A University of Bristol multidisciplinary team from Bristol and Bath University has been working to understand the increase in deaths from taking both opioids and benzodiazepines (benzos). Here they reflect on how this approach has enhanced their research and made it more useful.

The problem

Drug use is a leading cause of premature death in many countries. Such deaths are increasing.

There are many reasons for this increase, including changes in the types of people who use drugs, and the rise in the use of fentanyls and other synthetic opioids.

Taking more than one drug at a time is another cause. For example, taking benzodiazepine (diazepam, etizolam, bromazolam) or z-drugs (zolpidem, zopiclone) along with opioids (heroin, methadone, buprenorphine) increases the chances of overdose and death.

Although many epidemiological and post-mortem studies have identified this risk, we still don’t know why combining these drugs increases mortality.

As a team our expertise ranges from human research (social and behavioural science, public health and epidemiology, pharmacy and drug treatment) through to animal behaviour (control of respiration) and neuropharmacology (studying the effects of drugs on single brain cells).

This multidisciplinary approach reflects the importance of understanding the world in which people live, how this contributes to the risks of drug dependence and how drugs work within the body to alter breathing, leading to overdose. We wanted to bring these insights together in one project rather than running parallel studies. We hoped this would generate a more complete, academically rigorous, relevant and impactful understanding of how and why using benzodiazepines and opioid together is so high risk.

How are we tackling it?

There are two parts to the project.

First, we interviewed 48 people who use both benzodiazepines or z-drugs and opioids in Bristol, Teesside and Scotland. Researchers from Bristol University and people with lived experience who had been trained ran the interviews. People were asked:

• How and why they use the two types of drugs together
• What effects the two types of drugs have on them
• What role both types of drugs have played in their experience of overdose

We used this information to design laboratory experiments to help us understand how benzodiazepines or z-drugs and opioids interact in the brain and influence breathing control and respiration.

Opioid drugs act on specific targets in the brain, called z-opioid receptors, while benzos and z-drugs act at a different target, the GABAA receptor. Both types of receptors exist throughout the brain but the risk of overdose results from their actions on the brain cells responsible for controlling breathing called respiratory neurons. These neurons can be slowed to the point that not enough oxygen is taken in and a person has a fatal overdose.

There are several potential mechanisms by which benzodiazepines or z-drugs can increase the depressant effect of opioids on breathing. At the cellular level, both drugs may act individually at their respective receptors in the same respiratory neuron to enhance its depression. At the brain level, both drugs could combine their effects on different brainstem areas that control airway and chest muscles, which would also work together to depress breathing.

We started with the interviews so that they could inform the later experiments.

How we work together

Our approach to working together in this project has evolved organically and relies on communication and mobilising knowledge between teams. Everyone has aimed to be transparent and open to questions from researchers from other disciplines. Importantly we have learnt not to take an understanding of our own disciplines for granted.

The researchers meet together regularly to hear what each team has been doing and reflect on how their findings relate to each other and the overarching aim. As a result, important insights from the human experience identified in interviews are fed back to the lab team. It also means the value of the findings from a pharmacological perspective are explained to the qualitative team.

Even though the researchers have very different skills and background knowledge, regularly sharing their insights has benefitted the whole project. For example, preclinical experiments gained insight into the physiology underlying how using both benzodiazepine and opioids affects breathing. This led to the qualitative researchers asking additional questions during interviews about how breathing is affected in people when using these drugs.

Interviews uncovered that some people use both drugs to achieve a ‘glow’. Some participants described this as being akin to the ‘Ready Brek’ glow in TV adverts. This led to an entirely new avenue of research not in our original plans, using laboratory animals to look at whether using benzodiazepines or z-drugs with opioids may help overcome the loss of pleasure (anhedonia) experienced by long-term opioid use.

What are the benefits of working this way?

Without this approach our teams would be working separately and would be unlikely to see each other’s work or indeed read each other’s publications. Even if we were to read each other’s papers, a critical benefit to this way of working is that we do not have to wait for the research to be published to learn from and apply the findings of each team. Instead, we are able to use the findings in real time.

By continually asking questions, each team is encouraged to consider their approach from different perspectives. For the qualitative researchers, we gained numerous prompts that we had not thought to ask, to elicit more detail. When people reported specific experiences from taking a drug or combination of drugs the pharmacology team could help identify what was important to follow up and explore further. Without this input, we would have missed these valuable opportunities to learn more from our participants.

The pharmacologists also encouraged the qualitative team to look at the patterns of co-use at a more granular level than is traditional in qualitative research to inform the experiments. This included what people take, when and how much, supporting translation back to the lab experiments.

There is also a human benefit for us as researchers of working this way. Working together and generating ideas as a multidisciplinary team is incredibly stimulating and helps us generate more ideas for future research. For lab researchers, it can be challenging and take time to translate important pharmacological research into real-world impact. By working with qualitative data capturing how people experience drugs in the real world, the study is more relevant to and ecologically informed by the lives and experiences of people who use drugs.

What has helped us work this way?

As a team we have continually refined a common language and reached a sufficient level of understanding of each other’s disciplines, including their potential and limitations. For instance, the potential to extrapolate from animal to human. There is also no hierarchy – professors and junior researchers work together on an equal footing as we all have something new to learn about the methods, approaches and field. We have respect for each other’s discipline, try to speak without making assumptions and use plain English!

What have we learnt?

We’ve all been part of multidisciplinary projects before, but this one feels different, because we are working so closely together and pooling our expertise. We’ve learnt about each other’s disciplines and about science communication on both sides. We’ve also learned how qualitative research can bring the lab team closer to the people to which the work relates.

What are we going on to do?

The team is working hard to continue this collaboration and explore how this approach can be used for future projects both with the current team, and with other collaborators.

We’ve identified that our qualitative findings can not only inform the laboratory work but can inform the advice and guidance used in practice to try to prevent drug related deaths. This has led to further qualitative work to build in the views of people who work in drug treatment settings, to help shape our thinking and understanding.

The underlying motivation for this project is to minimise drug related harm. By taking such a multi-disciplinary approach in the study we hope to design evidence-based, realistic approaches that will have real impact.

This piece was written by members of the Benzo Opioid Group (Graeme Henderson, Ana Paula Abdala, Chris Bailey, Jo Kesten, Matt Hickman, Jenny Scott, Ai Na Ng, Gabriele Vojt, Hannah Family, Hannah Poulter, Damiana Cavallo, Rebecca Okubadejo, Sara Karimi).