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

摘要 虽然剂量和递送速度都会影响药物滥用的可能性，但烟草控制 战略主要侧重于高滥用烟草产品提供的尼古丁总量 潜在的-如香烟和电子香烟（EC）。此外，系统的人类研究检查了 尼古丁剂量和释放速率对滥用的个体效应和交互效应之间的关系 潜力缺乏。同样，也不知道尼古丁的剂量和输送速率是否会影响其潜在的 有益效果（即，缓解吸烟欲望和戒断）及其滥用的可能性。 这种知识差距部分是由于无法通过实验控制尼古丁的输送速率， 吸入的烟草制品。在一项使用静脉（IV）尼古丁输注的初步研究中， 控制递送速率-我们发现，1 mg/70 kg尼古丁，即通过 吸烟，静脉输注超过1分钟，产生更大的积极主观影响-表明更大的 滥用可能性-与在5或10分钟内提供相同数量的尼古丁相比。相比之下，两者 1分钟和5分钟的分娩率在减少吸烟欲望方面同样有效。这些发现 支持递送速率对尼古丁滥用潜力的影响大于其对抑制尼古丁滥用潜力的影响。 吸烟的欲望-支持交付率的作用，以告知监管科学和减少危害 烟草使用。尽管如此，与烟草香烟或EC提供的喷烟大小的尼古丁递送不同，我们的初步研究 受到尼古丁持续注入的限制因此，为了提高我们设计的生态有效性，我们 进一步完善了我们的IV尼古丁输注程序，通过开发脉冲尼古丁输注作为模型， 尼古丁通过吸入烟草产品如EC释放。利用这个程序，我们试图系统地检查 尼古丁剂量和递送速率对滥用风险的影响-通过阳性测量评估 主观效果和强化-与潜在的有益效果-通过吸烟措施评估 冲动和戒断症状。我们提出了一项双盲，安慰剂对照研究，采用混合 设计：尼古丁剂量为受试者间因素，给药速率为受试者内因素。70个吸烟者 将随机分配至0.2 mg/70 kg或1 mg/70 kg尼古丁剂量组。在5个测试会话中， 每个剂量组，受试者将被分配至5种治疗条件的随机序列，包括 安慰剂（盐水）和4种不同的尼古丁递送速率。在每节课中，参加者将获得10个 尼古丁或生理盐水脉冲输注，每30秒一次。与脉冲输注同时，参与者将 吸入烟草味的EC，这将允许吸入烟草使用的感官方面更接近匹配。 对于安慰剂试验阶段，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 这是证明尼古丁输送速率作为基准的潜在效用的重要一步， 降低EC和其他尼古丁输送产品的风险。

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.