Two drugs currently used to treat heroin and prescription painkiller addiction may work together to fight cocaine as well — without causing dependence themselves, according to a new study in rats.
A clinical trial in humans is currently enrolling patients, and if future research is successful, the new drug combination — buprenorphine plus naltrexone — could be the first medication developed for the treatment of cocaine addiction. The drug would likely work for methamphetamine and other stimulant addictions, too.
The new research originated with Dr. Nora Volkow, director of the National Institute on Drug Abuse, who asked George Koob of the Scripps Institute in California to lead the study. “I had been intrigued by the clinical trials showing that when you use buprenorphine, use of cocaine goes down significantly,” says Volkow, referring to previous studies of people with heroin addiction who reduced their use of cocaine while being treated with buprenorphine.
But buprenorphine (Suboxone, Subutex) is an opioid, which means that it can cause physical dependence and has the potential for misuse. So, for people who use cocaine but aren’t already addicted to heroin or a similar drug, buprenorphine could make their problem worse. The last thing addiction treatment providers want to do is add a new class of drug to a client’s repertoire.
That complication precluded the possibility of testing buprenorphine on its own in cocaine addicts. It was scientifically plausible, however, to think that using it in combination with another medication that blocks some of its opioid effects could prevent this problem. As it turns out, naltrexone (reVia, Vivitrol) fits the bill.
Buprenorphine itself is a marvel of multiplicity. At low doses, it acts like an opioid, cutting physical and emotional pain and reducing anxiety by activating a class of opioid receptors, known as mu receptors. At high doses, it has the opposite effect: preventing opioid-like action and inducing withdrawal symptoms rather than relief. That’s what makes it an especially safe drug for maintenance of people with opioid addictions. But buprenorphine has another action as well: it blocks the kappa opioid receptor, a target that has long intrigued pharmacologists because it seems to be one of the “brakes” on the pleasure-producing dopamine system.
When people repeatedly take drugs — particularly stimulants like cocaine and methamphetamine — the brain releases excessive amounts of dopamine. This triggers a feedback loop: it overactivates kappa opioid receptors, which in turn shuts dopamine down. Now “it’s payback time,” says Koob, because your brain’s pleasure pathways conform to an austerity plan, getting increasingly stingy with the joy juice.
The distress and dysphoria associated with rising kappa activation seem to be what drives addicts to seek more drugs, in a vain attempt to feel better. Ultimately, however, that makes matters worse as the feedback dials the pleasure volume down even further. “I call it pharmacological Calvinism,” Koob says, noting that while the human brain is wired to enjoy everyday pleasures, frequent drug use triggers the stress system, which prevents the party from lasting forever.
“The reward system’s sensitivity decreases profoundly and that leads the addicted person to feel very little pleasure from almost any reward, including the drug itself,” Volkow says.
So, how do you allow buprenorphine’s positive effects on kappa receptors while blocking its effect on the mu receptors associated with addiction? Add naltrexone, which blocks only mu. To test whether this drug combo could actually reduce the distress associated with cocaine addiction without leading to opioid dependence, researchers studied the cocktail in rats.
The animals were studied in two conditions: one comparable to casual cocaine users, the other similar to cocaine addicts. The casual users were the “short access” rats: they were given access to cocaine for only one hour a day. Like many weekend-only human users, these rats “really don’t develop any signs of dependence,” says Koob, noting that he’s had animals in this condition for more than a year without seeing compulsive behavior.
Rodents given access to cocaine for six hours a day, however, have a different story, especially if they are offered few alternative activities. These rats will compulsively seek cocaine and put in more and more work to get it, if you make the drug more difficult to obtain.
The scientists figured that if kappa activation is indeed causing the pain and distress of addiction by turning down the dopamine system, treating addicted rats with buprenorphine and naltrexone should reduce their cocaine use, since their compulsion is caused by the feedback loop. In rats that aren’t compulsive, however, blocking kappa activation shouldn’t matter because they haven’t experienced the extreme dopamine elevations that would have caused the feedback loop to kick in.
And indeed, that is what the study showed, at least for treatment combinations that included the lowest dose of naltrexone. While higher doses of naltrexone prevented buprenorphine from reducing cocaine use, at the lowest dose, the drug combo was able to cut drug use in compulsive rats, but not the others.
Most importantly, this dose was still adequate to prevent significant withdrawal symptoms from occurring when the buprenorphine was stopped. That suggests that it hit the sweet spot and allowed buprenorphine to reduce dysphoria and cravings without triggering a high or dependence.
“When I heard the results, I was very pleased,” says Volkow of the study, which was published this week in Science Translational Medicine. The initial clinical trial in humans is being conducted in people who use both cocaine and opioids, but if the combination works for them without producing withdrawal, future trials may include people with cocaine addiction alone. Since methamphetamine and cocaine act similarly in the brain, Volkow thinks the treatment could work for meth users as well.
And because buprenorphine and naltrexone are already approved for medical use, if clinical trials pan out, the treatment could potentially be used immediately to help the 1 million Americans who struggle with cocaine addiction and the several hundred thousand who have other stimulant addictions.
The drug combination might also be useful in chronic pain, depression, obsessive-compulsive disorder and schizophrenia — all disorders in which kappa receptors may be involved in tuning pleasure levels down too low and distorting motivation. Although researchers are seeking kappa-blocking drugs that aren’t also opioids, as buprenorphine is, so far none of the compounds has proved both safe and effective.
“I think this is an understudied area, but a rich target,” says Koob.