Skip to main content
Log in

Adverse Effects and Tolerability of Medications for the Treatment of Tobacco Use and Dependence

Drugs Aims and scope Submit manuscript

Abstract

Tobacco use is the leading cause of preventable death and disability in the world. Although gradually declining in most developed countries, the prevalence of tobacco use has increased among developing countries. Treatment for tobacco use and dependence is effective, although long-term abstinence rates remain disappointingly low. In response, new treatments continue to be developed. In addition, many of the pharmacotherapies that have been available for years have found new applications with the use of medication combinations, higher doses and a longer duration of therapy for approved medications.

There are now seven medications (nicotine patch, nicotine gum, nicotine lozenge, nicotine inhaler, nicotine nasal spray, bupropion sustained release and varenicline) approved for tobacco dependence treatment in most countries, and many national and professional society practice guidelines recommend their use. Although each of the medications used for tobacco dependence treatment has been rigorously tested for efficacy and safety, broader experience in clinical trials and in observational population-based studies suggests that adverse events associated with these medications are relatively common. Since 2008, two of the medications (varenicline and bupropion) have come under increasing scrutiny because of reports of unexplained serious adverse events (SAEs), including behaviour change, depression, self-injurious thoughts and suicidal behaviour. To date, this association has not been shown to be caused by these medications, but concerns about medication safety continue. Prescribers require a working knowledge of the common adverse effects for all of these medications as well as a more detailed knowledge of the SAE potential.

Nicotine replacement therapy (NRT) has been rigorously tested in clinical trials for over 30 years. A number of adverse effects are commonly associated with NRT use, although SAEs are rare. The adverse effects associated with NRT are due to the pharmacological action of nicotine as well as the mode and site of the NRT application. Bupropion has been tested in over 40 controlled clinical trials and has been associated with higher rates of treatment discontinuation due to adverse events than NRTs. A number of SAEs are associated with bupropion and new warnings were recently added to bupropion prescribing information because of observed neuropsychiatric symptoms including suicidal thoughts and behaviours. Varenicline is the most recently approved medication for tobacco dependence treatment and, although proven safe in clinical testing, new safety concerns have arisen based on postmarketing reports. Warnings have been added to the prescribing information for varenicline because of neuropsychiatric symptoms also including suicidal thoughts and behaviours.

Informed decision making regarding the use of pharmacotherapy for the treatment of tobacco dependence requires knowledge about the risks of drug treatment that is weighed against the risks of continued tobacco use and the benefits of treatment. Over half of all long-term smokers will die of a tobaccorelated disease and the risk of a serious or life-threatening adverse event with tobacco cessation pharmacotherapy is vanishingly small. Pharmacotherapy for tobacco dependence is also among the most cost-effective preventive health interventions. Given these factors, the benefit: risk ratio is strongly in favour of pharmacotherapy for tobacco dependence treatment in virtually all smokers who are motivated to quit.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Table III
Table IV
Table V
Table VI

References

  1. Shafey O, Eriksen M, Ross H, et al. The tobacco atlas. 3rd ed. Atlanta (GA): American Cancer Society, 2009

    Google Scholar 

  2. Mokdad AH, Marks JS, Stroup DF, et al. Actual causes of death in the United States, 2000. JAMA 2004; 291: 1238–45

    Article  PubMed  Google Scholar 

  3. Centers for Disease Control and Prevention (CDC). Annual smoking-attributable mortality, years of potential life lost, and economic costs: United States, 1995–1999. MMWR Morb Mortal Wkly Rep 2002; 51(14): 300–3

    Google Scholar 

  4. Cancer facts and figures 2007. American Cancer Society, 2007 [online]. Available from URL: http://www.cancer.org [Accessed 2010 Feb 3]

  5. CDC. National health interview survey [online]. Available from URL: http://www.cdc.gov/nchs/data/nhis/earlyrelease/200912_08.pdf [Accessed 2010 Feb 11]

  6. Fiore MC, Jaén CR, Baker TB, et al. Treating tobacco use and dependence: 2008 update. Clinical practice guideline. Rockville (MD): U.S. Department of Health and Human Services, Public Health Service, 2008 May

  7. Schroeder SA. What to do with a patient who smokes. JAMA 2005 Jul 27; 294(4): 482–7

    Article  PubMed  CAS  Google Scholar 

  8. Lancaster T, Hajek P, Stead LF, et al. Prevention of relapse after quitting smoking: a systematic review of trials. Arch Intern Med 2006 Apr 24; 166(8): 828–35

    Article  PubMed  Google Scholar 

  9. Stead LF, Perera R, Bullen C, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 2008 Jan 23; (1): CD000146

  10. Food and Drug Administration. Postmarket drug safety information for patients and providers. Information for healthcare professionals: varenicline (marketed as Chantix) and bupropion (marketed as Zyban, Wellbutrin, and generics) [online]. Available from URL: http://www.fda.gov/ Drugs/DrugSafety/PostmarketDrugSafetyInformationfor PatientsandProviders/DrugSafetyInformationforHeathcare Professionals/ucm169986.htm [Accessed 2010 Sep 24]

  11. Food and Drug Administration. Public health advisory: important information on Chantix (varenicline) [online]. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInfor mationforHeathcareProfessionals/PublicHealthAdvisories/ucm051136.htm [Accessed 2010 Sep 24]

  12. Raw M, Regan S, Rigotti NA, et al. A survey of tobacco dependence treatment guidelines in 31 countries. Addiction 2009; 104: 1243–50

    Article  PubMed  Google Scholar 

  13. Zwar N, Richmond R, Borland R, et al. Smoking cessation pharmacotherapy: an update for health professionals. Melbourne (VIC): Royal Australian College of General Practitioners, 2007

    Google Scholar 

  14. West R, McNeill A, Raw M. Smoking cessation guidelines for health professionals: an update. Thorax 2000; 55: 987–99

    Article  PubMed  CAS  Google Scholar 

  15. Eisenberg MJ, Filion KB, Yavin D, et al. Pharmacotherapies for smoking cessation: a meta-analysis of randomized controlled trials. CMAJ 2008; 179: 135–44

    PubMed  Google Scholar 

  16. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 2007 Jan 24; (1): CD006103

  17. DiMatteo MR. Variations in patients’ adherence to medical recommendations: a quantitative review of 50 years of research. Med Care 2004; 42: 200–9

    Article  PubMed  Google Scholar 

  18. Rohsenow DJ, Colby SM, Monti PM, et al. Predictors of compliance with naltrexone among alcoholics. Alcohol Clin Exp Res 2000; 24(10): 1542–9

    Article  PubMed  CAS  Google Scholar 

  19. Burns EK, Levinson AH. Discontinuation of nicotine replacement therapy among smoking-cessation attempters. Am J Prev Med 2008; 34: 212–5

    Article  PubMed  Google Scholar 

  20. Vogt F, Hall S, Marteau TM. Understanding why smokers do not want to use nicotine dependence medications to stop smoking: qualitative and quantitative studies. Nicotine Tob Res 2008; 10(8): 1405–13

    Article  PubMed  Google Scholar 

  21. Mills EJ, Wu P, Lockhart I, et al. Adverse events associated with nicotine replacement therapy (NRT) for smoking cessation: a systematic review and meta-analysis of one hundred and twenty studies involving 177,390 individuals. Tob Induc Dis 2010; 8: 8

    Article  PubMed  Google Scholar 

  22. Tonnesen P, Paoletti P, Gustavsson G, et al. Higher dosage nicotine patches increase one-year smoking cessation rates: results from the European CEASE trial. Eur Resp J 1999; 13: 238–46

    Article  CAS  Google Scholar 

  23. Ossip DJ, Abrams SM, Mahoney MC, et al. Adverse effects of nicotine replacement therapy among quitline clients. Nicotine Tob Res 2009; 11: 408–17

    Article  PubMed  CAS  Google Scholar 

  24. Diagnostic and statistical manual of mental disorders, DSM-IV. 4th ed. Washington, DC: American Psychiatric Association, 1994

  25. Oncken C, Cooney J, Feinn R, et al. Transdermal nicotine for smoking cessation in postmenopausal women. Addict Behav 2007; 32: 296–309

    Article  PubMed  Google Scholar 

  26. Hughes JR, Lesmes GR, Hatsukami DK, et al. Are higher doses of nicotine replacement more effective for smoking cessation? Nicotine Tob Res 1999; 1: 169–74

    Article  PubMed  CAS  Google Scholar 

  27. Shiffman S, Dresler CM, Hajek P, et al. Efficacy of a nicotine lozenge for smoking cessation. Arch Intern Med 2002; 162: 1267–76

    Article  PubMed  CAS  Google Scholar 

  28. Schneider NG, Olmstead R, Mody FV, et al. Efficacy of a nicotine nasal spray in smoking cessation: a placebocontrolled, double-blind trial. Addiction 1995; 90: 1671–82

    Article  PubMed  CAS  Google Scholar 

  29. Sutherland G, Stapleton JA, Russell MAH, et al. Randomised controlled trial of nasal nicotine spray in smoking cessation. Lancet 1992; 340: 324–9

    Article  PubMed  CAS  Google Scholar 

  30. Hjalmarson AI, Franzon M, Westin A, et al. Effect of nicotine nasal spray on smoking cessation: a randomized, placebo-controlled, double-blind study. Arch Intern Med 1994; 154: 2567–72

    Article  PubMed  CAS  Google Scholar 

  31. Blondal T, Franzon M, Westin A. A double-blind randomized trial of nicotine nasal spray as an aid in smoking cessation. Eur Resp J 1997; 10: 1585–90

    Article  CAS  Google Scholar 

  32. Joseph AM, Norman SM, Ferry LH, et al. The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease. N Engl J Med 1996; 335: 1792–8

    Article  PubMed  CAS  Google Scholar 

  33. Joseph AM, Fu SS. Safety issues in pharmacotherapy for smoking cessation in patients with cardiovascular disease. Prog Cardiovasc Dis 2003; 45: 429–41

    Article  PubMed  CAS  Google Scholar 

  34. Areechon W, Punnotok J. Smoking cessation through the use of nicotine chewing gum: a double-blind trial in Thailand. Clin Ther 1988; 10(2): 183–6

    PubMed  CAS  Google Scholar 

  35. Fortmann SP, Killen JD, Telch MJ, et al. Minimal contact treatment for smoking cessation: a placebo controlled trial of nicotine polacrilex and self-directed relapse prevention: initial results of the Stanford Stop Smoking Project. JAMA 1988 Sep 16; 260(11): 1575–80

    Article  PubMed  CAS  Google Scholar 

  36. Harackiewicz JM, Blair LW, Sansone C, et al. Nicotine gum and self-help manuals in smoking cessation: an evaluation in a medical context. Addict Behav 1988; 13(4): 319–30

    Article  PubMed  CAS  Google Scholar 

  37. Schneider NG, Olmstead R, Nilsson F, et al. Efficacy of a nicotine inhaler in smoking cessation: a double-blind, placebocontrolled trial. Addiction 1996 Sep; 91(9): 1293–306

    Article  PubMed  CAS  Google Scholar 

  38. Glover ED, Glover PN, Franzon M, et al. A comparison of a nicotine sublingual tablet and placebo for smoking cessation. Nicotine Tob Res 2002 Nov; 4(4): 441–50

    Article  PubMed  CAS  Google Scholar 

  39. Shiffman S, Fergusin SG, Strahs KR. Quitting by smoking reduction using nicotine gum: a randomized controlled trial. Am J Prev Med 2009; 36: 96–104

    Article  PubMed  Google Scholar 

  40. McRobbie H, Hajek P, Gillison F. The relationship between smoking cessation and mouth ulcers. Nicotine Tob Res 2004 Aug; 6(4): 655–9

    Article  PubMed  Google Scholar 

  41. Lunell E, Molander L, Ekberg K, et al. Site of nicotine absorption from a vapour inhaler: comparison with cigarette smoking. Eur J Clin Pharmacol 2000; 55: 737–41

    Article  PubMed  CAS  Google Scholar 

  42. Hjalmarson A, Nilsson F, Sjostrom L, et al. The nicotine inhaler in smoking cessation. Arch Intern Med 1997; 157: 1721–8

    Article  PubMed  CAS  Google Scholar 

  43. Leischow SJ, Nilsson F, Franzon M, et al. Efficacy of the nicotine inhaler as an adjunct to smoking cessation. Am J Health Behav 1996; 20: 364–71

    Google Scholar 

  44. Tonnesen P, Norregaard J, Mikkelsen K, et al. A double-blind trial of a nicotine inhaler for smoking cessation. JAMA 1993; 269: 1268–71

    Article  PubMed  CAS  Google Scholar 

  45. Bende M, Burian P, Danielsson G P, et al. Evaluation of side effects after nicotine nasal spray in patients with chronic rhinitis. Rhinology 1998; 36: 98–100

    PubMed  CAS  Google Scholar 

  46. Greenland S, Satterfield MH, Lanes SF. A meta-analysis to assess the incidence of adverse effects associated with the transdermal nicotine patch. Drug Saf 1998; 18: 297–308

    Article  PubMed  CAS  Google Scholar 

  47. Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev 2007 Jan 24; (1): CD000031

  48. Johnston JA, Fiedler-Kelly J, Glover ED, et al. Relationship between drug exposure and the efficacy and safety of bupropion sustained release for smoking cessation. Nicotine Tob Res 2001; 3: 131–40

    Article  PubMed  CAS  Google Scholar 

  49. Hsyu PH, Singh A, Giargiari TD, et al. Pharmacokinetics of bupropion and its metabolites in cigarette smokers versus nonsmokers. J Clin Pharmacol 1997; 37: 737–43

    PubMed  CAS  Google Scholar 

  50. Davidson J. Seizures and bupropion: a review. J Clin Psychiatry 1989; 50: 256–61

    PubMed  CAS  Google Scholar 

  51. Johnston JA, Lineberry CG, Ascher JA, et al. A 102-center prospective study of seizure in association with bupropion. J Clin Psychiatry 1991; 52: 450–6

    PubMed  CAS  Google Scholar 

  52. Medicines Control Agency. Zyban safety update (080402. doc). London: Medicines Control Agency, Executive Agency of the Department of Health, 2002 Apr 11

  53. Peloso PM. Serum sickness-like reaction with bupropion [letter]. JAMA 1999; 282: 1817

    Article  PubMed  CAS  Google Scholar 

  54. Lineberry TW, Peters Jr GE, Bostwick JM. Bupropioninduced erythema multiforme. Mayo Clin Proc 2001; 76: 664–6

    PubMed  CAS  Google Scholar 

  55. US Food and Drug Administration. The smoking cessation aids varenicline (marketed as Chantix) and bupropion (marketed as Zyban and generics): suicidal ideation and behavior. FDA Safety Newsletter 2009; 2(1): 1–4

    Google Scholar 

  56. Boshier A, Wilton LV, Shakir SAW. Evaluation of the safety of bupropion (Zyban) for smoking cessation from experience gained in general practice use in England in 2000. Eur J Clin Pharmacol 2003; 59: 767–73

    Article  PubMed  CAS  Google Scholar 

  57. Hubbard R, Lewis S, West J, et al. Bupropion and the risk of sudden death: a self-controlled case-series analysis using The Health Improvement Network. Thorax 2005; 60: 848–50

    Article  PubMed  CAS  Google Scholar 

  58. Dobson R. Antismoking drug comes under scrutiny after deaths. BMJ 2001; 322: 452

    Article  PubMed  CAS  Google Scholar 

  59. Nides M, Oncken C, Gonzales D, et al. Smoking cessation with varenicline, a selective alpha4beta2 nicotinic receptor partial agonist: results from a 7-week, randomized, placebo-and bupropion-controlled trial with 1-year follow-up. Arch Intern Med 2006; 166: 1561–8

    Article  PubMed  Google Scholar 

  60. Oncken C, Gonzales D, Nides M, et al. Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist, varenicline, for smoking cessation. Arch Intern Med 2006; 166: 1571–7

    Article  PubMed  CAS  Google Scholar 

  61. Niaura R, Hays JT, Jorenby DE, et al. The efficacy and safety of varenicline for smoking cessation using a flexible dosing strategy in adult smokers: a randomized controlled trial. Curr Med Res Op 2008; 24: 1931–41

    Article  CAS  Google Scholar 

  62. Gonzales D, Rennard SI, Nides M, et al. 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

    Article  PubMed  CAS  Google Scholar 

  63. Jorenby DE, Hays JT, Rigotti NA, et al. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA 2006; 296: 56–63

    Article  PubMed  CAS  Google Scholar 

  64. Tonstad S, Tonnesen P, Hajek P, et al. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. JAMA 2006; 296: 64–71

    Article  PubMed  CAS  Google Scholar 

  65. Rigotti NA, Pipe AL, Benowitz NL, et al. Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease: a randomized trial. Circulation 2010; 121: 221–9

    Article  PubMed  CAS  Google Scholar 

  66. Tashkin DP, Rennard S, Hays JT, et al. Effects of varenicline on smoking cessation in mild-to-moderate COPD: a randomized controlled trial. Chest. Epub 2010 Sep 23

  67. Aubin HJ, Boback A, Britton JR, et al. Varenicline versus transdermal nicotine for smoking cessation: results from a randomized, open-label trial. Thorax 2008; 1: 1–8

    Google Scholar 

  68. Nakamura M, Oshima A, Fujimoto Y, et al. Efficacy and tolerability of varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, in a 12-week randomized, placebocontrolled, dose-response study with 40-week follow-up for smoking cessation in Japanese smokers. Clin Ther 2007; 29: 140–56

    Article  Google Scholar 

  69. Stapleton JA, Watson L, Spirling LI, et al. Varenicline in the routine treatment of tobacco dependence: a pre-post comparison with nicotine replacement therapy and an evaluation in those with mental illness. Addiction 2008; 103: 146–54

    Article  PubMed  Google Scholar 

  70. Tsai ST, Cho HJ, Cheng HS, et al. A randomized, placebocontrolled trial of varenicline, a selective a4b2 nicotinic acetylcholine receptor partial agonist, as a new therapy for smoking cessation in Asian smokers. Clin Ther 2007; 29: 1027–39

    Article  PubMed  CAS  Google Scholar 

  71. Gunnell D, Irvine D, Wise L, et al. Varenicline and suicidal behaviour: a cohort study based on data from the General Practice Research Database. BMJ 2009; 339: b3805

    Article  PubMed  CAS  Google Scholar 

  72. Russ C, Davies S, Flammer M, et al. Incidence of psychiatric adverse effects other than depression in randomized, double-blind, placebo-controlled varenicline clinical trials [poster]. 10th Annual Conference of the Society for Research on Nicotine and Tobacco-Europe; 2008 Sep 23–26; Rome

  73. Tonstad S, Davies S, Flammer M, et al. Incidence of depression in randomized, double-blind, placebo-controlled varenicline clinical trials [poster]. 10th Annual Conference of Society for Research on Nicotine and Tobacco-Europe; 2008 Sep 23–26; Rome

  74. Doll R, Peto R, Boreham J, et al. Mortality in relation to smoking: 50 years’ observations on male British doctors. BMJ 2004 Jun; 328: 1519–33

    Article  PubMed  Google Scholar 

  75. Kenfield SA, Stampfer MJ, Rosner BA, et al. Smoking and smoking cessation in relation to mortality in women. JAMA 2008; 299: 2037–47

    Article  PubMed  CAS  Google Scholar 

  76. Reimherr FW, Cunningham LA, Batey SR et al. A multicenter evaluation of the efficacy and safety of 150 and 300mg/d sustained-release bupropion tablets versus placebo in depressed outpatients. Clin Ther 1998; 20: 505–16

    Article  PubMed  CAS  Google Scholar 

  77. Evins AE, Mays VK, Rigotti NA, et al. A pilot trial of bupropion added to cognitive behavioral therapy for smoking cessation in schizophrenia. Nicotine Tob Res 2001; 3: 397–403

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

No funding was provided for the preparation of this review. The review represents the work of the authors, who had sole control over the collection of data, interpretation of data, preparation and approval of the manuscript. The authors have no relevant financial interests or other conflicts of interest to declare with regard to the contents of this review. All authors made substantial contributions to the preparation, review and final approval of the manuscript and meet criteria for authorship.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J. Taylor Hays.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hays, J.T., Ebbert, J.O. Adverse Effects and Tolerability of Medications for the Treatment of Tobacco Use and Dependence. Drugs 70, 2357–2372 (2010). https://doi.org/10.2165/11538190-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11538190-000000000-00000

Keywords

Navigation