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Despite rising rates of substance use disorders (SUD) in women and the narrowing of the SUD gender prevalence ratio in the U.S., large knowledge gaps in gender-specific treatment remain. The NIDA Clinical Trials Network (CTN) Gender Special Interest Group (GSIG) has provided opportunities to bring the gender lens to national multi-site clinical trials, ancillary studies, secondary data analyses, recommendations for data collection and demographic data, among other contributions to CTN and the SUD treatment field. This commentary provides background on gender differences and the knowledge gap, a history of the CTN GSIG, and its accomplishments via gender specific trials and key secondary analyses. The commentary will close with future directions and recommendations for research including improving the inclusion of intersectional identities in recruitment reach and analyses, reproductive health, pregnant and parenting people, and methodological considerations for clinical trials to enhance capacity to collect and understand data related to gender.
Background and objectives: Limited research has explored sex differences in opioid use disorder medication (MOUD) treatment outcomes. The purpose of this study was to examine MOUD initiation onto buprenorphine-naloxone (BUP-NX) versus extended-release naltrexone (XR-NTX) by sex, and sex differences in clinical and psychosocial outcomes.
Methods: Using data from a 24-week open-label comparative effectiveness trial of BUP-NX or XR-NTX (CTN-0051, X:BOT), this study examined MOUD initiation (i.e., receiving a minimum one XR-NTX injection or first BUP-NX dose) and 24-week self-report outcomes. We used regression models to estimate the probability of MOUD initiation failure among the intent-to-treat sample (N = 570), and the main and interaction effects of sex on outcomes of interest among the subsample of participants who successfully initiated MOUD (n = 474).
Results: In the intent-to-treat sample, the odds of treatment initiation failure were not significantly different by sex. In the subsample of successful MOUD initiates, the effect of treatment on employment at week 24 was significantly moderated by sex (p = .003); odds of employment were not significantly different among males by MOUD type; females randomized to XR-NTX versus BUP-NX had 4.63 times greater odds of employment (p < .001). Males had significantly lower odds of past 30-day exchanging sex for drugs versus females (adjusted odds ratios [aOR] = 0.10, p = .004), controlling for treatment and baseline outcomes.
Discussion and conclusions: Further research should explore how to integrate employment support into OUD treatment to improve patient outcomes, particularly among women.
Scientific significance: The current study addressed gaps in the literature by examining sex differences in MOUD initiation and diverse treatment outcomes in a large, national sample.
Related protocols: CTN-0051
In this study, the researchers sought to characterize the 3-year prevalence of mental disorders and non-nicotine substance use disorders among male and female primary care patients with documented opioid use disorder across large U.S. health systems.
This retrospective study used 2014–2016 data (from CTN-0074) from patients ages =16 years in six health systems. Diagnoses were obtained from electronic health records or claims data; opioid use disorder treatment with buprenorphine or injectable extended-release naltrexone was determined through prescription and procedure data. Adjusted prevalence of comorbid conditions among patients with opioid use disorder (with or without treatment), stratified by sex, was estimated by fitting logistic regression models for each condition and applying marginal standardization.
Females (53.2%, N=7,431) and males (46.8%, N=6,548) had a similar prevalence of opioid use disorder. Comorbid mental disorders among those with opioid use disorder were more prevalent among females (86.4% vs. 74.3%, respectively), whereas comorbid other substance use disorders (excluding nicotine) were more common among males (51.9% vs. 60.9%, respectively). These differences held for those receiving medication treatment for opioid use disorder, with mental disorders being more common among treated females (83% vs. 71%) and other substance use disorders more common among treated males (68% vs. 63%). Among patients with a single mental health condition comorbid with opioid use disorder, females were less likely than males to receive medication treatment for opioid use disorder (15% vs. 20%, respectively).
Conclusions: The high rate of comorbid conditions among patients with opioid use disorder indicates a strong need to supply primary care providers with adequate resources for integrated opioid use disorder treatment.
Related protocols: CTN-0074
Side effects of medications for opioid use disorder (MOUD) such as weight gain contribute to their stigma. Substantial evidence suggests that women have a more severe side effect profile to MOUD than men, and concerns about weight gain during treatment are prevalent. However, the few studies reporting sex differences in weight gain during treatment show conflicting results and are restricted to methadone. In addition, little is known about possible sex differences in weight gain to buprenorphine, which is the most commonly prescribed MOUD in the United States.
To address these issues, the authors performed a systematic review and meta-analysis on the few studies reporting longitudinal data on sex differences in body mass index (BMI) gain during methadone treatment (Study 1). In a separate study, they also re-analyzed data from trial CTN-0030 of the National Institute on Drug Abuse Clinical Trial Network (NIDA CTN), which involved a 12-week buprenorphine treatment regimen (Study 2; n = 360; 209 Male, 151 Female).
For Study 1, across all papers reporting longitudinal data (k = 4, n = 362 OUD patients), there were BMI increases that ranged from 2.2 to 5.4 BMI after at least one year of methadone treatment, but there were no significant sex differences in BMI increases (Standardized Mean Difference, Female > Male = 0.352, SE =0.270; 95 % CI = [-0.18 0.88]; p = .193). Study 2 showed no significant differences in weight before and after 12 weeks of buprenorphine treatment nor did it show sex differences in weight change with treatment (ß = 2.34, p = .511).
Conclusions: These analyses corroborate evidence of weight gain with methadone treatment but did not observe a sex-based disparity in weight gain with methadone or buprenorphine treatment for OUD.
Related protocols: CTN-0030
Recent studies indicate that sex-based differences exist in co-occurring psychiatric symptoms and disorders among individuals with opioid use disorders (OUD). Whether these associations are present in adolescent samples and change during OUD treatment is poorly understood.
In this study, researchers examined sex-based differences in psychiatric symptoms and relationships among sex, psychiatric symptoms, and opioid use outcomes in youth with OUD receiving buprenorphine/naloxone (Bup/Nal) and psychosocial treatment.
The study randomly assigned 152 youth (15-21 years old) diagnosed with OUD to either 12 weeks of treatment with Bup/Nal or up to 2 weeks of Bup/Nal detoxification with both treatment arms receiving weekly drug counseling as part of a multisite clinical trial (CTN-0010). Researchers compared psychiatric symptoms, assessed via the Youth Self Report (YSR) at baseline and week 12, across male and female OUD participants. The study used logistic regression models to identify sex and psychiatric symptom variables that were predictors of opioid positive urine (OPU) at week 12.
Compared to males, females with OUD had higher mean psychiatric symptom scores at baseline across broad-band and narrow-band symptom domains. The study observed significant reductions in psychiatric symptoms scores in both males and females during treatment, and by week 12, females only differed from males on anxious-depressive symptom scores. Females, in general, and youth of both sexes presenting to treatment with higher anxious depression scores were less likely to have a week-12 OPU.
Conclusions: Clinically significant sex-based differences in psychiatric symptoms are present at baseline among youth with OUD receiving Bup/Nal-assisted treatment and mostly resolve during treatment.
Related protocols: CTN-0010
This study examined the associations of multiple psychiatric and chronic conditions with the self-reported history of major depressive disorder (MDD) among patients with opioid use disorder (OUD) and tested whether the associations differed by gender. Using data from CTN-0027 (START), a clinical trial including 1,646 participants with OUD, of which 465 had MDD, a variable cluster analysis was used to classify chronic medical and psychiatric conditions. Multivariate logistic regression analyses were used to estimate their associations with MDD in subjects with OUD.
Nine variables were divided into three clusters: cluster 1 included heart condition, hypertension, and liver problems; cluster 2 included gastrointestinal (GI) problems and head injury; and cluster 3 included anxiety disorder, bipolar disorder, and schizophrenia. The overall prevalence of MDD in participants with OUD was 28.3% (22.8% for males and 39.5% for females). Gender, anxiety disorder, schizophrenia, liver problems, heart condition, GI problems, and head injury were significantly associated with MDD. Gender-stratified analyses showed that bipolar disorder, liver problems and individuals with one chronic condition were associated with MDD only in males, whereas heart condition, hypertension, and GI problems were associated with MDD only in females. In addition, anxiety disorder, head injury, individuals with one or more than two psychiatric conditions, and individuals with more than two chronic conditions were associated with MDD regardless of gender.
Conclusions: This study showed a high prevalence of MDD in individuals with OUD as compared to the general population. In those with OUD, there is a significant association between MDD and gender, anxiety disorder, liver problems, heart condition, GI problems, and head injury. Furthermore, multiple psychiatric and chronic conditions were significantly associated with MDD. Additionally, gender-stratified analyses showed that bipolar disorder, liver problems and one chronic condition was associated with MDD in males, while heart condition, hypertension, and GI problems were associated with MDD only in females. Treatment plans in patients with OUD should not only address MDD but also co-morbid psychiatric and chronic medical conditions that occur with MDD.
Related protocols: CTN-0027
Exercise may be beneficial for individuals in substance use disorder (SUD) treatment given the higher rates of both medical and psychiatric comorbidity, namely mood and anxiety disorders, compared to the general population. Gender and/or racial/ethnic differences in health benefits and response to prescribed exercise have been reported and may have implications for designing exercise interventions in SUD programs.
Using data from the NIDA Clinical Trials Network Stimulant Reduction Intervention using Dosed Exercise (STRIDE) trial, CTN-0037, gender differences and stimulant withdrawal severity across time were analyzed using linear mixed effects models.
The analysis found that males completed significantly more exercise sessions than females and were more adherent to the prescribed exercise dose of 12 Kcal/Kg/Week. Controlling for age, race/ethnicity, treatment group and stimulant withdrawal severity, there was a significant gender by time interaction for body mass index (BMI), waist circumferences, and heart rate measured prior to exercise sessions. For females, body mass index and waist circumference increased over time, while for males, BMI and waist circumference stayed unchanged or slightly decreased with time. Heart rate over time significantly increased for females at a higher rate than in males. Stimulant withdrawal severity was similar in males and females at baseline but males exhibited a significant decrease over time while females did not. Although baseline differences were observed, there were no time by race/ethnicity differences in physiologic responses.
Conclusions: Gender differences in response to exercise may have implications for developing gender specific exercise interventions in SUD programs.
Related protocols: CTN-0037
African Americans who use substances experience a particular risk for HIV. Negative attitudes towards condoms are a strong predictor of risk and can serve as barriers to safe sex. They also vary by gender. In this secondary analysis of data from two NIDA Clinical Trials Network studies, CTN-0018 and CTN-0019, the relationship between gender, unprotected sex, and condom barriers among 203 African Americans in substance use treatment was examined.
Results indicated that no gender differences were present in unprotected sex. Men reported more motivational barriers to condom use and were more likely to believe that condoms would impede sexual experience (the latter not statistically significant). For both genders, the perception that condoms might negatively impact sexual experience was associated with unprotected sex. Gender did not moderate the relationship between condom barriers and unprotected sex.
Conclusions: These findings suggest the need for gender and race-specific prevention strategies that focus on motivation and address pleasure-based concerns regarding condoms. Substance use treatment facilities are well-positioned to support interventions to target these issues.
Related protocols: CTN-0018, CTN-0019
This article examines age differences across genders in clinical characteristics in emerging adult (25 years or less) vs. older adult patients (26 years or older) with opioid use disorder (OUD). Participants included 570 people (30% female) entering a comparative effectiveness medication trial of buprenorphine vs. extended-release naltrexone (CTN-0051, X:BOT).
Analysis revealed similar differences across genders in clinical characteristics in emerging adult vs. older participants. However, women who were 26 years old or older reported more mental health problems compared with women 25 years old or younger, while men 25 or younger reported more mental health problems compared with men 26 or older.
Conclusions: Different strategies for emerging adult and older patients seeking OUD treatment may be necessary to address psychiatric comorbidities that differ across genders in this population. Comprehensive psychiatric assessment should be systematically included in OUD treatment for all genders. Treatment should focus on the emerging adult development phase when appropriate, with psychiatric treatment tailored for women and men, separately, across the lifespan.
Related protocols: CTN-0051
This ancillary investigation of data from NIDA Clinical Trials Network protocol CTN-0051, a randomized, controlled trial comparing extended-release naltrexone to buprenorphine, examined baseline gender differences in individuals with opioid use disorder (OUD) receiving inpatient services. Participants (N=570) provided demographic, substance use, and psychiatric history information.
Women were significantly younger; more likely to identify as bisexual, live with a sexual partner, and be financially dependent on someone else; and less likely to be employed. Women also reported significantly greater psychiatric comorbidity and risk behaviors, and had shorter duration, but similar age of onset, of opioid use.
Conclusions: Findings underscore economic, psychiatric, and infection vulnerability among women with OUD, which may complicate treatment initiation, retention, and recovery. Gender-specific interventions focused on these areas of disparity for women with OUD should be considered, including integration of OUD care with treatment for co-occurring psychiatric disorders and trauma, couples-based risk reduction interventions which address relational dynamics, and interventions that address the unique needs of sexual minority women.
Related protocols: CTN-0051
This ancillary investigation of data from NIDA Clinical Trials Network protocol CTN-0051, a randomized, controlled trial comparing extended-release naltrexone to buprenorphine, examined baseline sex differences in men and women (N=570) with opioid use disorder (OUD) receiving inpatient services. Women were significantly younger; more likely to identify as bisexual, live with a sexual partner, and be financially dependent on someone else; and less likely to be employed. Women reported significantly greater psychiatric comorbidity and risk behaviors, and had shorter duration, but similar age of onset, of opioid use.
Conclusions: Findings underscore economic, psychiatric, and infection vulnerability among women with OUD, which may complicate treatment initiation, retention, and recovery. Interventions targeting these disparities should be explored.
Related protocols: CTN-0051
There are sex differences in buprenorphine/naloxone clinical trials for opioid use. While women have fewer opioid-positive urine samples, relative to men, a significant decrease in opioid-positive samples was found during treatment for men, but not women. In order to inform sex-based approaches to improve treatment outcomes, research is needed to determine if opioid use, and predictors of opioid use, differs between men and women during treatment. This secondary analysis of the NIDA Clinical Trials Network study CTN-0003, a randomized clinical trial comparing 7-day vs. 28-day buprenorphine/naloxone tapering strategies, examined sex differences (men=347, women=169) in opioid-positive samples. Addiction-related problem areas were defined by Addiction Severity Index-Lite (ASI-L) domain composite scores.
Results found that women were more likely than men to use opioids during the course of the buprenorphine/naloxone clinical trial, and medical issues were positive related to submitting an opioid-positive sample during treatment for women. No ASI-L domain composite score was associated with opioid-positive samples during treatment for me.
Conclusions: Women were more likely than men to use opioids during the course of the buprenorphine/naloxone clinical trial, and medical issues predicted opioid use during treatment for women but not men. These findings suggest that additional tests of sex differences in buprenorphine/naloxone clinical trials are warranted to further verify that women have increased opioid use during treatment. In addition, sex-specific risk factors such as medical problems may assist in developing more precise treatment strategies to couple with buprenorphine/naloxone therapy. Our findings demonstrate an increase in opioid use during treatment in relation to medical problems for women, suggesting that complementary treatment for medical problems during opioid replacement therapy would benefit women. Failure to address these needs may result in less successful opioid treatment for women.
Sexual risk behavior is now the primary vector of HIV transmission among substance users in the United States with gender as a crucial moderator of risk behavior. This study examined gender differences in factors (age, race/ethnicity, education) that predict main-partner unprotected sexual occasions (USO) using the unique platform of two parallel NIDA Clinical Trials Network gender-specific safer sex intervention trials. Baseline assessments of male (N=430) and female (N=377) participants included demographic characteristics; past 3-month sexual activity; and a diagnostic assessment for alcohol, cocaine/stimulant, and opioid use disorders. Using mixed effects generalized linear modeling of the main outcome USO, two-way interactions of gender with age, race/ethnicity, and education were evaluated and adjusted by alcohol, cocaine/stimulant, or opioid use disorder.
When adjusted for alcohol use disorder, the interaction of education and gender was significant. For men, a high school or greater education was significantly associated with more USO compared to men with less than high school. For women, greater than high school education was significantly associated with less USO compared to women with a high school education. None of the other interactions were significant when adjusted for cocaine/stimulant or opioid use disorder.
Conclusions: This study demonstrates gender differences in the relationship of education, alcohol use disorder, and main-partner USO in individuals in substance abuse treatment. This underscores the importance of considering demographic and substance use factors in HIV sexual risk behavior and in crafting prevention messages for this population.
Related protocols: CTN-0018, CTN-0019
Recent evidence suggests that women may fare worse than men in cannabis trials with pharmacologic interventions. Identifying baseline clinical profiles of treatment-seeking cannabis-dependent adults could inform gender-specific treatment planning and development. The current study compared baseline demographic, cannabis use, and psychiatric factors between women (n=86) and men (n=216) entering the Achieving Cannabis Cessation-Evaluating N-acetylcysteine Treatment (ACCENT) study, a multi-site randomized controlled trial conducted within the National Drug Abuse Treatment Clinical Trials Network.
Results found that women reported greater withdrawal intensity (p=.001) and negative impact of withdrawal (p=.001), predominantly due to physiological and mood symptoms. Women were more likely to have lifetime panic disorder (p=.038) and current agoraphobia (p=.022), and reported more days of poor physical health (p=.006) and cannabis-related medical problems (p=.023). Women reporting chronic pain had greater mean pain scores than men with chronic pain (p=.006). Men and women did not differ on any measures of baseline cannabis use.
Conclusions: Cannabis-dependent women may present for treatment with more severe and impairing withdrawal symptoms and psychiatric conditions compared to cannabis-dependent men. This might help explain recent evidence suggesting that women fare worse than men in cannabis treatment trials of pharmacologic interventions. Baseline clinical profiles of treatment-seeking adults can inform gender-specific treatment planning and development. Cannabis-dependent women may benefit from integrated treatment focusing on co-occurring psychiatric disorders and targeted treatment of cannabis withdrawal syndrome.
Related protocols: CTN-0053
This study examined differences in sexual risk behaviors by gender and over time among 1281 patients (777 males and 504 females) from 12 community-based substance use disorder treatment programs throughout the United States participating in CTN-0032, a randomized controlled trial conducted within the NIDA Clinical Trials Network. Zero-inflated negative binomial and negative binomial models were used in the statistical analysis. Results indicated significant reductions in most types of sexual risk behaviors among substance users regardless of the intervention arms. There were also significant gender differences in sexual risk behaviors. Men (compared with women) reported more condomless sex acts with their non-primary partners (IRR=1.80, 95% CI 1.21–2.69) and condomless anal sex acts (IRR=1.74, 95% CI 1.11–2.72), but fewer condomless sex partners (IRR=0.87, 95% CI 0.77–0.99), condomless vaginal sex acts (IRR=0.83, 95%CI 0.69–1.00), and condomless sex acts within 2 hours of using drugs or alcohol (IRR=0.70, 95%CI 0.53–0.90).
Conclusions: Significant reductions in most types of sexual risk behaviors were observed among participants in substance use disorder treatment, in the forms of increased abstinence and decreased number of condomless sex acts. These findings provide evidence that substance use disorder treatment may lead to HIV risk reduction. For the most part, gender differences showed women to have higher levels of risk than men, having more unprotected sex with primary partners and partners of unknown HIV status than men. Women also reported 30% more condomless sex acts within two hours of using drugs or alcohol compared to men in the study group. Gender-specific intervention approaches are called for in substance use disorder treatment.
Related protocols: CTN-0032