'Opioid overdose deaths: Understanding the lethal interactions between benzodiazepines and opioids to develop new harm reduction strategies

Drug-related deaths are now at the highest ever recorded in the UK and the highest rate in Europe. In 2020 there were nearly 1200 opioid poisoning deaths - involving heroin or methadone or other opioids - in Scotland and over 2200 in England.

Many opioid users take other drugs as well - called poly-drug use - and the combination of opioids and benzodiazepines (colloquially known as benzos) has been identified as one possible reason for the increase in overdose deaths in the UK. In recent years, there has been a rise in the availability and use of illicit or "street" benzos such as Etizolam. In Scotland, there has been a doubling of the number of opioid overdose deaths in the last five years and over 75% of the deaths involved opioids and street benzos. The way these drugs interact in the brain and how they combine to increase the risk of overdose is not known and is the primary aim of this project. Our experiments will be informed also by what people who use opioids and benzos experience and what accounts they give of how and why they take benzos and opioids together.

This project brings together an experienced team of researchers from a range of disciplines including qualitative research, public health, physiology, and neuropharmacology; all with experience in studying opioid drugs. Together, we will take a co-ordinated, trans-disciplinary approach to investigate how benzos increase the risk of fatal opioid overdose.

Research with drug-users - Facilitated by our collaborators and stakeholders we will recruit and interview opioid users in three locations in the UK: Glasgow the site with the largest number of opioid overdose deaths in Scotland, North East England the site with the highest rate of opioid overdose deaths in England and Bristol an area with a high prevalence of opioid use but below average number of overdose deaths. Our interviews will explore in detail how people use benzos alongside opioids and why? When do they take each drug and at what doses? What is understood and experienced of the risks of overdose? Are specific benzos thought to be more likely to cause overdose? These findings will provide important information to our stakeholders and will also aid in the design of subsequent laboratory experiments aimed at determining how benzos increase the risk of fatal opioid overdose.

Laboratory research - Opioid drugs act on specific targets in the brain, called mu-opioid receptors, while benzos 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) which can be depressed or 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 benzos can increase the negative effect of opioids on breathing. Possible mechanisms include:
- At the receptor level: both drugs may interact directly at the opioid receptor. For example. benzos might reverse tolerance to opioids, thus enhancing their depressant effects on breathing.
- At the level of brain cells: both drugs may also act at individually their respective receptors in the same brain cell (a 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.
All these possible mechanisms would act to increase the risk of opioid overdose and will be investigated in this project.

By determining how and why benzos increase the risk of fatal opioid overdose we will then work with our research partners, local and national government agencies and drug treatment agencies to develop better harm reduction strategies. In the longer term our findings may pave the way towards novel treatments to prevent fatal overdose.

Poly-drug use of benzodiazepines (BZs) and opioids are an increasingly fatal combination but why BZs increase the risk of opioid overdose is not known.
We will take an integrated qualitative and experimental approach to determine
- How and why opioid users also use BZs
- How BZs and opioids interact to cause fatal respiratory depression

1. We will interview drug-users using a standardised topic guide exploring socio-demographic characteristics, health conditions, initiation and motivation of using BZs with opioids, how BZs are used alongside opioids and the role of different types of BZs and opioids in non-fatal overdose experiences. Interview participants will be sampled purposefully in three sites (Glasgow, Teesside, Bristol) reflecting varying opioid death rates and poly drug use, supported by our collaborators. Patient and public involvement will inform the study design and interviews will be conducted in collaboration with trained peer researchers. Data from each site will be triangulated and analysed using the framework method.

2. Using laboratory studies in mice to determine the mechanism(s) underlying BZ/opioid interactions we will:
- record from respiratory control centre neurons to investigate whether BZs and opioids interact at the mu-opioid receptor or single neuron level
- investigate whether the interaction occurs at the network level by interfering with the neuronal control of respiration
- study how the combined effects of the drugs alter different respiratory parameters in the whole animal.
We will investigate additive/synergistic effects of BZs and opioids, whether BZs affect the ability of naloxone to reverse the opioids, and whether BZs reverse tolerance to the effects of opioids. To determine if the interactions depend on specific drugs we will use three opioids (morphine (active metabolite of heroin), methadone, and buprenorphine) and the BZs (diazepam, etizolam and alprazolam) that are most associated with opioid overdose.