Smoking is a major cause of morbidity and mortality across the world and accounts for over 60% of deaths in people who do smoke. The World Health Organisation estimates that tobacco kills almost 6 million people per year, with 5 million as a result of direct tobacco use. Innovative treatment approaches aimed at improving smoking cession are urgently needed to reduce death and disability caused by smoking. Pharmacotherapy is considered a first line treatment for those who wish to give up smoking, and is recommended by the National Institute for Health and Care Excellence (NICE). The most commonly prescribed pharmacological treatments are bupropion and varenicline. The efficacy of these treatments used in isolation has been discussed in previous elf blogs (here and here).

Early evidence suggests that a combination of pharmacotherapies may improve treatment outcomes. Adaptive treatment in which nicotine replacement therapy (NRT) is combined with bupropion following poor response to NRT alone has shown some promise. Furthermore, a combination of bupropion (sustained release – SR) and NRT has been shown to be more effective that NRT alone, and a pilot study using a combination of varenicline and bupropion SR led to greater abstinence rates than previous single therapy trials. In a recent study published in The Journal of the American Medical Association, the authors set out to investigate the additive effects of combined pharmacotherapy over monotherapy for smoking cessation.

Methods

A randomised, blinded, placebo-controlled, multi-centre clinical trial was conducted. Individuals were invited to take part if they were at least 18 years of age, smoked at least 10 cigarettes per day for six months and were motivated to quit. Participants were excluded if they had a serious medical or psychiatric illness. Following the initial screening, 506 participants attended a clinic, given brief behavioural counselling and measures of exhaled-air carbon monoxide and tobacco use status were taken. Participants were then randomised into one of two conditions:

1. One group received varenicline and bupropion SR (combination therapy),
2. and the second group received varenicline and placebo (monotherapy).

Both groups received 12 weeks of treatment (treatment phase) and were followed up for 52 weeks. In both groups 0.5 mg of varenicline was administered daily for 3 days, which was then titrated to 0.5 mg twice daily until day 7. They were then maintained on a dose of 2 mg per day for 11 weeks. In the combination therapy group 150 mg bupropion was titrated for the first 3 days, then 300 mg for the remainder of treatment. The main outcome measures of the study were biochemically confirmed (using carbon monoxide measures) prolonged and 7 day point-prevalence abstinence at the end of the treatment phase. Secondary outcomes were prolonged and 7 day point-prevalence abstinence at weeks 26 and 52. Weight gain and adverse effects of the medication were also examined.

Results

Smoking Cessation

• At the end of the treatment phase (12 weeks) prolonged smoking abstinence was greater in the combined therapy group (OR = 1.49, 95% CI 1.05 to 2.12, p= .03)
• Prolonged abstinence was also greater in the combined therapy group after 26 weeks (OR = 1.52, 95% CI 1.04 to 2.22, p= .03)
  • However, there were no significant differences in prolonged abstinence between the groups at 52 weeks (OR = 1.39, 95% CI 0.93 to 2.07, p=.11)
• No significant differences in 7 day point-prevalence abstinence between the groups were observed at any time point

Weight gain and adverse effects

• In participants who remained abstinent after 12 weeks, weight gain was significantly lower in the combination therapy group (1.1 kg [95% CI 0.5 to 1.7] p< .001) compared to the monotherapy group (2.5 kg [95% CI 2.0 to 3.0], p< .001)
• At 26 and 52 weeks differences in weight gain were not observed

Higher percentages of both depression (3.6% versus 0.8%; p =.03) and anxiety (7.2% versus 3.1%, p= .04) were reported in the combination therapy.

Discussion

A combination of both varenicline and bupropion increased the likelihood of smoking cessation during treatment and at a 26 week follow up, compared to treatment with varenicline alone.  However, the improved cessation rate was not evidence at 52 weeks or using point-prevalent abstinence measures.

Combination therapy also led to attenuation in weight gain following smoking cessation. As weight gain can be a predictor smoking relapse following cessation the authors suggest that:

combination therapy could provide a clinical option for patients concerned about weight gain.

Limitations

Whilst these results show initial promise there are some limitations:

• Firstly, the combination of pharmacotherapies actually increased reported incidences of both depression and anxiety, which may prove detrimental to long-term abstinence rates
• Secondly, the study has limited generalizability to the smoking population as a whole, as individuals with physical or mental health problems were excluded

To conclude, future research should continue to examine the safety and efficacy of combination therapies for smoking, as these may be the best opportunity to advance treatment in the absence of any new therapies being developed.

Links

Ebbert JO, Hatsukami DK, Croghan IT, et al. Combination Varenicline and Bupropion SR for Tobacco-Dependence Treatment in Cigarette Smokers: A Randomized Trial. JAMA. 2014;311(2):155-163. doi:10.1001/jama.2013.283185. [Abstract]

Ebbert JO, Croghan IT, Sood A, Schroeder DR, Hays JT, Hurt RD. Varenicline and bupropion sustained-release combination therapy for smoking cessation. Nicotine Tob Res. 2009 Mar;11(3):234-9. doi: 10.1093/ntr/ntn031. Epub 2009 Feb 25. [PubMed abstract]