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, norepinephrine, epinephrine, and physiologic reactivity were assessed. Doxazosin (4 and 8 mg/day vs placebo) decreased cigarettes per day during the 21-day titration period. Following titration, doxazosin (4 and 8 mg/day vs placebo) decreased tobacco craving. During the laboratory session, doxazosin (8 mg/day vs 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.

Keywords: Smoking; doxazosin; noradrenergic; smoking cessation; stress.

Figure 1

Timeline of study procedures to evaluate the effect of doxazosin on the ability to resist smoking and subsequent smoking self-administration.

Figure 2

Baseline differences collapsed across stress and neutral imagery conditions for mean (±SE) subjective tobacco craving ratings (a). Effect of medication (4 and 8 mg/day doxazosin vs. placebo) and imagery (stress vs. neutral) on change (pre- to post-imagery) in tobacco craving ratings during the smoking-lapse paradigm (b). NOTE: The post-imagery timepoint occurs prior to smoking. *Doxazosin significantly different vs. placebo; ^#4 mg/day doxazosin significantly different vs. 8 mg/day doxazosin.

Figure 3

Mean (± SE) latency to initiate smoking (min) by imagery condition (stress vs. neutral) by medication. *Doxazosin significantly different vs. placebo.

Figure 4

Mean (± SE) cigarettes smoked during the 60-minute ad-libitum smoking period during the smoking-lapse task. Doxazosin was collapsed across medication because 4 and 8 mg/day doxazosin did not differ by medication. *Doxazosin significantly different vs. placebo.

Figure 5

Effect of medication (4 and 8 mg/day doxazosin, placebo) and imagery (stress vs. neutral) on cortisol levels during the smoking-lapse paradigm. A-prori contrasts of change (pre- to post-imagery) demonstrated that cortisol levels differed by medication group by imagery condition (p < 0.05). NOTE: The post-imagery timepoint occurs prior to smoking. *Stress significantly different vs. neutral imagery in the 8 mg/day doxazosin group.

Figure 6

Effect of medication (4 and 8 mg/day doxazosin vs. placebo) and imagery (stress vs. neutral) on change (pre- to post-imagery) in epinephrine plasma levels (ng/ml) during the smoking-lapse paradigm (b). NOTE: The post-imagery timepoint occurs prior to smoking. *Stress significantly different vs. neutral imagery in the 8 mg/day doxazosin group.

Figure 7

Effect of medication (doxazosin vs. placebo) on change (pre- to post-imagery) in systolic blood pressure (a), mean (±SE) diastolic blood pressure (mmHg) by imagery condition (stress vs. neutral) by medication (b), mean (±SE) heart rate (bpm) by medication (c) during the smoking-lapse paradigm. Doxazosin was collapsed across medication for systolic blood pressure and heart rate because 4 and 8 mg/day doxazosin did not differ by medication. *Doxazosin significantly different vs. placebo.

Figure 7

Effect of medication (doxazosin vs. placebo) on change (pre- to post-imagery) in systolic blood pressure (a), mean (±SE) diastolic blood pressure (mmHg) by imagery condition (stress vs. neutral) by medication (b), mean (±SE) heart rate (bpm) by medication (c) during the smoking-lapse paradigm. Doxazosin was collapsed across medication for systolic blood pressure and heart rate because 4 and 8 mg/day doxazosin did not differ by medication. *Doxazosin significantly different vs. placebo.