This article, written by Owen Underwood from the University of Nottingham, was a runner up for our Pharmacology Matters Writing Competition for early career pharmacologists in 2020.
Opioid-related deaths have hit the US and Europe like a tidal wave. According to the US Department for Health and Human Services, in 2018 in the US, nearly 130 people died each day of opioid overdose and 10.3 million people abused opioids, a number that has only increased during the COVID-19 pandemic. But opioids provide unrivalled pain relief for those who need it most, for example during bone breaks, postoperative care, and labour, and despite their downsides, opioids remain one of the main methods of treating severe pain across the globe. The main cause of death by overdose is respiratory depression, the slowing of the rate and depth of breath, and therefore the opioid research community have focused on finding ways to enhance the pain-relieving effects of opioids, while reducing this respiratory depression. Though other side effects such as nausea, constipation, and addiction contribute massively to the intolerability of opioids, generally these effects don’t directly result in deaths. Understandably, there was a great deal of excitement in the opioid research community in the year 2000, when mice with a genetic alteration removing a key signalling protein showed reduced respiratory depression when given opioids compared to their unaltered, or ‘wild type’ siblings.
The mice in this landmark study were ‘knockout’ mice – they had a genetic alteration that removed, or inactivated, a specific gene. The target gene was for β-Arrestin 2, a protein that arrests, or stops, the signalling of opioid receptors, which are the target of pain-relieving opioids. Normally, pain travels from a stimulus in the peripheral tissues, through the spinal cord, and up to the base of the brain via a series of nerves. At the junction of nerves in the spinal and cerebral regions, the mu-opioid receptor can be activated by certain peptides, such as endorphins. Endorphins are molecules made by the body when it doesn’t want to feel pain, after exercise for example. A series of molecules found in high concentrations in some plants, such as certain strains of poppies and a specific species of tree, are able to mimic the effects of these endorphins by binding the receptor.
Activation of the mu-opioid receptor changes the electrical conductance of these nerves, effectively blocking the pain signals from reaching the reflex arc in the spinal cord or the brain. In the 2000 paper, the mice showed prolonged pain relief and reduced tolerance to repeated doses. The implications of this finding were that in the clinic, this could mean fewer dosages, and no need to increase the dose over time as patients feel less and less of an effect.
Further β-Arrestin 2 knockout mouse studies in 2005 highlighted two pathways that the receptor could utilise – the pain-relieving pathway, and the β-Arrestin pathway, with the latter thought to be the one responsible for respiratory depression. Normally, opioids and endorphins activate both pathways simultaneously, and so the race was on to find a new molecule that could activate the pain relief-related pathway without the β-Arrestin pathway.
Several companies and research laboratories discovered new drugs, all of which claimed to, and most were shown to, activate the pain relief pathway to a greater extent than the β-Arrestin pathway in laboratory tests. However, only one has been approved by the US Food and Drug Administration at the time of writing (March, 2020). Unfortunately, all of the drugs tested in humans and animals exhibited the very complication they were meant to reduce – respiratory depression.
Independent labs repeated the experiments carried out by the drug companies, and their conclusions were the same; the drugs selectively activated the supposed pain relief pathway. The scientists were all asking the same question – why do these drugs still cause respiratory depression? All eyes turned on the 2005 mouse study. Experiments were repeated by a consortium of labs in the UK, Germany, and Australia and published in the British Journal of Pharmacology. The previous results could not be replicated; when β-Arrestin 2 knockout mice were given morphine and fentanyl, the mice showed respiratory depression that was not significantly reduced compared to their unaltered siblings. Other studies demonstrated that mice with mu-opioid receptors that were not able to interact with β-Arrestin 2 also showed opioid-induced side effects. This was a blow to the original hypothesis, and contrary evidence was mounting.
The thoughts of this consortium were that the original study did not have the model mouse it thought it did. In order to generate a useful mouse model, multiple generations of crossbreeding, or breeding of different mouse strains with the same ‘knockout’, must occur. One of the crossbred strains used by the original study had shown poor responses to morphine. This led to mice that had weak responses to morphine in both pathways and could not be relied upon to give clear and meaningful results with regards to the separation of pain relief and respiratory depression. As such, it was found that, while bias for the signalling pathways was possible and may be exploitable, the results of separating these pathways on side effects were limited at best.
The drugs whose history resides in these studies have not been without value, as their characteristics are useful for exploring different research avenues, but their clinical use is limited. Selective activation of one pathway over another, termed ‘bias’, has been deployed in fields such as high blood pressure and cardiovascular disease. A lack of understanding of the mechanism which leads to some opioids causing more respiratory depression than others is the issue – one which researchers are working to correct. Multiple studies have shown that the pain relief pathway and the β-Arrestin pathway are more intertwined than previously thought. Other studies have shown that opioids with a more limited signalling capacity (or low efficacy) show a much better side effect profile and are much more easily tailored to the patient. It is not quite back to the drawing board, and many avenues are opening up to help improve the lives of those taking opioids.
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