As anticipated, gender was a moderating factor in several outcomes in this RCT of naltrexone augmentation of nicotine patch in the treatment of nicotine addiction. Among treatment completers, women in the 100 mg dose condition experienced higher smoking cessation rates compared to placebo and women in the two lower doses experienced less weight gain. These comparisons were not significant for men. In addition to these effects, women achieved higher concentrations of naltrexone than men did. Women but not men reported dose related differences in medication compliance. These data suggest that naltrexone exposure is important for abstinence in female smokers, but possibly less so in male smokers.
Women who were randomized to naltrexone 100 mg/d were significantly more likely to obtain and maintain abstinence than those women randomized to placebo among treatment completers, but this effect was not significant in men. These data are interesting in light of the growing literature suggesting gender differences in response to naltrexone treatment for nicotine addiction (Covey et al., 1999
; King et al., 2006
). Secondary analyses of RCTs indicate that naltrexone enhances smoking cessation in female samples (Byars et al., 2005
; Covey et al, 1999
; King et al., 2006
), and reduces urges to smoke to relieve negative affect and withdrawal to a greater degree in women than in men (King et al., 2006
). Consistent with King et al., (2006)
, women receiving nicotine patch plus placebo naltrexone in our study had somewhat lower quit rates than men had (41.0% versus 55.6%); with naltrexone 100 mg their quit rates were similar (71.4% vs. 71.8%).
The better response to the highest naltrexone dose (100 mg) compared to placebo observed among women but not men, also suggested that gender related differences in drug exposure might have contributed to outcome. Women did indeed have significantly higher serum naltrexone and naltrexol concentrations than men. The significance of this difference was not altered when medication compliance was included in the statistical analysis. Women, however, received a higher weight adjusted dose. A two-way analysis that included weight weakened the independent association of naltrexone concentrations with gender although a trend persisted, suggesting that differences in drug exposure might be multi-factorial. We focused on concentrations of the parent compound, naltrexone, because a recent report indicated that in primates, naltrexone is approximately 100 times more active than its major metabolite, 6-beta naltrexol (Holden et al., 2006
With respect to negative affect and abstinence, our failure to find gender differences in negative affect as assessed via IVR or smoking abstinence during the first five post-quit days is somewhat surprising as depression is more common in women and is a strong predictor of smoking recidivism (Borland, 1990
). We did observe a greater degree of negative affect as measured by IVR in the first post-quit week in those women who were perimentrual versus not perimenstrual when they quit smoking. However, this relationship did not reach the level of significance and did not appear to impact abstinence outcomes in this small sample. A recent study suggests that women who currently smoke are twice as likely to experience PMS (both physical and mood symptoms) than nonsmokers (Bertone-Johnson et al., 2008
), a phenomenon thought to contribute to reduced rates of smoking abstinence in those women quitting in the luteal phase of the menstrual cycle (Perkins et al., 2000
; Carpenter et al., 2008
; Franklin et al., 2008
). These findings are consistent with data from a sub-group of subjects in this RCT who completed two months of daily ratings prior to their quit day suggesting greater negative affect in luteal phase women and heightened risk for relapse compared to men and follicular phase women (Epperson et al., 2005
). Whether perimenstrual mood changes are an independent risk factor for smoking recidivism in women continues to be unclear, but of considerable interest.
Although there was no gender difference in the emergence of negative affect after quitting, the expected relationship between negative affect and abstinence was found in study completers. In this study, naltrexone treatment condition, gender and negative affect together contributed to abstinence, particularly early in the course of treatment. However, the effect of reproductive status (pre vs. post menopause) was not a factor and the impact of menstrual cycle phase/menstrual status on outcome was relatively modest. Although negative affect and weight gain may vary by menstrual cycle stage, the relatively small sample size of women who could be characterized reliably as peri or not perimenstrual limited our ability to covary for these factors in our assessment of impact on abstinence. Interestingly, Allen and colleagues (2009)
failed to find a relationship between short-term weight gain and phase of menstrual cycle during attempted smoking cessation. As is the case with the vast majority of RCTs, measurement of ovarian hormones, the gold standard for determining menstrual cycle phase, was not included in this study. Off setting this limitation, the female participants in this study provided the dates of their three menstrual periods prior to enrollment and prospectively reported their menstrual flow during the 6-week study. Without blood confirmation of ovulation, and thus luteal phase, we opted to include perimenstrual status as a more reliable dichotomous variable than menstrual cycle phase (follicular vs. luteal). It is the few days before and after onset of menstrual flow that is most associated with negative physical and mood symptoms related to the menstrual cycle (Ross et al., 2003
). Indeed, we found a trend for women who quit outside the perimenstrual period to have greater success in remaining abstinent throughout the entire study. There was no effect of menstrual cycle phase (follicular vs. luteal) on smoking outcomes.
Interestingly, a recent smoking cessation study using nicotine replacement therapy plus a behavioral intervention found a significant benefit of quitting during the follicular versus luteal phase with only 3 of 16 (19%) and 11 of 21 (52%) of subjects in each group, respectively, smoking at Day 3 post quit day (Franklin et al., 2008
). However, Allen and colleagues (2008)
using hormonally confirmed menstrual cycle phases found that women quitting without pharmacologic treatment or nicotine replacement in the early to mid-follicular phase when the estradiol/progesterone ratio was highest did not fair as well as those women who quit in the mid-luteal phase when the estradiol/progesterone ratio would be at its nadir. The authors suggest that their findings could be explained by estradiol’s enhancement of nicotine metabolism (Benowitz et al., 2006
) and/or the differential effects of estradiol and progesterone on the reinforcing effects of substances of abuse (Lynch et al., 2000; Roth et al., 2004
; Sofuoglu et al., 2004
). What role, if any, naltrexone addition to nicotine replacement therapy played in the disparity between our findings and those of Allen and colleagues is of interest.
In summary, this study provides additional evidence that gender may play a role in smoking cessation, and should be taken into consideration in large-scale RCTs. The results of this secondary analysis suggest that naltrexone augmentation of nicotine patch may be helpful to women trying to quit smoking. However, this study and all prior studies were not specifically designed to test this hypothesis and additional prospective research with adequate sample sizes is needed to test this hypothesis. Regardless of gender, our results suggest that negative affect in the days following the quit day can have a clinically meaningful impact on an individual’s ability to obtain continuous abstinence. As each of the RCT study participants was screened for mood disorders using sections of the SCID (First et al., 1995), it is unlikely that these individuals met criteria for a major depressive episode and that it was negative affect, which emerges with smoking abstinence that was an important factor in abstinence in this study. PMS is more common in women with nicotine addiction, but rarely identified in RCTs due to the requirement of prospective screening for two menstrual cycles. Although limited by recall bias, retrospective ratings for menstrual cycle and mood would provide an assessment of PMS/PMDD at baseline. Prospective daily ratings for women throughout the RCT may shed light on the relationship between negative affect, menstrual cycle phase and smoking abstinence in women undergoing various treatment regimens. Finally, documentation of gonadal steroids on the quit day would provide a more accurate assessment of reproductive status and menstrual cycle phase.