Substance Use Disorder

VA Research: Substance Use Disorder

By Craig Collins

SUBSTANCE USE DISORDER (SUD) – a pattern of using alcohol, drugs, or other psychoactive substances that results in health issues or problems at work, school, or home – is generally more prevalent among military veterans than among other Americans, for a number of reasons, including the demands of military service, the trauma of combat, and the difficulty many veterans experience in re-integrating into civilian society.

A 2011 Department of Veterans Affairs (VA) study revealed that around 25 percent of Iraq and Afghanistan veterans 18 to 25 years old met the full criteria for substance use disorder. Because of its widespread availability, alcohol remains the substance most commonly used among veterans with SUD, though – as with the American population in general – the use of addictive opioid drugs, including prescription pain medications and illicit drugs such as heroin and fentanyl, rose sharply over the first decade of the 21st century. In 2015, about 68,000 veterans had opioid use disorder, a threefold increase over a period of 12 years, and the VA reported that veterans were twice as likely as nonveterans to die of accidental opioid overdose. Since the VA’s launch of its Opioid Safety Initiative in 2013, the rate of opioid prescriptions has declined, while the percentage of veterans receiving treatment for opioid use disorder has increased.

Among the factors that make SUD treatment challenging for veterans to access is that substance use is often concurrent with other psychiatric or medical conditions. A 2017 study by investigators at the Ralph H. Johnson VA Medical Center (VAMC) in Charleston, South Carolina, revealed that 63 Iraq and Afghanistan veterans diagnosed with an SUD also met criteria for post-traumatic stress disorder (PTSD) – and that those with this dual diagnosis were more likely to have additional psychiatric and medical conditions such as liver disease, HIV, anxiety disorders, schizophrenia, and bipolar disorder.

Despite the higher risk for veterans, however, the Charleston team pointed out that veterans with SUD receive treatment at about the same rate as other Americans – and that rate is low. Only about 10 percent of SUD-positive veterans receive any type of treatment.

VA investigators examine the problem of substance use from all angles: investigating how substances interact with the nervous system and other organ systems, conducting clinical trials of treatments, and leading big-picture evaluations of its own health care system, aimed at increasing the value of, and expanding access to, care delivered to veterans with substance use disorder.

BIOMEDICAL RESEARCH

VA research now includes several studies aimed at understanding – and ultimately, countering – the effects of substances on human tissues and cells, particularly in the central nervous system. Funded projects include investigations into biomarkers associated with alcohol misuse, the neurobiology of alcohol and nicotine co-addiction, and the mechanisms by which alcohol use accelerates other diseases. VA recently funded a study into whether a class of cell membrane proteins called calveolins may protect brain neurons from compulsive methamphetamine use. Several VA studies are underway investigating what role genetics may play in determining people’s vulnerability to alcoholism and addiction.

VA research now includes several studies aimed at understanding – and ultimately, countering – the effects of substances on human tissues and cells, particularly in the central nervous system.

Michael Charness, M.D., chief of staff of the VA Boston Healthcare System and a professor of neurology at both Harvard and Boston University, has spent much of his research career studying the problem of alcohol toxicity in the developing nervous system – a field of research that has implications for the growing number of women veterans of childbearing age. In previous studies, Charness and colleagues have established that alcohol disrupts the activity of a cell adhesion molecule, L1, that plays a role in neural cell growth and, more significantly, in moving new neurons to where they’re needed in the developing brain.

The March 6, 2018, issue of JAMA included a report of a long-term study that suggested the risks of opioid pain therapy – including side effects and addiction – outweighed the benefits. Roughly 10 percent of substance use disorder-positive veterans receive any kind of treatment.

“The L1 molecules on one cell stick to the L1 molecules on other cells,” explained Charness. “It serves as a guidepost. We’ve learned that alcohol inhibits the function of that molecule – two cells that depend on forming a nucleus together by sticking, through the actions of that molecule, won’t do so. They won’t migrate to the right place and their axons won’t make the right connections.” This failure may be a partial cause of the irreversible brain damage and growth problems known collectively as fetal alcohol spectrum disorder (FASD).

In a recently completed study building on this knowledge, Charness’ team discovered that alcohol’s effect on the L1 molecule can be blocked by other substances, known as antagonists, that essentially keep L1 sticky in the presence of alcohol. One of these antagonists, a peptide abbreviated as NAP, prevented both alcohol’s effect on the L1 molecule and the development of FASD in mouse embryos.

The implications of Charness’ findings, and of other research into the alcoholbinding sites of cellular molecules, go beyond the discovery of substances that can be used to block the harmful effects of alcohol on development: It suggests the possibility of genome editing for adults with alcoholism to alter the interaction of alcohol with critical amino acids in proteins that mediate the addictive properties of alcohol. Gene therapy would probably never become a firstline treatment for alcoholism, Charness said, but could present a solution for some adults with treatment-resistant alcoholism. “Maybe we could, through gene editing, flip just one amino acid in a critical part of the brain that’s necessary for alcohol to produce important effects. That’s a long way off – but it’s not total science fiction.”

TREATMENTS FOR SUD – AND NON-OPIOID TREATMENTS FOR PAIN

VA investigations of SUD treatments include trials of existing drugs that suggest novel treatments for substance dependency. A team at the VA Connecticut Healthcare System, for example, is studying the effectiveness of zonisamide, an anticonvulsant, in reducing heavy drinking and improving outcomes for veterans with alcohol dependency, while another Connecticut team is investigation the effectiveness of ketamine – a controlled substance traditionally used as an anesthetic – in rapidly treating major depression and alcohol use disorder. Researchers at the Michael E. DeBakey VAMC are evaluating the effectiveness of doxazosin, an antihypertensive drug, in blunting the acute effects of cocaine use.

Next to alcohol, cocaine accounts for the second-most common substance use disorder in the VA system, and there is currently no FDA-approved pharmacological treatment for cocaine use. This is a dangerous circumstance for veterans: According to Christopher Stauffer, M.D., a psychiatrist at the San Francisco VAMC and professor of psychiatry at the University of California-San Francisco, between 30 to 60 percent of patients receiving methadone maintenance treatment (MMT) for opioid use disorder are also actively using cocaine – and dropout rates from MMT and other opioid use treatment programs are as high as 80 percent for cocaine users. The mortality rate of concurrent users of cocaine and heroin is 14 times higher than the general population’s.

A model showing the location (dotted circle) where alcohol interacts with the L1 molecule to reduce its “stickiness.”

MICHAEL E. CHARNESS, M.D., CHIEF OF STAF, VA BOSTON HEALTHCARE SYSTEM

Two years ago, Stauffer began recruiting for a trial aimed at reducing active cocaine use among veterans receiving MMT therapy. Cocaine use is known to be driven by social stress and associated with hyperreactivity of the brain’s stress response system – the hypothalamic-pituitary-adrenal (HPA) axis. Stauffer hypothesized that administering the hormone oxytocin to cocaine users might help to weaken this hyperreactivity (oxytocin, which plays a role in parent-child and social bonding, is produced in the hypothalamus and released by the pituitary gland), improve engagement in psychosocial treatments, and perhaps reduce subjects’ desire for cocaine.

“There is a lot of animal data showing that oxytocin is helpful for almost every substance of abuse, [including] alcohol, opioids, cocaine, methamphetamine,” Stauffer said. “We don’t really know why yet. Substance abuse highjacks the same neuro-circuitry that is used for social relationships, the same reward. And we know that when people develop a substance abuse disorder, their relationships with other people kind of fall to the wayside.” It’s also known, Stauffer said, that the brains of cocaine users down-regulate the production of oxytocin. “So, the thought is that if maybe we give them oxytocin from the outside, that might help rebalance things.”

This isn’t Stauffer’s only study involving oxytocin and substance use, and he hasn’t yet found that oxytocin, by itself, has reduced subjects’ substance use – though he has noticed, anecdotally, that patients receiving oxytocin seem more engaged in the clinic’s activities: They attend more often and seem more engaged.

“I’m starting to believe that you need to give patients something to shift their attention toward,” Stauffer said. “Just giving them the oxytocin without giving them the support I don’t think is going to be as helpful. I think you need the oxytocin plus a positive social relationship to kind of transfer their reward system onto.”

Several recent and ongoing studies are aimed at reducing the prescription and use of opioids within the VA health care system – a principle outlined in the new VA/DOD Clinical Practice Guideline for Opioid Therapy for Chronic Pain. A VA researcher from the W.G. (Bill) Hefner VA Medical Center in Salisbury, North Carolina, is part of a team working to develop a new non-opioid drug that works on the same pain receptor, and also activates a receptor that blocks addictive effects. While not yet ready for trials with human subjects, the new substance, AT-121, may have the potential to safely and effectively relieve pain, and also to treat prescription opioid abuse.

Since the OSI launched in 2013, the rate of opioid prescriptions has decreased, whereas the percentage of veterans receiving treatment for opioid use disorder has increased.

NIH-DOD-VA COLLABORATORY

In the March 6, 2018, issue of JAMA, a VA research team from the Minneapolis VA Health Care System’s Center for Chronic Disease Outcomes Research published a study immediately recognized as a landmark in opioid research. The team, led by Erin Krebs, M.D., MPH, studied the use of opioid and non-opioid pain medications over a period of one year among 240 veterans with chronic pain – and discovered that opioids were not only slightly less effective than nonopioid drugs (i.e., acetaminophen or lidocaine) at reducing pain over time, but also far more likely to involve negative side effects. It was the first rigorous long-term study to suggest that the risks of opioid pain therapy, including side effects and addiction, outweighed the benefits.

IMPROVING QUALITY AND ACCESS

Andrea Finlay, Ph.D., of the Palo Alto VA’s Center for Innovation to Implementation (Ci2i), is among the considerable number of VA investigators aiming to improve the quality of VA’s overall SUD care, and to increase the number of veterans who take advantage of it. Finlay recently led a team in exploring the reasons why, among veterans with opioid use disorder (OUD) being treated in VA residential facilities, only about 21 percent are receiving medications to treat their disorder.

Medications such as methadone, buprenorphine, and naltrexone target the same receptors as opioids and have proven effective in reducing opioid use and the related symptoms. They also increase the likelihood that a person will remain in treatment, employed, and out of trouble. Methadone, in particular, reduces the likelihood of overdose death by nearly 60 percent, according to the National Institute on Drug Abuse.

So why are so few veterans in VA residential facilities being prescribed these medications? Finlay’s team discovered that though this number was lower than among veterans with OUD overall (35 percent), the barriers to pharmacotherapy weren’t unique. Among the most significant was a strong cultural anti-drug treatment bias at these residential facilities.

To address these barriers, VA leaders reached out to educate and enable providers at these residential facilities. “They made sure every residential treatment program had appropriate access to a provider, so that they could prescribe buprenorphine for them,” Finlay said. “They did intensive educational programs in the residential settings … to give them the knowledge they need to improve access and use of these medications.”

Patients in residential settings, of course, are easy to reach; the vast majority of VA’s SUD treatment programs are in clinics or other outpatient facilities. The power of even the most effective treatments to help veterans recover from SUD will remain limited as long as only about 10 percent of veterans with SUD are receiving them.

This shortfall has made VA SUD treatment one of 10 high-priority issues addressed by VA’s Health Services Research and Development (HSR&D) Service, through its CREATE initiative: Collaborative Research to Enhance and Advance Transformation and Excellence. The SUD CREATE is a cluster of studies aimed at increasing the value of, and veteran access to, VA SUD treatment.

One of the SUD CREATE investigators is Christine Timko, Ph.D., a senior research career scientist at the Palo Alto VA studying the problem of how to deliver SUD treatment to veterans who’ve been discharged from inpatient detoxification programs. For a variety of reasons – some of them patient centered, such as motivational or environmental; some system related, such as the number of available treatment slots – most veterans don’t engage in SUD treatment after detox.

Timko recently completed a study designed to extend the reach of SUD counseling professionals and coaches through enhanced telephone monitoring.

“The coach and the patient talk for maybe 15 to 30 minutes, every other week for three months,” Timko said. “The coach is encouraging the patient to think about getting treatment and supporting patients in getting that kind of help. It’s a very low-intensity, lowdemand kind of help.”

The results of the study, Timko said, were surprising: “The main outcome was the group that got the telephone calls was less likely to go back into detox again. But they were not more likely to actually get substance abuse treatment.” She speculated that the phone calls in themselves may have functioned as a kind of informal counseling intervention, keeping patients’ attention on their substance use. “When the telephone calls stopped, the improved outcomes for the telephone patients also stopped.”

Two areas of further research have opened up as a result of Timko’s study: She’s leading a team in examining whether telephone monitoring might be beneficial to veterans with SUD who aren’t in detox, but who have both medical/surgical conditions and untreated problems related to alcohol use. Another team has a project designed to guide research priorities for the management of severe alcohol withdrawal syndrome. Timko is leading the translation of this research for communities to improve population outcomes, including reduced morbidity and mortality among alcohol detoxification patients.

The SUD CREATE is led by Keith Humphreys, Ph.D., M.A., a senior research career scientist at the Palo Alto VA and the Esther Ting Memorial Professor at the Stanford University School of Medicine. He’s also conducting his own study of the effectiveness of a web-based intervention to reduce alcohol use among veterans with Hepatitis C and other liver diseases. So far his team has designed the intervention, tailoring it to more narrowly focus on a group of about 140 veterans with liver disease who use alcohol, and delivered it in a randomized clinical trial at sites in San Francisco and Palo Alto.

“All the data is collected,” Humphreys said. “We’re analyzing it now to see whether or not the intervention lowered their drinking, and also whether it affected any other areas of their health. And then last, what the implications might be for their health care utilization. You know, if it works, maybe they’ll be less likely to end up in the hospital later. That’s the hope.”

A successful web-based intervention, said Humphreys, would constitute a lowcost alternative to treatment for patients with a critical need. “It’s a computer program,” he said. “We can make a million copies by pressing a button. It doesn’t cost anything, and it’s all free and public access.” If it proves even moderately effective, Humphreys said, the VA could email an invitation to participate out to thousands of veterans with current or prior alcohol use disorder and liver disease. “If ... only half the people look at it, and only 25 percent of those complete the whole thing and they cut their drinking a bit, that’s a great investment of VA resources,” he said.

Two of the SUD CREATE projects are bigger-picture evaluations of how VA’s SUD treatment system is working overall. Austin Frakt, Ph.D., a health economist at the Boston VA, is studying how funding models and staffing levels influence patient outcomes. At the Ci2i in Palo Alto, Alex Harris, Ph.D., is working to validate more than 40 new measures of addiction treatment quality. Most of these measures are developed by VA mental health experts such as Humphreys – “But sometimes,” Humphreys said, “expert judgment is wrong.” Harris is using data, gathered from interventions with veteran patients, to see if VA programs are, in fact, improving outcomes.

“The interesting thing,” said Humphreys, “is that we assume a lot of quality measures we track and encourage clinicians to follow help patients, but sometimes they don’t. So this is really important work.” Like the CREATE’s more patient-focused investigations, these studies of how VA administers and delivers SUD treatment are aimed at the same objectives: lowering the overall cost of care, improving its quality and value, and maximizing the number of veterans who can be helped by it.

Medications such as methadone, buprenorphine, and naltrexone target the same receptors as opioids and have proven effective in reducing opioid use and the related symptoms.