By Dr. Geoffrey Modest
A couple of recent articles dealt with issues of smoking cessation:
- The lancet had a study finding no significant increase in psychiatric risk with any of the smoking cessation medications (see doi.org/10.1016/S0140-6736(16)30272-0 ). The FDA had issued an early warning on neuropsych concerns with varenicline, later extended to bupropion, based on case reports, and issued a post-marketing requirement for makers of both drugs to do RCTs to assess these risks. Hence this drug-company sponsored study.
- 8144 smokers smoking at least 10 cigarettes/d in the past year, 4116 having underlying psych disorders/4028 in the non-psych cohort. In terms of the cohorts:
- Nonpsych cohort: mean age 46, 50% female, 83% white/13% black, wt 80 kg, 47% US/33% Western Europe/11% Eastern Europe/10% Central/South America, Fagertstrom Test for Cigarette Dependence (FTCD) score 5.5 [a score signifying moderate dependence], 13 years duration of smoking, 21 cigs/day in past month, 3.3 prior quit attempts
- Psych cohort: mean age 47, 62% female, 80% white/16% black, wt 80 kg, 58% US/29% Western Europe/9% Eastern Europe/4% Central/South America, Fagertstrom Test for Cigarette Dependence (FTCD) score 6.0, 12 years duration of smoking, 21 cigs/day in past month, 3.5 prior quit attempts. 70% with unipolar or bipolar depression, 20% anxiety disorder, 9% psychotic. 33% on antidepressants, 15% anxiolytics, 16% antipsychotics [of note: all had to be stable for the prior 6 months and not at risk for self-injury]
- Randomized to nicotine patch 21 mg/d with taper, varenicline 1mg bid, or bupropion SR 150mg bid for 12 weeks with 12 week non-treatment follow-up. Done in 14 centers in 16 countries between 2011-2015 (this was a double-blind, triple dummy, placebo controlled trial – i.e. everyone took pills from 2 different unmarked bottles and used a patch)
- All had brief smoking cessation counseling (no more than 10 minutes, at each clinic visit)
- Quit date was 1 week after randomization, coinciding with end of uptitration of bupropion and varenicline and initiation of patch
- Main outcomes: composite measure of moderate and severe neuropsych events; and biochemically confirmed continuous abstinence from smoking for weeks 9-12.
- The same percent (78%) of each group completed the study
- In the non-psychiatric cohort: moderate-to-severe neuropsych adverse events occurred in
- Varenicline: 13 of 990 people (1.3%)
- Bupropion: 22 of 989 (2.2%)
- Patch: 25 of 1006 (2.5%)
- Placebo: 24 of 999 (2.4%)
- The only significant difference between active drug and placebo: varenicline-placebo risk difference was 1.28. Of note, there were essentially zero patients with psychosis, panic, mania, suicidal ideation or behavior, anxiety, or depression.
- In the psychiatric cohort:
- Varenicline: 67 of 1026 people (6.5%)
- Bupropion 68 of 1017 (6.7%)
- Patch: 53 of 1016 (5.2%)
- Placebo: 50 of 1015 (4.9%)
- No significant risk differences between active drug and placebo, though there were 14 of patients (2%) in the psych group who developed suicidal ideation
- Quit rates at 9-12 weeks, vs placebo (documented by exhaled carbon monoxide measurements):
- Varenicline (statistically significantly better than the other 2 active treatments), with OR 3.61 (3.07-4.24); most frequent adverse effect: 25% nausea
- Bupropion: OR 2.07 (1.75-2.45); most frequent adverse effect: insomnia 12%
- Patch: OR 2.15 (1.82-2.54); most frequent adverse effect: abnormal dreams 12%
- Placebo: headache in 10%
- Quit rates looking at weeks 9-24 showed some deterioration over those from weeks 9-12, but the order and significance of efficacy remained as above
So, this study adds a few things to the literature:
- As a large study, it showed that neither varenicline nor bupropion posed a significant risk to smokers with or without a psych history.
- The odds ratios for efficacy in smoking cessation did not vary by initial psych status: those with underlying psych issues had similar abstinence rates to those without
- And, this is pretty important since the likelihood of smoking is 2-3x higher in those with underlying psych disorders (perhaps as self-medication with nicotine, a pretty potent psychoactive drug/anxiolytic: evidence shows improved vigilance, attention and cognition; decreased perceived stress, embarrassment, irritability, or depression; nicotine can be both a stimulant and relaxant, with initial epinephrine release causing stimulation but increasing dosages causing sedation)
- A few caveats:
- As per prior blog (http://blogs.bmj.com/bmjebmspotlight/2016/03/28/primary-care-corner-with-geoffrey-modest-md-abrupt-vs-gradual-smoking-cessation/) there might have been more success if the patch had been started earlier than 1 week before the quit date
- I would still be concerned about using varenicline in those with psychotic disorders, since these were pretty underrepresented in the psych cohort (as were those with personality disorders, <1% of the cohort). But importantly, a large % (34%) had a history of suicidal ideation and 13% had a history of suicidal behavior. Also of importance, this study did not include patients with underlying with substance use disorders, including alcohol, in the past 12 months.
- Although varenicline outshined the others, this trial only looked at monotherapy, and there are many studies showing the superior efficacy of multi-therapies
- The evaluation of smoking cessation at 12 weeks should be viewed with some caution, since this may not reflect long-term abstinence
- So, bottom line, varenicline, as a single agent, seemed to be the most effective in smoking cessation and did not seem to have any real increased neuropsych risk, even in those with underlying psych disorders (i.e.: assessing the confidence intervals above, it did not appear that there could be more than a 1.5 percentage point increase in neuropsych events by either varenicline or bupropion in those without psych disorders, or more than 4 percentage points in those with psych disorder). For patients with underlying psych disorders who meet the above criteria (including being stable psychiatrically and non-other-substance using), any of these methods seemed to work well and be well-tolerated, though I would really follow them more closely.