Core IM: 5 Pearls on Treatment of Alcohol Use Disorder

November 7, 2018


By Kate Lawerence MD, Marty Fried MD, Irene Swanenberg MD, Shreya P. Trivedi MD || Illustration by Caroline Srisarajivakul-Klein MD || Audio Editing by Harit Shah. Quiz yourself on the 5 Pearls we will be covering:

  1. Throwback: At what levels of drinking does unhealthy alcohol use start, and how do you screen for unhealthy alcohol use? (1:47)
  2. What does the brief intervention and counseling part of SBIRT entail? (4:43)
  3. What are the first line medications for AUD, and contraindications to them? (11:11)
  4. What are the  second-line medications for AUD and their limitations? (18:14)
  5. What new therapies are being studied for for alcohol use disorder? (22:09)
  6. Pearls Recap (25:06)

Many thank yous for peer review: Dr. Jennifer McNeely Associate Professor at NYU School of Medicine, Dr. Oscar Bukstein, Harvard Professor and Dr. Anthony Accurso from NYU Brooklyn as well as a special mention to Dr. Bill Fuller from Columbia and Dr. Evan Harmon from UVA!

Show Notes

Pearl 1 (Throwback)

  1. Unhealthy alcohol use is a catch-all term meant to describe a spectrum of drinking ranging from risky use to alcohol use disorder. Alcohol use disorder (AUD) is a problematic pattern of alcohol use leading to clinically significant impairment or distress.
  2. Risky drinking is thought of as daily and weekly alcohol limits:
    1. For  men less than 65 years:  more than 4 drinks/day or 14 drinks/week for
    2. For women and men over 65 years: more than 3 drinks/day or 7 drinks/week
  3. The AUDIT-C tool is the recommended screening tool for unhealthy alcohol use.
  4. A single-item screening question has also been validated: how many times in the last year, have you had more than three drinks (four drinks for men) in a day?

Pearl 2

  1. First-line non-pharmacotherapies for AUD are captured in the mnemonic S-BIRT: screening, brief intervention, referral to treatment. It is a comprehensive approach identify and intervene in patient with unhealthy alcohol use. Basic tenets of BI include:
    1. raising the subject
    2. giving feedback about the level of risk
    3. encouraging the patient’s motivation to change, and
    4. setting goals or making a plan to implement that change.
  2. BI alone has not been shown to be effective in patients with alcohol use disorder

Pearl 3

  1. Patients who meet criteria for AUD should be offered medications in addition to non-pharmacologic therapies for treatment
  2. First-line pharmacotherapies for moderate to severe AUD include naltrexone and acamprosate
  3. Common side effects for naltrexone are largely gastrointestinal, and include abdominal pain, nausea, and diarrhea; naltrexone is contraindicated in patients with cirrhosis or who are actively using or at high risk for using opiates
  4. Acamprosate requires three-times-a-day dosing, and is not for use in patients with ESRD or CrCl<30; neuro-pysch side effects in including suicidality may also limit its use

Pearl 4

  1. Second-line pharmacotherapies include topiramate and gabapentin
  2. Their well-known side effect profiles (including memory impairment and somnolence, respectively) at the doses required to achieve efficacy may hinder their broader use in the outpatient setting

Pearl 5

  1. Novel therapeutic options currently under investigation for AUD include neuromodulation, nalmafene, and psychaedelics
  2. Neuromodulation, such as deep brain stimulation, is thought to work on the nucleus accumbens to target centers of reward behavior and reduce cravings
  3. Nalmafene is a long-acting k-opioid antagonist which is used in Europe
  4. Psychedelics like psilocybin and LSD are experiencing a resurgence in the study of a variety of diseases, including AUD, PTSD, and depression

Transcript

Throwback Pearl: Screening

K: Alright Marty, what’s the deal with flipping the order of the podcast – I thought we had a good thing going with 4 new pearls followed by a throwback pearl from a prior episode.  What gives?

M: Yes, and I’m fully open to criticism.  But hear me out. On unhealthy alcohol use – part one we discussed disease definitions, screening, risks and benefits of alcohol use on a macro level.  Now we’re going to zoom in specific therapeutic options.  And since interventions often start with screening, which is the 1st part of *super sweet* acronym – SBIRT – I figured we should go there.

S: Remember that SBIRT is an acronym that stands for Screening, Brief Intervention, and Referral to Treatment.  This framework helps diagnose unhealthy alcohol use and quickly initiate treatment. We’ll get to the rest of BIRT part of SBIRT in our next pearl.

K: So Marty, do you remember whats the difference btw unhealthy alcohol use vs. alcohol use disorder?.

M: Right, so unhealthy alcohol use is a catch-all phrase that incorporates risky use – think the college binge drinker – to alcohol use disorder – which is really ANY amount of drinking behavior that has negative health or social outcomes.  

K: In terms of screening,  for those who like hard numbers, what are some red flags for high risk drinking?

M: That’s the 3, 7… 4, 14 – right?

S: Yes Marty! To translate those numbers:  The number for women of any age or men older than 65 for risky drinking is defined as more than 3 drinks at any one sitting or more than 7 in a week. For men less than 65yo there is a bit more leeway –  more than 4 drinks in one day or 14 drinks per week means they have unhealthy alcohol use and should be then be assessed for health or social impacts.

K: Awesome, thanks Shreya.  And do you guys remember some validated measures to screen for unhealthy alcohol use?  

M: I’m all about the AUDIT-C, mostly because I can remember it’ s a three-item questionnaire and just open it up on my EMR rather than remember any specific questions.

S:  Right, and those questions are basically (1) how often do you have any alcohol-containing drink, (2) how many drinks do you have on a typical day when you’re drinking, and (3) how often do you drink 6 or more drinks?

K: Then some plugging into a Audit C calculator will risk stratify for you. And if you want you can shorten that to the single-item screener, the most sensitive Q to ask is just how often in the last year did you have more than 3 drinks in any night (or 4 or more for men).  

S: Any number greater than one night is an indication to probe further.

M: Nice – so that covers the S in SBIRT – that’s screening – and our throwback pearl.   Let’s move on to our first pearl and the rest of the acronym!

S: BIRT!

Pearl 1: What is first-line non-pharmacotherapy therapy for AUD?

K: So let’s start with a scenario…  

You are seeing a Mr ‘new patient’ in clinic. He is a 46 man who had an urgent care appointment for abdominal pain that resolved with mylanta and a PPI and now is here to establish care.  He has hypertension but no other medical problems.

M: Right. So we discussed screening all patients for unhealthy alcohol use, but in this patient my spidey sense is really firing for alcohol issues because (A) this is a podcast about alcohol and (b) he has TWO alcohol-related medical problems that we know about –

K: – alcoholic gastritis and HTN-

M: – and possibly more that we have yet to diagnose!

S: Yep, and he screens positive using the single-item screener, saying that he’s drinking more than 4 beers at least once a week.  Its about 16 beers/week and when asked more about his alcohol use, it looks like drinking doesNT appear to be affecting his work or his social life, so he’s more in the unhealthy alcohol use category.

K: I must say that in real life it’s not often tee’d  up this perfectly for an opportunity to intervene – as we all know -, but when the stars align like this I give myself a silent internal “fist pump” and proceed to the next part of SBIRT, which is Brief Intervention.   

M: Perfect.  Let’s B-I the heck out of this guy.  How do I start?

K: Alright easy there Marty. Let’s not overwhelm the poor guy.  Think about the brief intervention as a type of focused motivational counseling intervention where the provider spends about 5 minutes after screening doing the following. 1) raising the subject, 2)giving feedback about the level of risk, 3) encouraging the patient’s motivation to change, and 4) setting goals or making a plan to implement that change.

S: Kate that sounds great and all but my Q is why should I spend 5 minutes of my 20 min visit on this?  What’s the degree of evidence supporting the SBIRT protocol? I mean, Are we talking like statins-in-the-water pretty much proven benefit or are we more like Vitamin D – maybe works but not really causing problems so why not?

M: That’s a great question Shrey!  I actually looked into this because I had the same healthy skepticism (no offense Kate).

K: None taken!

M: A 2006 article in American Journal of Preventive Medicine did this massive systematic review of many different clinical preventive services from tetanus immunization to mammography and ranked them based on their effectiveness.  SBIRT was near the top of the list with same score as colon cancer screening – ABOVE both pap smears for cervical cancer screening and routine lipid screening.  We’ll include the paper in the show notes for those who want to dig deeper.

K: Wow that’s huge.  Makes you think about the amount of time we spend on paps and lipid screening relative to alcohol screening.  

S: Right my ears are perked! Let’s break down each component down little more. How might a conversation like this go?

M: The caveat is we should point out that everyone has their own style of interviewing, so we’ll give you some examples that we’ve found to be effective and you can try them out to see what feels right

K: OK. So in this scenario we may have raised the subject, which is the 1st step, by screening him but after, it helps to open the convo with something like “Do you mind if we talk a little more about this, about the effects of alcohol on your health?” & get into understanding his views a little better.

S: Next, giving feedback is often as simple as“I am concerned about your drinking and how it may be affecting your health. Do you know the recommended limits of drinking alcohol?”

M: I would argue that pointing out the relationship between his drinking and hypertension or GERD & and then asking if he’s thought about this would also satisfy as feedback.  

S: And then for the third part, I would imagine the motivation to change is the old 1=10 motivational interviewing scale?

K: I mean, if it works!  

M: Yep so its on a scale of 1-10, how ready they are to change.  

S: Then the follow-up question is the most important here – once you have them commit to a number about how ready they are to change, you ask the patient why DIDN’T they choose a lower number

M: for example if our patient says “Not really interested, probably a 5” you respond with “I see, well tell me why you didn’t say a 3 or a 4”

S: This allows the patient to talk about whatever motivation they have instead of dwelling on the motivation they may lack.  

K:  Exactly Shreya.  And the final part of the brief intervention is goal setting and planning to finish the session. And here I want to mention not to get too overzealous – short term, achievable goals (even if it’s something like cutting out one or two extra drinks a day) are more effective than grand, idealistic ones. Goals can also be focused on starting counseling, or a referral to and addiction treatment program or peer support group.  

S: By peer support group do you mean AA?

K: Yea that’s one example. AA, or alcoholics anonymous, is just one of a number of “12-step” peer support groups that are pretty popular.  There are also groups for people who use opioids – narcotics anonymous, or NA – marijuana, cocaine groups, all kinds of things. The common theme to these groups is that sobriety is obtained through personal exploration and acceptance, and belief in some spiritual higher power is also emphasized. Which may not appeal to everyone.

M:  An alternative to these 12-step programs is a method called SMART Recovery – SMART stands for Self-Management and Recovery Training.  SMART is a trademarked process that replaces the spiritual-foundation of AA for more flexible cognitive-behavioral framework. It is newer and the meetings are significantly fewer than AA.

K: If it’s trademarked, marty, does that mean we’re allowed to mention it on this show? What kind of kick backs are you getting?

M: oh I wish Kate…

K: Right so, SMART Recovery can be a good for pts interested in groups but for whom AA isn’t the best fit.  

S: To summarize this section:  After a postive screening, a simple “brief intervention” in the office followed by referral to treatment that is tailored to the patient’s specific goals and beliefs and is effective.  

M: And remember the brief intervention for people with uncomplicated unhealthy alcohol use. it consists of four parts – raise the subject, provide feedback, evaluate motivation and finally set goals.  

Pearl 2: What is first-line pharmacotherapy therapy for AUD?

K: Let’s revisit our case.  Despite a perfectly executed S-BIRT, our patient misses his next appointment and returns to clinic several months later.  You notice from a quick chart review that he has been admitted to the hospital twice for alcohol withdrawal, and you discover that he has been fired from work, and then he admits that his drinking has gotten out of hand.  So what now?

S: so at this point, our patient’s formerly unhealthy alcohol use has now progressed to alcohol use disorder.  And patients w/ alcohol use disorder should get a multimodal approach which blends the nonpharm approaches we talked about with meds.

M: We spoke with Dr. Oscar Bukstein, one of the authors of the American Psychiatric Association’s guideline for the pharmacologic treatment of alcohol use disorder. He mentioned … the idea of providing patients with a menu of therapeutic options to choose from which I really loved.   

K: Yea that’s very patient-centered. We’ve already covered the nonpharma options, which certainly belong on that menu – SBIRT, AA meetings, SMART recovery. Now we’ll expand that menu with some medications to offer.  

M: so let’s start with the first-line meds for our patients who are using alcohol and are interested in  quitting

S: Or, Marty – even just interested in cutting down!

M: Oh welllll excuse me!

K: Don’t be sassy Marty. Shreya makes a good point – these options are for people who want to quit AND for those who want to just cut down – harm reduction man!

M: Point taken. So let’s stick with this  menu metaphor here – what are the meds are on the entree list for alcohol use disorder?

K: OK, so most major professional societies recommend either naltrexone or acamprosate as first line therapy for patients with alcohol use disorder.  

S: I think what really helps hammer home these meds being 1st line are their NNT! Naltrexone has a NNT of 12 to prevent returning to heavy drinking. And if you look at their NNT to prevent ANY drinking, naltrexone is 20 while acamprosate is 12.

K: Ya Shreya those are good numbers.

M: Ok, so it sounds like we have two solid options here. Let’s talk about the opioid antagonist, naltrexone, first.  The mechanism here is pretty interesting, thought to work on the reward pathway to blunt that anticipatory excitement that people with AUD typically experience just before drinking.  

K: Naltrexone can generally be started same-day, with the starting dose of 50mg daily, and can go up to 100mg for some, with the goal to complete a 6-12 month course of treatment.

S: there’s also a long-acting depo naltrexone injection called vivitrol, which is given every 4 weeks.

M: The important thing to keep in mind is that naltrexone should be avoided in pts with cirrhosis – so this is maybe not a great med for people with advanced alcoholic liver disease…

K: And people should be screened for concomitant opioid use, because naltrexone can actually precipitate withdrawal symptoms in patients who are physically dependent on opioids.

M: Can’t emphasize that enough – must wait at least 7-14 days after opioid use to start naltrexone or else you’re going to have some pretty salty patients

S:  Speaking of a salty patients, are there any side effects I should be warning my patients about?

K: Yes, good question patient! Naltrexone is actually really well tolerated, but as far as side effects Gi stuff is most common – Nausea, abdominal pain, and diarrhea are seen in about 10-30% of patients. which would be good to tell patients about so they don’t give up on the treatment! Also injection site irritation for the depo shot.

S: AND, if the pt has used opiods in the past, it is so important yo let them know that they can have a fatal overdose if they stop their naltrexone and start again with the same dose of heroin or opioids again as they were on before

K: Right this is what kills patients after naltrexone. Their mu-receptors, which were blocked while they were on the naltrexone, are much more sensitive to those opiates when the naltrexone is out of their system!

M: For this reason, the APA recommends against its use in patients w/ ongoing or potential use of opioids in the future

S: So that’s a good review of naltrexone. What about acamprosate?

K: So acamprosate is a centrally acting medication (with maybe some GABA and some NMDA activity), that also has some good data to support its use.

M: Despite also working on neurotransmitters, the mechanism of acamprosate is entirely different: It’s thought to reduce the physical and psychological discomfort.. like sweating, anxiety and insomnia many alcohol-dependent individuals experience once they stop drinking.

K: And it usually reaches its full effectiveness in 5-8 days so you can tell your patients that they may be uncomfortable for that first week..

S: Realistically, I find acamprosate is a little more difficult for patients to manage –  its three times daily dosing !

K: For sure, that amount of pills can be challenging for some people.  Another limitation for acamprosate is that end stage renal disease is a contraindication –

S: – Right if CrCl <50, the dose is half – one tab three times daily, and it’s contraindicated if creatinine clearance <30

K: and also that is does carry the risk diarrhea and of some neuropsych side effects like irritability, and rarely but most seriously suicidality – which probably has to do with its actions on those neural receptors we talked about.

M: Super important to warn patients about those! Ok so for naltrexone and acamprosate,  any guidance about duration of therapy?

S: For sure – usually prescribing for up to 6 months, or longer for those who benefit from the drug who want to continue with it – i am sure this is patient-clinician dependent choice

K: And then what about those who continue to drink while on the naltrexone or acamprosate?

M: Yeah again this is a patient-specific decision, but if the desired outcome isn’t achieved after 4–6 weeks it’s probably time to try another strategy

S: So, to sum up our third pearl, when our patients are ready to start pharmacotherapy the best first-line medications are naltrexone and acamprosate.  Each have their own contraindication co-morbidity – use naltrexone with caution in liver disease and acamprosate should be dose-reduced in mild CKD and avoided in severe renal disease.

M: Just one more point I want to add, treatment is key bc less than 9% of patients who needed treatment for an alcohol use disorder received a single prescription. I’m sure there are a lot of reasons for that but we should try to to close that gap and offer these patients treatment that may help them.

Pearl 3: What are second-line pharmacotherapies therapy for AUD?

M: I’m unofficially titling this next section “the benchwarmers”.  

S: The who-what-ers?

M: The benchwarmers!  The following group of medications are just waiting in the wings for their time to shine.  They are being used to treat alcohol use disorder and are slowly being studied, but don’t have the first-line, starter recognition yet.

K: Ok Marry im going to call you out on this whole mixed metaphors – i thought we were talking about entrees, and now youre making some sports reference. SHouldn’t it be something like – if naltrexone and acamprosate are the entres shouldn’t this group be like the side dishes or something?

S: Yes!  So in that case topiramate is the waffle fries and gabapentin is the mac and cheese.  For no reason other than they are both delicious and underappreciated dishes.

K: And that makes disulfiram the green beens of meds for alcohol use disorder?

M: Yeah, no one ever really wants the green beans

S: Exactly, we really don’t need to spend too much time on disulfiram on this podcast because it is rarely used in office-based, primary care settings.  Technically it is a first-line recommendation FDA approved.  As Dr. Bukstein put it – a medication used exclusively for the fear of its adverse effects is not a great design.  

M: Got it. No disulfiram.  Shrey I’m intrigued by the waffle fries and mac and cheese, that is topiramate and gabapentin, respectively, right?

S:  Yes. so for topiramate for alcohol use disorder – you know how much i love NNT –  It’s an effective medication with a NNT of 12 to significantly reduce heavy drinking days – comparable to that naltrexone and acamprosate.  

K: Ya the VA and Department of Defense  actually list topiramate as a first line medication for this very reason!

M: What concerns me about this medication is the, umm, shoot what were we talking about again?

K: Nicely done Marty.  We all know that topiramate is associated with cognitive dysfunction or mental “fog”.  the reality is that the NNH for cognitive dysfunction is also 12. Meaning that for every person that topiramate helps control their drinking we are going to cause a person clinically significant mental fog.  

S: Man! And the number needed to harm for taste issues and paresthesias are even worse – 7 and 4, respectively.

M: So what I’m hearing is that this is an effective medication, but side effects limit its utility.  What’s next?

K: Gabapentin is another medication that has some supportive data.  

S: The largest randomized trial on gabapentin showed a nice dose-dependent responsein  abstinence rates when gabapentin 1800mg/day was compared with 900 mg/day and placebo. On the high-dose regimen, 17% of patients were able to achieve abstinence after 12 weeks, compared with 11% in the low-dose and 4% in the placebo group.

M: 1800 mg/day!  Sheesh that’s a healthy dose of gabapentin.  

K: It is, which is why it can be a tough sell.  The study that Shreya just mentioned says there was a 43% dropout rate, largely due to medication side effects like drowsiness.

M: So definitely mac and cheese  to be used with caution!

K:  And finally, we’d be remiss if we didn’t mention bacofen in this group of meds but only because the data about it isnt that great. This med got a lot of buzz early on, bu the early studies that showed positive effects that weren’t replicated, and the side effects are pretty severe.

S: Ok so to review our “side dish” options: Topiramate and gabapentin both have reasonable efficacy data but their use is limited by small studies with mixed results and significant adverse effects that seem to accumulate at doses required to curtail alcohol use.

Pearl 4: What are emerging and/novel therapies for AUD?

M: So lastly, let’s talk quickly about some novel therapeutics that are in the pipeline for treating alcohol use disorder but a little out of left field.

K: A new sports metaphor? Really marty!

S: The therapies we’ve already mentioned are some of the better known ones, and ones that have the most data behind them. But it’s true that they don’t work for everyone, and there’s still a lot of room out there for other therapies.

K: There’s a few that have been making ‘the medicine literature’ headlines that I’m kind of excited about. The first is neuromodulation –

S: – like deep brain stimulation?

K: yea, exactly. The neuro psych community is trying to target the nucleus accumbens (which has been shown integral in mediating reward behavior). There were a bunch of preliminary studies in animal models showed promise , and now there’s more than 60 articles in the medline literature showing that brain stim decreases cravings and consumption. Clinical trials are still ongoing obviously.

M: one that I’m kind of excited about, but I don’t know if we’ll ever see it in the States is Nalmefene.

K: ohhh, that’s the one they use in Europe right?

M: Yea, it’s a kappa opioid receptor antagonist.   Apparently it has a longer half life and better bioavailibity than naltrexone.  I’ve looked into this and have no idea why it’s not yet available in the US – if anyone listening has insider drug pharm info, let us know!

S:  #Medtwitter

K: And the last one that I’ve been following pretty closely actually is – and don’t laugh –

S: ooh what?

K: psychaedelics!

M: Far out man!

S:  How are they even doing research on those these days?

K: Yea I think the drug regulators have started to come around on this a bit because (at least from my review) the data is really compelling. They actually started doing large cohort research on alcohol use and LSD in the 1950s and early 60s – and that data showed a global reduction in alcohol use by over 50 percent!

M: obviously that data got slammed for the rigor of methods and the (ahem) bias of the researchers.

K: Yea, but the community has recognized the potential, and there’s now several new, better designed studies that show LSD may have comparable effects to naltrexone and acamprosate – in a single dose[SL3] .

M: There’s now hundreds on ongoing trials looking at the role of psychedelics like LSD, psilocybin, and MDMA for things like substance use, PTSD, and depression.

S: Very cool guys!  To review this last section – therapies that are on the horizon include deep brain stimulation, nalmaphene – which is currently in use in Europe, and psychedelics including psilocybin and LSD.

References

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  3. Kranzler, H. R., & Soyka, M. (2018). Diagnosis and pharmacotherapy of alcohol use disorder: a review. JAMA, 320(8), 815-824. https://jamanetwork.com/journals/jama/article-abstract/2698498
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  8. Coles AS, Kozak K, George TP. A review of brain stimulation methods to treat substance use disorders. Am J Addict. 2018 Mar;27(2):71-91. https://www.ncbi.nlm.nih.gov/pubmed/29457674
  9. Krebs TS, Johansen PØ. Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials. J Psychopharmacol. 2012 Jul;26(7):994-1002. https://www.ncbi.nlm.nih.gov/pubmed/22406913
  10. Pollan, M. (2018). How to change your mind: What the new science of psychedelics teaches us about consciousness, dying, addiction, depression, and transcendence. New York: Penguin Press.
  11. Rösner S, et al. Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev. 2010. https://www.ncbi.nlm.nih.gov/pubmed/21154349
  12. Rosner S, et al. Acamprosate for alcohol dependence. Cochrane Database Syst Rev. 2010. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277871/
  13. Salib AN, et al. Neuromodulatory Treatments for Alcohol Use Disorder: A Review. Brain Sci. 2018 May 28;8(6). https://www.ncbi.nlm.nih.gov/pubmed/29843426

 

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