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. 2017 Jul;31(7):830-840.
doi: 10.1177/0269881117699603. Epub 2017 Apr 25.

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

Terril L Verplaetse  1 , Andrea H Weinberger  2   3 , Lindsay M Oberleitner  1 , Kathryn Mz Smith  4 , Brian P Pittman  1 , Julia M Shi  5 , Jeanette M Tetrault  5 , Meaghan E Lavery  1 , Marina R Picciotto  1 , Sherry A McKee  1
Affiliations

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

Terril L Verplaetse et al. J Psychopharmacol. 2017 Jul.

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.

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Conflict of interest statement

DECLARATION OF CONFLICTING INTERESTS

Sherry A. McKee has consulted to Cerecor and Embera, has received research support for investigator-initiated studies from Pfizer, Inc. and Cerecor, and has ownership in Lumme, Inc. All other authors declare that there is no conflict of interest.

Figures

Figure 1
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
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
Figure 3
Mean (± SE) latency to initiate smoking (min) by imagery condition (stress vs. neutral) by medication. *Doxazosin significantly different vs. placebo.
Figure 4
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
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
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
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
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.
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