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The use of medications, including nicotine replacement therapy, bupropion and varenicline, is safe even when used by individuals who are still smoking cigarettes. Concomitant use of nicotine replacement therapy and bupropion or nortriptyline is generally well-tolerated.

Nicotine replacement therapy (NRT), bupropion, and varenicline have been used to reduce smoking to either prompt or prepare smokers for quitting or to decrease the health risks of smoking. NRT aids reduction (Hughes & Carpenter, 2005) and NRT-assisted reduction does increase later quitting (Batra et al., 2005; Bolliger et al., 2000; Hughes & Carpenter, 2006; Kralikova et al., 2009; Rennard et al., 2006; Wennike et al., 2003). In addition, several NRTs are currently registered in several countries to help smokers quit gradually. Whether NRT-assisted reduction in the absence of cessation decreases health risks is unclear (Bolliger et al., 2002; Hatsukami et al., 2005; Hughes & Carpenter, 2006). The efficacy of bupropion or varenicline to reduce smoking is unclear. 

Typically, use of NRT to reduce smoking does not increase nicotine levels; although a minority of smokers who use NRT for this do have higher than usual nicotine levels (Fagerström & Hughes, 2002). Despite this, adverse events from concurrent use of NRT and smoking do not appear to be higher than that when NRT is used alone.

For example, many participants in the Lung Health Study continued smoking while using nicotine gum (despite instructions not to use them concurrently) and reduced their baseline rate of smoking by 75% at 4 months, 33% at 8 months, and over 50% at 12 months. No increased risk of cardiovascular or other morbidity or mortality effects were observed in smokers who continued to smoke and use nicotine gum on a daily basis, over a five-year period (Murray et al., 1996).

In 1985, five unpublished case reports of myocardial infarctions (MI) among smokers with cardiac problems who used the patch and smoked at the same time led the Food and Drug Administration (FDA) to review these cases shortly after they were reported (US FDA, 1992). The FDA noted that heavy smokers with pre-existing cardiac problems frequently have MI when they are not using NRT, and concluded that the occurrence rate of MI in these cases was no greater than the expected rate in a population of middle-aged smokers.

In clinical trials of nicotine patch treatment for patients with known cardiovascular disease, many subjects continued to smoke while using NRT. Three such trials showed no difference in adverse events, including the occurrence of angina, arrhythmias, ischemic episodes, overall cardiac symptoms, worsening cardiac function or death, comparing nicotine- and placebo-treated smokers (Tzivoni et al., 1998; Working Group, 1994; Joseph et al., 1996). In an experimental study on the use of the nicotine patch in patients with severe coronary artery disease, the patch reduced smoking and nicotine levels and this decreased total exercise-induced perfusion defect size (coincident with increases in plasma nicotine levels) suggesting that nicotine does not pose safety concerns in such individuals (Mahmarian et al., 1997). Two experimental studies addressed the question of whether it was safe to smoke while using the nicotine patch (Benowitz et al., 1998; Zevin et al., 1998). The data from both of these reports are based on a study with 12 healthy males, who were instructed to smoke ad libitum, while concurrently exposed to one of four nicotine patch doses (placebo, 21, 42, and 63 mg/day), on four separate and consecutive days.  Nicotine intake from cigarettes was suppressed by the nicotine patch in a dose-related manner (3, 10, and 40% in the 21, 42, and 63 mg nicotine patch conditions, respectively). No significant adverse events were reported even at the highest dose (63 mg/day).

When used for smoking cessation, bupropion and  varenicline are  used for a 1- to 2-week period  while continuing smoking prior to the actual smoking cessation. Two clinical trials that were done with this recommendation reported no adverse events that were specific to bupropion use and concomitant smoking (Hurt et al., 1997; Jorenby et al., 1999). Similarly, no adverse events specific to varenicline and concomitant smoking were reported in 3 clinical studies (Gonzales et al., 2006; Jorenby et al., 2006; Tonstad et al., 2006).

One trial reported on the safety of combining nicotine patch plus bupropion (Jorenby et al., 1999). In general, adverse events were more prevalent with both the combined nicotine patch and bupropion, but usually not significantly more so than with placebo, patch or bupropion alone. There were more subjects from the combined treatment who discontinued from the trial than from the placebo group. Also, there was a non-significant trend towards a higher or new incidence of hypertension in those receiving both bupropion and nicotine patch than in the placebo group. Hypertension developed in 6.1% of subjects treated with the combination of bupropion and NRT, compared to 2.5%, 1.6% and 3.1% of those treated with bupropion, NRT and placebo, respectively. The majority of subjects who developed hypertension had evidence of pre-existing hypertension. Monitoring of blood pressure is recommended for subjects who receive the combination of bupropion and NRT.

Trials of combining various NRTs (Stead et al., 2008) or combining nortriptyline with NRT (Hughes et al., 2007) did not report that combination treatment produced increased adverse events.

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Kralikova E, Kozak JT, Rasmussen T, Gustavsson G, Le Houezec J. Smoking cessation or reduction with nicotine replacement therapy: a placebo-controlled double blind trial with nicotine gum and inhaler. BMC Public Health. 2009; 9: 433.

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US Food and Drug Administration. Transcript of the 23rd meeting of the U.S. Food and Drug Administration. 1992. (not available on-line)

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Mahmarian JJ, Moyé LA, Nasser GA, Nagueh SF, Bloom MF, Benowitz NL, Verani MS, Byrd WG, Pratt CM. Nicotine patch therapy in smoking cessation reduces the extent of exercise-induced myocardial ischemia. J Am Coll Cardiol. 1997; 30: 125-130.

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Zevin S, Jacob P 3rd, Benowitz NL. Dose-related cardiovascular and endocrine effects of transdermal nicotine. Clin Pharmacol Ther. 1998; 64: 87-95.

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Hurt RD, Sachs DP, Glover ED, Offord KP, Johnston JA, Dale LC, Khayrallah MA, Schroeder DR, Glover PN, Sullivan CR, Croghan IT, Sullivan PM
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Jorenby DE, Leischow SJ, Nides MA, Rennard SI, Johnston JA, Hughes AR, Smith SS, Muramoto ML, Daughton DM, Doan K, Fiore MC, Baker TB. A controlled trial of sustained- release bupropion, a nicotine patch, or both for smoking cessation. N Eng J Med. 1999; 340: 685-691.

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Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, Billing CB, Gong J, Reeves KR; Varenicline Phase 3 Study Group
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Tonstad S, Tønnesen P, Hajek P, Williams KE, Billing CB, Reeves KR; Varenicline Phase 3 Study Group. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. JAMA. 2006; 296: 64-71.

Stead LF, Perera R, Bullen C, Mant D, Lancaster T. Nicotine replacement therapy for smoking cessation. Cochrane Database of Systematic Reviews 2008; 1.

Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database of Systematic Reviews 2007; 1. logo
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