How the brain disease model of addiction drives innovation in drug development
In the U.S., 8% to 10% of people 12 and older, meaning roughly 20 to 22 million people, are addicted to alcohol or other drugs. For centuries, addiction has been viewed as a form of moral weakness. The inability to ‘detox’ was seen as simply not having enough willpower or personal strength to overcome addiction.
But science tells a different story, as Nora Volkow, Director of the National Institute on Drug Abuse (NIDA), and her co-authors, George Koobs and Thomas McLellan wrote in their article on addiction in this week's NEJM.
"In the last two decades, research has increasingly supported the view that addiction is a disease of the brain," the authors wrote. "Although the brain disease model of addiction has yielded effective preventive measures, treatment interventions and public health policies to address substance-use disorders, the underlying concept of substance abuse as a brain disease continues to be questioned."
The brain disease model of addiction
The brain disease model of addiction posits that addiction is an acquired brain disease, in which certain interactions between the substance, genetic predisposition, environment and numerous other factors, predispose the brain to neurologic re-wiring and “damage” as a result of the use of addictive substances.
Based on this model, the idea is that like any other disease—cancer, diabetes, heart disease, etc.—effective interventions can help patients recover, and in some cases, heal completely. This is the model that has been driving drug development in this space.
According to Dr. Volkow and her colleagues, addiction can be divided into three recurring stages: the binge and intoxication stage; followed by the withdrawal and negative effect stage; and finally, the preoccupation and anticipation stage.
Each stage is driven by specific types of neurologic activity—thereby providing a context for targeted therapeutic intervention.
At its root, alcohol and drug addiction is related to dopamine regulation in the brain and the impact that drug-induced dopamine release has on the brain’s neuroplasticity—specifically changes in synaptic signaling in key areas of the brain that control emotions, stress, desire, mood, executive function and self-control.
One of the most challenging parts of drug addiction is that it is associated with changes in the reward and emotional circuits of the brain that affect function in the prefrontal cortical regions. This is where pharmaceutical R&D comes in, with a focus on both prevention and treatment.
On the prevention side, much of the innovation has focused on developing abuse-deterrent opioids to allow patients to enjoy the benefits of pain management, while decreasing the risk of abuse. Two relatively new contributions to this class include Targiniq ER from Purdue and Zohydro from Zogenix. As the FDA continues to solidify its guidance on development of abuse-deterrent opioids, there is evidence that they are at least somewhat effective.
“Abuse deterrent medications make safety sense," said Thomas McLellan, co-founder and board chair of the Treatment Research Institute and one of the co-authors of this week’s NEJM review article on addiction, in an interview with BioPharma Dive.
"They are of course more costly to produce but they do not interfere with the action of medications if taken in the prescribed manner. For those who are determined to over-ride the safety measures, there will usually be a way. But like locks on doors, they make it just that much harder to do so and sometimes that will be enough to prevent an overdose.
"Finally, because these safeguards make it harder for prescription opioids to be used inappropriately, they are not as attractive and thus do not have the street value that other pharmaceutical opioids have. In turn, this reduces the likelihood of theft and the likelihood of “doctor shopping” – both very good things for public health and public safety," he said.
Innovation in treatment of addiction—focusing on delivery
There are drugs, such as methadone and buprenorphone which have proven effective as maintenance drugs during treatment of opioid addiction. In terms of alcohol addiction, both naltrexone and acamprosate have proven effective. However, regardless of which drug is used, relapse continues to be a problem.
Titan Pharma has approached this problem using an innovative drug delivery approach. Their product, Probuphine, which is in phase 3 development, is a small, subdermal, rod-like implant that is embedded into the arm and releases buprenorphine. In a late-stage trial, 96.4% of opioid-addicted patients responded to Probuphine versus 87.6% who responded to the oral medication.
In addition, there was a statistically significant difference between the number of participants who passed monthly urine tests checking for the presence of opiates between the two groups. About 72% of the oral medication patients passed all six of the six monthly urine tests, while 88% of Probuphine users passed all six tests.
Innovation is changing the way addiction is treated—and viewed
When BioPharma Dive spoke to Titan's President, Sunil Bhonsle, at last summer's BIO convention, he explained the advantages of using Probuphine versus taking buprenorphone pills.
“Probuphine has a couple of advantages," he said. "One is, of course, compliance. Another has to do with maintaining a very stable level of medication so you don't see a trough and peak type pattern. And each of those has benefits for the patient and the doctor."
Although Titan has submitted Probuphine to the FDA twice (once in late 2012 and then again in early 2013), they have had favorable FDA committee responses and are now on track to submit once again.
Given the skyrocketing rate of opioid abuse and addiction, the time is ripe to not only affirm the brain-disease model of addiction—and all that goes with it—but to also support the innovation that is driving the development of more effective prevention and treatment strategies and drugs.