Opioid-Related Disorders

iStock, aprott While the regulator has not approved their use in type 1 diabetes, off-label prescribing for GLP-1 receptor agonists has sharply increased, according to researchers, who warn about the risk of serious side effects such as ketoacidosis. GLP-1 receptor agonists, including the blockbuster drugs semaglutide and tirzepatide, are increasingly being prescribed to patients with type 1 diabetes, despite having no FDA approval for this indication, according to a study published Wednesday in the Journal of the American Medical Association . From 2010 to 2023, the percentage of type 1 diabetes (T1D) patients that were given GLP-1 therapies surged from 0.3% to 6.6%. This increase was statistically significant, with a p-value less than 0.001, according to the study, which looked at electronic health record data from the healthcare database Epic Cosmos. Overall, the study included data from nearly 950,000 patients with T1D. Novo Nordisk’s semaglutide—marketed as Ozempic for type 2 diabetes (T2D) and Wegovy for weight loss—saw the biggest jump in T1D uptake, jumping from 0.2% in 2018 to 4.4% in 2023. Meanwhile, Lilly’s tirzepatide—approved as Mounjaro for T2D and Zepbound for obesity—was prescribed to 1.3% of T1D patients within a year of its initial approval in 2022 . Of note, the researchers pointed out that GLP-1 receptor agonists were most commonly prescribed to T1D patients with obesity. Aside from GLP-1 analogs, researchers also looked at the prescribing patterns of SGLT2 inhibitors—another popular class of T2D medication—and found similar trends. In 2010, 0.1% of T1D patients were treated with SGLT2 inhibitors, rising significantly to 2.4% in 2023. Corresponding author Hui Shao, of the Emory University Rollins School of Public Health, in a statement cautioned that the use GLP-1 and SGLT2 therapies in T1D “has increased sharply over the past decade,” despite their safety concerns in this indication—including ketoacidosis—a serious and potentially life-threatening complication that develops when the body fails to produce enough insulin. “This increase is likely to continue due to their significant benefits in weight management and cardiorenal protection observed in individuals with type 2 diabetes and the general obese population,” Shao said, noting that “urgent studies are needed” to better elucidate the benefits and risks of the GLP-1 and SGLT2 drug classes in T1D. Meanwhile, “caution should be used” when treating T1D patients with these medications. The warning from researchers comes amid the potential myriad of therapeutic benefits of GLP-1 receptor agonists beyond diabetes and obesity. Novo Nordisk in March won the FDA’s approval for Wegovy to lower the risk of cardiovascular death, heart attack and stroke in overweight or obese patients with cardiovascular diseases. Meanwhile, Lilly is also positioning Zepbound as an answer to obstructive sleep apnea , with an FDA decision expected as early as the end of the year. In addition, several studies have also detected signals of efficacy for a variety of other conditions, including Alzheimer’s disease , opioid overdose , tobacco use disorder and cirrhosis in metabolic dysfunction-associated steatotic liver disease .

*仅供医学专业人士阅读参考阿片类药物以优异的镇痛效果广为人知，但是相应带来的成瘾性极大限制了药物使用。停止或减少使用阿片类药物会产生持久且严重的戒断症状。自主神经失调是阿片类药物戒断的特征之一，表现为出汗、心跳加速、血压波动和胃肠道问题。戒断期间，位于大脑第四脑室的蓝斑（LC）过度激活，产生多种厌恶性戒断症状，如焦虑、烦恼、恶心呕吐等。为了明确与戒断反应相关的神经投射，来自加拿大卡尔加里大学的研究人员评估了LC到脊髓自上而下神经回路在戒断过程中的作用机制。研究结果显示，戒断期间，脊髓投射的LC神经元过度兴奋，降低神经元活性可以有效减少小鼠的戒断行为。小胶质细胞pannexin-1（Panx1）通道对LC活性有关键的调节作用，Panx1阻断药物——丙磺舒及其之后的合成化合物EG-2184——可以有效降低小鼠戒断导致的身体症状和条件性位置厌恶。研究发表在《自然·通讯》杂志上。研究人员选择了条件性位置厌恶（CPA）对小鼠进行厌恶测试。将吗啡依赖小鼠限制在两个连通的活动室中，在其中一个活动室给予小鼠戒断药物，小鼠不仅表现出震颤、跳跃、湿狗颤抖等戒断行为，还明显对接受戒断药物的活动室表现出CPA。小胶质细胞是神经系统的免疫细胞，负责应对神经炎症和修复神经损伤。当发生戒断反应时，小胶质细胞的Panx1通道激活，与脊髓的突触长期增强有关。研究人员发现，相比于正常小鼠，Panx1缺陷小鼠依旧表现出吗啡带来的急性精神作用和奖励特性，但是戒断症状和CPA显著减少。这也就意味着，Panx1可能是戒断反应的关键通道。小胶质细胞Panx1缺失减轻吗啡戒断诱导的条件性地方厌恶接下来，研究人员开始深挖Panx1在大脑中的作用机制。在药物戒断期间，多个大脑区域的神经元活性显著增加，LC中小胶质细胞Panx1表达水平增加，小胶质细胞Panx1通道激活；Panx1通道激活之后，小胶质细胞还可以释放ATP。针对性抑制LC或者LC中小胶质细胞活性，或者抑制LC小胶质细胞的ATP释放，都可以减轻小鼠的戒断反应。由此可以得知，LC中的小胶质细胞Panx1以及ATP都是戒断反应的必需底物。戒断反应使LC脊髓神经元过度兴奋在戒断反应的下游，LC神经元激活投射至腰脊髓。戒断反应中，LC脊髓神经元的活性显著增加，活跃神经元比例由之前的23.4%增加至60.2%。并且，LC脊髓神经元的过度兴奋也离不开小胶质细胞Panx1的支持，Panx1缺陷吗啡依赖小鼠中，戒断药物诱导的LC脊髓神经元兴奋性减弱。在明确小胶质细胞Panx1在阿片类药物戒断反应机制中的重要作用之后，研究人员开始寻找能够靶向Panx1的治疗方法。丙磺舒是一种FDA批准的广谱Panx1抑制剂，较高剂量的丙磺舒给药可以减轻吗啡戒断诱导的CPA。高剂量丙磺舒处理减轻小鼠戒断行为和CPA为了提高药物治疗效果和递送效率，研究人员在丙磺舒的基础上合成化合物EG-2184，提高药物的亲脂性，可以在更低剂量下显著减少戒断行为。总的来说，研究确定了小胶质细胞Panx1是调节阿片类药物戒断的核心机制，通过破坏LC→脊髓的功能连接，可以减轻戒断行为。参考文献：Kwok C H T, Harding E K, Burma N E, et al. Pannexin-1 channel inhibition alleviates opioid withdrawal in rodents by modulating locus coeruleus to spinal cord circuitry[J]. Nature communications, 2024, 15(1): 6264.本文作者丨王雪宁

Narcan nasal spray was made available over-the-counter by the FDA in March last year. Image credit: Shutterstock/ AnAdventureADa. Emergent BioSolutions has pledged to donate 20,000 doses of Narcan nasal spray (naloxone) to communities affected by opioid overdoses. Emergent said it is “working with businesses” to consider the availability of Narcan to sites including workplaces, facilities, and hospitality venues, amongst others, where accidental opioid emergencies could occur, as per an 8 October press release. The drive comes alongside the White House Challenge to Save Lives from Overdose, a nationwide initiative introduced by the Biden-Harris administration to increase training and access to opioid overdose reversal medications like Narcan. Emergent joined the Challenge in March this year as one of the main manufacturers of medication that treats opioid overdoses. An Emergent spokesperson confirmed to Pharmaceutical Technology that the donation is separate from the White House Challenge and builds upon the company’s existing donation programme. Narcan’s accessibility significantly increased last year when the US Food and Drug Administration (FDA ) approved the nasal spray for over-the-counter (OTC) use in March. At the time, it became the first opioid reversal medication available without the need for a prescription. Narcan generated $110m in revenue for Emergent in Q4 2023, up 22% from the year prior. See Also: FDA declines to approve Zealand Pharma’s hypoglycaemia therapy in infants Ipsen’s Elafibranor gains MHRA approval for PBC treatment Narcan works as an opioid receptor antagonist – it binds to opioid receptors and blocks the effects of opiates. The medication is recommended for use immediately after a suspected or known overdose of an opioid has occurred. Emergent has handed out more than 2,700 opioid emergency kits containing one carton of Narcan nasal spray and educational resources across several college campuses and public venues. As part of its inclusion in the White House’s Challenge, the biopharma has installed more than 40 opioid emergency wall units near first aid stations and automatic external defibrillators in its offices and facilities, along with providing 1,300 cartons of the medication to its employees this year. There are more than 80,000 deaths in America related to opioid overdose each year. However, for the first time, data points to the first meaningful decline in opioid overdose deaths – putting a stop to a death rate that had increased by more than 250% from 1999 to 2019. The Centers for Disease Control and Prevention (CDC), which reported the data , did not provide reasons for the downturn, but the decrease in deaths coincided with the availability of Narcan, along with other approved opioid overdose treatments. Emergent’s CEO Joe Papa said: “It is promising to see the recent decline in opioid overdose deaths for the first time in years.” Papa added the company remains “committed to playing [its] part in bringing down the number of opioid-related deaths by continuing to expand access efforts through the OTC availability of Narcan”. The news comes at a time when many of the lawsuits against drug manufacturers of prescription opioids are being settled . These include companies and pharmacy chains that have been accused of deceptive marketing practices, downplaying addiction risks and oversupplying prescription drugs. One of the largest opioid settlements to date included Johnson & Johnson , AmerisourceBergen , Cardinal Health and McKesson – together agreeing to pay $26bn to seven states in 2021. Pharmaceutical companies are also beginning to shift away from opioid-based pain medications, with several companies developing non-opioid candidates to manage pain including Vertex Pharmaceuticals and Lexicon Pharmaceuticals . Emergent meanwhile has been helping fight a different public health concern in the infectious disease space. The company won FDA approval to use its smallpox vaccine for the prevention of mpox in August, making it one of only two vaccine manufacturers against the disease, alongside Bavarian Nordic .