PROMETA Postmortem

How the latest miracle cure for addiction failed to deliver.

PROMETA™: Last seen going down fast, smoke pouring from all engines.

As reported here at Addiction Inbox, a double-blind placebo-controlled evaluation of PROMETA™ by W. Ling and associates, published online last month in the journal Addiction, found that the much-publicized treatment protocol for meth addiction “appears to be no more effective than placebo in reducing methamphetamine use, retaining patients in treatment or reducing methamphetamine craving.” The authors of the journal paper didn’t accuse Hythiam, the company that makes and sells the product, of not telling the truth. They just said that the treatment didn’t work. The study authors did, however, find evidence of “potential financial conflicts of interests among its advocates…”

An earlier CBS News "60 Minutes" news report in 2009 had raised similar questions, but generated a great deal of publicity for PROMETA™. And the only testing available, a small open study from Texas, had shown positive results. Testimonials began mounting, and a few prominent doctors in the addiction field lent their names to the marketing effort. More conservative voices, like Richard Rawson and the University of Pennsylvania’s Tom McClellan, warned that there was insufficient scientific evidence to push forward with the new treatment—but their concerns were swept aside amid the general enthusiasm for a long-sought antidote to the ravages of methamphetamine addiction.

So how did it happen? And what, if anything, does it teach us about the enterprise of addiction research and treatment?

An editorial by Dr. Keith Humphreys of the Stanford University Medical Centers, which  accompanied the report of the clinical trial in Addiction, attempted to analyze the saga of how “a former junk bond trader with no medical background raised $150 million in capital to market a combination of three medications (gabapentin, flumazenil and hydroxyzine) as a treatment for methamphetamine addiction.” Bear in mind that only one of the drugs—gabapentin—had ever been involved in clinical trials against addiction, with decidedly mixed results. As for the other ingredients, a prominent neuroscientist who blogs pseudonymously as Neuroskeptic, commented at the time: “What the hell kind of a cocktail is that? Gabapentin—OK, it might reduce anxiety and stabilize mood, although the evidence is poor and if you wanted to do that, there are better drugs. Ditto for hydroxazine. And why you want both of those is unclear. But flumazenil? That doesn't do much if you haven't taken a benzodiazepine. But if it did do anything it would be to antagonize the gabapentin.”

All in all, not a promising analysis.

The three drugs are approved for various uses by the FDA, and there is the rub: Off-label practices allow physicians to prescribe medications for uses other than those listed on the official package insert. As useful as this practice can be, it creates a situation in which a “combination of previously approved medications can be marketed without review as a new treatment protocol, despite the fact that none of the individual medications had any evidence nor were originally approved as a treatment for the condition the new protocol targets.”

Under this directive, Hythiam was free to promote the combination of approved medications as a new addiction treatment advance without any significant testing, Humphreys contends.

If the treatment, in the end, proved to be no better than placebo for meth addiction, what made it seem like such a successful new thing under the sun at the outset? Wishful thinking, Humphreys believes: “Many serious, good-hearted people will be shocked at Ling’s negative results because they believed sincerely… we must not yield to our powerful collective desire to believe before we have hard evidence of effectiveness from disinterested, respected sources. The simpler, faster and more miraculous-seeming the cure, the greater should be our skepticism.”

Furthermore: "As was the case with another would-be ‘miracle cure’—ultra-rapid opiate-detoxification—a manufacturer was able to market an untested treatment protocol to addicted patients…”

Why? Because “off-label use of medications is well-established in medical practice and has significant value in many cases, but a balance must be struck with the risk this creates for evasion of the normal safety and efficacy checks by creators of new treatment protocols."

"We have a huge advantage at this historical moment which was not available to people in prior eras who could not determine whether ‘Dr. Keeley’s Double Chloride of Gold Injections’, ‘Dr. Revaly’s Guaranteed Remedy for the Tobacco Habit’ and ‘Dr. Meeker’s Addiction Antidote’ were effective,” writes Humphreys. Namely, “a well-developed addiction treatment research enterprise." And because of that, we should “point with pride to Ling et.al.’s work as an example of how high-quality science can inform suffering people about what will help them and what will not; and those who set public research budgets need look no further for an example of return on investment.”

HUMPHREYS, K. (2012). What can we learn from the failure of yet another ‘miracle cure’ for addiction? Addiction, 107 (2), 237-239 DOI: 10.1111/j.1360-0443.2011.03652.x

Photo Credit: http://blog.nebraskahistory.org

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

Vote of No Confidence For Prometa

Addiction drug loses major funding.

It is composed of three common and inexpensive drugs used for other purposes. It has never been subjected to clinical double blind testing. It costs thousands of dollars for the full treatment package, and the company that markets it says it cures about 80 percent of the drug addicts who use it.

If that description sounds familiar—if it seems to give off a faint whiff of blue-green algae and multi-level marketing—such concerns have not stunted the promotion and acceptance of the anti-addiction drug Prometa. But MSNBC reported last week that Prometa, the drug “cocktail” designed to combat addiction to cocaine and methamphetamine, was dealt a severe blow when accountants in Pierce County, Washington froze the funding for an $800,000 pilot program, citing irregularities in testing.

The treatment involves intravenous infusions of Flumazinil, a reversal agent for benzodiazepines like Valium and Klonopin. The second drug, hydroxyzine, is an antihistamine, and the third, sold as Neurontin, as an anti-seizure medication frequently used “off prescription” as a treatment for a number of ailments, including alcoholism and hearing loss.

The treatment does not require approval by the Food and Drug Administration (FDA) because all three ingredients are already in common use in clinics and hospitals. The Prometa Regimen marketed by Hythium involves formulating the protocol and contracting with doctors to deliver the medications.

To date, there is no published clinical data to support treatment for addiction with these three drugs in proprietary combination.

Marketed heavily by anecdote and personal testimonials, the Prometa marketing campaign included ads in 2006 featuring the late comedian Chris Farley, who died of a drug overdose.

Hythiam, the company that markets Prometa, has touted the treatment with claims of success rates as high as 98 per cent, but Pierce County Councilman Shawn Bunney found the results of the county audit “alarming,” according to MSNBC. “It’s clear to me that we are much more involved in a marketing scheme…”

Hythiam Executive Vice President Richard Anderson disagreed. “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.”

The dispute centers on the manner in which dropouts were counted in surveys done by Hythiam’s non-profit arm, the Pierce County Alliance. The Alliance had been responsible for administering the Prometa program in Pierce County drug courts. According to county auditors, dropouts and no-shows (patients who fail to show up for drug testing) were not included in the Alliance’s final report on 35 patients over a 14-month period. In Pierce and neighboring counties of Washington, drug courts record no-shows as equivalent to positive drug tests. This was not how the alliance scored it, although alliance spokespeople have insisted that county officials have misunderstood the mechanics of the study.

An investigation by the Tacoma News Tribune threw more cold water on the Prometa numbers. “According to the multiple public statements by the alliance,” wrote Sean Robinson, 86 percent of the Prometa clients ‘remained drug-free’ at the end of the 14-month program. According to county auditors, the number was 50 percent.”

Furthermore, the alliance “defined success in the Prometa program as 60 or more days of clean drug tests…. In Pierce County, drug-court clients must show 90 days of clean drug tests… In Snohomish and Thurston counties, drug-court clients must show six months.”

Investors in Hythiam, which is publicly traded, were counting on the Pierce program after similar programs in Fulton County, Georgia, and in Idaho 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,” claimed Lori Karan of the Drug Dependence Research Laboratory at the University of California-San Francisco.

Double-blind studies of Prometa are underway at the University of California-Los Angeles and at the University of South Carolina.