the reinforcing effects of alcohol and people? If you gave naltrexone before a person drank and it was in their system binding and locking those endorphin receptors before the positive reinforcing effects of alcohol had a chance to kick in, could it extinguish the behaviour in the same way that it could in rat?

His word eventually led to some Saul trials in humans. Preliminary results suggested that this was actually possible, but this required a huge shift in paradigm. It was the idea that for the medicine to work subjects actually had to drink alcohol with the medicine. Up to this point, trials had required a period of detoxification before entry.

The patients were never still drinking. In fact, everything was done that could be done to support sobriety. So now we're getting to the good stuff. We get to look at the studies using targeted dose naltrexone for the treatment of alcohol use disorder, and initial open-label pilot study of targeted dosing in 1997 showed positive results in drinking-related outcomes.

The first randomized controlled trial in 2001 the daily dosing for 12 weeks, and then targeted dosing for 20 weeks, and it showed a sustained risk of relapse over placebo 3% versus 27%. 2003 randomized controlled trials showed that eight weeks of targeted treatment led to a decreased risk of any drinking and of heavy drinking.

A secondary analysis of data published in a 2006 randomized controlled trial showed a decrease the number of drinks per day. In 2007 a study of Nalmefene, which is the same class of medicine, so targeted dosing to be superior to daily dosing and for endpoints.  A 2009 randomized control trial showed significantly less drinking in the targeted group versus the daily group and fewer drinks on drinking days. This is the article published in 2013 in CNS Drugs, which is available as a public access document through the Department of Health and Human Services here in the US. The authors reviewed the data, looking at targeted dosing of naltrexone and Nalmefene.

They concluded that quote, the targeted or as a needed approach to treatment with opioid antagonists is an efficacious harm reduction strategy for problem drinking and alcohol dependence. Quote. At this time Nalmafene has been approved in Europe by the European medicines agency as an as-needed, adjunctive treatment for alcohol dependence.

In the US the method of targeted dosing of naltrexone is not widely known. Most physicians are still operating the paradigm that treatment for alcohol use disorder requires the removing of alcohol and are not familiar with the data from these trials. This presents a significant barrier to getting this treatment to the patients who need the help the most.

There are a number of advantages of beginning treatment for AUD while patients are still drinking. The most obvious advantage is that it doesn't require the patient to stop drinking. This makes the treatment more appealing to many patients, especially those who have failed other methods requiring sobriety.

Another advantage is that patients do not have to experience the withdrawal symptoms of suddenly stopping alcohol. Which can include anxiety, hallucinations, the shakes and seizures, and no withdrawal symptoms means we don't need to use benzodiazepines. Medications, which can be addicting in their own right, and that are potentially high risk to prescribe due to the possibility of a patient combining them with alcohol.

And if you don't have to go through detox, you don't need to be admitted to a clinic, which saves a lot of money. Alcohol treatment facilities often cost thousands of dollars just for a few days, and the ones that aren't expensive are often very unpleasant to be in. Another advantage of targeted naltrexone treatment is that it can be done in a primary care setting.

The combined trial was published in 2006 and the journal of the American medical association. It is the largest known controlled clinical trial, evaluating medications and other treatments both separately and in combination for treating alcohol dependence. It was supported by the National Institute on Alcohol abuse and Alcoholism and evaluated 1,383 patients from 11 sites in the US.

There were four different medication groups, naltrexone plus placebo pills, naltrexone plus acamprosate, aacamrosate plus placebo pills, or placebo pills alone. All the patients taking medication got what was called medical management, which was basic advice from the private prescribing clinician using an easy to follow manual.

They educated their patients about their disease, gave them advice for reducing drinking, discussed medication side effects, and emphasize the importance of routinely taking medications as prescribed. The initial time was 45 minutes, and followups were 20 minutes each. In addition to medical management, half of the patients in each group were also given speciality alcohol therapy called combined behavioural intervention for up to approximately 20-50 minutes sessions.

The combined behavioural intervention was specially developed to include a strategic blend of behavioural treatments that had previously been shown to be successful. For example, motivational enhancement therapy and cognitive behavioural therapy by providing speciality therapy to only half of the patients taking medications.

This study was designed to assess the advantage of combining speciality treatment with medications. So the way it worked out was like this. There were nine different treatment groups. Eight of them involve some form of pills and one without any pills. The group that got pills, groups that got pills, all had either medical management alone just talking to the clinician or had the behavioural intervention also.

And here are the results. Every group benefited in terms of reduced drinking rates. But here's something you might not have guessed. The patients given naltrexone with just medical management actually did better than naltrexone with combined behavioural intervention. Just so you really get this, it means that the patients who just had their treatments treatment explained to them by the doctor actually did better than the ones who also went through the fancy combined behavioural intervention program.

The implications of this are enormous. It means that targeted naltrexone treatment can be given in a primary care setting by clinicians just like us without having to send our patients through a program that their insurance might not pay for or that they can't afford, or that they don't have time off work to attend.

We have patients who desperately want treatment, but they can't afford to check into a treatment centre. They can't take time off of work, or they can't afford the fancy outpatient programs. Now we have a solution. We have something that works with the studies to back it up. It doesn't just decrease drinking, but it removes craving by pharmacological extinction.

It's affordable at just a little over a dollar a pill, and patients don't need to take any time off work for treatment, and they can start treatment the day you see them in the office. In Finland, targeted dose naltrexone is very commonly used for alcohol treatment. Dr Roy Scapa, in his book, The Cure for Alcoholism reports that upwards of 70,000 patients have been treated in Finland. And the clinics there are reporting somewhere between 75 and 80% success rates. This is around the same success rates that other groups are reporting, both in the US, now all around the world. For example, Chord, a nonprofit group working in rural in North India. As we look at these success rates, we need to keep in mind that no one treatment is going to work for everyone.

Not all drinkers are addicted to alcohol. If we follow our theory of naltrexone working by pharmacological extinction, it stands to reason that we should not expect it to work on someone who's drinking is not endorphin mediated. If alcohol does not cause endorphin release in a patient, then blocking the endorphin receptors would not be expected to be a benefit.

But even if it doesn't work all the time, prescribing naltrexone is worth a try. Naltrexone is generally well tolerated, inexpensive and easy to prescribe. Even if the success rates were greatly exaggerated we're still looking at millions of people who could benefit because so many millions of patients are affected.

The American cancer society in the US has a slogan that says, that says that cancer is preventable, treatable, and beatable. What if we could say the same thing about alcohol use disorders. What if you had a patient with a family history of alcoholism and you gave them naltrexone to take before that glass of wine in the evening?

Could we prevent alcohol use disorders from ever beginning? What if every prep parent who sent their kid off to college or university sent a bottle of naltrexone along with them? Would the world be a different place? So now we're going to go through some case studies of patients that I have worked with personally.

Our first case is a 51-year-old female in good health except for migraines and some myofascial pain. Her life was great, with no issues. She was a little overweight with a BMI of 27, and she had been working on cleaning up her diet in order to lose some weight, but she knew that the wine that she liked to have in the evening was an issue and her use was slowly creeping up.

So was she was started on naltrexone 50 milligrams, one tablet an hour before her first glass of wine in the evenings. At a followup visit, a little over three months later, she was feeling really well. She was going to bed earlier, waking up refreshed, and her energy was much better. She reported that she had a response in the first week with a major reduction in the amount of alcohol consumed by about one half.

At the time of her followup, she was drinking about one glass of wine per day and was also having days where she would prefer not to drink at all.

Our next case is a 46-year-old female with depression, obesity. She used to crave sugar and need a lot of it until having gastric bypass surgery. After the surgery, she found that she couldn't eat sugar without getting sick.

She found that as she ate less sugar, she was consuming more alcohol. After several stressful events occurring in her life, she lost control of the amount of alcohol she was consuming. At the time of her visit with me, she was finding that after that first glass of wine, she would have, she couldn't stop and would keep drinking for the next few days.

She would eventually stop, but then after two to three days, her cravings were too strong, and she would start drinking again. She had failed multiple rehab and treatment programs. Her longest period of sobriety in the past few years was three or four months. At her initial visit with me she was discouraged and sceptical, but we started her on naltrexone 50 milligrams, one tablet before for her first drink of the day.

She took her first tablet that night and then contacted me the next day. She stated that she was unable to finish the glass of wine that she poured that night, and she wondered if this was normal. I told her that it could be like that for some people. We touched base again after a week, and things were going well, and she stated that she couldn't be more pleased with her three-month point.

She was no longer having alcohol cravings and actually rarely felt like drinking.

Our next case is a 30-year-old male who was raised by alcoholic parents. He was brought in to see me by a family member and a close friend. He had a long history of alcohol, starting with his first drink at age nine years old.

He became a daily drinker at 12 years old. His first encounter for treatment was between 13 and 14 years of age. When he came to see me at 30, he had failed multiple programs and really felt like he was out of options. He was having a very strong cravings for alcohol and sugar. He was drinking a fifth of vodka per day, which is about the same size as a standard bottle of wine.

And he would split it into one half-pint portions starting at breakfast around 6:00 AM until bedtime between eight and 10:00 PM he would often get up in the middle of the night to do a shot of alcohol if you start having bad withdrawal symptoms. We started him naltrexone, 50 milligrams per day. He had family staying within the first month for moral support. At his one month point, he had gone from one-fifth of vodka per day, the six beers per day and he was completely off of heavy liquor. However, at this point, he decided to stop the naltrexone and to get his advice because he felt like he'd be fine without it. He made it about another month maintaining the same level of drinking, but then he connected with an old friend and lost touch with his family. Historically that had meant relapse, so his family was concerned. I include this case to illustrate how important it is to make sure that patients understand the program and that they do not stop the naltrexone this early, especially if they’re still consuming alcohol. The good news is that recently the family has heard from him again and he may restart the program. So they're hopeful.

This next case is a 40-year-old male with obesity, interested in cutting back on alcohol intake to lose weight. He was drinking more than he wanted to and had already failed other methods of trying to cut back. I prescribed naltrexone 50 milligrams, one tablet a day before drinking, and then the first three months he actually didn't notice any difference.

However, then he realized that he wasn't taking it before he started drinking just after he was drinking. Once he started giving it a full hour before he took us the first drink, things started improving. At his one year followup, he was feeling better and eating more healthy. His alcohol consumption was down about 80% from his previous level, and he had lost about 25 pounds.

His level of intake at that time was three to four drinks per week. He felt that naltrexone had been life-changing for him like he finally had control over his consumption. He told me that after he had a few drinks, he was done. He said that previously, ever since he was 15 years old, he'd never had that experience of his body telling him that he was done.

Our last case is a 23-year-old female who started drinking as a teenager, but not heavily until she started college. She had her first alcohol withdrawal seizure at 19 years of age. She had been through multiple treatment programs without success. She was struggling in college just to get through the days and not doing well in her classes.

When she came to see me for her first appointment, she was with her mother. At that time she was consuming one to two handles of vodka per week. A handle is a large bottle of the handle on it, which contains about 1.75 litres. She was drinking from 4:00 AM when she woke up until bedtime at seven to 8:00 PM, she had strong alcohol cravings, and when she was not drinking alcohol, she was drinking sugary drinks.

The scariest thing for her was that going cold turkey off alcohol was likely to cause a seizure. The day she saw me in the office for her first appointment, it was late morning, and she was already having withdrawal symptoms because she hadn't had a drink yet, but at the time she got home from her appointment, she had tremors, nausea, and then vomited.

She started naltrexone at just 25 milligrams per day due to nausea. One week into treatment her mother reported that it was definitely making a difference. She reported that her daughter was in good spirits and that she seemed more hopeful than she had seen her in a long time. Because of daytime drowsiness, we changed her to night time dosing, 50 milligrams with another half tablet at the 12 hours mark later. She did well, but then stopped the daytime dose due to sleepiness. After that, it was several weeks before her consumption started trending down again. At the ten-week point with just one tablet a day at bedtime, her consumption is consistently trending down. She was feeling encouraged and no longer had any side effects. In addition, she is currently passing two college classes, whereas the previous semester she had failed both.

Now I have some testimonials from patients of mine that I want to read to you.

Things are going well. Life is back to normal. I am now a social drinker again, with the help of TSM and turning around my desire to drink more and more to deal with some difficult personal issues during a period of my life. TSM combined with healthy life changes. This makes a big difference in my life. I no longer have the urge to go drink when dealing with life issues, and when I do drink, I can stop when I want to. I'm doing great. It's a good medication, and even at half a dose, it makes me feel full after a drink or two. I've been using it extensively. I'm currently in full abstinence though because I'm dieting for summer, but we'll definitely continue using it after I resumed drinking to ensure I don't overdo it from loss of tolerance.

Another. Three months ago, I was in a very miserable state of mind trying to balance battle. My problem is with alcohol addiction. I take full responsibility for my actions in my addiction. I thought I was functioning prior to my last binge drinking episode. Soon I found my life was in a terrible downward spiral. I have been to rehabs without feeling as if I have really gained anything positive at all, and I was very upset because I thought I was, was going to actually relate to people and learn how to function in society without my addiction cravings. This did not happen after rehab. My oldest daughter sent me an article about naltrexone. I was skeptical of the drugs. Since proper dosage includes drinking and after taking medicine, but I was desperate for the solution, and I found a doctor to prescribe it to me. After almost three months, I have no cravings, and I rarely feel like drinking. I still have one day a month that I may want more than a glass of wine, but the binge drinking has gone away. I truly believe this drug has saved my life.

Another, the Sinclair method has been transformational for me and that I'm no longer under the thumb of alcohol abuse. Armed with naltrexone, I can participate in social functions completely satisfied with one or two drinks. Also, I no longer have the intense, overwhelming craving to binge drink and secrets. A drinking bottle that I would always lose. despite my best efforts. I now have a normal relationship with alcohol, and that translates to a newfound sense of empowerment that literally affects my entire life. This treatment feels like a miracle. It is just incredible.

So, in summary, alcohol use disorder is a huge problem both in this country and all around the world. The burden of disease is very great, both in financial and social ways. We need to be screening all our patients for alcohol, and there are very simple ways to do this.

Once we identify people who need help, we need to offer medication. Telling the patient to stop drinking rarely works for a patient who has endorphin mediated drinking. Naltrexone is FDA approved for the treatment of alcohol disorder and targeted naltrexone treatment has multiple randomized clinical trials supporting its use.

A review article of targeted naltrexone dosing published in CNS drugs concluded that the treatment was an efficacious harm reduction strategy for problem drinking alcohol dependence. For patients who have endorphin mediated drinking 50 milligrams naltrexone, given one hour prior to drinking every day for at least three months consecutively, can reverse the pathways in the brain that cause patients to crave alcohol, essentially, curing alcohol use disorder. Multiple clinics are showing the success rate of about 70% the treatment is inexpensive at around $1 per pill attracted to patients and doesn't require any time off of work or any inpatient stays. It allows patients to maintain their dignity and privacy during treatment.

Going forward, we may be able to use as needed dosing of naltrexone to prevent AUD in at-risk populations such as young adults and the children of alcoholics. Alcohol use disorder should become print of preventable, treatable, and beatable. Send your patients to the website for the C3 foundation.

Encourage them to watch the movie: One Little Pill, an excellent documentary by Claudia Christian. Suggest to them the paperback book by Dr Roy Scapa, The Cure for Alcoholism and never give up on them. Thank you.

Linda Elsegood:  Thank you for listening to this presentation. All past conference presentations can be found on our website, www.ldnresearchtrust.org.