hydrocodone and Chemical-and-Drug-Induced-Liver-Injury

During the opioid epidemic, misuse of acetaminophen-opioid products resulted in supratherapeutic acetaminophen ingestions and cases of hepatotoxicity. In 2014, the US Food and Drug Administration (FDA) limited the amount of acetaminophen in combination products to 325 mg, and the US Drug Enforcement Administration (DEA) changed hydrocodone/acetaminophen from schedule III to schedule II. This study assessed whether these federal mandates were associated with changes in acetaminophen-opioid supratherapeutic ingestions.. We identified emergency department encounters at our institution of patients with a detectable acetaminophen concentration and manually reviewed these charts.. We found a decline in acetaminophen-opioid supratherapeutic ingestions after 2014. A downtrend in hydrocodone/acetaminophen ingestions accompanied a relative increase in codeine/acetaminophen ingestions from 2015 onwards.. This experience at one large safety net hospital suggests a beneficial impact of the FDA ruling in reducing likely unintentional acetaminophen supratherapeutic ingestions, carrying a risk of hepatotoxicity, in the setting of intentional opioid ingestions.

Topics: Acetaminophen; Analgesics, Opioid; Chemical and Drug Induced Liver Injury; Humans; Hydrocodone

Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds. Individual data for all 223 compounds are presented here and interrogated to determine what level of an alert to consider termination of a compound. The analysis showed that 76% of drugs with a daily dose of <100 mg were non-hepatotoxic (p < 0.0001). Drugs with a daily dose of ≥100 mg or with GSH adduct formation, marked P450 MDI, or covalent binding ≥200 pmol eq/mg protein tended to be hepatotoxic (∼ 65% in each case). Combining dose with each bioactivation assay increased this association significantly (80-100%, p < 0.0001). These analyses were then used to develop the decision tree and the tree tested using 196 of the compounds with sufficient data (49% hepatotoxic; 51% non-hepatotoxic). The results of these outcome analyses demonstrated the utility of the tree in selectively terminating hepatotoxic compounds early; 45% of the hepatotoxic compounds evaluated using the tree were recommended for termination before candidate selection, whereas only 10% of the non-hepatotoxic compounds were recommended for termination. An independent set of 10 GSK compounds with known clinical hepatotoxicity status were also assessed using the tree, with similar results.

Topics: Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Decision Trees; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Glutathione; Humans; Liver; Pharmaceutical Preparations; Protein Binding

Effective acute pain management is an essential but sometimes challenging component of dental practice. Numerous studies have examined the efficacy of various analgesic agents in dental postoperative models. This article combines an evaluation of the available evidence with current prescribing patterns to provide dental practitioners prescribing recommendations for acute pain, based on the anticipated severity of post-procedural pain. An important consideration when prescribing analgesics is to determine for whom opioid analgesics are necessary and appropriate, and if so, the dose and quantity that should be prescribed. This is partly because of the prevalence of substance and alcohol abuse that can be expected to be encountered within the dental patient population, and because substance abusers in the community frequently obtain prescription drugs from friends and family for misuse.

Topics: Acetaminophen; Acute Disease; Analgesics; Anesthetics, Local; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Drug Prescriptions; Facial Pain; Humans; Hydrocodone; Opioid-Related Disorders; Oral Surgical Procedures; Pain, Postoperative

This study determined the risk of serious hepatotoxicity resulting in hospitalizations among patients prescribed opioid/acetaminophen combinations.. A retrospective cohort study using an insurance claims database was conducted. Adult patients with ≥1 claim for oxycodone/acetaminophen or hydrocodone/acetaminophen combinations were included (N = 1,228,356). A pre-post design was employed to compare serious hepatotoxicity risk before versus after initiation of opioid/acetaminophen combination. Serious hepatotoxicity risk between the opioid/acetaminophen group and a control group of opioid-alone users (N = 11,809) was also examined. Within the opioid/acetaminophen group, risk of hepatotoxicity-related hospitalizations pre- versus post-opioid/acetaminophen treatment was compared using the normal approximation with the binomial distribution. The incidence rate of hepatotoxicity-related hospitalizations for the opioid/acetaminophen group was compared with the opioid-alone group using multivariate Poisson regression adjusting for baseline differences between groups.. Of the opioid/acetaminophen cohort, hepatotoxicity-related hospitalization risk in the 6-month post-opioid/acetaminophen period was lower than that in the pre-period with a risk reduction of 1.2 per 10,000 (pre-period = 0.12%; 95% confidence interval [CI], 0.12 to 0.13; post-period = 0.11%; 95% CI, 0.11 to 0.12). In the 12-month period, risk increased in the post-period by 2.4 per 10,000 (pre-period = 0.14%; 95% CI, 0.14 to 0.15; post-period = 0.17%; 95% CI, 0.16 to 0.18). After adjusting for confounders, the opioid-alone group did not demonstrate a lower rate of hepatotoxicity-related hospitalizations than the opioid/acetaminophen group (incidence rate ratio of opioid-alone over opioid/acetaminophen = 2.9; 95% CI, 1.8 to 4.7).. There is no population data-based evidence supporting elevated risk of hepatotoxicity-related hospitalization associated with opioid/acetaminophen combinations.

Topics: Acetaminophen; Adult; Aged; Analgesics, Opioid; Chemical and Drug Induced Liver Injury; Drug Combinations; Female; Hospitalization; Humans; Hydrocodone; Male; Middle Aged; Oxycodone; Pain; Risk Factors