Acamprosate For Alcohol: Why the Research Might Be Wrong

Calcium may be curbing the urge to drink.

“Occasionally,” reads the opening sentence of a commentary published online last month in Neuropsychopharmacology, “a paper comes along that fundamentally challenges what we thought we knew about a drug mechanism.” The drug in question is acamprosate, and the mechanism of action under scrutiny is the drug’s ability to promote abstinence in alcoholics. The author of the unusual commentary is Markus Heilig, Chief of the Laboratory of Clinical and Translational Studies at the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

Acamprosate, in use worldwide and currently the most widely prescribed medication for alcohol dependence in the U.S., may work by an entirely different mechanism than scientists have believed on the basis of hundreds of studies over decades. Rainer Spanagel of the Institute of Psychopharmacology at the University of Heidelberg, Germany, led a large research group in revisiting research that he and others had performed on acamprosate ten years earlier. In their article  for Neuropsychopharmacology, Spanagel and coworkers concluded that a sodium salt version of acamprosate was totally ineffective in animal models of alcohol-preferring rats.

“Surprisingly,” they write, “calcium salts produce acamprosate-like effects in three animal models…. We conclude that N-acetylhomotaurinate is a biologically inactive molecule and that the effects of acamprosate described in more than 450 published original investigations and clinical trials and 1.5 million treated patients can possibly be attributed to calcium.”

At present, the Food and Drug Administration (FDA] has approved three drugs for alcoholism— Antabuse, naltrexone, plus acamprosate in 2004. In addition, there is considerable clinical evidence behind the use of four other drugs—topiramate, baclofen, ondansetron, and varenicline. Acamprosate as marketed is the calcium salt of N-acetyl-homotaurinate, a close relative of the amino acid taurine. It has also been found effective in European studies.

What did scientists think acamprosate was doing? Various lines of research had linked acamprosate to glutamate transmission. Changes in glutamate transmission have been directly implicated in active alcoholism. A decade ago, the Spanagel group had decided that acamprosate normalized overactive glutamate systems, and hypothesized that acamprosate was modulating GABA transmission. So it became known as a “functional glutamate antagonist.”  But specific mechanisms have remained elusive ever since.

Now, as Heilig comments, “the reason it has been difficult to pin down the molecular site of acamprosate action may simply be because it does not exist. Instead, the authors propose that the activity attributed to acamprosate has all along reflected actions of the Ca++ it carries.” As the researcher paper explains it: “N-acetylhomotaurinate by itself is not an active psychotropic molecule…. We have to conclude that the proposed glutamate receptor interactions of acamprosate cannot sufficiently explain the anti-relapse action of this drug.” Further work shows that acamprosate doesn’t interact with glutamate binding sites at all.  In other words, calcium appears to be the major active ingredient in acamprosate. Animal studies using calcium chloride or calcium gluconate reduced alcohol intake in animals at rates similar to those seen in acamprosate, the researchers claim.

Subsequently, the researchers revisited the earlier clinical studies, subjected them to secondary analysis, and concluded that “in acamprosate-treated patients positive outcomes are strongly correlated with plasma Ca++ levels. No such correlation exists in placebo-treated patients.” In addition, calcium salts delivered via different carrier drugs replicated the suppression of drinking in the earlier animal findings. 

Where there cues pointing toward calcium? The researchers conclude that “calcium sensitivity of the synapse is important for alcohol tolerance development, calcium given intraventricularly significantly enhances alcohol intoxication in a dose-dependent manner,” and “activity of calcium-dependent ion channels modulate alcohol drinking.”

Interestingly, in the late 50s and early 60s, there was a brief period of interest in calcium therapy for the treatment of alcoholism. In 1964, the Journal of Psychology ran an article titled “Intensive Calcium Therapy as an Initial Approach to the Psychotherapeutic Relationship in the Rehabilitation of the Compulsive Drinker.” Now it appears possible that a daily dose of acamprosate is effective for some abstinent alcoholics because it raises calcium plasma levels. Calcium supplements may be in for a round of intensive clinical testing if these findings hold up.

The authors now call for “ambitious randomized controlled clinical trials,” to directly compare “other means of the Ca++ delivery as an approach to treat alcohol addiction. Data in support of a therapeutic role of calcium would open fascinating clinical possibilities.”  Indeed it would.

Spanagel R., Vengeliene V., Jandeleit B., Fischer W.N., Grindstaff K., Zhang X., Gallop M.A., Krstew E.V., Lawrence A.J. & Kiefer F.  (2013). Acamprosate Produces Its Anti-Relapse Effects Via Calcium, Neuropsychopharmacology, 39 (4) 783-791. DOI: 10.1038/npp.2013.264

End of the Line for Prometa?

Controversial meth treatment program fails in major study.

Prometa—the drug cocktail designed to combat addiction to cocaine and methamphetamine—has fallen flat on its face in a double-blind, placebo-controlled 108-day study just published in the journal Addiction. Dogged all along by a lack of published clinical data as well as major doubts about its success rates, Prometa has been a controversial treatment right from the start. In 2006, marketed heavily by anecdote and personal testimonials, the Prometa campaign included ads featuring the late comedian Chris Farley, who died of a drug overdose.

Hythiam,  the company that markets Prometa, had touted reports that 80% or more of Prometa users experienced “significant clinical benefit.” But MSNBC reported in 2008 that accountants in Pierce County, Washington froze the funding for an $800,000 pilot program, citing irregularities in testing. Investors in Hythiam, which is publicly traded, had been counting on the Pierce program after similar programs in Fulton County, Georgia, and in Idaho had failed to get off the ground. Things only got worse when the Tacoma News Tribune revealed that several county officials who had gotten behind the program also owned Hythiam stock.

Small rural communities that have felt the impact of meth sales and production in their communities are looking for help, and represent a significant market for an anti-addiction medication. However, in the case of Prometa, “The marketing is way ahead of the science,” said Lori Karan of the Drug Dependence Research Laboratory at the University of California-San Francisco. At the same time, Hythiam Executive Vice President Richard Anderson voiced strong objections to the Pierce County decision: “The people who are using it,” he said, “the doctors, patients, administrators, and drug court judges—are seeing an impact with it, so I think the treatment will carry it at the end of the day.”

But the day has ended, and the treatment did not carry it. The study in Addiction by a team of researchers at UCLA found no difference between Prometa and placebo in a group of 120 methamphetamine-addicted adults. The Prometa regimen, which can cost as much as $12,000 to $15,000 a month, “appears to be no more effective than placebo in reducing methamphetamine use, retaining patients in treatment or reducing methamphetamine craving,” the investigators conclude.

Ironically, the study was funded by Hythiam, as a response to complaints from the scientific community about a lack of rigorous testing. When it first launched the treatment, Hythiam was able to skim past the pesky drug approval process by exploiting a loophole in the FDA’s regulatory system that allows combinations of previously approved drugs to be marketed without formal review. Prometa was a blend of three existing medications: Neurontin (gabapentin) for epilepsy, Vistaril (hydrozyzine) for allergies, and Romazicon (flumazenil) for reversing benzodiazepine overdoses.

Ling, W., Shoptaw, S., Hillhouse, M., Bholat, M., Charuvastra, C., Heinzerling, K., Chim, D., Annon, J., Dowling, P., & Doraimani, G. (2011). Double-blind placebo-controlled evaluation of the PROMETA™ protocol for methamphetamine dependence Addiction DOI: 10.1111/j.1360-0443.2011.03619.x

Why are Treatment Centers Afraid of Anti-Craving Medications?

Using What Works

Why do so many drug treatment centers continue to shun science by ignoring medications that ease the burden of withdrawal for many addicts? That’s the question posed in an article by Alison Knopf in the May-June issue of Addiction Professional, titled “The Medication Holdouts.”

“Nowhere else in medicine,” Knopf writes, “are the people who treat a condition so suspicious of the very medications designed to help the condition in which they specialize.”

Acamprosate, a drug used to treat alcoholism, is a good case in point. A dozen European studies examining thousands of alcohol test subjects found that the drug increased the number of days that most subjects were able to remain abstinent. But when a German drug maker decided to market the drug in the U.S., fierce advocates for drug-free addiction therapy came out in force, even though the drug was ultimately approved for use.

Disulfiram, naltrexone, acamprosate, methadone, buprenorphine—the evidence for all of them is solid. Knopf cites the case of buprenorphine:

“‘There are scores of peer-reviewed journal articles that evaluate the success of buprenorphine,’ says Nicholas Reuter, MPH, senior public health adviser in the Division of Pharmacologic Therapies at the federal Center for Substance Abuse Treatment (CSAT). ‘It's well established that the data and the evidence are there. Not treating patients with a medication consigns most of them to relapse, adds Reuter. While some opioid-addicted patients, as many as 20 percent, do respond to abstinence-based therapy, ‘That still leaves us with the 80 percent who don't,’ he says.”

Dr. Charles O'Brien, one the nation’s most respected addiction professionals and a Professor of Psychiatry at the University of Pennsylvania, is incensed that anti-craving medications are not more widely used. “It's unethical not to use medications,” he says. “This is a subject that I feel very strongly about.” O’Brien told Addiction Professional he no longer cares who he offends on the subject. “If you're discouraging people from taking medications, you are behaving in an unethical way; you are depriving your patients of a way to turn themselves around. Just because you don't like it doesn't mean you have to keep your patients away from it.”

And at the Association for Addiction Professionals, “the prevailing philosophy is pro-medication,” Knopf writes. Misti Storie, education and training consultant for the group, told Knopf that the “disconnect” at treatment centers is due to a “lack of education about the connection between biology and addiction.” Counselors working in centers that do not allow anti-craving medications are in a tough spot, Storie acknowledged.

It is continually astonishing that treatment centers--where the primary goal is supposed to be the prevention of relapse, even though the success rate remains abysmal--would spurn medications that often help to accomplish precisely that goal. Relapse rates hover around 80%, by an amalgam of estimates, so it’s not like rehabs are wildly successful at what they do. What’s really behind the resistance?

What stands between many addicts and the new forms of treatment is “pharmacological Calvinism.” I would love to claim this term as my own, but it was coined by Cornell University researcher Gerald Klerman. Pharmacological Calvinism may be defined as the belief that treating any psychological symptoms with a pill is tantamount to ethical surrender, or, at the very least, a serious failure of will. As Peter Kramer quoted Klerman in Listening to Prozac: If a drug makes you feel better, then by definition “somehow it is morally wrong and the user is likely to suffer retribution with either dependence, liver damage, or chromosomal change, or some other form of medical-theological damnation.”

Photo credit: www.life123.com

Drug That Blocks Stress Receptor May Curb Alcohol Craving

Anxiety, drugs, and the brain’s “fear center.”

A brain receptor for a neurotransmitter involved in stress and anxiety has become a primary target in the scientific war on alcoholism—the only kind of drug war that really matters.

Researchers at the National Institute of Alcohol Abuse and Alcoholism (NIAAA), working with colleagues at Lilly Research Laboratories and University College in London, announced that a drug that blocks the so-called NK1 receptor (NK1R) reduced alcohol cravings in a study of 25 detoxified alcoholic inpatients. The drug “suppressed spontaneous alcohol cravings, improved overall well-being, blunted cravings induced by a challenge procedure, and attenuated concomitant cortisol responses.”

The study, published in the current issue of Science magazine, (look here for abstract) demonstrates that investigators continue to work toward more effective anti-craving drugs from a variety of angles. The NIAAA researchers are making effective use of recent findings about the role played by corticotropin-releasing hormone (CRH) in the addictive process. CRH is crucial to the neural signaling pathway in areas of the brain involved in both drug reward and stress.

Another neurotransmitter of this type is substance P, together with its preferred receptor, NK1R. As it happens, NK1R sites are densely concentrated in limbic structures of the mid-brain, such as the amygdala, or so-called “fear center.” The experimental drug, known as LY686017, blocks NK1R receptors, shutting off substance P, which in turn diminishes anxiety-related drug cravings.

Other researchers had previously demonstrated that deletion of NK1R sites eliminated opiate use in animal models. It has also been known for some time that alcohol and the opiates share certain common chemical pathways in the brain. And in humans, at least one earlier study showed decreased stress and anxiety reactions in human subjects taking a drug that blocked the Neurokinin 1 receptors.

The authors of the study suggest that “blockade of NK1Rs might modulate stress- and reward-related processes of importance for excessive alcohol use and relapse.”

According to NIAAA director Dr. Ting-Kai Li, “These findings advance our understanding of the link between stress and alcohol dependence and raise the prospect of a new class of medications for treating alcoholism.”

The early finding will require more research. “To our knowledge,” the authors conclude, “no data are presently available to address this hypothesis.”

graphic credit: http://www.ibiblio.org/rcip/ptsdmemory.html