Most drugs have a significant rate of failure. In the pharmaceutical industry, it is widely understood that some 90% of all medicines work adequately in only 30% to 50% of patients. This results in staggering waste in the quality of care for individuals and and costs to the healthcare system. But for people with addiction, the problem is especially acute because there are so few effective drugs available. In addition, the drugs likely have subpar effectiveness, working in a smaller than average percentage of people and with only modest effects.
“[Doctors] seem to just try one drug or another with no particular preference,” says Dr. Thomas Kosten of Baylor College of Medicine. “Yes, they change dose, but do not have good data to support such changes.”
Pharmacogenetics and Gene Testing
Kosten is a leading addiction researcher who focuses on pharmacogenetics—how genes and gene mutations influence how well a drug works. This is one part of a large cutting-edge trend in healthcare called personalized medicine—often described as providing the right drug to the right patient at the right time.
The idea is that the best, most effective and most cost-effective care will come from personalizing it for each individual patient (and their genes). By studying what factors (such as genetic makeup) distinguish the people who get benefit from a treatment from those who do not, researchers will be able to help doctors target treatment with far greater accuracy than is currently possible.
For any research to have relevance in the clinic, gene testing has to be widely available to patients. We are not there yet. There are already some 2,000 tests to identify mutations that either cause, or are linked to, specific inherited diseases, such as a form of breast cancer. The cost of genetic testing can range from several hundred to several thousand dollars. Many are routine tests, but in addition to being expensive, the results can be confusing to doctors who have limited knowledge of genetics and how to best use these genetic markers to improve treatment. Still, most experts agree that pharmacogenetics and gene testing, together, are the wave of the medical future.
There are three approved compounds for alcohol addiction: naltrexone (and its injectable form, the brand drug Vivitrol), acamprosate (Campral) and disulfiram (Antabuse).
Naltrexone is the most widely prescribed drug for alcoholism. It is an opioid receptor antagonist; it works by blocking opioid receptors in the brain, which can blunt both cravings and, when alcohol or opioids are consumed, intoxication. However, it’s no silver bullet.
A recent Cochrane review found that naltrexone has a modest effect: Among 7,800 alcoholics, the drug reduced the risk of heavy drinking by a mere 15% and the number of drinking days by only about 4%.
Personalized medicine begs the question, what makes one person respond well to naltrexone while another person doesn’t? The most promising pharmacogenetic target for alcohol use disorders appears to be the mu-opioid receptor, which binds to the endorphins released by alcohol or opioid use resulting in a buzz.
While the anti-alcohol drug naltrexone can bind to numerous types of opioid receptors, it binds most tightly to mu-opioid. One factor in how well a medication works is how accurately its active ingredients hit their targets. A mutation in a gene associated with the workings of a target—say, a specific brain receptor like mu-opioid—typically alters its “shape,” making a clean fit—with, say, the drug naltrexone—either more or less difficult.
Several studies have found that naltrexone works best in people who carry a specific mutation in a gene related to the workings of mu-opioid. From 15% to 25% of whites have this mutation, whereas only 5% of African Americans carry it. A clinical replication study by Dr. Raymond Anton and colleagues at the Medical University of South Carolina found that this gene variation can improve relapse outcomes: more days abstinent and fewer heavy drinking days.
Other studies, however, have not shown that naltrexone works differently in people with different genes. “We thought we would have the answers by now, but it’s complicated,” says Dr. Markus Heilig, chief of the Laboratory of Clinical and Translational Studies at the National Institute on Alcohol Abuse and Alcoholism (NIAAA).
Anton’s results, if eventually confirmed, could be used to help personalize treatment by testing people with alcohol addiction for this gene mutation before prescribing them naltrexone.
Other studies are investigating how mutations affect response to disulfiram (Antabuse) and topiramate (Topamax), an anti-epilepsy drug that has shown promise for treating alcoholism. In recent work, Dr. Henry Kranzler, a professor of psychiatry and the director of the Center for Studies of Addiction at the University of Pennsylvania, found that a mutation in a type of glutamate receptor improves the efficacy of topiramate. (Gutamate is a neurotransmitter, like serotonin and dopamine; all play important roles in the process of addiction in the brain.) “If replicated in alcohol dependence, it will allow personalized treatment in more than 40% of European ancestry individuals with the disorder,” Kranzler says.
A third promising pharmacogenetic target for alcohol addiction is the serotonin receptor and its related transporter molecule, which carries serotonin from one neuron to another. (Serotonin is most widely known as the brain chemical that the anti-depressant Prozac-type drugs target, increasing levels in the brain and thereby improving mood.) Dr. Bankole Johnson, chairman of psychiatry and professor of neurobiology at the University of Maryland School of Medicine, is a leading researcher in this area. In a noted study in 2011, Johnson and team found that drinkers with a specific mutation in a gene associated with the serotonin transporter had better abstinence while taking the anti-nausea drug ondansetron, a serotonin-3 receptor antagonist. Kosten agrees that the serotonin transporter is a promising target for treating people with both depression and alcoholism.
Nicotine medications work for very few people trying to kick the smoking habit. Current treatments—the various nicotine replacement therapies as well as the drugs bupropion (Zyban or Wellbutrin) and varenicline (Chantix)—have poor long-term success: More than 75% of smokers relapse within a year of treatment.
One difficulty is that nicotine affects many different receptors and neurotransmitters, while the drugs hit only a few targets, leaving the symptoms of nicotine addiction, such as cravings, inadequately treated. While the one-size-fits-all drug model is outdated for all addictions, and most diseases in general, it is especially ill-equipped for nicotine, which is implicated in so many brain processes.
There are, however, several promising targets the could both help researchers develop better anti-smoking drugs and help doctors prescribe available treatments more accurately. New research suggests that variations in nicotinic receptors, which bind nicotine and help it exert its effects on the brain and body, can make some people more apt to become addicted and alter how others respond to drugs for nicotine addiction.
A gene involved in how the body metabolizes nicotine may also play a role. “Variation in a gene that encodes a metabolic enzyme has been shown to moderate [descrease] the response to bupropion for smoking cessation,” Kranzler says. In another recent study, scientists found that nicotine replacement therapy is more effective for people with high nicotine metabolism related to the same gene.
3. Heroin, cocaine and methamphetamine
There has been a lot less pharmacogenetic research into how people respond to drugs for addiction with heroin or stimulants. One reason is that no drugs have been approved for addiction with stimulants. While three drugs have been approved for opiate addiction—naltrexone and the two replacement therapies, methadone and buprenorphine, running clinical trials of heroin addicts can be difficult because studies that require a placebo (no treatment) group are unethical: No patient can be denied treatment for reasons of medical research if a treatment is available that can benefit them.
However, Kranzler offers up a mixed message: “A [single mutation] in the gene that encodes the delta opioid receptor was shown in one study to predict response to treatment with buprenorphine and methadone in African-Americans. But another study found that [mutations in the same gene] were shown to predict response to buprenorphine only in European-American women.”
For cocaine, there’s the possibility that dopamine-beta-hydroxylase, or DBH, could be used as a pharmacogenetic target. DBH is an enzyme that converts dopamine to norepinephrine (another brain chemical)—if it is blocked, more dopamine is available. Oddly enough, disulfiram (Antabuse), which blocks DBH, may be a possible treatment for cocaine addiction. Yet, according to Kranzler, “there is not enough consistency in the evidence to warrant using the DBH genotype to individualize treatment.”
Translating Lab Discoveries to Clinical Practice
Patients and doctors want to know how soon pharmacogenetic research will be translated into clinical applications? And will the tests be affordable and accessible?
Personalized medicine is still finding its feet, unfortunately. Kranzler thinks that the nicotine addiction field may see results over the next five to ten years. “I believe that once there is clear validation, these moderator effects will be useful in the clinic,” he says. “The approach will be embraced—slowly—by clinicians.”
As the cost of whole-genome sequencing goes down, paying for genotype tests that identify only a single or a handful of relevant mutations will become moot. Heilig predicts that in the not too distant future, people will go to the doctor, have their entire genome sequenced and keep it on a card or microchip under the skin for easy access by doctors looking to see which mutations and medications might interact.
Whether or not people with addictions and their doctors will have a decent number of treatments at their disposal is another question.
“Whether that’s 10 or 15 years away, I can’t say,” Heilig says, “but that’s clearly where we’re going to end up.”
Jeanene Swanson is a journalist specializing in science and health. Her work has appeared in a variety of publications, including Scientific American, Salon, the Huffington Post, The Fix and an array of scientific trade magazines. Her previous piece for Substance.com was about the 10 most important studies in the field of addiction research.
Substance.com/Jan. 12, 2015
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