Safety of smoking cessation
medications
Last updated March 2011

Safety section
Chair
Neal Benowitz
Carolyn Dresler
Steve S Hecht
John Hughes
Anne M Joseph
Jacques Le Houezec
Cheryl Oncken
Maxine Stitzer
Last updated March 2011
University of California San Francisco,
USA
Arkansas Department of Health, USA
University of Minnesota, USA
University of Vermont, USA
Minneapolis VA Medical Center, USA
Freelance consultant (France),
and University of Nottingham, UK
University of Conneticut, USA
Johns Hopkins University, USA

Nicotine vs. tobacco smoke
• The main adverse effect of nicotine from tobacco is
addiction, which sustains tobacco use1-2
• Other toxicants in tobacco smoke, not nicotine, are
responsible for majority of adverse health effects3,4
– > 4000 different chemicals
– tar, carbon monoxide, irritant and oxidant gases
– > 80 carcinogens (11 are group 1 carcinogens)5
• Nicotine dependence leads to continued exposure to
toxicants in tobacco smoke
1 USDHHS. The Health Consequences of Smoking: Nicotine Addition. 1988.
2 Royal College of Physicians. London: 2008.
3 Benowitrz. In Nicotine Safety and Toxicity; pp 185–195 NY: OUP.
4 Hoffman and Hoffman. J Toxicol Environ Health 1997; 50: 307–64.
5 Smith et al. Food Chem Toxicol 2003; 41: 807–817.
Last updated March 2011

Nicotine and cancer
• Nicotine per se is not a substantial cause of cancer1-2
• Any cancer-related risks from short-term NRT are
insignificant compared to the risks of smoking
• Other tobacco smoke constituents are believed to be
responsible for cancers3,4
1 US Department of Health and Human Services, Bethesda, MD, 2001.
2 Surgeon General's report 2010
3 Hoffman and Hecht. IN Handbook of Experimental Pharmacolgy, pp 63–102; 1990 Heidelberg: Springer-Verlag
4 Hecht. J Natl Cancer Inst. 1999; 91: 1194–1210.
Last updated March 2011

Nicotine and cancer
• Studies carried out in rodents demonstrate that under normal
conditions nicotine is not carcinogenic1
• Carcinogenic, nicotine-derived nitrosamines may be formed in the
body under certain conditions2–4
– levels would be low and represent minimal risk during short term NRT
– further research required to establish any risk associated with long
term use of NRT
• Nicotine can inhibit apoptosis (cell death) and enhance
angiogenesis in cell and experimental animal test systems5-9
• This could in theory promote the spread of cancers. However this
risk has not been documented in people
1 US Department of Health and Human Services, Bethesda, MD, 2001.
2 Benowitz et al. J Pharmacol Exp Ther 1994; 268: 296–303.
3 Hecht et al. Proc Natl Acad Sci USA. 2000; 97: 12493-12497.
4 Carmella et al. Carcinogenesis 1997; 18: 101–106.
Last updated March 2011
5 Porubin et al. J Agric Food Chem, 2007; 55: 7199-7204.
6 Stepanov et al. Cancer Res. 2009; 69: 8236-8240.
7 Cooke. Life Sci, 2007; 80: 2347-2351.
8 West et al. J Clin Invest, 2003; 111: 81-90.
9 Dasgupta et al. Proc Natl Acad Sci USA, 2006; 103: 6332-6337.

Smoking and cardiovascular disease
• Smoking increases risk of CVD
• Smoking-related factors contributing to CV risk:
–
–
–
–
increased thrombogenesis
carbon monoxide
oxidative damage
hyperlipidaemia
• Smoking cessation significantly reduces risk within 1–3
years1-2
• Smoking cessation using NRT has a favourable effect on
these contributing factors3
1 Rosenberg et al. N Engl J Med. 1990; 322: 213–217.
2 Rosenberg et al. N Engl J Med. 1985; 313: 1511–1514.
3 Ludviksdottir et al. J Intern Med. 1999; 246: 61–66.
Last updated March 2011

NRT and cardiovascular disease
• NRT can be used safely by majority of people with
cardiovascular disease, even with concomitant smoking1–
3
• Meta-analyses show no difference in rate of acute MI
between NRT patch and placebo4-6
– N.B. majority of studies excluded patients with CVD at baseline
• The benefits of NRT outweigh the risks, even in smokers
with cardiovascular disease7–9
1 Joseph et al. N Engl J Med. 1996; 335:1792–1798.
2 Tzivoni et al. Cardiovasc Drugs Ther. 1998; 12:239–244.
3 Working Group. Arch Intern Med. 1994; 154:989–995.
4 Greenland et al. Drug Saf. 1998; 18: 297–308.
Last updated March 2011
5 Mills et al. Tob Induc Dis. 2010; 8: 8.
6 Hays & Ebbert. Drugs. 2010; 70: 2357-2372.
7 Benowitz. Prog Cardiovasc Dis. 2003; 46: 91-111.
8 Joseph & Fu. Prog Cardiovasc Dis. 2003; 45: 429-441.
9 Hubbard et al. Tob Control. 2005; 14: 416–21.

Smoking, NRT and pregnancy
• Maternal smoking is associated with poor pregnancy and
childhood outcomes1–5
• Many toxicants in tobacco smoke could be responsible
• Nicotine is a potential foetal teratogen
• Nicotine may contribute to obstetrical complications in pregnant
women and to sudden infant death syndrome6,7
• Benefits of NRT outweigh the risks of smoking during
pregnancy8
– reduce or eliminate the exposure of fetus to other toxicants
in tobacco smoke
– reduce overall dose and duration of exposure to nicotine
1 USDHHS. Surgeon General's Report. 2001.
2 Steyn et al. Paediatr Perinat Epidemiol. 2006; 20: 90-99.
3 Fried et al. Neurotoxicol Teratol. 1998; 20: 293-306.
4 Jacobsen et al. Neuropsychopharmacology. 2007; 32: 2453-2464.
Last updated March 2011
5 Romano et al. Pediatrics, 2006; 117: 2101-2110.
6 Slotkin et al.. Brain Res Bull. 1995; 38: 69-75.
7 Slotkin et al. Neuropsychopharmacology. 2006; 31: 2462-2475.
8 Benowitz & Dempsey. Nicotine Tob Res. 2004; 6 Suppl 2: S189-202.

Nicotine replacement therapy
• NRT delivers nicotine without the toxicants from tobacco1
• NRT helps combat the symptoms of withdrawal2
• Nicotine dose from NRT is lower and administered more
gradually than with smoking and this reduces the
addictive potential1,3
1 Benowitz & Gourlay. J Am Coll Cardiol. 1997; 29: 1422-1431.
2 Silagy et al. Cochrane Database Syst Rev. 2004; (3): CD000146.
3 Le Houezec. Int J Tuberc Lung Dis. 2003; 7: 811-819.
Last updated March 2011

Plasma nicotine levels (smoking and NRT)
Increase in nicotine concentration
( ng/ml )
14
12
10
8
Cigarette
Gum 4 mg
6
Gum 2 mg
4
Inhaler
Nasal spray
Patch
2
0
5
10
15
20
25
30
Source: Balfour DJ & Fagerström KO. Pharmacol Ther. 1996; 72: 51-81.
Last updated March 2011

Minutes
Abuse liability of NRT
• Prevalence of abuse and dependence with current NRT
products is nil (patch) or very low (<10% gum, nasal
spray, inhaler)1
• Likely to be greatest with products that deliver nicotine
rapidly, but less than that of cigarettes2–4
• Even if dependence develops, there is likely to be overall
health benefit if individual no longer smokes
1 West et al. Psychopharmacology. 2000; 149: 198-202.
2 Stitzer & de Wit. In: Benowitz, NL. Nicotine Safety and Toxicity. pp. 1998 119-131 New York, Oxford University Press.
3 Henningfield & Keenan. J Consult Clin Psychol. 1993; 61: 743-750.
4 Hughes. In Nicotine Safety and Toxicity, 1998; pp. 147-157. New York: OUP
Last updated March 2011

Safety of Bupropion
• Bupropion is generally well tolerated by smokers
• The benefits of buproprion to aid smoking cessation
outweigh the risks of buproprion in most smokers1–3
• Clinical trials of bupropion in smokers with
cardiovascular disease found no significant adverse
cardiovascular side effects4-5
• Data on safety in pregnancy are inconclusive
• Bupropion appears not to have significant abuse
liability6–9
1 Hurt et al. N Engl J Med. 1997; 337: 1195-1202.
2 Jorenby et al. N Engl J Med. 1999; 340: 685-691.
3 Cox et al. J Gen Intern Med. 2004; 19: 828-834.
4 Joseph & Fu. Prog Cardiovasc Dis. 2003; 45: 429-441.
5 Tonstad et al. Eur Heart J. 2003; 24: 946-955.
Last updated March 2011
6 Peck et al. Br J Clin Pharmacol. 1979; 7: 469-78.
7 Miller & Griffith. Psychopharmacology. 1983; 80: 199-205.
8 Margolin et al. Drug Alcohol Depend. 1995; 40: 125-31.
9 Rush et al. Exp and Clin Psychopharmacol. 1998; 6: 32-44.

Safety of Varenicline
• Varenicline is generally well tolerated by smokers1-3
• The most common side effect is nausea (30-40%),
sometimes with vomiting4-6
• Varenicline is licensed for all smokers 18, except those
with severe renal impairment, pregnant or breastfeeding
smokers
• Warnings have been issued after a number of reports of
psychiatric disturbances, including suicide in smokers
taking varenicline, but not observed in studies7-8
1 Williams et al. Curr Med Res Opin. 2007; 23: 793-801.
2 Cahill et al. Cochrane Database Syst Rev. 2011; (2): CD006103.
3 Stapleton et al. Addiction. 2008; 103: 146-54.
4 Gonzales et al. JAMA. 2006; 296: 47-55.
Last updated March 2011
5 Jorenby et al. JAMA. 2006; 296: 56-63. Erratum in: JAMA, 2006; 296: 1355.
6 Tonstad et al. JAMA. 2006; 296: 64-71.
7 Gunnell et al. BMJ. 2009; 339: b3805.
8 Stapleton et al. Addiction. 2008; 103: 146-154.

Safety of other medications
• Nortriptyline, moclobemide and clonidine have been
found in smoking cessation trials in healthy smokers to
be safe in doses approved for the treatment of
depression/hypertension1-5
• Not approved by regulatory authorities for such use
• All of these drugs are associated with severe toxicities in
overdose
1 Hughes et al. Cochrane Database Syst Rev. 2007; (1): CD000031.
2 Hughes et al. Nicotine Tob Res. 2005; 7: 491-499.
3 Berlin et al. Clin Pharmacol Ther. 1995; 58: 444-452.
4 Gourlay et al. Cochrane Database Syst Rev. 2004; (3): CD000058.
5 Fiore. Respir Care. 2000; 45: 1200-1262.
Last updated March 2011

Concomitant smoking
• Concomitant use of NRT, bupropion or varenicline and
smoking is well tolerated1–7
• Number of cigarettes smoked is likely to be less than at
baseline
• This might result in reduced health hazards
• Such benefit has yet to be scientifically demonstrated
• NRT-assisted reduction does increase later quitting8-12
1 Benowitz et al. J Pharmacol Exp Ther. 1998; 287: 958-962
2 Bjornson-Benson et al. Addict Behav. 1993; 18: 491-502.
3 Hurt et al. N Engl J Med. 1997; 337: 1195-202.
4 Jorenby et al. N Engl J Med. 1999; 340: 685-91.
5 Zevin et al. Clin Pharmacol Ther. 1998; 64: 87-96.
6 Gonzales et al. JAMA. 2006; 296: 47-55.
Last updated March 2011
7 Jorenby et al. JAMA. 2006; 296: 56-63.
8 Bolliger et al. BMJ. 2000; 321: 329-333.
9 Wennike et al. Addiction. 2003; 98: 1395-1402.
10 Batra et al. Clin Pharmacol Ther. 2005; 78: 689-696.
11 Rennard et al. Nicotine Tob Res. 2006; 8: 555-564.
12 Kralikova et al. BMC Public Health. 2009; 9: 433.

‘Reduced risk’ cigarettes
• Includes low tar and ‘light’ cigarettes, and novel products that deliver
nicotine with minimal tobacco combustion
• Low tar cigarettes have not be shown to substantially reduce health
hazards of smoking but do provide sufficient nicotine to sustain
addiction1-6
• Some novel products may deliver fewer or lower levels of toxicants
but some deliver more carbon monoxide. Not shown to reduce risk
of smoking or aid cessation7-9
• Smoking cessation medications are most likely safer than any
‘reduced risk’ cigarette
1 NCI Monograph 13. 2001.
2 NCI Monograph 7. 1996.
3 Hecht et al. Cancer Epidemiol Biomarkers Prev. 2005; 14: 693-698.
Erratum in: Cancer Epidemiol Biomarkers Prev. 2006; 15: 1568.
4 Benowitz et al. Cancer Epidemiol Biomarkers Prev. 2005;
14: 1376-1383.
Last updated March 2011
5 Bernert et al. Nicotine Tob Res. 2005; 7: 729-738.
6 Blackford et al. Cancer Epidemiol Biomarkers Prev. 2006; 15: 1799-1804.
7 Fagerström et al. Tob Control. 2000; 9: 327-333.
8 Pauly et al. Cancer Epidemiol Biomarkers Prev. 1998; 7: 967-979.
9 Buchhalter & Eissenberg. Nicotine Tob Res. 2000; 2: 39-43.

Electronic Nicotine Delivery Devices
• Electronic Nicotine Delivery Devices are basically
oropharyngeal nicotine delivery devices
• Systemic dose of nicotine obtained with ENDD is relatively
small, but amount of nicotine in the cartridge is substantial
(up to 16-18 mg)1
• Small amounts of contaminants (e.g. TSNA) found in some
products which raise health concerns2
• some case reports, surveys and small studies seem to
indicate that it may help smokers to quit smoking3-6
• Standardisation of products (regulatory oversight) and
clinical and non-clinical studies are needed2
1 Bullen et al. Tob Control. 2010; 19: 98-103.
2 Etter et al. Tob Control. 2011; 20: 243-248.
3 Etter. BMC Public Health. 2010; 10: 231.
19: 1945-1953.
Last updated March 2011
4 Siegel et al. Am J Prev Med. 2011; 40: 472-475.
5 Trtchounian et al. Nicotine Tob Res. 2010; 12: 905-912.
6 Vansickel et al. Cancer Epidemiol Biomarkers Prev. 2010;

Smokeless tobacco
• Snuff or chewing tobacco has been suggested as a
potential aid to harm reduction or smoking cessation1
• However, such products known to cause oral cancer2–3
• Country variation in composition may mean toxicity of
smokeless tobacco products varies4–7
• Smokeless tobacco is addictive and not recommended for
smoking cessation
• Safety and efficacy of NRT, bupropion, and varenicline are
better demonstrated
1 Radical strategies for prevention and harm reduction in nicotine addiction. Royal College of Physicians; 2008.
2 International Agency for Research on Cancer. IARC Monographs Vol. 89. Smokeless Tobacco and Some Tobacco-specific N-Nitrosamines. 2007.
3 US Surgeon General. Public Health Service, Bethesda, MD, NIH Publ. No. 86-2874, 1986
4 Hecht. Chem Res Toxicol. 1998; 11: 559-603.
5 Hoffmann et al. J Natl Cancer Inst. 1995; 87: 1832-1869.
6 Osterdahl. International Agency for Research on Cancer Scientific Publications 105, 235-237, 1991.
7 Stepanov et al. Nicotine Tob Res. 2008; 10: 1773-1782.
Last updated March 2011

Long-term pharmacotherapy
• Goal of long-term pharmacotherapy is to replace
smoking1-3
• Long-term use of NRT, bupropion or varenicline is likely
to be much safer than smoking but efficacy has not yet
been demonstrated4-7
• Experience with long term buproprion use for depression
suggests it is well tolerated6
• Evidence of a persistent health risk, even with prolonged
reduction of cigarette consumption8
1 Anderson & Hughes. Addiction. 2000; 95 Suppl 1: S9-11.
2 IOM report. Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction. Washington DC, 2001.
3 Radical strategies for prevention and harm reduction in nicotine addiction. Royal College of Physicians; 2008.
4 Stead & Lancaster. Cochrane Database Syst Rev. 2007; (3): CD005231.
5 Murray et al. Chest. 1996; 109: 438-445.
6 Cox et al. J Gen Intern Med. 2004; 19: 828-834.
7 Tonstad et al. JAMA. 2006; 296: 64-71.
8 Godtfredsen et al. J Epidemiol Community Health. 2003; 57: 412-416.
Last updated March 2011

Safety in adolescents
• Many adolescents are addicted to nicotine1
• Little reason to believe that any risk associated with NRT,
bupropion or varenicline is greater in adolescents who
smoke than in adults who smoke
• Efficacy of NRT and bupropion in adolescents is
unclear2-10
• Efficacy of varenicline in adolescents has not been
studied
1 USDHHS. A Report of the Surgeon General. 1994.
2 Colby & Gwaltney. JAMA. 2007; 298: 2182-2184.
3 Hanson et al. Nicotine Tob Res. 2003; 5: 515-526.
4 Hanson et al. Drug Alcohol Depend. 2008; 95: 164-168.
5 Killen et al. J Consult Clin Psychol. 2004; 72: 729-735.
Last updated March 2011
6 Monuteaux et al. J Clin Psychiatry. 2007; 68: 1094-1101.
7 Moolchan et al. Pediatrics. 2005; 115: e407-e414.
8 Muramoto et al. Arch Pediatr Adolesc Med. 2007; 161: 1068-1074.
9 Roddy et al. Tob Control. 2006; 15: 373-376.
10 Upadhyaya et al. J Am Acad Child Adolesc Psychiatry. 2004; 43: 199-205.

Recommendations
• All smokers, even those with cardiovascular disease,
should be offered nicotine replacement therapy,
bupropion or varenicline to aid cessation.
• Pregnant smokers should be encouraged to attempt
cessation using educational and behavioral interventions
before using pharmacological approaches. If such quit
attempts are unsuccessful, the risks and benefits of
pharmacotherapy should be considered and explained to
the woman. The decision to use pharmacotherapy
should be made on an individualized basis after
discussion between the woman and her physician.
Last updated March 2011

Areas for further research
• Safety of nicotine and other medications to aid smoking cessation in
pregnant smokers, including impact on the health and development
of newborns of mothers who received medication during pregnancy.
• Preclincal and clinical studies on the role of nicotine vs other
toxicants in the onset of SIDS.
• Safety of bupropion in high risk groups (pregnancy, alcohol abuse,
history of stroke or other brain injury).
• Safety of varenicline in high risk groups (psychiatric disease,
cardiovascular disease, alcohol and drug abuse, pregnancy)
• Safety of nicotine and other medications to aid smoking cessation in
adolescents.
• Beneficial and harmful health effects of novel nicotine delivery
devices, including their potential for use to initiate smoking (in
adolescents), to increase overall nicotine intake via concurrent use
with cigarettes, and potential adverse effects on smoking cessation
(i.e. switching instead of quitting).
Last updated March 2011

Areas for further research
• Development of biomarkers of exposure and surrogate markers of
health effects of tobacco and related products.
• Safety of long term nicotine replacement or other medication as
would be used to reduce cigarette smoking or maintain tobacco
abstinence.
• Safety and efficacy of oral tobacco products (e.g. snus) for smoking
cessation, for harm reduction or for withdrawal relief during
temporary abstinence.
• Does use of novel tobacco products or oral tobacco products for
non-cessation reasons undermine motivation to quit?
• More rigorous studies of the association of varenicline with
psychiatric disorders, including prospective studies.
• Better epidemiological studies of the association of smoking
reduction and reduced risk of smoking.
Last updated March 2011
