Effect of doxazosin on stress reactivity and the ability to resist smoking

Abstract

Preclinical findings support a role for α1-adrenergic antagonists in reducing nicotine motivated behaviors, but these findings have yet to be translated to humans. The current study evaluated whether doxazosin would attenuate stress-precipitated smoking in the human laboratory. Using a well-validated laboratory analogue of smoking-lapse behavior, this pilot study evaluated whether doxazosin (4 and 8 mg/day) versus placebo attenuated the effect of stress (vs. neutral imagery) on tobacco craving, the ability to resist smoking and subsequent ad-libitum smoking in nicotine-deprived smokers (n=35). Cortisol, adrenocorticotropin (ACTH), norepinephrine, epinephrine, and physiologic reactivity were assessed. Doxazosin (4 and 8 mg/day versus placebo) decreased cigarettes per day during the 21-day titration period. Following titration, doxazosin (4 and 8 mg/day versus placebo) decreased tobacco craving. During the laboratory session, doxazosin (8 mg/day versus placebo) further decreased tobacco craving following stress versus neutral imagery. Doxazosin increased the latency to start smoking following stress, and reduced the number of cigarettes smoked. Dosage of 8 mg/day doxazosin increased or normalized cortisol levels following stress imagery and decreased cortisol levels following neutral imagery. These preliminary findings support a role for the noradrenergic system in stress-precipitated smoking behavior, and support further development of doxazosin as a novel pharmacotherapeutic treatment strategy for smoking cessation.

A preliminary investigation into the effects of doxazosin on cognitive functioning in tobacco‐deprived and ‐satiated smokers

“…This effect was most evident among participants receiving 4-mg/day doxazosin-those receiving 8 mg/day reported an increase in withdrawal symptoms during deprivation. As reported in the parent study and in prior investigations (Stoschitzky et al, 2003;Verplaetse et al, 2017), doxazosin increases heart rate, suggesting that the drug may paradoxically have sympathomimetic effects under certain circumstances. These effects may have strengthened at higher doses, potentially offsetting the beneficial effects of the drug on withdrawal symptoms.…”

“…Participants attended a premedication baseline assessment session and two laboratory testing sessions, including a nondeprivation session and a deprivation session. Adverse event and other methodological details not pertinent to the current report are described in the parent publication (Verplaetse et al, ).…”

The protective role of emotional intelligence in smoking relapse during a 12-month follow-up smoking cessation intervention

“…Further prospective experimental studies manipulating EI abilities and stress reactivity are needed to confirm the causal inferences of our findings. In this regard, there are a set of human laboratory studies that have investigated smoking relapse behaviour through the manipulation of the stress response by medication and imagery inductions [49,50]. For example, Verplaetse et al [50] showed that a pharmacotherapeutic treatment aimed at attenuating the effect of stress by the use of doxazosin (α1-adrenergic antagonist) improved the ability to resist cravings and begin smoking.…”

“…In this regard, there are a set of human laboratory studies that have investigated smoking relapse behaviour through the manipulation of the stress response by medication and imagery inductions [49,50]. For example, Verplaetse et al [50] showed that a pharmacotherapeutic treatment aimed at attenuating the effect of stress by the use of doxazosin (α1-adrenergic antagonist) improved the ability to resist cravings and begin smoking. The evaluation or training of EI abilities in experimental studies could be a very informative step forward for understanding the mechanisms by which EI could influence smoking relapse.…”

Stress Allostasis in Substance Use Disorder: Promise, Progress, and Emerging Priorities

“…With respect to NE α1 antagonists, three small phase II trials (N = 17-35) provided preliminary support for positive impacts on stress-relevant surrogate end points and short-term clinical outcomes for prazosin in AUD (Fox et al 2012a, Simpson et al 2009 and for doxazosin in tobacco smokers (Verplaetse et al 2017). However, a fourth small trial (N = 41) observed no effect of doxazosin on its primary clinical outcomes in patients with AUD (Kenna et al 2016).…”