The EAGLES study (Evaluating Adverse Events in a Global Smoking Cessation Study) is a landmark study, the largest smoking cessation clinical trial that looked at the potential for various side effects from smoking cessation medications in patients with and without a history of psychiatric disorder. The study took place across 16 countries and 140 centres, with over 8000 participants.

In 2009 the FDA in the US ruled that it was necessary for varenicline (Champix) to contain a black box warning (the strongest type of warning) on the product in 2009, highlighting the risk of serious neuropsychiatric events including suicidal thoughts and behaviour and aggressive/irrational behaviour. A similar warning was also required on Zyban.

The two companies who made the drugs, Pfizer (who makes Champix) and Glaxo Smith Kline (who makes Zyban) collaborated on an extensive study to evaluate the safety and efficacy of smoking cessation medications in smokers with and without psychiatric disease. The EAGLES study results were published in The Lancet in June 2016.

Results from the Study
The study looked at four different treatment groups (varenicline, bupropion, nicotine patch or placebo). Within each group, individuals did not know what treatment they were assigned. For example, all individuals wore a patch, and they didn’t know whether the patches contained active medication or whether they were placebo. All individuals took a pill, and they didn’t know what medication was contained in the pill or whether it was a placebo.

Each treatment group also received 10 minutes of smoking cessation counselling at each weekly visit with the healthcare provider/researcher.

There were 2000 patients in each group, 1000 patients had stable psychiatric illnesses. Those in the psychiatric group included individuals with a mood disorder (71%) such as depression or biopolar, anxiety disorder such as post-traumatic stress disorder (19%), or psychotic disorder such as schizophrenia (9%). About half of the group were taking psychotropic medications, 34% had a history of suicidal ideation and 13% of suicidal behaviour. They were clinically stable and judged not at high risk of self-injury or suicidal behaviour.

Neuropsychiatric adverse events
The researchers measured the number of neuro-psychiatric events that occured during the treatment (12 weeks) and up to 30 days after the last dose. For example, neuropsychiatric events may include anxiety, depression, hostility, agitation, hallucations, panic, suicidal ideation and more.

As expected, the psychiatric group had more neuropsychiatric adverse events compared to the non-psychiatric group. The rate of occurance of neuropsychiatric adverse events was about 5-6% in the psychiatric group and about 1-2% in the non-psychiatric group. However, the interesting observation was that within the psychiatric group and within the non-psychiatric group, the difference in the rate of occurrence between the four difference treatments (varenicline, buproprion, nicotine patch, and placebo) was minimal.

Among the various neuropsychiatric events looked at, agitation occurred more frequently across all groups.

Overall, about 10-12% of the psychiatric group had an adverse event; this includes both those who used a medication/patch, as well as those who didn’t use either (placebo).

Between each of the groups, there was no significant difference found in suicidal ideation and behaviour.

Other side effects
The most common adverse events reported included nausea (varenicline 25%, bupropion 10%, patch 10% and placebo 7%), headache (varenicline 12%, bupriopion 9%, patch 12% and placebo 10%, abnormal dreams (varenicline 10%, bupropion 7%, patch 12% and placebo 5%) and insomnia (varenicline 9%, bupropion 12%, patch 10% and placebo 7%).

The researchers measured how effective the drugs were to help people quit by looking at how many individuals stayed smokefree for 4 weeks post-treatment. They found that the groups taking either of the 3 active drugs had higher quit rates than the placebo group. Quit rates were higher among the non-psychiatric group. Varenicline produced higher quit rates than either of the other treatments (bupriopion or patch).

These results are very important because it highlights the fact that smoking cessation drugs are effective and can be safely used by individuals with a psychiatric history when monitored appropriately.

Updated Warning on Champix:
As a result of this study, the FDA modified the warning required on Champix. It’s no longer a “black box warning”, but is now a regular warning advising:

“Clinicians should be aware of the possible emergence of serious neuropsychiatric symptoms in patients attempting to quit smoking, with or without treatment.”

“Smoking cessation, with or without pharmacotherapy, has been associated with exacerbation of underlying psychiatric illness (e.g. depression, anxiety). Patients with a history of psychiatric symptoms should be monitored for worsening or new symptoms when attempting to quit smoking, regardless of how well controlled symptoms may be when starting smoking cessation treatment. Patients should be instructed to report strongly atypical and concerning symptoms to their healthcare provider, so that dose adjustments of psychiatric medications or CHAMPIX may be considered.”

“Patients should be informed that if they experience thoughts, moods or behaviours that are strongly atypical and concerning while on smoking-cessation medication, including CHAMPIX, the medication should be discontinued immediately, with urgent medical help sought as needed, and the symptoms reported to their healthcare provider.”

Anthenelli, R. M., Benowitz, N. L., West, R., St Aubin, L., McRae, T., Lawrence, D., . . . Evins, A. E. (2016). Neuropsychiatric safety and efficacy of varenicline, bupropion and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomized, placebo-controlled clinical trial. The Lancet, 387, 2507-2520.