{"title":"纳洛酮的剂量:一个不断发展的不受管制的药物景观,护理环境的考虑和研究的需要。","authors":"James S. H. Wong, Anthony Lau, Pouya Azar","doi":"10.1111/add.70144","DOIUrl":null,"url":null,"abstract":"<p>Gonzalez Utrilla <i>et al</i>. [<span>1</span>] present a timely and nuanced discussion of the complexities of naloxone dosing in the era of highly potent synthetic opioids (HPSOs). They highlight the risks of both underdosing and over-antagonism, advocate for a tailored approach to naloxone administration and emphasize the importance of non-pharmacological interventions. We generally agree with the principle of titrating naloxone to clinical effect where feasible, recognizing this approach is more practicable in acute care settings than in community settings.</p><p>While minimizing adverse effects from naloxone over-antagonism is important, the foremost priority in opioid overdose management, across all settings, is preserving life. Overdose reversal hinges on prompt first aid, including airway management, ventilation and cardiopulmonary resuscitation, in tandem with timely naloxone administration [<span>2</span>]. That said, to mitigate the risk of precipitated withdrawal, naloxone should be reserved for restoring respiration rather than used solely in cases of decreased consciousness. Reduced consciousness may resolve as the opioid is gradually cleared, without the need for naloxone.</p><p>Despite robust evidence supporting naloxone dosing for heroin overdoses, guidance for fentanyl and other HPSOs remains limited [<span>3, 4</span>]. Current recommendations are largely informed from clinical experience, animal studies, <i>in silico</i> models, healthy volunteer studies and data on heroin-related overdoses, all of which have uncertain applicability to HPSO-related events. Moreover, polysubstance use, including benzodiazepines, xylazine and stimulants, further complicates the overdose response. These challenges highlight the need for clinical trials involving people who use synthetic opioids and polysubstance combinations to inform real-world, evidence-based practice.</p><p>Compounding these issues are the distinct pharmacological characteristics of HPSOs [<span>3</span>]. Fentanyl and its analogs exhibit higher receptor binding affinity and slower dissociation compared with heroin, suggesting that higher naloxone doses may be needed for effective reversal. Additionally, substantial variability in naloxone pharmacokinetics have been observed among healthy volunteers, and this variability may be even greater among people who use HPSOs. These pharmacodynamic and pharmacokinetic considerations should guide future research into dosing strategies that are effective across diverse healthcare environments.</p><p>In acute care settings, intravenous naloxone is preferred for its rapid onset and capacity for precise titration, enabling clinicians to restore respiration while minimizing severe withdrawal or rare complications, such as pulmonary edema and cardiac arrhythmias, thought to result from a catecholamine surge. Our clinical experience with intravenous naloxone, used in a different context to induce mild to moderate withdrawal for rapid buprenorphine initiation within minutes, has demonstrated how precisely the dose can be titrated to elicit the desired response without precipitating severe withdrawal [<span>5</span>]. When intravenous access is unavailable, intramuscular naloxone provides a relatively rapid onset of action and permits dose titration, albeit with less precision and fine control than intravenous administration.</p><p>Community settings, such as emergency medical services and take-home naloxone programs, present different challenges. Intramuscular naloxone is the recommended route in these contexts, offering a practical balance between speed and titratability. Non-clinical responders can be trained to administer and titrate intramuscular naloxone, and there are reports of community overdose responders doing so successfully.</p><p>Intranasal naloxone, though perceived as easier to administer and safer, has more limited capacity for dose titration and has shown variable efficacy compared with intramuscular naloxone. High-dose intranasal formulations, frequently introduced by pharmaceutical manufacturers, have been marketed with limited independent evidence and come at significantly higher costs, raising questions about their utility [<span>1</span>]. While further research is warranted, in scenarios lacking titration options or trained responders, it may be prudent to err on the side of higher initial dosing. In light of the volatility in the unregulated drug supply, the risk of inadequate reversal in overdoses involving fentanyl analogs such as carfentanil or nitazenes often outweighs the potential harms of over-antagonism.</p><p>Given these issues, nalmefene may be a promising alternative in specific contexts. With higher receptor affinity and a longer half-life than naloxone, it could reduce the risk of re-narcotization, particularly in rural and remote areas with delayed access to medical care. However, the potential for prolonged withdrawal symptoms, limited clinical data and lack of global availability warrant further investigation before broader adoption [<span>6</span>].</p><p>Challenges in naloxone dosing parallel those seen in opioid agonist therapy in the HPSO era [<span>7-9</span>]. Both domains are marked by limited evidence, an unpredictable drug supply and the need for individualized approaches. Addressing these gaps requires well-designed clinical trials and translational research. In the absence of definitive data, collaboration among clinicians, researchers, policymakers and people with lived or living experience is essential to developing pragmatic, equitable and evidence-informed naloxone strategies. A coordinated and adaptive response is needed to address the urgency of this evolving public health crisis.</p><p><b>James S. H. Wong:</b> Conceptualization (lead); writing—original draft (lead). <b>Anthony Lau:</b> Conceptualization (supporting); writing—review and editing (supporting). <b>Pouya Azar:</b> Conceptualization (supporting); supervision (lead); writing—review and editing (supporting).</p><p>PA was a consultant on Indivior-led buprenorphine extended-release studies (terminated in 2023) and receives honoraria for presentations organized by Indivior, which are unrelated to this commentary. All other co-authors report no conflicts of interest.</p>","PeriodicalId":109,"journal":{"name":"Addiction","volume":"120 11","pages":"2177-2178"},"PeriodicalIF":5.3000,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/add.70144","citationCount":"0","resultStr":"{\"title\":\"Naloxone dosing: An evolving unregulated drug landscape, care setting considerations, and the need for research\",\"authors\":\"James S. H. Wong, Anthony Lau, Pouya Azar\",\"doi\":\"10.1111/add.70144\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Gonzalez Utrilla <i>et al</i>. [<span>1</span>] present a timely and nuanced discussion of the complexities of naloxone dosing in the era of highly potent synthetic opioids (HPSOs). 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Reduced consciousness may resolve as the opioid is gradually cleared, without the need for naloxone.</p><p>Despite robust evidence supporting naloxone dosing for heroin overdoses, guidance for fentanyl and other HPSOs remains limited [<span>3, 4</span>]. Current recommendations are largely informed from clinical experience, animal studies, <i>in silico</i> models, healthy volunteer studies and data on heroin-related overdoses, all of which have uncertain applicability to HPSO-related events. Moreover, polysubstance use, including benzodiazepines, xylazine and stimulants, further complicates the overdose response. These challenges highlight the need for clinical trials involving people who use synthetic opioids and polysubstance combinations to inform real-world, evidence-based practice.</p><p>Compounding these issues are the distinct pharmacological characteristics of HPSOs [<span>3</span>]. Fentanyl and its analogs exhibit higher receptor binding affinity and slower dissociation compared with heroin, suggesting that higher naloxone doses may be needed for effective reversal. Additionally, substantial variability in naloxone pharmacokinetics have been observed among healthy volunteers, and this variability may be even greater among people who use HPSOs. These pharmacodynamic and pharmacokinetic considerations should guide future research into dosing strategies that are effective across diverse healthcare environments.</p><p>In acute care settings, intravenous naloxone is preferred for its rapid onset and capacity for precise titration, enabling clinicians to restore respiration while minimizing severe withdrawal or rare complications, such as pulmonary edema and cardiac arrhythmias, thought to result from a catecholamine surge. Our clinical experience with intravenous naloxone, used in a different context to induce mild to moderate withdrawal for rapid buprenorphine initiation within minutes, has demonstrated how precisely the dose can be titrated to elicit the desired response without precipitating severe withdrawal [<span>5</span>]. When intravenous access is unavailable, intramuscular naloxone provides a relatively rapid onset of action and permits dose titration, albeit with less precision and fine control than intravenous administration.</p><p>Community settings, such as emergency medical services and take-home naloxone programs, present different challenges. Intramuscular naloxone is the recommended route in these contexts, offering a practical balance between speed and titratability. Non-clinical responders can be trained to administer and titrate intramuscular naloxone, and there are reports of community overdose responders doing so successfully.</p><p>Intranasal naloxone, though perceived as easier to administer and safer, has more limited capacity for dose titration and has shown variable efficacy compared with intramuscular naloxone. High-dose intranasal formulations, frequently introduced by pharmaceutical manufacturers, have been marketed with limited independent evidence and come at significantly higher costs, raising questions about their utility [<span>1</span>]. While further research is warranted, in scenarios lacking titration options or trained responders, it may be prudent to err on the side of higher initial dosing. In light of the volatility in the unregulated drug supply, the risk of inadequate reversal in overdoses involving fentanyl analogs such as carfentanil or nitazenes often outweighs the potential harms of over-antagonism.</p><p>Given these issues, nalmefene may be a promising alternative in specific contexts. With higher receptor affinity and a longer half-life than naloxone, it could reduce the risk of re-narcotization, particularly in rural and remote areas with delayed access to medical care. However, the potential for prolonged withdrawal symptoms, limited clinical data and lack of global availability warrant further investigation before broader adoption [<span>6</span>].</p><p>Challenges in naloxone dosing parallel those seen in opioid agonist therapy in the HPSO era [<span>7-9</span>]. Both domains are marked by limited evidence, an unpredictable drug supply and the need for individualized approaches. 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引用次数: 0
摘要
Gonzalez Utrilla等人提出了一个及时和细致入微的讨论,在强效合成阿片类药物(HPSOs)时代纳洛酮剂量的复杂性。他们强调了剂量不足和过度拮抗的风险,提倡量身定制的纳洛酮给药方法,并强调非药物干预的重要性。我们普遍同意在可行的情况下根据临床效果来滴定纳洛酮的原则,认识到这种方法在急性护理环境中比在社区环境中更可行。虽然尽量减少纳洛酮过度拮抗剂的不良反应很重要,但在所有情况下,阿片类药物过量管理的首要任务是保护生命。药物过量逆转取决于及时的急救,包括气道管理、通气和心肺复苏,同时及时给予纳洛酮[10]。也就是说,为了减轻急性停药的风险,纳洛酮应保留用于恢复呼吸,而不是仅用于意识下降的情况。意识减退可能随着阿片类药物的逐渐清除而消失,不需要纳洛酮。尽管有强有力的证据支持纳洛酮治疗海洛因过量,但芬太尼和其他hpso的指导仍然有限[3,4]。目前的建议主要来自临床经验、动物研究、计算机模型、健康志愿者研究和与海洛因有关的过量服用数据,所有这些都不确定是否适用于与hpso有关的事件。此外,多种物质的使用,包括苯二氮卓类药物、二嗪和兴奋剂,使过量反应进一步复杂化。这些挑战突出表明,需要对使用合成阿片类药物和多物质组合的人进行临床试验,为现实世界的循证实践提供信息。使这些问题复杂化的是HPSOs b[3]独特的药理学特征。与海洛因相比,芬太尼及其类似物表现出更高的受体结合亲和力和更慢的解离,这表明可能需要更高剂量的纳洛酮才能有效逆转。此外,在健康志愿者中观察到纳洛酮药代动力学的显著差异,而在使用hpso的人群中,这种差异可能更大。这些药效学和药代动力学方面的考虑应该指导未来在不同医疗环境中有效的给药策略研究。在急性护理环境中,静脉注射纳洛酮是首选,因为它起效快,能够精确滴定,使临床医生能够恢复呼吸,同时最大限度地减少严重的停药或罕见的并发症,如肺水肿和心律失常,被认为是由儿茶酚胺激增引起的。我们静脉注射纳洛酮的临床经验,在不同的情况下用于诱导轻度至中度戒断,以便在几分钟内快速启动丁丙诺啡,已经证明了如何精确地滴定剂量以引起所需的反应,而不会引起严重的戒断bb0。当无法静脉给药时,肌注纳洛酮可提供相对快速的起效,并允许剂量滴定,尽管精度和精细控制不如静脉给药。社区环境,如紧急医疗服务和纳洛酮带回家计划,提出了不同的挑战。肌内纳洛酮是在这些情况下推荐的途径,提供了速度和滴定性之间的实际平衡。非临床反应者可以接受训练,以管理和滴定肌内纳洛酮,有报告说,社区过量反应者成功地做到了这一点。鼻内纳洛酮虽然被认为更容易给药和更安全,但与肌内纳洛酮相比,剂量滴定的能力更有限,并且显示出不同的疗效。高剂量鼻内制剂经常由制药商推出,但在上市时独立证据有限,而且成本明显较高,这引发了对其效用的质疑。虽然需要进一步的研究,但在缺乏滴定选择或训练有素的应答者的情况下,错误地选择较高的初始剂量可能是谨慎的。鉴于不受管制的药物供应的波动性,涉及芬太尼类似物(如卡芬太尼或尼塔尼)的过量用药逆转不足的风险往往超过过度拮抗的潜在危害。考虑到这些问题,纳美芬在特定情况下可能是一种有希望的替代品。与纳洛酮相比,它具有更高的受体亲和力和更长的半衰期,可以降低再麻醉的风险,特别是在获得医疗服务延迟的农村和偏远地区。然而,戒断症状可能延长,临床数据有限,缺乏全球可用性,在广泛采用bbb之前需要进一步调查。 在HPSO时代,纳洛酮剂量的挑战与阿片类激动剂治疗的挑战相似[7-9]。这两个领域的特点是证据有限,药物供应不可预测,需要个性化的方法。解决这些差距需要精心设计的临床试验和转化研究。在缺乏明确数据的情况下,临床医生、研究人员、政策制定者和有实际或生活经验的人之间的合作对于制定务实、公平和循证的纳洛酮战略至关重要。需要采取协调和适应性的应对措施,以应对这一不断演变的公共卫生危机的紧迫性。James S. H. Wong:概念化(lead);写作——原稿(引子)。刘德华:概念化(辅助);写作-审查和编辑(支持)。Pouya Azar:概念化(支持);监督(领导);写作-审查和编辑(支持)。PA是独立公司主导的丁丙诺啡缓释研究(于2023年终止)的顾问,并因独立公司组织的报告而获得酬金,这些报告与本评论无关。所有其他共同作者报告无利益冲突。
Naloxone dosing: An evolving unregulated drug landscape, care setting considerations, and the need for research
Gonzalez Utrilla et al. [1] present a timely and nuanced discussion of the complexities of naloxone dosing in the era of highly potent synthetic opioids (HPSOs). They highlight the risks of both underdosing and over-antagonism, advocate for a tailored approach to naloxone administration and emphasize the importance of non-pharmacological interventions. We generally agree with the principle of titrating naloxone to clinical effect where feasible, recognizing this approach is more practicable in acute care settings than in community settings.
While minimizing adverse effects from naloxone over-antagonism is important, the foremost priority in opioid overdose management, across all settings, is preserving life. Overdose reversal hinges on prompt first aid, including airway management, ventilation and cardiopulmonary resuscitation, in tandem with timely naloxone administration [2]. That said, to mitigate the risk of precipitated withdrawal, naloxone should be reserved for restoring respiration rather than used solely in cases of decreased consciousness. Reduced consciousness may resolve as the opioid is gradually cleared, without the need for naloxone.
Despite robust evidence supporting naloxone dosing for heroin overdoses, guidance for fentanyl and other HPSOs remains limited [3, 4]. Current recommendations are largely informed from clinical experience, animal studies, in silico models, healthy volunteer studies and data on heroin-related overdoses, all of which have uncertain applicability to HPSO-related events. Moreover, polysubstance use, including benzodiazepines, xylazine and stimulants, further complicates the overdose response. These challenges highlight the need for clinical trials involving people who use synthetic opioids and polysubstance combinations to inform real-world, evidence-based practice.
Compounding these issues are the distinct pharmacological characteristics of HPSOs [3]. Fentanyl and its analogs exhibit higher receptor binding affinity and slower dissociation compared with heroin, suggesting that higher naloxone doses may be needed for effective reversal. Additionally, substantial variability in naloxone pharmacokinetics have been observed among healthy volunteers, and this variability may be even greater among people who use HPSOs. These pharmacodynamic and pharmacokinetic considerations should guide future research into dosing strategies that are effective across diverse healthcare environments.
In acute care settings, intravenous naloxone is preferred for its rapid onset and capacity for precise titration, enabling clinicians to restore respiration while minimizing severe withdrawal or rare complications, such as pulmonary edema and cardiac arrhythmias, thought to result from a catecholamine surge. Our clinical experience with intravenous naloxone, used in a different context to induce mild to moderate withdrawal for rapid buprenorphine initiation within minutes, has demonstrated how precisely the dose can be titrated to elicit the desired response without precipitating severe withdrawal [5]. When intravenous access is unavailable, intramuscular naloxone provides a relatively rapid onset of action and permits dose titration, albeit with less precision and fine control than intravenous administration.
Community settings, such as emergency medical services and take-home naloxone programs, present different challenges. Intramuscular naloxone is the recommended route in these contexts, offering a practical balance between speed and titratability. Non-clinical responders can be trained to administer and titrate intramuscular naloxone, and there are reports of community overdose responders doing so successfully.
Intranasal naloxone, though perceived as easier to administer and safer, has more limited capacity for dose titration and has shown variable efficacy compared with intramuscular naloxone. High-dose intranasal formulations, frequently introduced by pharmaceutical manufacturers, have been marketed with limited independent evidence and come at significantly higher costs, raising questions about their utility [1]. While further research is warranted, in scenarios lacking titration options or trained responders, it may be prudent to err on the side of higher initial dosing. In light of the volatility in the unregulated drug supply, the risk of inadequate reversal in overdoses involving fentanyl analogs such as carfentanil or nitazenes often outweighs the potential harms of over-antagonism.
Given these issues, nalmefene may be a promising alternative in specific contexts. With higher receptor affinity and a longer half-life than naloxone, it could reduce the risk of re-narcotization, particularly in rural and remote areas with delayed access to medical care. However, the potential for prolonged withdrawal symptoms, limited clinical data and lack of global availability warrant further investigation before broader adoption [6].
Challenges in naloxone dosing parallel those seen in opioid agonist therapy in the HPSO era [7-9]. Both domains are marked by limited evidence, an unpredictable drug supply and the need for individualized approaches. Addressing these gaps requires well-designed clinical trials and translational research. In the absence of definitive data, collaboration among clinicians, researchers, policymakers and people with lived or living experience is essential to developing pragmatic, equitable and evidence-informed naloxone strategies. A coordinated and adaptive response is needed to address the urgency of this evolving public health crisis.
James S. H. Wong: Conceptualization (lead); writing—original draft (lead). Anthony Lau: Conceptualization (supporting); writing—review and editing (supporting). Pouya Azar: Conceptualization (supporting); supervision (lead); writing—review and editing (supporting).
PA was a consultant on Indivior-led buprenorphine extended-release studies (terminated in 2023) and receives honoraria for presentations organized by Indivior, which are unrelated to this commentary. All other co-authors report no conflicts of interest.
期刊介绍:
Addiction publishes peer-reviewed research reports on pharmacological and behavioural addictions, bringing together research conducted within many different disciplines.
Its goal is to serve international and interdisciplinary scientific and clinical communication, to strengthen links between science and policy, and to stimulate and enhance the quality of debate. We seek submissions that are not only technically competent but are also original and contain information or ideas of fresh interest to our international readership. We seek to serve low- and middle-income (LAMI) countries as well as more economically developed countries.
Addiction’s scope spans human experimental, epidemiological, social science, historical, clinical and policy research relating to addiction, primarily but not exclusively in the areas of psychoactive substance use and/or gambling. In addition to original research, the journal features editorials, commentaries, reviews, letters, and book reviews.