News & Analysis Medical News & Perspectives More Treatments on Deck for Alcohol Use Disorder Jeff Lyon hirteen years have passed since the Raye Z. Litten, PhD, acting director of the ment for AUD were actually prescribed an US Food and Drug Administration NIAAA’s Division of Medications Develop- AUD medication. T (FDA) last approved a new medica- ment and principal investigator of the trial, It is a complicated problem, says John tion to help the nation’s millions of people says the agency is “excited.” Rotrosen, MD, a psychiatrist and addiction withalcoholusedisorder(AUD)stopormod- Nevertheless, the science of alcohol ad- specialist at New York University School of erate their drinking. diction has seen its share of medicines that Medicine. “To a large extent primary care Only 3 such formulations exist, and 1, failed to live up to their early promise dur- physicians don’t screen for alcoholism,” he disulfiram, dates to the Prohibition era. ing full-scale testing. So Litten said the said. “When they do, they may note it, but Known commercially as Antabuse and agency isn’t putting all its eggs in one bas- don’t really do anything about it.” introduced in 1923, it makes people memo- ket. “You need as many weapons as pos- As far as the failure to prescribe exist- rably ill if they ingest alcohol, but it doesn’t sible to treat a complex disease like alcohol ing medications for AUD, Rotrosen blames stop the cravings. The other 2, naltrexone use disorder,” he said. a lack of knowledge. “A lot of doctors in and acamprosate, approved in 1994 and But therein lies a second difficulty. primary care haven’t been educated 2004, respectively, can alleviate cravings What few medications are out there remain in medical school about treatment for but only in some people. vastly underused. A 2015 NIAAA study alcohol and other addictions. [They] don’t Attempts are under way to remedy found that only 8.7% of US adults who think these drugs work, which is untrue. this lack of options. At least 5 promising, if have had AUD in the past have ever sought And a lot of them are uncomfortable pre- mostly repurposed medications, are at medical treatment from health care practi- scribing for addictive disorders they don’t some point in the pipeline as the National tioners for the disorder, probably because know how to manage.” Many primary care Institute on Alcohol Abuse and Alcoholism they are not ready to quit, lack health insur- physicians also don’t see managing addic- (NIAAA) steps up efforts to bring more ance, or fear being stigmatized. Most only tion as part of their role. therapeutics to the marketplace. One of see a physician for the comorbid ailments those is a familiar name, gabapentin. The that result from their addiction. AUD on the Increase 1990s-era anticonvulsant, which has Meanwhile, of the 8.7% who have In 2015, the number of Americans 18 years shown some efficacy against alcohol sought medical help, even fewer received or older with AUD was pegged at 15.1 mil- addiction in early studies, was the subject prescriptions for their condition. Although lion, according to the National Survey on of a just-completed national trial spon- precise population-wide data do not exist, Drug Use and Health conducted by the sored by the NIAAA. The final results of a 2012 study by the Veterans Health Ad- Substance Abuse and Mental Health Ser- the trial are still being analyzed and will ministration found that less than 4% of all vices Administration. But a study led not be reported for several months, but military veterans seeking medical treat- by NIAAA researchers in conjunction with the 2012-2013 National Epidemiologic Sur- vey on Alcohol and Related Conditions reported that a far larger number, 32.6 mil- lion, had AUD in the previous 12 months. Moreover, a staggering 70.4 million— 29.1% of the adult population—have had AUD at some point in their lives. Notably, the study also found that the rate of AUD increased substantially over the decade following 2001-2002. Given these numbers, AUD affects at least as many, if not more, people than depression, a condition that often coin- cides with it and is estimated to affect some 16.1 million adults. Yet in startling contrast with the armamentarium for alco- holism, there are currently more than 20 medications approved by the FDA to fight depression, and the big pharmaceutical companies are heavily involved in market- ing to that population. jama.com (Reprinted) JAMA Published online May 24, 2017 E1 © 2017 American Medical Association. All rights reserved. Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/jama/0/ on 05/24/2017 News & Analysis der the name Horizant, will seek a new drug Other Potential Treatments for Alcohol Use Disorder application (NDA). Additional medications the National Institute on Alcohol Abuse and Alcoholism (NIAAA) Helping to pave the way for the current is pursuing that have shown potential against alcohol use disorder (AUD) include: trial was a smaller, 3-month study of gabapentin that was completed with 85 of Varenicline Citicoline its original 150 participants several years ago The NIAAA and others conducted a 2013 A well-tolerated, over-the-counter trial on this drug, which under the name supplement, this medication modulates at the Scripps Research Institute in La Jolla, Chantix is marketed for smoking cessa- cholinergic systems. Results of California, under the leadership of Barbara tion. It significantly reduced heavy a 12-week placebo-controlled trial to see Mason, PhD, director of the Pearson Center drinking days and cravings among 200 if citicoline reduces heavy drinking are for Alcoholism and Addiction Research. smokers and nonsmokers. forthcoming. The drug may mitigate The medication significantly improved initiation and maintenance of substance the rate of abstinence and no heavy drink- ABT-436 abuse by enhancing cognitive function ing, Mason’s team reported. At 1800 mg A 2016 phase 2 trial of this antianxiety and better decision-making via medication that works by blocking the V1b increased acetylcholine signaling. a day, the abstinence rate observed was receptor of the stress-inducing hormone 17%, compared with 4.1% for the placebo vasopressin had a statistically significant Baclofen group, and the no-heavy-drinking rate was effect on abstinence, especially in people An agonist of metabotropic GABA B 44.7% vs 22.5% for placebo. The drug’s with high baseline anxiety. (γ-aminobutyric acid) receptors that has number-needed-to-treat (NNT)—the aver- been approved by the US Food and Drug Glucocorticoid Receptor Administration for muscle spasticity. It age number of patients one must treat to Antagonist has shown mixed results in small trials have a beneficial effect on 1 patient—was 8 Better known as mifepristone, or but is currently undergoing additional for abstinence and 5 for no heavy drinking, RU-486, this abortifacient has also been testing and review in the United States putting it in the efficacy range of main- found to reduce alcohol intake in and Europe. stream antidepressants. humans. Like ABT-436, it works on the This compares favorably with the effi- stress system by regulating the amygdala. A clinical trial assessing the efficacy of cacy of acamprosate and oral naltrexone mifepristone in treating AUD is currently based on a 2014 meta-analysis. For promot- under way at Brown University. ing abstinence, acamprosate had an NNT of 12 and oral naltrexone, an NNT of 20. For pre- venting a return to heavy drinking, naltrex- “The drug industry has been able to cre- the effectiveness of 1200 mg a day of one had an NNT of 12, and acamprosate was ate huge markets for antidepressants, and gabapentin enacarbil (the enacarbil is for not associated with improvement. it’s continuing to develop more,” noted increased bioavailability) with a placebo. Although gabapentin showed some ef- Rotrosen, “but in general there is little mo- The desired efficacy end point was a favor- fectiveness at reducing cravings and the tivation to do the same for addiction.” able percentage of participants who expe- amount of alcohol consumed, it is particu- He attributed this lack of interest to rienced no heavy drinking days during the fi- larly helpful against withdrawal symptoms, stigma. “The historical view of addicts is that nal 4 weeks of treatment. Such an outcome said Mason. they are street people, poor, and homeless. is 1 of 2 end points the FDA considers cru- “Usually people who are cutting down They are seen as not having insurance or cial when deciding whether the medication or quitting not only have cravings but get ir- ways to pay for medicine.” is efficacious or not, the other, of course, ritable, dysphoric, and anxious, plus they do Other experts cite alternative reasons being total abstinence. not sleep well. This prompts many people in for the gap, including the reluctance of Heavy drinking days are officially de- earlyrecoverytoreturntodrinking,”shesaid. many people with AUD to recognize that fined as more than 4 standard drinks a day “Evidence suggests that gabapentin not only they have a problem and the difficulty for males and more than 3 for females. Any- has an effect on cravings, but also on sleep patients with AUD have in adhering to pre- thing below this is considered “low-risk” and mood. Sleep improves without seda- scribed regimens. drinking because it is less likely to cause in- tion or daytime drowsiness.” toxication and associated injuries and health Mason considers drugs like naltrexone Gabapentin on the Scene risks, as well as associated chronic medical that work by blocking reward receptors a Gabapentin, if it performs to expectations and mental health conditions.