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Charles P. O’Brien, M.D., Ph.D.
Vice Chair and Kenneth Appel Professor of Psychiatry
University of Pennsylvania
Member, Dana Alliance for Brain Initiatives
Dana Foundation Grantee 2007-2009
You are leading an NIH-funded clinical trial testing whether naltrexone, a medication primarily used for alcoholism, might prevent relapse in people whose heroin addictions landed them in prison. Why naltrexone?
Charles O’Brien: Naltrexone was actually developed by the National Institute on Drug Abuse (NIDA) in the 1970s as a treatment for heroin addiction. It was first investigated as part of NIDA’s effort to find a non-addicting pain killer. While addictive opioid pain relievers are agonists that turn on the opioid receptor, naltrexone and others like it are antagonists–they’re designed to bind with the opioid receptor but not activate it. Naltrexone totally blocks the effects of opioids. This made it unsuitable as a pain reliever but perfect for heroin addiction, which was a major problem with returning Vietnam veterans.
It is the antagonist property of naltrexone that my research lab has been interested in. In a pilot study funded by the Dana Foundation and now in the NIH-funded trial, we are giving it to parolees recently released from prison who have a history of opiate addiction and relapse. We reasoned that if we put them on naltrexone, they could not relapse, and this would help them get rehabilitated and resume their roles in society. The pilot trial results confirmed that people on naltrexone were less likely to be reincarcerated and less likely to relapse.
What is the current status of the NIH-funded clinical trial?
Based on the results from the Dana-funded pilot study, NIH funded a five-year study (2009-2014) at five sites, including the University of Pennsylvania; New York University; New York State Psychiatric Hospital; Rhode Island Hospital; and Friends Research Institute in Baltimore. We plan to enroll about 250 people, and are about two-thirds of the way there. [i]
We have published our pilot data [ii] and think a larger sample will be much more impressive. So far it looks as though people who take naltrexone are not only less likely to relapse, but are also less likely to die as a result of an overdose. The study design disallows the use of placebo (“treatment as usual” constitutes the control group), so we know which patients are getting naltrexone and which are not. We’ve already had three deaths and four overdoses in the treatment-as-usual group, and none in the naltrexone group.
That result is important because there is a very high rate of overdose in former prisoners; they often don’t realize that they have lost their tolerance for opiates. The same dose of heroin or oxycodone that used to make them feel good may now kill them. This is a real risk. It is such a problem in Europe that the British are now giving people addicted to opiates syringes with a dose of naloxone, a short-acting version of naltrexone that quickly blocks opiate receptors to prevent lethal drug overdose.
Why study prisoners?
If you can keep these people from relapsing, there is an immediate benefit to society. Prison costs between $40,000 and $60,000 yearly, per bed. There are some 2.2 million people in prisons in the United States. Left to themselves, most of these people would go right back to prison in a kind of revolving door. This is a real waste of money when we have effective medications that could help those with addictions stay away from drugs and the drug-related crimes that land them in prison.
Naltrexone also can help people who’ve been arrested for driving under the influence of alcohol. In California, studies by the Butte County Traffic Court and others have shown that people who were sentenced to take naltrexone had a much lower rate of re-arrest for drunk driving. These medications can really help people and help society as well.
My hope is that the data will convince judges, prosecutors, and parole officers that naltrexone will help addicts stay off drugs, help prisons empty out a bit, and save a lot of money.
Prescribing medication as part of sentencing raises some thorny ethical questions. How have you dealt with these?
In the criminal justice system, requiring people to do anything always sends off alarms. That’s because in the past, medical research has not considered the ethical ramifications adequately, and has done some studies on prisoners that would not be considered ethical today. We’ve had to deal with these issues. I organized a symposium on the ethics of this research and invited bioethicists to discuss it with us. The consensus has been that it is ethical as long as the prisoner has an option–as long as you’re not forcing them to take the medication. So we’re very careful about that.
You have been studying addiction for more than 40 years, since before addiction was recognized by most to be a brain disorder. How has addiction research changed since those days?
It has changed a great deal. Addiction is one mental illness where we have a pretty good understanding of the neurophysiological changes that occur. In disorders such as schizophrenia, depression, anxiety, or bipolar disorder, by contrast, we have a lot of hypotheses but few hard facts.
The reason we know a lot about addiction is because we have good animal models, which have enabled us to study the brain during drug self-administration. This has revealed which parts of the brain are involved in addiction and what changes are occurring in the brain. We also know that some of these changes can be addressed with specific medications. These insights have been confirmed by studies in humans using noninvasive brain imaging, which are ethical and safe to conduct because the animal studies have paved the way.
How has research progress advanced the ability to treat addiction medically?
As we’ve studied addiction more, we have come to understand that drug craving is a major symptom of people who are addicted. Now we even understand the physiology of craving, and we have good medications that reduce them.
We know that craving is a conditioned response, a learned response. Addiction is essentially an over-learned memory that doesn’t disappear. Memories that are reinforced by direct action on the reward system can last a long time. They physically change the brain by altering synapses and circuits in a particular way. You can get someone off heroin or alcohol pretty easily in a hospital setting, but they’ll keep going back to the drug because the brain has changed as a result of their addiction. The memory is still there. Even months or years later, craving can reoccur if they’re put in an environment that triggers the memory of drug use.
When craving reoccurs, the brain’s reward system is activated. We see increased blood flow through this system and neurotransmitters being released. We can measure this with modern neuroimaging: you show a stimulus (such as a picture of people getting high) to a person with addiction who is in the scanner and ask him or her to rate the intensity of the craving he or she feels. The subjective ratings are directly proportional to the amount of dopamine released in the brain. You can make beautiful curves that show the correlation between the subjective feeling of craving and the release of dopamine. There’s no other psychiatric symptom for which we have that kind of direct correlation between a change in the brain and the expression of subjective symptoms.
Yet addiction is still undertreated in this country, and the relapse rate is high even in people who receive therapy. What barriers are preventing research advances from translating into better care at the bedside?
There is an incredible amount of ignorance on the part of physicians who choose not to use medications that were developed by the NIH and have been approved by the FDA. In the case of alcoholism, for example, there are so few doctors in the United States who know about treating alcoholism with medications that the vast majority of people who seek treatment don’t receive medications. This is true even for those who go to very expensive programs, which may charge tens of thousands of dollars a month. It’s just a shame, because in some of these people, naltrexone would take away their cravings for alcohol and they would feel great. Treatment for opiate addiction faces similar hurdles.
In some cases, doctors are actively against using medication. They say it’s against their philosophy or that they don’t believe in giving medications for a drug problem. Yet, the double-blind studies show that the medications work. This is a tragedy, because patients who happen to fall into the hands of physicians with that lack of knowledge may be condemned to keep relapsing.
Clinicians are not merely uninformed, but are actively advocating against the use of medications like naltrexone to treat addiction?
Some of them are. In certain cases it’s almost a religious issue; there are a lot of religious aspects to Alcoholics Anonymous (AA) groups, for example. I think AA is wonderful, but it’s not based on science. It can help, but it’s not enough. People who are on naltrexone can get a lot of benefit from AA. But too often the people who are running rehabilitation programs are untrained non-medical professionals, and they may tell a patient who is on medication, be it naltrexone for alcoholism or lithium for bipolar disorder, to stop taking it. Or they may disparage the medication by suggesting that it is “just” a crutch.
This is what’s so frustrating about this field. It’s hard enough to study it, but when you find something that works and doctors are actively encouraging their patients not to take it, it’s really a pity.
You’ve advocated for better medical-school training on addiction. Why?
We think addiction is one of the most important illnesses that physicians will encounter. No matter which specialty you’re in, there are a tremendous number of patients who have some sort of substance abuse problem. Fortunately, many different kinds of medications have been developed to treat addictions.
Unfortunately, this is largely unknown to clinicians who are treating addiction. As a result, given the large number of people who need treatment, we have relatively few patients getting treatment of any kind. And, most of those getting treatment are not being given medications. That’s a pity because, as I mentioned, we have very good, controlled, double-blind trials showing the benefits of medication.
It’s one of the neglected areas in medicine. As a result of this neglect, a lot of non-physician self-help programs have been developed. While these programs can be very good, they’re not complete. If people have only them, and not a well-trained doctor they can go to for medical treatment as well, they risk missing out on all the scientific advances that have been made in understanding and treating addiction over the past several decades.
[i] As of September 1, 2011
[ii] Coviello DM, Cornish JW, Lynch KG, Boney TY, Clark CA, Lee JD, Friedmann PD, Nunes EV, Kinlock TW, Gordon MS, Schwartz RP, Nuwayser ES, O’Brien CP. A multi-site pilot study of extended-release injectable naltrexone treatment for previously opioid-dependent parolees and probationers. Substance Abuse. In press.