Previously, Pettinati et al.13
found that CAD women and men had different treatment outcomes with high-dose naltrexone treatment, in which CAD men reduced their cocaine and alcohol use whereas women did not. In the present exploratory study, we attempted to investigate potential explanations for the gender differences in outcome, focusing on treatment attrition.
Our findings indicate that women generally reported nausea more frequently than men. While the overall attrition differences between men and women were not statistically significant, the differential rates of attrition between the subgroup of naltrexone-treated men and women approached significance. In attempting to predict treatment attrition, we found that men receiving placebo treatment and BRENDA were more likely to discontinue treatment. However, women reporting higher psychiatric problem severity and more frequent bouts with nausea in treatment were more likely to dropout from treatment.
In our study, high psychiatric severity was a predictor for CAD women discontinuing the treatment. Women obtained significantly higher psychiatric severity scores than men at baseline. Sixty-three percent of women and 46% of men reported high psychiatric symptoms prior to entering the treatment. If psychiatric severity, as demonstrated in our analysis, is making a significant impact on treatment attrition (and, subsequently, on their substance use), female patients with pre-treatment psychiatric symptoms may require symptom management (e.g., pharmacotherapy or psychotherapy) at the onset of substance use treatment. This would be an important clinical issue, given the high prevalence co-occurring substance use and mental disorders.34, 35
In general, the research findings on attrition rates between male and female substance abusers in various treatment settings are mixed.18, 19, 36, 37
In a recent injectable naltrexone trial using various doses, nausea was the only adverse event (AE) that occurred differentially for women and men in 10% or more patients, and the rate of nausea was significantly higher for women at a higher dosage (vs. placebo).11
Additionally, higher doses of naltrexone (vs. lower doses and placebo) resulted in higher rate of treatment discontinuation, secondary to adverse events (e.g., nausea), although the difference in attrition was not examined between men and women.11
Our findings are in line with those found in naltrexone-treated, alcohol dependent patients from O’Malley et al.,8
who previously reported that female alcohol dependent patients receiving naltrexone (50mg) were 7.2 times more likely to experience nausea than male patients, and that experiences of nausea was significantly associated with poor medication adherence and treatment discontinuation. These findings suggest that high-dose naltrexone treatment affects women differently.8, 38, 39
Due to sample size limitations, potential interaction effects of nausea and gender with treatment condition (naltrexone vs. placebo) on attrition were not examined. However, our data suggest there exist differential, though non-significant rates of both nausea and psychiatric severity for men and women in the two different treatment conditions. Future trials using naltrexone in female alcohol disordered patients, with or without cocaine dependence should focus on the impact of nausea and psychiatric problems on treatment attrition and treatment response.
Although our results have a number of potential implications for treating female CAD patients with high-dose naltrexone, due to the exploratory nature of the study, we cannot come to a definite conclusion. Clinically, our findings indicate that female CAD patients may require closer supervision during high-dose naltrexone treatment, especially given the possibility of gender effect in one naltrexone trial with large enough female alcoholic sample.11
In one recent preclinical study with rhesus macaques,40
a variant of the μ-opioid receptor gene (OPRM1C77G) was linked to increased alcohol consumption and preference, as well as alcohol intoxication, in male macaques only; this gender effect suggests μ-opioid receptor blockade may impact alcohol consumption and treatment response dissimilarly for men and women. Preliminary genetic research investigations indicate that alcohol dependent patients with certain genotypes respond better to naltrexone than those without comparable genetic profiles.41–43
Identifying specific genotypes of CAD women, who do not experience naltrexone-associated side effects and who responds positively to naltrexone treatment, would enhance the effectiveness of high-dose naltrexone treatment (on genomic approach, see O’Brien (2008)).44
The interpretation of our findings needs to be examined in light of the following methodological limitations. First, our findings are specific to outpatient treatment-seeking CAD patients, and may not be representative of the general CAD population. Second, the ratio between male and female subjects in our sample was unbalanced. The number of female subjects was small, although this male-female distribution is within the expected range in the treatment sample.8, 36
Due to these sample-related limitations, we were only able to conduct two separate logistic regression analyses, each for men and women, rather than directly examining the interaction effects between gender and the predictors in our regression model. Similarly, potentially relevant interactional term, such as the interactional effect between cocaine or alcohol use and gender, was not included in the model due to sample size limitations. Given that this is an exploratory study, further research is needed to examine any gender differences in naltrexone treatment using an ample and a comparable number of female subjects per group to investigate the gender interaction. Third, although the use of logistic regression is the most appropriate statistical test in our investigation, the backward stepwise elimination procedures require a number of statistical tests. Thus, additional predictors increase the likelihood of Type I error occurring in analyses. It is recommended that cross-validation samples be conducted in future investigations, in order to reduce the risk of Type I error.
In conclusion, our findings showed a significant relationship between treatment discontinuation, and psychiatric problem severity and frequency of nausea in CAD women in high-dose naltrexone treatment. For men, those in placebo and BRENDA treatments were more likely to discontinue treatment. Further research is needed on how outcomes may be affected by gender differences in pre-treatment characteristics as well as potential pharmacokinetic-differential effects of high-dose naltrexone.