Effects of varenicline on sympatho-vagal balance and cue reactivity during smoking withdrawal: a randomised placebo-controlled trial
More details
Hide details
Department of Cardiology and Pneumology, University Medical Centre Göttingen, Göttingen, Germany
Department of Anaesthesiology, University Medical Centre Göttingen, Göttingen, Germany
Mannheim Biomedical Engineering Laboratories, Medical Faculty at Heidelberg University, Mannheim, Germany
Lung Clinic Immenhausen, Immenhausen, Germany
Health Behaviour Research Centre, University College London, London, UK
Submission date: 2015-10-19
Acceptance date: 2016-08-01
Publication date: 2016-08-08
Corresponding author
Tobias Raupach   

Department of Cardiology and Pneumology, University Medical Centre Göttingen, D-37099 Göttingen, Germany
Tobacco Induced Diseases 2016;14(August):26
Varenicline is an effective smoking cessation medication. Some concern has been raised that its use may precipitate adverse cardiovascular events although no patho-physiological mechanism potentially underlying such an effect has been reported. The aim of this study was to test the hypothesis that varenicline impacts on sympatho-vagal balance during smoking withdrawal.

In this randomised, placebo-controlled trial, muscle sympathetic nerve activity (MSNA), baroreflex sensitivity (BRS), heart rate, and blood pressure were assessed in 17 smokers four weeks before a quit attempt (baseline) and again on the third day of that quit attempt (acute smoking withdrawal).

Regarding the primary endpoint of our study, we did not find a significant effect of varenicline compared to placebo on changes in MSNA burst incidence between baseline and acute smoking withdrawal (−3.0 ± 3.3 vs.−3.9 ± 5.0 bursts/100 heart beats; p = 0.308). However, heart rate and systolic blood pressure significantly decreased in the placebo group only, while no significant changes in these parameters were observed in the varenicline group. Exposure to smoking cues during acute withdrawal lead to a significant increase of heart rate in the placebo group, while heart rate decreased in the varenicline group, and the difference in these changes was significant between groups (+2.7 ± 1.0 vs.−1.8 ± 0.5 1/min; p = 0.002). In all 17 participants combined, a significant increase in heart rate during smoking cue exposure was detected in subjects who relapsed in the course of six weeks after the quit date compared to those who stayed abstinent (+2.5 ± 1.2 vs.−1.1 ± 0.7; p = 0.018). Six-week abstinence rates were higher in the varenicline group compared to placebo (88 vs. 22 % p = 0.015).

We did not find evidence of adverse effects of varenicline on sympatho-vagal balance. Varenicline probably blunts the heart rate response to smoking cues, which may be linked to improved cessation outcome.

Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev. 2013;5, CD009329.
Rigotti NA, Pipe AL, Benowitz NL, Arteaga C, Garza D, Tonstad S. Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease: a randomized trial. Circulation. 2010;121:221–9.
Singh S, Loke YK, Spangler JG, Furberg CD. Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis. CMAJ. 2011;183:1359–66.
Triposkiadis F, Karayannis G, Giamouzis G, Skoularigis J, Louridas G, Butler J. The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications. J Am Coll Cardiol. 2009;54:1747–62.
Graham LN, Smith PA, Stoker JB, Mackintosh AF, Mary DA. Sympathetic neural hyperactivity and its normalization following unstable angina and acute myocardial infarction. Clin Sci. 2004;106:605–11.
Grassi G. Assessment of sympathetic cardiovascular drive in human hypertension: achievements and perspectives. Hypertension. 2009;54:690–7.
Hering D, Kucharska W, Kara T, Somers VK, Narkiewicz K. Smoking is associated with chronic sympathetic activation in hypertension. Blood Press. 2010;19:152–5.
Grassi G, Seravalle G, Quarti-Trevano F, Dell'oro R. Sympathetic activation in congestive heart failure: evidence, consequences and therapeutic implications. Curr Vasc Pharmacol. 2009;7:137–45.
Narkiewicz K, van de Borne PJ, Hausberg M, Cooley RL, Winniford MD, Davison DE, Somers VK. Cigarette smoking increases sympathetic outflow in humans. Circulation. 1998;98:528–34.
Dinas PC, Koutedakis Y, Flouris AD. Effects of active and passive tobacco cigarette smoking on heart rate variability. Int J Cardiol. 2013;163:109–15.
Barutcu I, Esen AM, Kaya D, Turkmen M, Karakaya O, Melek M, Esen OB, Basaran Y. Cigarette smoking and heart rate variability: dynamic influence of parasympathetic and sympathetic maneuvers. Ann Noninvasive Electrocardiol. 2005;10:324–9.
Ramakrishnan S, Bhatt K, Dubey AK, Roy A, Singh S, Naik N, Seth S, Bhargava B. Acute electrocardiographic changes during smoking: an observational study. BMJ Open. 2013;3.
Arosio E, De Marchi S, Rigoni A, Prior M, Lechi A. Effects of smoking on cardiopulmonary baroreceptor activation and peripheral vascular resistance. Eur J Clin Invest. 2006;36:320–5.
Munjal S, Koval T, Muhammad R, Jin Y, Demmel V, Roethig HJ, Mendes P, Unverdorben M. Heart rate variability increases with reductions in cigarette smoke exposure after 3 days. J Cardiovasc Pharmacol Ther. 2009;14:192–8.
Dols M, van den Hout M, Kindt M, Willems B. The urge to smoke depends on the expectation of smoking. Addiction. 2002;97:87–93.
Sayette MA, Wertz JM, Martin CS, Cohn JF, Perrott MA, Hobel J. Effects of smoking opportunity on cue-elicited urge: a facial coding analysis. Exp Clin Psychopharmacol. 2003;11:218–27.
Rollema H, Shrikhande A, Ward KM, Tingley 3rd FD, Coe JW, O'Neill BT, Tseng E, Wang EQ, Mather RJ, Hurst RS, Williams KE, de Vries M, Cremers T, Bertrand S, Bertrand D. Pre-clinical properties of the alpha4beta2 nicotinic acetylcholine receptor partial agonists varenicline, cytisine and dianicline translate to clinical efficacy for nicotine dependence. Br J Pharmacol. 2010;160:334–45.
Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO. The fagerstrom test for nicotine dependence: a revision of the fagerstrom tolerance questionnaire. Br J Addict. 1991;86:1119–27.
Raupach T, Shahab L, Neubert K, Felten D, Hasenfuss G, Andreas S. Implementing a hospital-based smoking cessation programme: evidence for a learning effect. Patient Educ Couns. 2008;70:199–204.
Gonzales D, Rennard SI, Nides M, Oncken C, Azoulay S, Billing CB, Watsky EJ, Gong J, Williams KE, Reeves KR. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA. 2006;296:47–55.
Hughes JR. Effects of abstinence from tobacco: valid symptoms and time course. Nicotine Tob Res. 2007;9:315–27.
Sundlof G, Wallin BG. The variability of muscle nerve sympathetic activity in resting recumbent man. J Physiol. 1977;272:383–97.
Parati G, Di Rienzo M, Bertinieri G, Pomidossi G, Casadei R, Groppelli A, Pedotti A, Zanchetti A, Mancia G. Evaluation of the baroreceptor-heart rate reflex by 24-hour intra-arterial blood pressure monitoring in humans. Hypertension. 1988;12:214–22.
Raupach T, Bahr F, Herrmann P, Luethje L, Heusser K, Hasenfuss G, Bernardi L, Andreas S. Slow breathing reduces sympathoexcitation in COPD. Eur Respir J. 2008;32:387–92.
Lucini D, Bertocchi F, Malliani A, Pagani M. Autonomic effects of nicotine patch administration in habitual cigarette smokers: a double-blind, placebo-controlled study using spectral analysis of RR interval and systolic arterial pressure variabilities. J Cardiovasc Pharmacol. 1998;31:714–20.
Harte CB, Meston CM. Effects of smoking cessation on heart rate variability among long-term male smokers. Int J Behav Med. 2014;21:302–9.
Minami J, Ishimitsu T, Matsuoka H. Effects of smoking cessation on blood pressure and heart rate variability in habitual smokers. Hypertension. 1999;33:586–90.
Hasenfratz M, Thut G, Battig K. Twenty-four-hour monitoring of heart rate, motor activity and smoking behavior including comparisons between smokers and nonsmokers. Psychopharmacology (Berl). 1992;106:39–44.
Su C, Bevan JA. Blockade of the nicotine-induced norepinephrine release by cocaine, phenoxybenzamine and desipramine. J Pharmacol Exp Ther. 1970;175:533–40.
Kruger C, Haunstetter A, Gerber S, Serf C, Kaufmann A, Kubler W, Haass M. Nicotine-induced exocytotic norepinephrine release in guinea-pig heart, human atrium and bovine adrenal chromaffin cells: modulation by single components of ischaemia. J Mol Cell Cardiol. 1995;27:1491–506.
Niaura R, Abrams DB, Monti PM, Pedraza M. Reactivity to high risk situations and smoking cessation outcome. J Subst Abuse. 1989;1:393–405.
Niaura R, Shadel WG, Abrams DB, Monti PM, Rohsenow DJ, Sirota A. Individual differences in cue reactivity among smokers trying to quit: effects of gender and cue type. Addict Behav. 1998;23:209–24.
Friese M, Hofmann W, Wiers RW. On taming horses and strengthening riders: Recent developments in research on interventions to improve self-control in health behaviors. Self Identity. 2011;10:336–51.
Yucha CB. Use of microneurography to evaluate sympathetic activity in hypertension: a brief review. Appl Psychophysiol Biofeedback. 2000;25:55–63.
Jennings GL. Noradrenaline spillover and microneurography measurements in patients with primary hypertension. J Hypertens Suppl. 1998;16:S35–8.
Eckberg DL. Sympathovagal balance: a critical appraisal. Circulation. 1997;96:3224–32.
Hagbarth KE. Microelectrode recordings from human peripheral nerves (microneurography). Muscle Nerve Suppl. 2002;11:S28–35.
West R, Hajek P, Stead L, Stapleton J. Outcome criteria in smoking cessation trials: proposal for a common standard. Addiction. 2005;100:299–303.
Erblich J, Bovbjerg DH, Sloan RP. Exposure to smoking cues: cardiovascular and autonomic effects. Addict Behav. 2011;36:737–42.
Svanstrom H, Pasternak B, Hviid A. Use of varenicline for smoking cessation and risk of serious cardiovascular events: nationwide cohort study. BMJ. 2012;345, e7176.
Prochaska JJ, Hilton JF. Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation: systematic review and meta-analysis. BMJ. 2012;344, e2856.
Mills EJ, Thorlund K, Eapen S, Wu P, Prochaska JJ. Cardiovascular events associated with smoking cessation pharmacotherapies: a network meta-analysis. Circulation. 2014;129:28–41.
Ware JH, Vetrovec GW, Miller AB, Van Tosh A, Gaffney M, Yunis C, Arteaga C, Borer JS. Cardiovascular safety of varenicline: patient-level meta-analysis of randomized, blinded, placebo-controlled trials. Am J Ther. 2013;20:235–46.
Cardiovascular injury induced by tobacco products: assessment of risk factors and biomarkers of harm. A Tobacco Centers of Regulatory Science compilation
Daniel Conklin, Suzaynn Schick, Michael Blaha, Alex Carll, Andrew DeFilippis, Peter Ganz, Michael Hall, Naomi Hamburg, Tim O’Toole, Lindsay Reynolds, Sanjay Srivastava, Aruni Bhatnagar
American Journal of Physiology-Heart and Circulatory Physiology
Decrease in Resting Heart Rate Measured Using Smartphone Apps to Verify Abstinence From Smoking: An Exploratory Study
Aleksandra Herbec, Ella Parker, Harveen Ubhi, Tobias Raupach, Robert West
Nicotine & Tobacco Research
Smoking cessation medicines and e-cigarettes: a systematic review, network meta-analysis and cost-effectiveness analysis
Kyla Thomas, Michael Dalili, José López-López, Edna Keeney, David Phillippo, Marcus Munafò, Matt Stevenson, Deborah Caldwell, Nicky Welton
Health Technology Assessment
Predictors of hemodynamic instability during and persistent after carotid artery stenting
Hongchen Zhao, Zigao Wang, Yifeng Ling, Yiting Mao, Qiang Dong, Wenjie Cao
Journal of Stroke and Cerebrovascular Diseases
Cue-reactivity targeted smoking cessation intervention in individuals with tobacco use disorder: a scoping review
Miaoling Luo, Quan Gan, Yu Fu, Zhuangfei Chen
Frontiers in Psychiatry
Journals System - logo
Scroll to top