“Better is possible. It does not take genius. It takes diligence. It takes moral clarity. It takes ingenuity. And above all, it takes a willingness to try.”
– Better: A Surgeon’s Notes on Performance, Atul Gawande
Welcome to the first post to start the “Let’s Learn Psychopharmacology A to Z” series! Through this series, I will discuss some of the most highly-cited, landmark articles in psychopharmacology. A lot of this knowledge is relatively new. Medications were introduced into the practice of psychiatry in the 1950’s starting with the use of chlorpromazine and lithium. Since then, the list of psychotropic medication has exploded. There are 143 drugs described in Stahl’s Essential Psychopharmacology, Prescriber’s Guide, Sixth Edition (which is a highly recommended reference material decorating many psychiatrists’ offices) and more are being developed in pharmaceutical pipelines.
Disclaimer: This discussion is intended to briefly and superficially review the medical literature that describes the use of a medication. As new studies are published every day, information presented here may be obsolete. Ultimately, selecting a medication remains a decision between a patient and their doctor. Doctors recommending and patients using these medications are strongly advised to consult information provided by the manufacturer.
Today’s topic is acamprosate (brand name: Campral).
Let’s start with basic facts. Acamprosate is an amino acid derivative of taurine that acts as a modulator of GABA neurotransmission. It is FDA-approved for maintenance of alcohol abstinence. Theoretically, it reduces excitatory glutamate neurotransmission and increases inhibitory GABA neurotransmission. Because alcohol withdrawal can lead to excessive glutamate activity and deficient GABA activity, acamprosate can act as “artificial alcohol” to mitigate these effects.
Acamprosate appears to work best for individuals who have already abstained from alcohol. Other medications used frequently for alcohol use disorder include naltrexone and disulfiram.
In 2004, Bouza and colleagues published a meta-analysis of 13 acamprosate studies with 4000 total participants. The major findings confirmed that acamprosate improved the continuous abstinence rate with a number needed to treat of 10, and also significantly improved cumulative abstinence. Unfortunately, this study also showed that the rate of adherence to prescribed medication was a problem. Compliance varied widely among the studies, ranging between 40% to 90%. Overall, only about half of the people receiving acamprosate continued to take it throughout the assigned treatment period. The reasons for drop-out are unclear, though a minority reported discontinuation of medication due to adverse side effects, with gastrointestinal issues affecting approximately 17% of patients assigned to take acamprosate.
Next up is a randomized controlled trial – the COMBINE study, which was published in JAMA in 2006.
The COMBINE study is one of the largest studies on acamprosate. It was a randomized controlled trial that studied medication management (MM) and combined behavioral intervention (CBI) for the treatment of alcohol use disorder. Medications used include acamprosate and naltrexone. Primary outcome measures were 1) percent days abstinent and 2) time to first heavy drinking day. A heavy drinking day was defined as ≥ 4 drinks per day for women and ≥ 5 drinks per day for men
Participants were first divided into three groups: 1) MM only, 2) MM+CBI, and 3) CBI only. Within the groups that received medication management (MM), participants were further divided into four groups: acamprosate only, naltrexone only, both acamprosate + naltrexone, and placebo. This resulted in nine total groups.
Surprisingly, the COMBINE study showed that acamprosate had no significant effect on drinking versus placebo, either by itself or with any combination of naltrexone, CBI, or both. This result was different from the prior studies. The authors hypothesize that the negative result is perhaps because the COMBINE trial required only 4 days of abstinence before participants could join the trial, versus a longer pretreatment abstinence period.
A meta-analysis published in 2008 stated that acamprosate is efficacious, but in different ways than naltrexone. Rösner and colleagues write that acamprosate improves continuous abstinence rates over placebo with a number needed to treat of 8. However, acamprosate did not influence alcohol consumption after the first drink (i.e. reducing the amount consumed or risk of a lapse becoming a relapse.) Naltrexone reduced relapse rates, time to relapse, and also reduced heavy drinking in a subgroup of non-abstinent patients. From this, acamprosate appears to be the treatment of choice if the goal is complete abstinence, whereas naltrexone is preferred if choosing a harm-reduction strategy to prevent excessive drinking in non-abstinent patients.
“Individually allocating patients to treatments according to their motivational status could further enhance the effectiveness of treatments of alcohol dependence.”
– Rösner and colleagues 2008, citation below
The final article presented here was published in 2008 by Kranzler and colleagues. This report contributed to the United States Food and Drug Administration (FDA) approval of acamprosate for use in conjunction with psychosocial support in the maintenance of abstinence in alcohol-dependent patients. Kranzler et al re-analyzed three European pivotal trials, which were published in 1995, 1996, and 1997. These trials took place in France, Belgium, and Germany and examined a total of 623 patients.
Krazler et al applied a more rigorous definition of abstinence than the initial studies; for example, patients with missing data or with unknown status were also considered non-abstinent. With a more restrictive definition of abstinence, the calculated rates of abstinence were lower than the rates previously published, but remained significantly higher for patients treated with acamprosate than placebo. Rates of complete abstinence for placebo ranged between 9-13%, while rates for acamprosate ranged from 16-38%. Secondary outcomes for percent days abstinent and time to first drink also showed efficacy favoring acamprosate.
Overall, acamprosate is a well-studied, safe, and effective medication. There is also some evidence to show that the benefits of acamprosate in maintaining sobriety can extend for at least up to 12 months after drug discontinuation. Acamprosate has some limitations in its use. For example, it is most likely to be successful in people who have already maintained a period of sobriety. However, it can still be a valuable treatment option for many people.
Bouza C, Angeles M, Muñoz A, Amate JM. Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction. 2004 Jul;99(7):811-28. doi: 10.1111/j.1360-0443.2004.00763.x. Erratum in: Addiction. 2005 Apr;100(4):573. Magro, Angeles [corrected to Angeles, Magro]. PMID: 15200577.
Anton RF, O’Malley SS, Ciraulo DA, Cisler RA, Couper D, Donovan DM, Gastfriend DR, Hosking JD, Johnson BA, LoCastro JS, Longabaugh R, Mason BJ, Mattson ME, Miller WR, Pettinati HM, Randall CL, Swift R, Weiss RD, Williams LD, Zweben A; COMBINE Study Research Group. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006 May 3;295(17):2003-17. doi: 10.1001/jama.295.17.2003. PMID: 16670409.
Rösner S, Leucht S, Lehert P, Soyka M. Acamprosate supports abstinence, naltrexone prevents excessive drinking: evidence from a meta-analysis with unreported outcomes. J Psychopharmacol. 2008 Jan;22(1):11-23. doi: 10.1177/0269881107078308. PMID: 18187529.
Kranzler HR, Gage A. Acamprosate efficacy in alcohol-dependent patients: summary of results from three pivotal trials. Am J Addict. 2008 Jan-Feb;17(1):70-6. doi: 10.1080/10550490701756120. PMID: 18214726.