Varenicline may reduce heavy drinking and increase smoking abstinence in men with alcohol use disorder (AUD) who smoke cigarettes, new research suggests.
A study comparing varenicline to placebo in heavy drinkers with AUD found that, although the mean change in percentage of heavy drinking days (PHDD) was not significantly different, there was a larger decrease in PHDD in men vs women.
Participants taking varenicline were also more successful than those taking placebo in achieving prolonged smoking abstinence.
“Given the high comorbidity between heavy drinking and smoking, one take-home message of the study is that clinicians and health systems should attend to these co-occurring problems,” lead investigator Stephanie O’Malley, PhD, professor of psychiatry, Yale School of Medicine, New Haven, Connecticut, told Medscape Medical News.
“The findings revealed that patients taking varenicline were more likely to quit smoking, even though they were not seeking or given smoking cessation counseling, suggesting the possibility that first-line medications designed to help people quit smoking should be offered to patients, even if they are not ready to quit,” she said.
The study was published online December 20 in JAMA Psychiatry.
Sex Differences
Cigarette smoking is more than twice as common among individuals with AUD than among the general population and is associated with poorer outcomes in patients treated for AUD, the authors write.
“Identifying pharmacotherapies to treat both AUD and smoking represents an important step in integrating addiction treatment into mainstream care,” they state.
Varenicline tartrate, which is approved by the US Food and Drug Administration as treatment for smoking cessation, acts at nicotinic and acetylcholine receptors involved in alcohol and nicotine reward.
In animal models and preclinical human studies, varenicline was found to reduce alcohol seeking and consumption and attenuate dopamine release when ethanol and nicotine were administrated together. But clinical trials of the impact of varenicline in AUD have yielded mixed results.
To investigate the potential role of varenicline in AUD, the researchers conducted a phase 2 randomized, double-blind, placebo-controlled clinical trial that evaluated the effects of varenicline, used in conjunction with medical management, on alcohol consumption in people seeking treatment for alcohol use but not for smoking.
The secondary aim of the study was to evaluate the impact of varenicline on smoking cessation.
To be eligible to participate, individuals had to have reported heavy drinking two or more times a week for 90 days and to have been abstinent for seven or fewer consecutive days prior to intake.
The study included 131 alcohol-dependent smokers aged 18 to 70 years (mean age, 42.7 years; SD, 11.7 years). Thirty-nine (29.8%) of the participants were women; 92 (70.2%) were men. Most respondents (69; 52.7%) identified their race/ethnicity as black.
The participants were randomly allocated to receive varenicline 2 mg (n = 64) or placebo (n = 67). The treatment period lasted 16 weeks; follow-up occurred on weeks 26, 39, and 52.
After randomization, participants attended 12 treatment research sessions (weeks 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 15, and 17) and met with a medical professional for medical management.
The first four sessions focused on tolerability and supported medication adherence. In the remaining sessions, participants received help in finalizing drinking goals and in developing and implementing strategies.
The sessions did not address smoking cessation, but participants were offered a referral to the state Tobacco Quitline at the last session.
At intake and at each session, participants underwent the following assessments: the Timeline Follow-Back Interview, in which daily drinking and smoking were recorded; the Systematic Assessment for Treatment Emergent Effects; the Columbia Suicide Severity Rating Scale; the Overt Aggression Scale; and the Positive and Negative Affect Schedule.
To assess smoking, carbon monoxide and plasma cotinine levels were measured at intake and at monthly sessions.
Overall, of the total number of pills that could have been taken during the 16-week treatment period by the varenicline and placebo treatment groups, the median percentage of pills taken was similar, but of the patients who received varenicline, women took fewer pills than men and were more likely than men to reduce the number of pills taken or to discontinue use of varenicline.
In the placebo groups, the median interquartile range (IQR) percentage of pills taken by women was similar to the median IQR percentage taken by men. Among the patients who received varenicline, the median number of treatment sessions attended by women was comparable to that attended by men.
During the last 8 weeks of treatment, the mean change from baseline in PHDD did not differ (F 1106 = 0.06; P = 0.80) among patients receiving varenicline (least square [LS] mean [SE], 1.69 [0.20]) and those receiving placebo (1.77 [0.20]) with respect to the sex of the participants or the site.
However, a significant medication by sex by time interaction (F1106 = 4.66; P = 0.03) was found. Compared with placebo, the decrease in PHDD was greater among men taking varenicline (LS mean difference for change from baseline, 0.54; 95% confidence interval [CI], -0.09 to 1.18; P = 0.09; Cohen d = 0.45). The decrease in PHDD among women was smaller (LS mean difference, -0.69; 95% CI, −1.63 to 0.25; P = 0.15; Cohen d = −0.53).
Further analysis was conducted on the effect of varenicline with respect to days on which there was no heavy drinking during the last 8 weeks of treatment. In that analysis, when missing data were treated as indicative of heavy drinking, it was found that for 29% men who received varenicline, there were days on which there was no heavy drinking; 6% of men taking placebo experienced days on which there was no heavy drinking (Cohen h = 0.64; 95% CI, 0.22-1.03).
In contrast, 5% of women who received verenicline had days on which there was no heavy drinking, compared with 25% of participants taking placebo (Cohen h = −0.60; 95% CI, -1.21 to 0.04). Results were similar when missing data were not treated as being indicative of heavy drinking.
During the last 28 days of treatment, there were more days of abstinence from smoking among patients who took verenicline than among patients taking placebo (13% vs 0%; P = .003; Cohen h = 0.72; 95% CI, 0.38 – 1.07).
An exploratory integrated response analysis that focused on the number of days in which there was no heavy drinking and the number of days in which patients abstained from smoking found a “marked advantage” of varenicline over placebo in men (20 of 45 [44%] vs 8 of 47 [17%]; Cohen h = 0.60) but not in women (6 of 19 [32%] vs 7 of 20 [35%]; Cohen h = −0.06).
Varenicline was generally well tolerated, although more patients in the varenicline group — especially women — reported abnormal dreaming.
Although participants were not seeking nor did they receive smoking cessation counseling, the overall sample of participants who received varenicline experienced a significant increase in 1-month prolonged smoking abstinence at the end of treatment, the authors summarize.
“Based on our findings, we concluded that varenicline could be considered to reduce heavy drinking in men who also smoke, but we did not see a similar benefit of varenicline on reducing heavy drinking in women,” Dr O’Malley said.
She cautioned that “we cannot draw conclusions about the role of varenicline for drinking in women, given that our sample of women was small and women differed from men on other characteristics prior to treatment, including severity of alcohol dependence and nicotine dependence.”
Don’t Wait Until They’re “Ready”
Commenting on the study for Medscape Medical News, Eden Evins, MD, MPH, professor, Center for Addiction Medicine, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, who was not involved with the study, noted that an important take-home message is that “treatment of smokers with effective pharmacotherapies should not be limited to people who say they are ready to quit smoking.”
Dr Evins, who is the coauthor of an accompanying editorial, pointed out that “we do not wait for someone with high blood pressure to be ‘ready’ to change diet and exercise habits before treating with antihypertensives, and we can give smokers effective treatment to quit, regardless of whether they say they are ready.”
Larger studies that examine differences in treatment response and that take into account the sex of the participants, dosing, and heaviness of drinking are needed, she said.
Dr O’Malley added, “The fact that no one quit smoking while taking placebo and receiving alcohol counseling suggests that alcohol counseling alone does not lead to smoking cessation and that clinicians should actively address smoking as part of their alcohol treatment.”
The trial was supported in part by grants from the National Institutes of Health and by the State of Connecticut Department of Mental Health and Addiction Services. Varenecline and placebo pills were donated by Pfizer. Dr O’Malley has been a consultant or an advisory board member for Alkermes, Amygdala, Arkeo, Cerecor, Mitsubishi Tanabe, Opiant, Pfizer; a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which is supported by Abbott, Amygdala, Ethypharm, Lilly, Lundbeck, Otsuka, Pfizer, Arbor Pharmaceuticals, and Indivior; a coinvestigator on studies that received donated medications from AstraZeneca and Novartis; a site principal investigator for a multisite trial by Lilly; and a scientific panel member for Hazelden Foundation. Disclosures of other investigators are listed at the end of the article. Dr Evins has received supplemental research grant support for her institution from Forum Pharmaceuticals; has received fees for her advisory and grant review work from Pfizer; and has equity in Brain Solutions, LLC.
JAMA Psychiatry. Published online December 20, 2017. Abstract, Editorial
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