IV Pulsed-Nicotine as a Model of Smoking: The Effects of Dose and Delivery Rate

摘要 虽然剂量和投放率都会影响滥用药物的可能性，但烟草控制 战略主要关注滥用程度高的烟草产品提供的尼古丁总量。 潜力--如香烟和电子烟(EC)。此外，系统的人体研究检查了 尼古丁剂量和释放率对其滥用的个体效应和交互作用的关系 潜力不足。同样，尼古丁的剂量和释放速率是否对其潜在的影响也是未知的。 有益的影响(即缓解吸烟的冲动和戒烟)及其滥用潜力。 这种知识差距的部分原因是无法通过实验控制尼古丁的释放速度。 吸入烟草产品。在一项使用静脉(IV)尼古丁输注的试点研究中-它提供了精确的 控制释放速度-我们发现1毫克/70千克尼古丁，平均释放尼古丁的量 抽一支烟，静脉注射超过1分钟，会产生更大的积极主观影响--表明 潜在的滥用--相比之下，在5或10分钟内摄入等量的尼古丁。相比之下，两者都 1分钟和5分钟的送货率在减少吸烟冲动方面同样有效。这些发现 支持递送率对尼古丁滥用潜力的影响大于其对抑制的影响 敦促吸烟-支持递送率的作用，以告知监管科学并减少 烟草使用。尽管如此，与香烟或EC提供的烟雾弹大小的尼古丁输送不同，我们的初步研究 受到尼古丁持续输注的限制。因此，为了提高我们设计的生态有效性，我们 进一步改进了我们的静脉尼古丁输注程序，开发了一种脉冲尼古丁输注作为 通过吸入烟草制品如EC传递尼古丁。使用这个程序，我们试图系统地检查 尼古丁剂量和递送率对潜在滥用风险的影响--通过积极的衡量标准进行评估 主观影响和强化-与潜在的有益影响-通过吸烟的测量进行评估 冲动和戒断症状。我们提出了一项双盲、安慰剂对照的研究，采用混合 设计：受试者间为尼古丁剂量，受试者内因素为产出率。七十个吸烟者 将被随机分配到0.2毫克/70公斤或1毫克/70公斤的尼古丁剂量。跨5个测试会话，在 每个剂量组，参与者将被分配到5个治疗条件的随机序列，包括 安慰剂(生理盐水)和4种不同的尼古丁释放率。在每节课中，参与者将获得总计10个 每30秒注射一次尼古丁或生理盐水。在脉冲输液的同时，参与者将 吸入烟草味的EC，这将允许更紧密地匹配吸入烟草使用的感官方面。 在安慰剂测试阶段，参与者将接受10次脉冲生理盐水输注。总之，这项研究代表了 展示尼古丁释放率作为基准的潜在效用的重要一步 降低ECS和其他尼古丁递送产品的风险。

Abstract Although both the dose and the rate of delivery impact the abuse potential of drugs of abuse, tobacco control strategies focus primarily on the total amount of nicotine delivered by tobacco products with a high abuse potential – such as cigarettes and electronic cigarettes (EC). Further, systematic human studies examining the relationship between the individual and interactive effects of the dose and delivery rate of nicotine on its abuse potential are lacking. Likewise, it is also unknown if the dose and delivery rate of nicotine impact its potentially beneficial effects (i.e., alleviation of smoking urges and withdrawal) and its abuse potential in a distinct manner. This knowledge gap is partly due to the inability to experimentally control the rate of nicotine delivery with inhaled tobacco products. In a pilot study using intravenous (IV) nicotine infusion – which provides precise control over delivery rate – we found that 1 mg/70kg nicotine, the average amount of nicotine delivered by smoking a cigarette, infused IV over 1 minute, produced greater positive subjective effects – indicating greater abuse potential – compared to the same amount of nicotine delivered over 5 or 10 minutes. In contrast, both the 1-minute and 5-minute delivery rates were equally effective in reducing smoking urges. These findings support a greater impact of the rate of delivery on nicotine’s abuse potential, than its effects on suppressing urges to smoke – supporting the role of delivery rate to inform regulatory science and reducing harm from tobacco use. Still, unlike the puff-sized nicotine delivery provided by tobacco cigarettes or EC, our pilot study was limited by a continuous infusion of nicotine. Hence, to improve the ecological validity of our design, we further refined our IV nicotine infusion procedure, by developing a pulsed-nicotine infusion as a model for nicotine delivery by inhaled tobacco products like EC. Using this procedure, we seek to systematically examine the impact of nicotine dose and delivery rate on the risk of abuse potential – assessed by measures of positive subjective effects and reinforcement – vs. potentially beneficial effects – assessed by measures of smoking urges and withdrawal symptoms. We propose a double-blind, placebo-controlled study employing a mixed design: nicotine dose as the between-subject and delivery rate as the within-subject factors. Seventy smokers will be randomized to a dose of either 0.2 mg/70 kg or 1 mg/70 kg of nicotine. Across 5 test sessions, within each dose group, participants will be assigned to random sequences of 5 treatment conditions, including placebo (saline) and 4 different delivery rates of nicotine. In each session, participants will receive a total of 10 nicotine or saline-pulsed infusions, every 30 seconds. Concurrently with the pulsed infusions, participants will inhale tobacco-flavored EC, which will allow a closer matching of the sensory aspects of inhaled tobacco use. For the placebo test session, participants will receive 10 pulsed-saline infusions. In sum, this study represents an important step in demonstrating the potential utility of the rate of nicotine delivery as a benchmark for reducing the risks from ECs and other nicotine delivery products.