Conference Coverage

Ketamine emerging as top treatment for cocaine dependence



– The prospect on the horizon of two new effective therapies for chronic cocaine dependence – sustained-release dextroamphetamine and subanesthetic ketamine infusions – was among the top developments of the year in addiction medicine, Wim van den Brink, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.

Other highlights on his list included:

• Studies establishing that comorbid attention-deficit/hyperactivity disorder (ADHD) and substance use disorder now can be treated effectively with either extended-release mixed amphetamine salts or high-dose methylphenidate.

Dr. Wim van den Brink

Dr. Wim van den Brink

• Evidence that the alpha-1 blocker doxazosin is an effective treatment for alcoholism in a specific well-defined subset of patients, opening the door to a personalized medicine approach to this disease.

• Release of a puzzling array of conflicting studies on the use of high-dose baclofen for treatment of alcohol dependence. It’s tough to reconcile this mishmash of polar opposite results. And that dictates it’s time to declare a moratorium on the use of this therapy in clinical practice, which in many places is now widespread, said Dr. van den Brink, professor of psychiatry and addiction at the University of Amsterdam and director of the Amsterdam Institute for Addiction Research.

“It’s too strange that we have such conflicting evidence out there. Too many people are prescribing crazy-high doses of baclofen with no strong supporting evidence,” Dr. van den Brink said.

Cocaine dependence

Dr. van den Brink was a coinvestigator in a Dutch multicenter randomized, double-blind, placebo-controlled trial of multitreatment-refractory comorbid cocaine dependence in 73 heroin-dependent patients in heroin-assisted treatment. Patients assigned to 60 mg/day of sustained-release dextroamphetamine, in addition to the background methadone and diacetylmorphine all participants were on for their heroin dependence, had significantly fewer days of cocaine use in the 12-week study: a mean of 44.9 days, compared with 60.6 days in placebo-treated controls. Adverse events were transient and well tolerated (Lancet. 2016 May 28;387[10034]:2226-34).

“A lot of medications have been tried for treatment of cocaine dependence, but actually none of them has been shown to be effective with the exception of substitution treatment with stimulants. Ours is one of the most successful trials. These patients were using cocaine an average of 24 days per month along with a lot of other drugs, despite being in heroin treatment for 4 years,” Dr. van den Brink said. “Patients were very willing to take the sustained-release dextroamphetamine. In the last 4 weeks, 84% of them used at least 80% of their medication. And they were blinded to what they were using.

“We saw good effect sizes: 0.6-0.7 for self-report measures and 0.31 for negative urine samples. So this is a very promising approach. But it also means that, like with tobacco dependence or alcohol dependence, we have to start thinking about substitution therapy in stimulant-dependent patients,” he said.

Dr. van den Brink said subanesthetic ketamine as a novel treatment for cocaine dependence is not yet ready for prime time use in clinical practice, because it’s just not practical to bring patients in for a roughly hour-long intravenous infusion on a daily basis, as was done in a highly impressive proof-of-concept study. But new formulations of ketamine are under development that should better lend themselves to use in clinical practice.

In the proof-of-concept study, investigators at the New York State Psychiatric Institute brought into the laboratory cocaine-dependent volunteers not seeking treatment or abstinence and administered 52-minute infusions of ketamine at 0.41 or 71 mg/kg or lorazepam at 2 mg (Biol Psychiatry. 2014 Jul 1;76[1]:40-6). Lorazepam had absolutely no effect on motivation to change, but ketamine was a different story.

“As soon as you give a low dose of ketamine, you see a wonderful effect on motivation to change and on craving ratings in assessments at 24 hours post infusion. This looks like another promising way of treating cocaine dependence,” he said.

Doxazosin for alcoholism

Investigators at the National Institute on Alcohol Abuse and Alcoholism and several U.S. universities hypothesized that the norepinephrine system could be an important treatment target in alcohol dependence. They conducted a double-blind, placebo-controlled randomized trial in which alcohol-dependent patients seeking outpatient treatment were assigned to the alpha1-adrenergic blocker doxazosin (Cardura) titrated to a maximum of 16 mg/day or placebo. They found doxazosin significantly reduced drinks per week and the number of heavy drinking days per week, but only in the subgroup of patients with a strong family history of alcoholism. In patients without such a family history, doxazosin paradoxically increased drinking (Addict Biol. 2016 Jul;21[4]:904-14).

One of the reasons adult ADHD is greatly underrecognized is that it tends to occur in combination with flashier substance use disorders. “Addiction is very comorbid with all kinds of disorders, but especially with externalizing childhood disorders like conduct disorder and ADHD,” Dr. van den Brink said.

It was shown half-a-decade ago that normal doses of methylphenidate have no effect on ADHD symptoms or substance use in comorbid adults. Then Swedish investigators reported that treating criminal offenders with high-dose methylphenidate – roughly three times greater than standard dosing – was effective in reducing both ADHD symptoms and comorbid substance use in criminal offenders. Those findings prompted investigators at the New York State Psychiatric Institute and the University of Minnesota to examine whether prescribing extended-release mixed amphetamine salts in adults with comorbid cocaine use disorder and ADHD would achieve improvement in both conditions. Indeed, it did, Dr. van den Brink said.

One hundred twenty-six affected patients were randomized to 60 or 80 mg/day of extended-release mixed amphetamine salts or placebo for 13 weeks coupled with weekly individual cognitive-behavioral therapy for all in this double-blind, three-arm clinical trial.

“They showed a number-needed-to-treat of about 2.5 in order to achieve a significant reduction in cocaine use and a very nice reduction in ADHD symptoms with a number-needed-to-treat of 3,” Dr. van den Brink said.

The rate of continuous cocaine abstinence in the last 3 weeks of the trial was 30% in the 80-mg group and 17.5% with 60 mg of extended-release mixed amphetamine salts, compared with just 7% with placebo (JAMA Psychiatry. 2015 Jun;72[6]:593-602).

Interpreting baclofen studies

The first high-quality multicenter, randomized, placebo-controlled, double-blind clinical trial, conducted in Germany, showed baclofen (Lioresal) at a mean dose of 180 mg/day was effective in maintaining alcohol abstinence (Eur Neuropsychopharmacol. 2015 Aug;25[8]:1167-77).

“They got wonderful results, with a number-needed-to-treat of 2.3. That is something we’re not used to seeing in the treatment of alcoholism. But there was no dose-response effect, which is a little unusual,” the psychiatrist observed.

Then a multicenter group of Dutch investigators, including Dr. van den Brink, carried out what they believed would be a confirmatory randomized, double-blind, placebo-controlled trial. However, it showed no difference between high- or low-dose baclofen and placebo in time to relapse (Eur Neuropsychopharmacol. 2016 Dec;26[12]:1950-9).

Little further light was shed by the two large French randomized, placebo-controlled clinical trials presented at the 2016 World Congress for Alcohol and Alcoholism in Berlin. One, the BACLOVILLE trial, included 320 patients treated in 60 family practice clinics; it showed strongly positive results for high-dose baclofen. In contrast, the 316-patient ALPADIR study proved negative. These conflicting results were particularly disappointing because France has been at the forefront of using high-dose baclofen to treat alcoholism, Dr. van den Brink said.

“Maybe some 100,000 people have been treated with high-dose baclofen for alcoholism in France,” he said. “What is the conclusion from all these baclofen studies? You can interpret them in many ways. Maybe there are two positive trials and two negative trials, or maybe there are two positive trials and two failed trials. The debate is not closed, even after four randomized trials.”

Dr. van den Brink reported receiving research funding from and/or serving as a consultant to more than half a dozen pharmaceutical companies.

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