Accelerating the pace of substance use research through international collaboration

Almost 20 years ago, MUSC substance use researcher Kathleen Brady, M.D., Ph.D., launched a collaboration with a group of like-minded Australian investigators that continues to thrive today. This productive partnership began when the Australians reached out to Brady and fellow MUSC researcher, Sudie Back, Ph.D., about a project focused on substance use and trauma.

Like Brady, Back and other MUSC researchers, the Australian investigators, now at the Matilda Centre of the University of Sydney, believe that treating underlying trauma is key to improving outcomes in patients who have substance use disorders. Soon after an initial meeting, Brady and Back traveled to Sydney to collaborate with the Australian investigators – Brady as a National Institute on Drug Abuse-sponsored visiting scholar and Back as a Fulbright Scholar.

“We have substantial overlap in our areas of interest, and so, there really was some synergy in coming together around further development of some of the treatments for post-traumatic stress disorder and substance use disorders,” said Brady.

"By having two groups work together, consulting back and forth, we have been able to advance the science much more rapidly.”

-- Dr. Kathleen Brady

Funded by five Fulbright awards and other types of sponsorship, many more researchers and trainees from MUSC and the Matilda Centre have crisscrossed the globe over the years to collaborate on substance use research. These include MUSC researchers Lindsay Squeglia, Ph.D., Carla Kmett Danielson, Ph.D., and Julianne Flanagan, Ph.D.; Matilda Centre investigators Louise Mewton, Ph.D., and Emma Barrett, Ph.D.; and Monash University researcher Shalini Arunogiri, Ph.D. Just this year, eight trainees from MUSC traveled to Australia, and five trainees from Sydney will be making the trek to Charleston.

To date, this international collaboration has led to approximately 25 joint publications, 15 national and international conference presentations and $15 million in grant funding.

Together, the MUSC and Australian researchers have drawn attention to the need to treat substance use disorders and PTSD together, showed the efficacy of a treatment pioneered at MUSC for doing so and worked to augment that therapy and adapt it for new populations, including military veterans and adolescents.

The collaboration also places a strong emphasis on prevention, leveraging data from the Adolescent Brain Cognitive Development (ABCD) study, the MUSC site of which is led by Squeglia, to explore the effect of substance use on the developing brain. Their findings have informed public health initiatives to curb drinking among pregnant women in Australia.

Recognizing trauma as a driver of substance use

Research has shown that roughly 8 in 10 of those with a substance use disorder have experienced a traumatic event in childhood. Almost 6 in 10 of those with post-traumatic stress disorder, or PTSD, who experience flashbacks and other symptoms following a terrifying traumatic event, have issues with substance use.

“We know that many people with PTSD use substances in part because of their traumatic experiences and to try to reduce some of the distressing PTSD symptoms they are experiencing,” explained Back. “By treating PTSD and the substance problems together, we thought we could help people to recover from both of those debilitating psychiatric conditions.”

Treating trauma to improve outcomes

In the 1990s, Brady pioneered a therapy to address the underlying trauma driving people to use substances. The treatment uses prolonged exposure therapy to address PTSD while also teaching patients cognitive behavioral skills to reduce substance use. The treatment, now known as COPE, or the Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure, was developed with collaborators in Australia as well as at Yale University and the University of Pennsylvania. COPE, which is administered in 12 sessions that last 90 minutes each, helps patients to approach and process the memory of the trauma along with other situations or activities they may be avoiding. A 2001 pilot study led by Brady demonstrated the safety and feasibility of the early treatment protocol.

At the time, it was controversial to treat both disorders together because many clinicians were concerned that prolonged exposure could further exacerbate substance use or cause a relapse. The pilot study provided preliminary evidence that prolonged exposure could be used safely in patients with cocaine use disorder. It also showed reduced PTSD symptoms and cocaine use in those who completed the treatment.

“By treating PTSD and the substance problems together, we thought we could help people to recover from both of those debilitating psychiatric conditions.”

-- Dr. Sudie Back

Brady and Back then joined forces with Maree Teesson, Ph.D., now the director of the Matilda Center, and Katherine Mills, Ph.D., also of the Matilda Center, on a randomized controlled clinical trial of COPE that was conducted in Sydney, Australia. The trial’s findings, published in 2012 in the Journal of the American Medical Association, confirmed the pilot trial’s findings, providing strong evidence that COPE reduced PTSD symptoms and led to decreased substance use.

“These were very pioneering efforts – the first-ever peer-reviewed publications demonstrating efficacy for treatments for co-occurring substance use and PTSD,” said Danielson. “This innovation was possible because we had folks at both institutions with the same passion in the same area of science who really wanted to address the different challenges in bringing novel treatment approaches to fruition.”

Since then, COPE has been evaluated in the U.S., Australia and Europe and among military veterans and civilians with extensive trauma histories and different types of traumatic events. Five clinical trials have demonstrated the superiority of COPE in comparison to existing therapies for patients with both PTSD and substance use disorder. The COPE therapist manual and patient workbook were published in 2015 by Oxford University Press as part of their Treatments That Work series. COPE is also endorsed by the Veterans Administration (VA).

Bringing COPE to the clinic

Although COPE is now widely recognized as an effective treatment for co-occurring PTSD and substance use disorder, uptake by clinical practices has been slowed by a lack of access to COPE training.

“We've known for decades that these two problems co-occur, and yet our standard practice does not reflect that,” said Danielson.

“We got our clinicians trained up and have been delivering [COPE] now for three years. We’re now talking about how we will bring this into a routine care space in Australia.”

-- Dr. Shalini Arunogiri

To increase that uptake, the VA has funded a project led by Back to create COPEweb, an online training program for clinical providers in the delivery of the treatment. The project will test how COPEweb stacks up against in-person or live training.

Efforts to implement COPE into the clinical practice space are also underway in Australia. Thanks to  Arunogiri, COPE has been tested in several clinics in Melbourne.

“We were looking for an evidence-based intervention to bring to a clinical space in Melbourne for PTSD and co-occurring substances and knew we had found it in COPE,” said Arunogiri. “We got our clinicians trained up and have been delivering it now for three years. We’re now talking about how we will bring this into a routine care space in Australia.”

Augmenting and adapting COPE

The collaboration continues to improve on COPE, finding ways to augment its therapeutic effects or adapt it for new populations.

Back and others are studying whether patients will benefit more when COPE therapy sessions are augmented by oxytocin, while Arunogiri and others are exploring the same question for MDMA.

Brady, Back, Danielson and others are working with Mills, Barrett and Teesson of the Matilda Centre to adapt COPE for adolescents (COPE-A).

“The earlier we can intervene, the earlier we can bend trajectories in positive ways,” said Danielson. “You’re going to have a much higher likelihood of having a longitudinal impact, and it will be a lot less expensive if you treat earlier on before problems become extensive.”

“The earlier we can intervene, the earlier we can bend trajectories in positive ways.”

-- Dr. Carla Kmett Danielson

Danielson brings to the collaboration her extensive experience developing interventions for adolescents with co-occurring substance use disorders and PTSD. She is the creator of Risk Reduction through Family Therapy, the only evidence-supported treatment currently available for this population.

The collaboration is also streamlining COPE to encourage uptake by specific populations. For example, Tanya Saraiya, Ph.D., of MUSC, is working with Mills to adapt COPE for patients with opioid use disorder.

“Stakeholders and providers wanted something that was easier to implement than COPE in their clinics,” said Saraiya. “And so instead of 90-minute sessions, we are exploring 60-minute sessions. In addition, the therapy regimen can be tailored to patient needs, with as few as 10 sessions for some patients.”

Prioritizing prevention

Leveraging data from the ABCD study of almost 12,000 children and adolescents at 21 research sites across the U.S., Squeglia and Mewton showed that children whose mothers drank while pregnant were more likely to engage in alcohol experimentation by age 9 or 10. In the study, the rates of alcohol experimentation, as measured by alcohol sipping, almost doubled in children exposed to any alcohol during pregnancy and almost tripled in those exposed to alcohol throughout the pregnancy.

“One of the things that I really respect about the Matilda Centre is how proactively they approach issues, whereas in the U.S., we tend to be more reactive."

-- Dr. Lindsay Squeglia

Data from this study launched a public health campaign called “One Drink” in Western Australia intended to curtail drinking in pregnant women and drive home the fact that no amount of alcohol was safe during pregnancy.

Squeglia was impressed by how quickly and seamlessly research findings informed public health and preventive initiatives in Australia.

“One of the things that I really respect about the Matilda Centre is how proactively they approach issues, whereas in the U.S., we tend to be more reactive,” said Squeglia.

In turn, Mewton is appreciative of access to large data sets from ABCD and other national studies afforded by the collaboration.

“We don't have  anything on that scale,” said Mewton. “But we’re able to ask questions of those datasets because of the generosity of the MUSC investigators who teach us how to use them.”

Full circle

Today, almost 20 years after her first visit to Australia, Brady remains very grateful for the collaboration, believing it has helped to accelerate the pace of substance use research in both countries.

“By having two groups work together, consulting back and forth, we have been able to advance the science much more rapidly,” she said.