Safety of varenicline, bupropion and NRT in smokers

A number of smoking cessation pharmacotherapies are available with nicotine replacement therapy (NRT), bupropion (an atypical antidepressant) and varenicline (a partial nicotine receptor agonist) being the most common. Although there are mixed results concerning their efficacy (see this blog or that blog), a recent Cochrane review describes them as effective treatments for smoking cessation.

Although there are a large number of randomised controlled trails (RCTs) concentrating on the efficacy of these interventions, safety analyses tend to be secondary outcomes. These studies have generally concluded although some side effects are apparent, for example varenicline can cause nausea and bupropion can cause insomnia, they are generally well tolerated. It is notable that many of these RCTs exclude individuals with psychiatric comorbidities. Given the prevalence of psychiatric disorders in the UK (particularly anxiety and depression) and the elevated smoking rates in these populations, it is important to establish the safety of these pharmacotherapies in diverse populations.

The Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) trial (Anthenelli et al, 2016) is a double-blind, randomised placebo-controlled RCT exploring the safety of varenicline, bupropion, and NRT (in patches) in smokers with and without psychiatric illness. A secondary analysis of efficacy was also reported.

This trial compared the relative safety risk and efficacy of varenicline and bupropion with nicotine patch and placebo in smokers with and without mental illness.

Methods

8,144 participants were recruited across 140 treatment centres in 16 countries:

4,116 (4,074 included in the analysis) in the psychiatric cohort
4,028 (3,984 included in analysis) in the non-psychiatric cohort.

The psychiatric cohort included those with anxiety, mood, and psychotic disorders as well as borderline personality disorder.

Participants were randomly assigned to one of the four treatment groups (varenicline, bupropion, NRT and placebo). The study consisted of a 12 week treatment phase, and a 12 week non-treatment phrase, which included 12 face-to-face visits and 11 telephone calls. Participants were given a quit date one week into the trial.

The primary dependent variable was a composite measure of adverse psychiatric events. During all study visits, incidents of adverse events were assessed with open-ended questioning, observations and the Neuropsychiatric Adverse Events Interview (NAEI). Adverse events were defined incidents of one of 261 symptoms taken from 16 symptom categories listed in the Medical dictionary for Regulatory Activities (MedDRA). Notably, symptoms associated with anxiety, depression, feeling abnormal and hostility were classified as an adverse event only if rated as severe; all other symptoms were classified as an adverse event if rated moderate or severe. The secondary outcome was carbon-monoxide confirmed abstinence through weeks 9-12.

Moderate-to-severe adverse neuropsychiatric events include agitation, aggression, panic, anxiety, depression and suicide ideation.

Results

There were more incidents of adverse events reported in the group with psychiatric disorders (5.8%), than in the group without (2.1%), but there were similar rates of adverse effects across all treatment arms:
- 6.5% varenicline
- 6.7% bupropion
- 5.2% nicotine patch
- 4.9% placebo
The most common adverse events were:
- Nausea (varenicline)
- Insomnia (bupropion)
- Abnormal dreams (NRT)
- Headache (placebo)
For smokers without a psychiatric disorder, there was no significant increase in the incidence of adverse neuropsychiatric events across the four treatment groups:
- 1.3% varenicline
- 2.2% bupropion
- 2.5% nicotine patch
- 2.4% placebo

Primary analysis

Non-psychiatric cohort (Risk Differences)

Varenicline vs. Placebo -1.26 (95% CI -2.40 to -0.15)
Bupropion vs. Placebo -0.08 (95% CI -1.37 to 1.21)
Varenicline vs. NRT -1.07 (95% CI -2.21 to 0.08)
Bupropion vs. NRT 0.13 (95% CI -1.19 to 1.45)

Psychiatric cohort

Varenicline vs. Placebo 1.55 (95% CI -0.42 to 3.59)
Bupropion vs. Placebo 1.78 (95% CI -0.42 to 3.81)
Varenicline vs. NRT 1.22 (95% CI -0.81 to 3.25)
Bupropion vs. NRT 1.42 (95% CI -0.63 to 3.46)

Secondary analysis

Varenicline was superior to:

Bupropion (OR =1.75, 95% CI 1.52 to 2.01)
NRT (1.68, 95% CI 1.46 to 1.93)
Placebo (3.61 95% CI 3.07 to 4.24).

Bupropion was superior to:

Placebo (2.07 95%CI 1.75 to 2.45)

NRT was superior to:

Placebo (2.15 95%CI 1.82 to 2.54).

Smokers who took varenicline achieved higher abstinence rates than smokers on bupropion, nicotine patches or placebo.

Discussion

The current large multinational investigation suggests that there is no evidence that varenicline, bupropion and NRT increase adverse events, in either a psychiatric population or in a control group with no psychiatric symptoms. Furthermore there was evidence that all treatments improve abstinence compared to placebo, with varenicline being superior to the other interventions.

Limitations

There are some notable limitations with this study:

One key issue is that participants with addiction related illness were excluded from the study, given the prevalence of alcoholism with comorbid nicotine dependence this represents an important missing group.
In addition, as the authors acknowledge, there may be key moderating factors such as gender that were not explored in this study.

Conclusions

This study adds to the growing evidence for the efficacy of smoking cessation pharmacotherapies, and shows that they may be suitable in some populations with psychiatric illness. However, it is notable that although some of these pharmacotherapies have been used as abstinence maintenance tools as well, the safety of medium- to long-term use in diverse populations is yet to be established.

These findings may not apply to those with untreated or unstable mental illness. Further research is needed to prove efficacy and safety in that group.

Links

Primary paper

Anthenelli RM, Benowitz NL, West R, et al. (2016) Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet 2016; published online April 22. http://dx.doi.org/10.1016/S0140-6736(16)30272-0.