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

与毒品有关的死亡人数现在是英国有记录以来最高的，也是欧洲最高的。2020年，苏格兰有近1200人死于阿片类药物中毒--涉及海洛因、美沙酮或其他阿片类药物--英格兰有2200多人。许多阿片类药物使用者服用其他药物，也就是所谓的多药使用--阿片类药物和苯二氮卓类药物(俗称苯并二氮卓类)的组合已被确定为英国过量死亡增加的一个可能原因。近年来，非法或“街头”苯系物的可获得性和使用量有所增加，如依替唑仑。在苏格兰，阿片类药物过量死亡的人数在过去五年中翻了一番，75%以上的死亡涉及阿片类药物和街头苯系物。这些药物在大脑中相互作用的方式以及它们如何结合在一起增加过量服药的风险尚不清楚，这也是该项目的主要目标。我们的实验还将得到使用阿片类药物和苯并类药物的人的经历，以及他们对如何以及为什么同时服用苯并类药物和阿片类药物的描述。该项目汇集了来自定性研究、公共卫生、生理学和神经药理学等一系列学科的经验丰富的研究人员团队，他们都具有研究阿片类药物的经验。我们将共同采取协调、跨学科的方法来调查苯并物如何增加致命阿片类药物过量的风险。与吸毒者的研究-在我们的合作者和利益攸关方的帮助下，我们将在英国的三个地点招募和采访阿片类药物使用者：格拉斯哥是苏格兰阿片类药物过量死亡人数最多的地方，英格兰东北部是英格兰阿片类药物过量死亡率最高的地方，布里斯托尔是阿片类药物使用高发但低于平均过量死亡人数的地区。我们的采访将详细探索人们如何在使用阿片类药物的同时使用苯并，以及为什么？他们什么时候服用每种药物，剂量是多少？人们对过量用药的风险有何了解和体验？是否认为特定的苯系物更有可能导致服药过量？这些发现将为我们的利益攸关方提供重要信息，并将有助于设计后续实验室实验，以确定苯并物如何增加致命阿片类药物过量的风险。实验室研究-阿片类药物作用于大脑中的特定靶点，称为Mu-阿片受体，而苯并素作用于另一个靶点，GABAA受体。这两种类型的受体都存在于整个大脑中，但过量服药的风险来自于它们对负责控制呼吸的脑细胞(称为呼吸神经元)的作用，这些细胞可能会受到抑制或减慢，以至于没有足够的氧气被吸入，一个人就会出现致命的过量服药。苯并可通过几种可能的机制增加阿片类药物对呼吸的负面影响。可能的机制包括：-在受体水平：两种药物可能直接在阿片受体上相互作用。例如。苯并素可能会逆转对阿片类药物的耐受性，从而增强它们对呼吸的抑制作用。-在脑细胞层面：两种药物也可能分别作用于同一脑细胞(呼吸神经元)中各自的受体，以增强其抑郁。-在大脑层面：两种药物可以在控制呼吸道和胸肌的不同脑干区域结合作用，这也将共同抑制呼吸。所有这些可能的机制都会增加阿片类药物过量的风险，本项目将对此进行研究。通过确定苯并物如何以及为什么增加致命阿片类药物过量的风险，我们将与我们的研究伙伴、地方和国家政府机构以及药物治疗机构合作，制定更好的减少伤害战略。从长远来看，我们的发现可能会为预防致命过量的新疗法铺平道路。

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.