Prescription Opioid Use and Risk for Major Depressive Disorder and Anxiety and Stress-Related Disorders

Abstract

IMPORTANCEGrowing evidence suggests that prescription opioid use affects depression and anxiety disorders; however, observational studies are subject to confounding, making causal inference and determining the direction of these associations difficult.OBJECTIVE To investigate the potential bidirectional associations between the genetic liability for prescription opioid and other nonopioid pain medications and both major depressive disorder (MDD) and anxiety and stress-related disorders (ASRD) using genetically based methods. DESIGN, SETTING, AND PARTICIPANTSWe performed 2-sample mendelian randomization (MR) using summary statistics from genome-wide association studies (GWAS) to assess potential associations of self-reported prescription opioid and nonopioid analgesics, including nonsteroidal anti-inflammatories (NSAIDs) and acetaminophen-like derivatives use with MDD and ASRD. The GWAS data were derived from participants of predominantly European ancestry included in observational cohorts. Data were analyzed February 20, 2020, to May 4, 2020.MAIN OUTCOMES AND MEASURES Major depressive disorder, ASRD, and self-reported pain medications (opioids, NSAIDs, anilides, and salicylic acid). RESULTSThe GWAS data were derived from participants of predominantly European ancestry included in the population-based UK Biobank and Lundbeck Foundation Initiative for Integrative Psychiatric Research studies: approximately 54% of the initial UK Biobank sample and 55.6% of the Lundbeck Foundation Initiative for Integrative Psychiatric Research sample selected for the ASRD GWAS were women. In a combined sample size of 737 473 study participants, single-variable MR showed that genetic liability for increased prescription opioid use was associated with increased risk of both MDD (odds ratio [OR] per unit increase in log odds opioid use, 1.14; 95% CI, 1.06-1.22; P < .001) and ASRD (OR, 1.24; 95% CI, 1.07-1.44; P = .004). Using multivariable MR, these opioid use estimates remained after accounting for other nonopioid pain medications (MDD OR, 1.14; 95% CI, 1.04-1.25; P = .005; ASRD OR, 1.30; 95% CI, 1.08-1.46; P = .006), and in separate models, accounting for comorbid pain conditions. Bidirectional analyses showed that genetic liability for MDD but not ASRD was associated with increased prescription opioid use risk (OR, 1.18; 95% CI, 1.08-1.30; P < .001). These estimates were generally consistent across single-variable and multivariable inverse variance-weighted (MV-IVW) and MR-Egger sensitivity analyses. Pleiotropy-robust methods did not indicate bias in any MV-IVW estimates. CONCLUSIONS AND RELEVANCEThe findings of this mendelian randomization analysis suggest evidence for potential causal associations between the genetic liability for increased prescription opioid use and the risk for MDD and ASRD. While replication studies are necessary, these findings may inform prevention and intervention strategies directed toward the opioid epidemic and depression.

Prevalence and Trends of Opioid Use in Patients With Depression in the United States

“…The underlying mechanisms of prescription opioids in the pathophysiology of depression are still unknown, but they may include opioid-induced dysregulation of reward circuitry, which results in decreased reward perception or pleasure and relief generation, or other physical medical dysregulation, which may contribute to the physical symptoms of depression. Studies have reported that prolonged opioid use (more than 30 days) contributes significantly to developing depression, even more than high doses of opioids [25][26][27].…”

“…More than half of individuals with opioid use disorder have comorbid depression. This suggests that targeting opioid use prevention for patients with depression may help mitigate the US opioid epidemic [ 25 ].…”

A genetically-informed study disentangling the relationships between tobacco smoking, cannabis use, alcohol consumption, substance use disorders and respiratory infections, including COVID-19

“…Further, while we found some evidence that AUD may increase the risk for COVID-19; the largely null other current AUD findings does not support a broader AUD-respiratory disease relationship. However, like other recent psychiatric MR studies where the exposure instruments included a relaxed statistical threshold, our binge drinking and AUD instruments were comprised of independent SNPs associated with the respective drinking behavior (i.e., P-value < 5×10 −6 ) for SNP inclusion due to the lack of conventionally GWS SNPs (P-value < 5×10 −8 ), 29,30 which may impact the results. Because heavy alcohol consumption and AUD have been previously linked with acute respiratory distress syndrome 10 – one of the most severe complications of COVID-19, 73 future studies re-evaluating the links between heavy alcohol consumption and AUD when better powered GWAS data becomes available.…”

Association Between Insomnia and Migraine Risk: A Case–Control and Bidirectional Mendelian Randomization Study

“…[12][13][14] It has been adopted in a wide range of diseases, including cardiovascular diseases, cancers, neuropsychiatric disorders, ischemic stroke, Type 2 diabetes, infectious diseases, and so on. [15][16][17][18][19][20][21][22][23][24][25][26] In this case, we conducted a case-control study and a bidirectional MR analysis to determine whether insomnia is causally related to development of migraine. To ensure the authority and sophistication of the study, the instrumental variables for insomnia were derived from the largest genome-wide association study (GWAS) of 1,331,010 participants, while the genetic instruments for migraine were available from the largest meta-analysis of migraine with 59,674 cases and 316,078 controls.…”