This study confirms published clinical trial findings that side effects from varenicline are relatively common and, while generally mild to moderate in severity, can be associated with discontinuation of medication in a substantial portion of users, especially those who experience more severe symptoms. Our results additionally show a strong relationship between discontinuation of medication and relapse to smoking in the early weeks after beginning treatment, with over half of those who had discontinued varenicline found to be smoking 28 days after beginning the medication.
Although women reported varenicline side effects more frequently and at greater severity levels than men, they were no more likely to discontinue medication. Interestingly, despite previous studies demonstrating women’s experience of greater nicotine withdrawal symptoms while quitting without pharmacotherapy (Leventhal et al., 2007
) or with NRT (Wetter et al., 1999
), no difference in craving/desire to smoke, irritability/anger or depressed mood was seen in this trial, supporting an equal benefit from the partial nicotinic receptor agonist properties of varenicline. This is consistent with the varenicline clinical trials showing equivalent long-term abstinence rates among women and men (Schnoll, Patterson, and Lerman, 2007
While participants were not asked which symptom specifically caused them to stop taking their medication, nausea was the most commonly reported medication side effect among those who discontinued, reported by over two-thirds of those who stopped due to symptoms of any kind. Additionally, retching or vomiting were the only two symptoms reported more frequently by those who discontinued their medication than those who continued to take it, suggesting that among potential side effects, those causing gastrointestinal distress are the least bearable for smokers using varenicline.
From a clinical perspective, it appears that identifying patients who are experiencing such symptoms early in their treatment and focusing more aggressively on measures to ameliorate them may improve tolerance and thus continuation of medication. These could include reinforcing instructions to consistently take varenicline with food and water, temporarily or permanently reducing dosage, or prescribing concurrent anti-nausea or anti-emetic medications. Other factors that may predict more severe nausea or dyspepsia, such as concomitant smoking or pre-existing dyspepsia or gastro-esophageal reflux disease (GERD), should also be further explored and addressed.
Study participants who received any telephone counseling were less likely to discontinue their medication compared with those who were randomized to the web-only group. Although all participants received the same medication use instructions, including information about possible side effects and how to manage them, those assigned to the telephone counseling groups were called proactively, asked if they were experiencing any problems, and had an opportunity to discuss their questions or concerns about their treatment with a trained counselor. Those in the web only group were able to post queries on a discussion forum or call one of the study counselors, but did not receive individualized symptom management unless they took the initiative to call. This suggests that personalized support and counselors’ monitoring of symptom experience during the quitting process may improve medication compliance and success in achieving abstinence.
Along with the strengths of this study, which include a large sample size with a relatively high response rate and a “real world” setting, there are several limitations that must be considered. First of all, since this study is primarily an effectiveness trial of different types of behavioral support for treating tobacco dependence, there is no control condition in which participants did not receive varenicline, nor was there a baseline survey of symptoms before beginning the medication. Therefore, causality cannot be established between symptoms and medication discontinuation, nor can we determine the role symptom experience plays in the high rate at which those who stop the medication return to smoking. There is evidence that not completing other approved cessation pharmacotherapies is associated with relapse to smoking (Toll, McKee, Martin, Jatlow, and O’Malley, 2007
), and it is plausible that symptoms would contribute to this outcome, but also possible that return to smoking may precede symptoms or discontinuation of medication, or that patients have other reasons for failure to quit or remain abstinent.
Second, the results only examine reported symptoms, medication use, and smoking during the first month of varenicline treatment. However, since relapse most often occurs during the first few weeks of treatment, preventing discontinuation of medication during this critical period is likely to have a positive benefit on cessation. Third, patients were proactively asked about specific symptoms at the time of the survey, thus reporting rates of these symptoms are likely to be higher than if collected passively or via more general questions, while other symptoms that were common among clinical trial participants, such as headache, were not included on the list, and thus may have been underreported.
Fourth, while there were fewer medical exclusions for this study compared with the Phase 3 clinical trials, participants were screened for conditions related to poor health status and also excluded if unable to access the Internet and therefore may not represent all patients under general care, especially those who are more seriously ill. Finally, in light of recent FDA advisories regarding potential varenicline effects on mood and behavior, closer attention should be paid to the occurrence and impact of depression and other neuropsychiatric conditions on tobacco users trying to quit. While we only detected one serious psychiatric event requiring hospitalization out of over 1,000 participants in this trial, careful monitoring of patients on varenicline, especially those with prior diagnosis of mood disorders, is critical.
In summary, while varenicline was generally well-tolerated by most participants, medication side-effects and potential nicotine withdrawal symptoms were associated with discontinuation of the medication and smoking in the early weeks of treatment. Smokers who continued to take the medication had lower smoking rates and those who received proactive phone counseling in conjunction with the medication were more adherent to medication use. The results suggest that smokers may benefit from proactive assistance managing varenicline side-effects and symptoms of nicotine withdrawal, which in turn could enhance their success quitting smoking. Additional research on how to best help patients avoid or deal with treatment-related symptoms and side-effects is warranted.