When I saw this headline from Kaiser Health News, “Many Doctors Treating Alcohol Problems Overlook Successful Drugs,” the article stated that
“[I]t is rare for someone “struggling with an alcohol use disorder to even hear that medication therapy exists.”
I got excited. Perhaps some wonder drug had shown up since I was in training and I just missed it. To learn more about what’s new in the field, I decided to review the literature starting with a 2015 publication from the Substance Abuse and Mental Health Services Administration (SAMHSA) titled, “Medication for the Treatment of Alcohol Use Disorder: A Brief Guide.”
Disulfiram – an oldie, but still not a goodie
Until the mid-90s, the only drug available to treat alcoholics who wanted to stop drinking was Antabuse or disulfiram—a drug with some nasty side effects. Disulfiram works by blocking alcohol dehydrogenase, the enzyme that breaks down acetaldehyde, a breakdown product of alcohol. As acetaldehyde accumulates in the body, the patient experiences unpleasant reactions such as nausea, flushing, and heart palpitations. The drug does not reduce cravings for alcohol and only has inconsistent evidence of efficacy in reducing alcohol intake. Despite that, it has been reported that it has been used successfully as a “chaperone” in social situations—when you start to feel sick when drinking, you know you have to stop.
The severity of the reactions is related to both the dose of the drug as well as the amount of alcohol consumed. Disulfiram-alcohol interactions reactions can be so severe that they may require hospitalization. Because many folks dislike taking the drug, it is most effective when its use is monitored by a clinician or family member.
In 1994, naltrexone, an oral long-acting opioid antagonist was approved for the treatment of alcohol dependence, but it had low adherence and retention. It took until 2006 for an extended-release injectable formulation to be developed and approved for treatment of alcohol use disorder.
Although it is known that naltrexone has an affinity for opiate receptors in the brain, the exact neurobiological mechanism by which it reduces alcohol consumption in alcohol-dependent patients is not well understood. There are two major mechanisms of action that have been put forth:
- The drug suppresses alcohol-mediated beta-endorphin stimulation of dopamine neurons in the nucleus accumbens.
- It reduces beta-endorphin disinhibition of the tonic inhibition of dopamine cells by GABA neurons in the ventral tegmental.
The bottom line is the drug appears to reduce the pleasure you get from drinking and block the cravings that cause people with alcohol dependence to seek more alcohol. According to Joseph Volpicelli, MD, Ph.D, Associate Professor of Psychiatry at the University of Pennsylvania School of Medicine,
“Naltrexone sort of gets at the core of what addiction is. The way I like to describe it is that addiction is a condition in which when you do something, you want to do more and more of it.”
Instead of stopping after a few drinks, people with alcohol use disorder want to have more and more and more drinks. Dr. Volpicelli says that naltrexone seems to break that positive feedback loop so that people can have one or two drinks and then stop because they don’t feel like having any more.
Because naltrexone works via opioid neural pathways, there is a risk of severe opioid withdrawal in patients who are also opioid dependent. Side effects include nausea, vomiting, somnolence, headaches, dizziness, fatigue, and anxiety.
A major drawback of this formulation of naltrexone is that is must be injected into a large muscle, usually the gluteus (buttock)—this almost always requires a visit to a clinician. Injection site reactions can cause pain or tenderness at the injection site, some severe enough to require surgical intervention, such as debridement.
Extended-release naltrexone is only approved for use in patients who can refrain from drinking several days before treatment begins. A systematic review and meta-analysis by Jonas et al. published in JAMA in 2014, showed that oral naltrexone favorably impacted return to any drinking as well as a return to heavy drinking. Patients with intense cravings for alcohol during treatment and those with a family history of alcohol use disorder seem to be good candidates for this treatment.
Acamprosate (Campral), an oral delayed release synthetic compound, was approved for treating alcohol use disorder in 2004. Like naltrexone, the exact mechanism of action is not yet known. It appears to involve balancing the glutamatergic and GABAergic systems that are out of whack during chronic alcohol exposure and alcohol withdrawal. Its main utility is its ability to reduce unpleasant symptoms (insomnia, anxiety, restlessness, and unpleasant changes in mood) that can occur during the period immediately following alcohol withdrawal. It is thought that blocking those symptoms may help some alcoholics continue to refrain from alcohol. The main side effect of acamprosate is a mild and, usually, transient diarrhea, although rarely but significantly, suicidal ideation and suicide attempts have been reported.
Evidence suggests that acamprosate is most effective for patients who are abstinent from alcohol at the time treatment is initiated and who are motivated to maintain abstinence. It should also be considered in patients who can’t take naltrexone, such as those on multiple medications or those with liver disease or taking opioids for pain or addiction.
It is important to note that the Jonas meta-analysis found that,
“Both acamprosate and oral naltrexone were associated with reduction in return to drinking. When directly compared with one another, no significant differences were found between acamprosate and naltrexone for controlling alcohol consumption.”
The 2014 meta-analysis also evaluated off-label uses of other medications. The only ones with evidence of any effectiveness were as follows:
- Topirimate (Topamax), an anti-seizure medication, has been reported to be better than placebo at reducing drinking days and heaving drinking days as well as the number of drinks/drinking day.
- Nalmefene was associated with fewer heavy drinking days and drinks per drinking day.
- 2 small RCTs (a total of 88 people studied) found an association between the use of valproic acid and “improvement in some consumption outcomes”.
Experts usually recommend that psychosocial therapy (cognitive behavioral therapy, 12-step programs, motivational enhancement therapy) be used in combination with the medication.
The bottom line
Although there is no wonder drug that makes it easy to quit drinking alcohol in excess, there are medications that can help reduce cravings and cut back on heavy drinking, particularly when combined with proven psychosocial interventions. Clearly, there’s a lot of room for improvement when it comes to the treatment of alcohol use disorder—perhaps, we need a substance abuse “moonshot.”
- Medication for the Treatment of Alcohol Use Disorder: A Brief Guide, SAMHSA, 10/2015
- Pharmacotherapy for Adults With Alcohol Use Disorders in Outpatient Settings A Systematic Review and Meta-analysis, JAMA, 5/14/14
- Fighting Alcoholism with Medication, Accessed 11/28,16
- Medications for Alcohol Use Disorder, Clinical Key 3/15/16 (Subscription required)