Are prescription misuse and illicit drug use etiologically distinct? A genetically-informed analysis of opioids and stimulants

Abstract

Background Drug classes are grouped based on their chemical and pharmacological properties, but prescription and illicit drugs differ in other important ways. Potential differences in genetic and environmental influences on the (mis)use of prescription and illicit drugs that are subsumed under the same class should be examined. Opioid and stimulant classes contain prescription and illicit forms differentially associated with salient risk factors (common route of administration, legality), making them useful comparators for addressing this etiological issue. Methods A total of 2410 individual Australian twins [Mage = 31.77 (s.d. = 2.48); 67% women] were interviewed about prescription misuse and illicit use of opioids and stimulants. Univariate and bivariate biometric models partitioned variances and covariances into additive genetic, shared environmental, and unique environmental influences across drug types. Results Variation in the propensity to misuse prescription opioids was attributable to genes (41%) and unique environment (59%). Illicit opioid use was attributable to shared (71%) and unique (29%) environment. Prescription stimulant misuse was attributable to genes (79%) and unique environment (21%). Illicit stimulant use was attributable to genes (48%), shared environment (29%), and unique environment (23%). There was evidence for genetic influence common to both stimulant types, but limited evidence for genetic influence common to both opioid types. Bivariate correlations suggested that prescription opioid use may be more genetically similar to prescription stimulant use than to illicit opioid use. Conclusions Prescription opioid misuse may share little genetic influence with illicit opioid use. Future research may consider avoiding unitary drug classifications, particularly when examining genetic influences.

Specificity in genetic and environmental risk for prescription opioid misuse and heroin use

“…Though their assumptions regarding the nature of shared influences differ, both models identified substantial drug-specific additive genetic variance in POM (26–39% of the total phenotypic variance; 69–71% of the total genetic variance) that was not similarly present for heroin use (0% of the total phenotypic variance in both models; 0% of the total genetic variance in both models), the latter of which was primarily accounted for by variance shared with other drug use (79–80% of the total phenotypic variance). This supports past findings of smaller genetic and environmental correlations between POM and heroin use than would perhaps be expected (Dash et al, 2022 ).…”

“…First, such a pattern suggests that disaggregating POM and heroin use could increase the replicability of findings across samples with varying proportions of POM v. heroin use (Cheng et al, 2018; Dash et al, 2022). Second, the presence of POM-specific genetic influence unshared with heroin use has important implications for case–control selection in genomic studies of opioid use disorder (OUD), which typically do not differentiate POM-exposed individuals from heroin-exposed individuals, nor POM- v. heroin-based OUD (Cheng et al, 2018; Dash et al, 2022; Gelernter et al, 2014; Zhou et al, 2020). This is also salient considering that heroin-exposed individuals tend to progress to OUD at higher rates than POM-exposed individuals (Wu et al, 2011).…”

“…The present study aimed to explore specificity in genetic and environmental risk for POM and heroin use within a multivariate twin framework. Most twin studies using this approach have utilized an aggregate opioid use phenotype that combines POM and heroin use, potentially obscuring unique influences on each opioid type (Dash et al, 2022 ; Karkowski et al, 2000 ; Kendler et al, 1999 , 2003 ; Tsuang et al, 1998 ). Here, we aimed to identify whether and to what degree POM and heroin use are influenced by distinct etiologic influences and to explore how genetic and environmental influences on POM and heroin use are situated within a broader constellation of drug (mis)use behaviors.…”

“…To date, twin studies that have parsed POM and heroin use have only done so within univariate and bivariate frameworks (Dash et al, 2022 ; Gillespie et al, 2019 ). The present study aimed to expand on this emergent literature by modeling POM and heroin use as distinct phenotypes within a multivariate framework as a means of explicating the degree to which their genetic and environmental influences are shared both with each other and with other drug (mis)use more broadly.…”

“…Despite substantial effort to explicate the genetic etiology of opioid use and associated sequalae (Cheng et al, 2020 ; Deak et al, 2022 ; Jensen, 2016 ; Zhou et al, 2020 ), many twin and genomic studies have struggled to identify significant and/or replicable findings (Crist, Reiner, & Berrettini, 2019 ; Polimanti et al, 2020 ; Reed & Kreek, 2021 ). Heritability estimates of opioid use derived from twin studies have been varied, ranging from 0% to 79% (Dash, Martin, Agrawal, Lynskey, & Slutske, 2022 ; Karkowski, Prescott, & Kendler, 2000 ; Kendler, Aggen, Tambs, & Reichborn-Kjennerud, 2006 ; Kendler, Jacobson, Prescott, & Neale, 2003 ; Kendler, Karkowski, Neale, & Prescott, 2000a ; Kendler, Karkowski, & Prescott, 1999 ; Tsuang et al, 1998 ; Van den Bree, Johnson, Neale, & Pickens, 1998 ). Such discrepancies in findings regarding the relative influence of genes and environment on opioid use may be at least partially attributable to the operationalization of opioid use as a single behavior encompassing both prescription opioid misuse (POM) and heroin use: emerging evidence suggests that POM and heroin use may be differentially influenced by genes and environment, such that POM is more strongly influenced by genes and heroin use is more strongly influenced by common environment (Dash et al, 2022 ; Gillespie et al, 2019 ).…”