Cardiovascular Complications of Opioid Use: JACC State-of-the-Art Review.

Opioids are the most potent of all analgesics. Although traditionally used solely for acute self-limited conditions and palliation of severe cancer-associated pain, a movement to promote subjective pain (scale, 0 to 10) to the status of a "fifth vital sign" bolstered widespread prescribing for chronic, noncancer pain. This, coupled with rising misuse, initiated a surge in unintentional deaths, increased drug-associated acute coronary syndrome, and endocarditis. In response, the American College of Cardiology issued a call to action for cardiovascular care teams. Opioid toxicity is primarily mediated via potent µ-receptor agonism resulting in ventilatory depression. However, both overdose and opioid withdrawal can trigger major adverse cardiovascular events resulting from hemodynamic, vascular, and proarrhythmic/electrophysiological consequences. Although natural opioid analogues are devoid of repolarization effects, synthetic agents may be proarrhythmic. This perspective explores cardiovascular consequences of opioids, the contributions of off-target electrophysiologic properties to mortality, and provides practical safety recommendations.

Propoxyphene Mediates Oxyhemoglobin-Induced Injury in Rat Cortical Neurons Through Up-Regulation of Active-ß-Catenin.

Wnt/ß-catenin signaling is involved in various biological processes, including the development of the central nervous system. The dysfunction of mitochondria has been shown to participate in the progress of subarachnoid hemorrhage (SAH). Traumatic subarachnoid hemorrhage (tSAH) is a serious complication in acute craniocerebral trauma. Opioids can activate the canonical Wnt/ß-catenin signaling pathway. c-Myc, a downstream protein of Wnt/ß-catenin signaling, contributes to the fusion of mitochondria. Here, we investigated the protective roles of Propoxyphene (Pro) against Oxyhemoglobin (OxyHb)-induced primary cultured neuron apoptosis. The data indicated that Pro rescued active-ß-catenin from OxyHb-induced decline. Furthermore, Pro attenuated OxyHb-induced apoptosis and fission of mitochondria in primary cortical neurons. However, the protective effects were abrogated under active-ß-catenin-deficient conditions. Together, the data presented here showed that Pro, a weak opioid analgesic drug, attenuates OxyHb-induced mitochondria-dependent apoptosis in an active-ß-catenin-c-Myc-dependent manner.

Fatal poisonings involving propoxyphene before and after voluntary withdrawal from the United States' market: An analysis from the state of Florida.

The synthetic opioid propoxyphene was a schedule IV controlled substance with multiple reported health risks before the US Food and Drug Administration issued a request for voluntary market withdrawal in November 2010. The purpose of this study is to investigate the characteristics and occurrences of propoxyphene-related deaths in Florida before and after voluntary market removal. Decedent-level toxicology data from Florida's Medical Examiners Commission was used to compare the temporal, polysubstance use, sociodemographic, and geographic profiles associated with propoxyphene-involved deaths for a pre-withdrawal (November 2008-November 2010) and post-withdrawal (December 2010-December 2012) period. Sensitivity analyses using multiple data sources, including Florida's Prescription Drug Monitoring Program and other states' data, were conducted to examine potential reporting bias. Results showed that the number of propoxyphene-involved deaths declined by 84% from 580 deaths to 92 deaths after market withdrawal. The co-occurrence of other prevalent drugs, such as oxycodone (17.2% to 26.1%, p=0.0422) increased significantly in the post-withdrawal study period. A larger proportion of the propoxyphene-related deaths were reported from South Florida after the withdrawal (28.4% to 56.5%, p<0.0001). No significant changes in age and race/ethnicity were observed. Sensitivity analyses revealed that several deaths occurred in other states after market withdrawal, as recently as 2016. Our findings are consistent with previous studies that propoxyphene was still available after removal from the US market. Continued surveillance is recommended after highly abused opioids are withdrawn from the market due to on-going safety risks.

The influence of propoxyphene withdrawal on opioid use in veterans.

PURPOSE: Our aim is to determine if propoxyphene withdrawal from the US market was associated with opioid continuation, continued chronic opioid use, and secondary propoxyphene-related adverse events (emergency department visits, opioid-related events, and acetaminophen toxicity). METHODS: Medical service use and pharmacy data from 19/11/08 to 19/11/11 were collected from the national Veterans Healthcare Administration healthcare databases. A quasi-experimental pre-post retrospective cohort design utilizing a historical comparison group provided the study framework. Logistic regression controlling for baseline covariates was used to estimate the effect of propoxyphene withdrawal. RESULTS: There were 24,328 subjects (policy affected n = 10,747; comparison n = 13,581) meeting inclusion criteria. In the policy-affected cohort, 10.6% of users ceased using opioids, and 26.6% stopped chronic opioid use compared with 3.8% and 13.5% in the historical comparison cohort, respectively. Those in the policy-affected cohort were 2.7 (95%CI: 2.5-2.8) and 3.2 (95%CI: 2.9-3.6) times more likely than those in the historical comparison cohort to discontinue chronic opioid and any opioid use, respectively. Changes in adverse events and Emergency Department (ED) visits were not different between policy-affected and historical comparison cohorts (p > 0.05). CONCLUSIONS: The withdrawal of propoxyphene-containing products resulted in rapid and virtually complete elimination in propoxyphene prescribing in the veterans population; however, nearly 90% of regular users of propoxyphene switched to an alternate opioid, and three quarters continued to use opioids chronically.

Performance of time-dependent propensity scores: a pharmacoepidemiology case study.

PURPOSE: Pharmacoepidemiologic studies of acute effects of episodic exposures often must control for many time-dependent confounders. Marginal structural models permit this and provide unbiased estimates when confounders are on the causal pathway. However, if causal pathway confounding is minimal, analyses with time-dependent propensity scores, calculated for time periods defined by individual drug prescriptions, may have better efficiency. We justify time-dependent propensity scores and compare the performance of these methods in a case study from a previous investigation of the risk of medication toxicity death in current users of propoxyphene and hydrocodone, with both substantial time-dependent confounding and a large number of covariates. METHODS: The cohort included Tennessee Medicaid enrollees who filled a qualifying study opioid prescription between 1992 and 2007. We identified 22 time-dependent covariates that accounted for most of the confounding in the original study. We compared analyses with all covariates in the regression model with those based on time-dependent propensity scores and those from marginal structural models. RESULTS: We identified 489,008 persons with 1,771,295 propoxyphene and 4,088,754 hydrocodone prescriptions. The unadjusted hazard ratio (propoxyphene : hydrocodone) was 0.70 (95%CI, 0.46-1.07). Estimates from inclusion of all covariates in the model, time-dependent propensity score analysis with inverse probability of treatment weighting, and marginal structural models were 1.63 (1.04-2.57), 1.65 (1.01-2.72), and 1.64 (0.83-3.27), respectively. Findings varied little with use of alternative propensity score methods, time origin, or techniques for marginal structural model estimation. CONCLUSIONS: Time-dependent propensity scores may be useful for pharmacoepidemiologic studies with time-varying exposures when causal pathway confounding is limited.