alcohol use disorder meds

 A new systematic review and meta-analysis was published on the pharmacotherapy for alcohol use disorder, AUD (see alcohol use disorder meds JAMA2023 in dropbox, or doi:10.1001/jama.2023.19761)

 

Details:

-- 20,976 participants from 118 clinical trials were included, with sample sizes ranging from 12 to 921 individuals and treatment duration 12 to 52 weeks

-- nine pharmacologic therapies for alcohol use disorder were assessed: all were either approved by the FDA or are commonly used

    -- FDA-approved treatments: acamprosate, naltrexone, disulfiram

    -- off-label medications: baclofen, gabapentin, topiramate, varenicline, prazosin, and ondansetron

-- 74% of the studies included psychosocial interventions with the meds

-- acamprosate: a total of 23 studies, 16 were done in Europe and 4 in the US

-- naltrexone: 49 studies, 8 were done in Europe and 32 in the US

--all of the included studies had at least 12 weeks of treatment in an outpatient setting, and all had to assess alcohol consumption outcomes (including return to any drinking, return to heavy drinking, percentage of drinking days, percentage of heavy drinking days defined as at least 4 drinks per day for women and 5 drinks per day for men) or the number of drinks per drinking day; health outcomes (motor vehicle crashes, injuries, quality-of-life, function, or mortality); or adverse events

-- primary outcome: alcohol consumption

-- secondary outcomes: motor vehicle crashes, injuries, quality-of-life, function, mortality, and harms

 

Results:

--the number needed to treat (NNT) to prevent one person from returning to any drinking at all, vs placebo:

    -- acamprosate: 11 persons (1-32), 20 trials, n=6380

    -- oral naltrexone 50 mg: 18 persons (4-32), 16 trials, n=2347

    -- injectable naltrexone: no association with decreasing the return to any drinking, 2 trials, n=939

    -- disulfiram: no association with decreasing any drinking

-- NNT for return to heavy drinking, versus placebo:

    -- oral naltrexone 50 mg per day: 11 persons (5-41), 19 trails, n=2875

    -- no significant difference with injectable naltrexone, 2 trials, n=615

    -- no significant difference with acamprosate

-- decreased drinking days over 30-day treatment period:

    -- injectable naltrexone: -4.99 days (-9.49 to -0.49 days)

-- reduction in heavy drinking days:

    -- injectable naltrexone -4.7 days (-8.6 to -0.73)

[note here: there was an error in the article: the abstract stated -4.99 drinking days, the text said -4.99% of drinking days. my guess is that the former is likely the real value]

 

-- Studies comparing acamprosate with naltrexone directly (4 studies with 1141 participants):

    -- no statistically significant difference for improvement in alcohol use outcomes of return to any drinking or return to heavy drinking

 

-- gabapentin: not significantly associated with lower rates of return to any drinking or with significant reduction in harm to heavy drinking, with low strength of evidence in the 3 clinical trials reported

-- topiramate: absolute percentage of drinking days decreased 7.2%, percentage of heavy drinking days decreased 6.2%, and number of drinks per drinking day decreased by two drinks, moderate strength of evidence

-- varenicline, prazosin, and ondansetron had either low strength of evidence suggesting benefit or insufficient evidence and were not included in subsequent analysis

 

-- insufficient data to assess whether treatment with most medications was associated with improved health outcomes (e.g. motor vehicle crashes, injuries, quality-of-life, function, and mortality), as these were infrequently reported in the studies

 

-- Adverse effects, versus placebo:

    -- overall, the most common mild adverse effect was dizziness, found with naltrexone, baclofen, topiramate, and gabapentin

    -- acamprosate: largely GI distress, with diarrhea having a risk ratio of 1.58, (1.27-1.97)

    -- naltrexone: largely GI distress, mostly nausea having risk ratio 1.73 (1.51-1.98), and vomiting, RR 1.53 (1.23-1.91)

    -- baclofen was associated with higher rates of drowsiness, RR 1.46 (1.15-1.86) as well as numbness and sleepiness

    -- topiramate was associated with higher risks of many adverse events including paresthesias (RR 3.08), taste abnormalities (RR 3.01) and cognitive dysfunction (RR 2.37)

    -- gabapentin was associated with cognitive dysfunction (RR 2.76) and dizziness (RR 1.70)

 

Commentary:

-- there are a litany of potential problems associated with alcohol use disorder, including hypertension, heart disease, stroke, cognitive impairment, sleep problems, depression, anxiety problems, peripheral neuropathy, gastritis, gastric ulcers, liver disease, pancreatitis, osteoporosis, anemia, fetal alcohol spectrum disorders, and several cancers. There also are potentially severe social effects including homicide, suicide, motor vehicle crashes and deaths, sexual violence, domestic violence, and drowning. And there are the broader social disruptions in families and the community

-- the current data suggest that for several issues there should really be zero alcohol intake:

    -- even small amounts of alcohol are associated with hypertension: https://gmodestmedblogs.blogspot.com/2023/10/alcohol-even-small-amounts-assoc-with.html

    -- stroke risk seems to be lowest with zero alcohol consumption: https://gmodestmedblogs.blogspot.com/2019/05/stroke-risk-lowest-if-zero-alcohol.html

    -- all-cause mortality: no benefit for even occasional drinkers (as opposed to the older studies suggesting there might be benefit); and moderate alcohol consumption is associated with increased all-cause mortality, which increases progressively with higher alcohol consumption: https://gmodestmedblogs.blogspot.com/2023/04/alcohol-consumption-small-amounts-not.html

-- even small amounts of alcohol are dangerous in people with evidence of alcoholic liver disease: https://gmodestmedblogs.blogspot.com/2019/05/increasing-alcoholic-liver-disease.html

-- cardiovascular risk seems to increase with any alcohol consumption: https://gmodestmedblogs.blogspot.com/2023/04/mendelian-randomization-alcohol-does.html

-- cancer risk may also be increased with minimal alcohol consumption:

   -- breast cancer risk seems to increase with low levels of alcohol consumption: https://gmodestmedblogs.blogspot.com/2019/07/alcohol-and-breast-cancer.html

   -- overall cancer risk increases significantly when people drink one bottle of wine per week: https://gmodestmedblogs.blogspot.com/2019/04/a-bottle-of-wine-week-and-cancer-risk.html

 

-- the 2020 National Survey on Drug Use and Health found more than 28.3 million people age 12 years or older in the US met DSM-V criteria for alcohol use disorder (AUD) in the prior year

-- unhealthy alcohol consumption is the third leading preventable cause of death in the US, with 145,000 deaths annually

-- and, a woefully low number of people were on pharmacotherapy for alcohol use disorder when assessed in 2021, 0.9% of 29.5 million people, i.e. only 265,000 people

 

--this study supports using either oral naltrexone 50 mg per day or acamprosate as first-line pharmacotherapies for alcohol use disorder, in conjunction with psychosocial interventions (since such a high percentage of the studies included psychosocial intervention, this could not be disentangled from the effects of the medications; and presumably the combination is actually important)

    -- there were insufficient data to really assess naltrexone at the 100 milligram per day dose, or the benefits of injectable naltrexone

-- there were 4 studies cited that had direct comparisons between acamprosate and naltrexone, the longest was 4 months, and one of them found more benefit for the combination therapy: https://pubmed.ncbi.nlm.nih.gov/16467406/ . Also one used the 100mg naltrexone dose

 

-- several studies did find that patients who were not abstinent did better with naltrexone or acamprosate versus placebo (ie, it may not be necessary for the patients to completely abstain in order to have benefit from these meds)

 

-- there are a few important differences between these two medications:

    -- oral naltrexone is a once-a-day medication, whereas acamprosate is two pills three times a day. There has been argument in the medical literature that different people may benefit differently from these different dosage schedules: there are some people with AUD who might benefit from the reinforcement of taking medications three times a day; others may benefit from once-a-day medication that might lead to better medication adherence

    -- oral naltrexone is contraindicated in those with acute hepatitis or liver failure, as well as those who are on opioids or might be on them in the future

    -- acamprosate is contraindicated in those with severe kidney impairment (GFR<30) and does need dose adjustment in those with mild renal disease

-- topiramate did have moderate strength of benefit in the evidence for several of the measured benefits, however it did also have lots of adverse effects and probably should be lower on the list of meds to use

-- the other meds assessed should probably be avoided

-- and there are the intriguing early studies suggesting that GLP-1 receptor agonists might help with alcohol dependence: http://gmodestmedblogs.blogspot.com/2023/09/glp-1-receptor-agonists-for-alcohol.html

 

Limitations:

-- as a limitation of meta-analyses in general, the researchers are combining disparate studies with disparate groups of patients recruited through disparate means with disparate inclusion and exclusion criteria, disparate lengths of the study, etc. This makes a meta-analysis less statistically rigorous than individual RCTs

    -- there is an overlap of psychological conditions (particular depression and anxiety) with alcohol ingestion (sometimes in the context of patient self-medication). The included studies did not consistently provide information on the psychological state of the patients, treatments involved, etc.

    -- some of studies had fewer than 90% of the participants with alcohol use disorder, and these were combined with studies with 100% having AUD

-- most participants in the studies had moderate-to-severe AUD, potentially limiting generalizability to those with less alcohol intake

-- the mean age of the studies was between 40 and 49 years old, only 29 studies enrolled younger or older populations; and the majority were white males. all potentially limiting generalizability of their results

-- because the vast majority of studies included psychological therapies, it is not clear that these results would be sustained just by prescribing medications

-- there was a notable difference between acamprosate and naltrexone in terms of the sites of the studies being done: naltrexone studies were predominately in the United States and a acamprosate in Europe. Those in the US recruited patients largely through advertisements, while the majority of those clinical trials in other countries recruited patients from inpatient settings; this difference may have influenced the results (acamprosate had less efficacy in the relatively few US-based studies, where recruitment was more population-based than in the European ones)

-- most of the studies required patients to be abstinent for at least a few days before initiating the medication. These medications were prescribed as a means to maintain abstinence. In fact acamprosate and injectable naltrexone are FDA-approved only for use in patients who have established abstinence (though, as per above, a few studies found that acamprosate and oral naltrexone did work in some people who were not abstinent)

--the most useful studies in general would be direct comparisons between naltrexone and acamprosate, as opposed to each one versus placebo (where there were would be different protocols, exclusion/inclusion criteria, dosages of medications, patient populations, etc.). And there were pretty few such direct comparisons done.

    -- unfortunately these comparison studies were only a maximum of 4 months and had pretty different protocols, one using 100 mg of naltrexone. Would be great to have large, long-term studies comparing naltrexone 50 and 100mg po, injectable naltrexone, and acamprosate. Also of the combination of these 2 meds 

 

So,

-- alcohol intake is not only legal but is integrated into the social fabric of many societies, making reduction/elimination much more difficult

-- newer studies have found increased risk of many adverse outcomes even with small amounts of alcohol consumption

-- all of this make for a very difficult public health message, especially in light of the significant political power of the alcohol-related industries

-- alcohol use disorder, at the far end of alcohol consumption spectrum, is remarkably common, and clearly has adverse medical, psychosocial, family, and community problems

-- though there are effective medications (specifically naltrexone and acamprosate), these are not be prescribed regularly for AUD (there are studies suggesting that topiramate is a good choice, even old studies on disulfiram. but these are the relatively poor cousins of naltrexone or acamprosate, with lower benefit/effect ratios

-- as noted above, one intriguing option is the use of GLP-1 receptor agonists (which have worked well in a few of my patients who were on them for other reasons....): https://gmodestmedblogs.blogspot.com/2023/09/glp-1-receptor-agonists-for-alcohol.html. And these have the collateral benefits of helping treat diabetes and overweight/obesity

-- we clinicians are not terribly good at honing in on AUD and providing the medical and psychological care necessary to prevent the myriad of potential alcohol-related complications...

    -- we need to be regularly eliciting information about alcohol consumption with our patients, and aggressively promoting alcohol reduction/cessation with meds and/or psych/support therapies, with close patient follow-up to help them in this difficult task

    -- and our public health messaging needs to be in line with this goal, including restrictions on advertisements etc

 

geoff

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