STUDY/Drug overdoses from opioids and stimulants are a major cause of mortality in the United States. It is unclear if there are stable sex differences in overdose mortality for these drugs across states, whether these differ across the lifespan, and if so, whether they can be accounted for by different levels of drug misuse. This was a state-level analysis of epidemiological data on overdose mortality, across 10-year age bins (age range: 15–74), using the CDC WONDER platform for decedents in the United States in 2020–1. The outcome measure was rate of overdose death (per 100,000) for: synthetic opioids (e.g., fentanyl), heroin, psychostimulants with potential for misuse (e.g., methamphetamine), and cocaine.
Multiple linear regressions controlled for ethnic-cultural background, household net worth, and sex-specific rate of misuse (from NSDUH, 2018-9). For all these drug categories, males had greater overall overdose mortality than females, after controlling for rates of drug misuse. The mean male/female sex ratio of mortality rate was relatively stable across jurisdictions: synthetic opioids (2.5 [95% CI, 2.4–7]), heroin, (2.9 [95% CI, 2.7–3.1], psychostimulants (2.4 [95% CI, 2.3–5]), and cocaine (2.8 [95% CI, 2.6–9]). With data stratified in 10-year age bins, the sex difference generally survived adjustment (especially in the 25–64 age range).
Results indicate that males are significantly more vulnerable than females to overdose deaths caused by opioid and stimulant drugs, taking into account differing state-level environmental conditions and drug misuse levels. These results call for research into diverse biological, behavioral, and social factors that underlie sex differences in human vulnerability to drug overdose.
Introduction
Overdose deaths due to opioids (such as fentanyl and heroin), or stimulant drugs (such as methamphetamine and cocaine) have increased in recent years in the United States. This increase has accelerated since the onset of the COVID-19 pandemic (March 2020 and thereafter) for fentanyl and its analogs and stimulants such as methamphetamine, but not heroin, prescription opioids, or methadone. This was due in part to increases in the distribution of synthetic opioids such as fentanyl, and their use to lace other drugs, including illicit preparations disguised as prescription opioid analgesics, stimulant medications, or benzodiazepines .
Prevention of overdose death requires the identification of vulnerability factors, which are thought to include sex and age. Regarding sex as a biological variable, data from rodent models are inconclusive due to conflicting results: some such studies have shown that female rats escalate their intake of opioids or stimulant drugs more than male rats, but a large number of other studies have not. Similarly, some studies in human cohorts have shown that females escalated their intake of opioids or stimulant drugs more rapidly than males, but several other studies have not. A recent comprehensive review did not find robust sex differences in vulnerability to craving and relapse. Nonetheless, as reviewed below, epidemiological data have suggested a sex difference in risk of overdose death, and those findings need to be followed up on.
Regarding age, studies have suggested typical trajectories in which misuse of opioids or stimulant drugs begins in late adolescence or young adulthood and escalates thereafter. However, the onset of misuse may also occur later in the lifespan, and can be triggered iatrogenic ally. Recent data also point to an increase in older adults (aged 55 and older) seeking first-time treatment for OUD.
Epidemiological studies show that males tend to have greater overdose mortality compared to females. Thus, a recent report for 2019–20, for 25 states and the District of Columbia, showed an increase in overdose mortality for all drugs combined, with a greater rate in males versus females . Similarly, a US nation-level analysis showed an increase in overdose mortality from synthetic opioids (thus including fentanyl but not heroin) and psychostimulants (including methamphetamine but not cocaine) from March 2018 to March 2021, with highest mortality rates in males (especially from minoritized groups, e.g., African-American). A nation-level report on CDC data from 2017 to 2018 showed that males compared to females had greater overdose mortality for prescription opioids specifically, and for all opioids combined.
Here we examined sex differences in greater depth across the lifespan and determined whether their magnitude is consistent across state-level US jurisdictions, which exhibit a broad range of major demographic and socioeconomic variables, levels of misuse, and illicit drug market factors. We examined overdose mortality separately for specific categories of opioid and stimulant drugs, due to their differing mechanisms of toxicity .
Acute overdose mortality from opioids (mu-opioid receptor agonists) is primarily attributed to respiratory depression mediated by brainstem nuclei . Overdose mortality from fentanyl may be greater than that for heroin, due to greater potency, faster onset of action driven by high lipophilicity, and higher likelihood to trigger chest rigidity . It is not clear whether there are generalizable sex differences in sensitivity to respiratory depressant effects of mu-opioid agonists in humans . Epidemiological data do not directly address this question, but could provide evidence against it (or in favor of additional explanations) if the sex difference in overdose mortality is not consistent across state-level jurisdictions.
Acute overdose mortality by methamphetamine and cocaine in humans is primarily attributed to cardiovascular and neurological events such as malignant arrhythmias, strokes, or seizures . Some, but not all, human studies reported that females had either more prolonged or more pronounced cardiovascular effects than males after administration of stimulant drugs. Again, epidemiological data cannot directly address questions of biological vulnerability, but could constrain hypotheses, depending on whether the sex difference in overdose mortality is consistent across states that differ in major demographic, socioeconomic and drug use factors.
In addition to sex differences in direct pathophysiological effects of the drug, factors that could account for stable variations in rates of overdose include family and social interactions and related trauma, propensity toward risky behaviors (e.g., injecting alone, taking large doses, or using untrusted suppliers) , and propensity to seek treatment. We expect that differences in these gendered behavioral factors would be largely consistent across drug categories and states in the US. Other contributing factors which could differ by state within the US include ethnic-cultural background, socioeconomic variables, illicit drug supply, and availability of evidence-based care.
Using state-level nationally representative CDC data for 2020–1, the goal of this study was therefore to determine the extent to which sex differences in overdose mortality vary in four mutually exclusive drug categories (synthetic opioids, heroin, psychostimulants such as methamphetamine, and cocaine) and state, accounting for age. Different patterns of sex variability in overdose mortality would suggest (without proving or ruling out) different emphases on possible levels of causation.
Methods
This was a study of de-identified publicly available data on “multiple cause mortality”, from the CDC WONDER platform for the years 2020-1 , based on death certificates in the United States. Overdose mortality data that were “suppressed” (due to n < 10 per cell) or deemed “unreliable” were considered missing and were excluded from analysis. Data were analyzed from October 2022 to February 2023. This study followed STROBE reporting guidelines.
Data set
The main analyzed outcome variable was crude death rate per 100,000 population for Drug Poisonings (ICD-10 codes for overdoses; including unintentional X40-X44, suicide X60-X64, homicide X85, and undetermined intents Y10–Y14). Data were obtained for four mutually exclusive categories: synthetic opioids other than methadone (“synthetic opioids” hereafter; this predominantly reflects fentanyl and its analogs, but also compounds from other chemical scaffolds; T40.4), [55] heroin (T40.1), psychostimulants with potential for misuse (which predominantly reflects methamphetamine; T43.6) and for cocaine (T40.5). Data were stratified by sex and by six consecutive 10-year age bins (i.e., 15–24, 25–34, 35–44, 45–54, 55–64 and 65–74) obtained for 51 jurisdictions (50 states and the District of Columbia) for 2020–1 .
Nomenclature
This manuscript uses the terms “male” and “female” for data analyses, as this is the terminology currently used in death certificates, the root document for mortality data in CDC WONDER . For clarity, we use the term “stimulant drugs” to encompass compounds such as methamphetamine and cocaine overall and use the term “psychostimulants” for the CDC overdose category (T43.6) that predominantly reflects methamphetamine. As stated above, cocaine overdoses (T40.5) are analyzed separately.
Data analyses
Analyses were carried out with Graph Pad Prism V.9, using jurisdiction-level data. Univariate analyses included Spearman correlations on overdose mortality data (crude death rate per 100,000 population) for males and females, per jurisdiction. Mortality and misuse ratios in males/females were compared with Wilcoxon tests. Univariate mixed-effects ANOVAs (sex x age bin) then analyzed log-transformed overdose mortality rate across the lifespan, stratified in six consecutive 10-year age bins; significant effects were followed with post-hoc Bonferroni tests. Normality of the outcome variable was examined with the Agostino-Pearson test (p = 0.05 level), followed by visual examination of quantile-quantile plots, when necessary.
Results
Overall overdose mortality profiles (age range 15–74)
With ages combined (overall range 15–74 years), there was a broad range of overdose mortality rates for the four drug categories, across jurisdictions
There were positive Spearman correlations, nearing unity, in the rate of overdose mortality for males and females in the same jurisdiction, for each of the drug categories (Spearman correlations ranged from +0.94 to +0.97; all p values were <0.0001) . Simple linear regressions provided a strong fit for these data (R2 values of 0.95, 0.88, 0.92 and 0.95, for synthetic opioids, heroin, psychostimulants and cocaine respectively). The mean ratios for mortality in males/females (all ages combined) were in the 2.4–9 range: ratios were 2.5 (95% CI: 2.4–7) for synthetic opioids, 2.9 (95% CI: 2.7–3.1) for heroin, 2.4 (95% CI: 2.3–5) for psychostimulants and 2.8 (95% CI: 2.6-9) for cocaine.
Source: Nature.com