Management of Acetaminophen Poisoning in the US and Canada: A Consensus Statement.

Importance: The US and Canada currently have no formal published nationwide guidelines for specialists in poison information or emergency departments for the management of acetaminophen poisoning, resulting in significant variability in management. Objective: To develop consensus guidelines for the management of acetaminophen poisoning in the US and Canada. Evidence Review: Four clinical toxicology societies (America's Poison Centers, American Academy of Clinical Toxicology, American College of Medical Toxicology, and Canadian Association of Poison Control Centers) selected participants (n = 21). Led by a nonvoting chairperson using a modified Delphi method, the panel created a decision framework and determined the appropriate clinical management of a patient with acetaminophen poisoning. Unique to this effort was the collection of guidelines from most poison centers in addition to systematic collection and review of the medical literature. Comments from review by external organizations were incorporated before the guideline was finalized. The project began in March 2021 and ended in March 2023. Findings: The search retrieved 84 guidelines and 278 publications. The panel developed guidelines for emergency department management of single or repeated ingestion of acetaminophen. In addition, the panel addressed extended-release formulation, high-risk ingestion, coingestion of anticholinergics or opioids, age younger than 6 years, pregnancy, weight greater than 100 kg, and intravenous acetaminophen use. Differences from current US practice include defining acute ingestion as an ingestion presentation from 4 to 24 hours after overdose was initiated. A revised form of the Rumack-Matthew nomogram was developed. The term massive ingestion was replaced with the term high-risk ingestion and denoted by a specific nomogram line. Other recommendations include specific criteria for emergency department triage, laboratory evaluation and monitoring parameters, defining the role of gastrointestinal decontamination, detailed management of acetylcysteine treatment, associated adverse effects, and stopping criteria for acetylcysteine treatment, as well as criteria for consultation with a clinical toxicologist. Finally, specific treatment considerations, including acetylcysteine dosing, fomepizole administration, and considerations for extracorporeal elimination and transplant evaluation, were addressed. Conclusions and Relevance: This qualitative study provides a consensus statement on consistent evidence-based recommendations for medical, pharmacy, and nursing education and practice to optimize care of patients with acetaminophen poisoning.

A Multi-Omic Mosaic Model of Acetaminophen Induced Alanine Aminotransferase Elevation.

BACKGROUND: Acetaminophen (APAP) is the most common cause liver injury following alcohol in US patients. Predicting liver injury and subsequent hepatic regeneration in patients taking therapeutic doses of APAP may be possible using new 'omic methods such as metabolomics and genomics. Multi'omic techniques increase our ability to find new mechanisms of injury and regeneration. METHODS: We used metabolomic and genomic data from a randomized controlled trial of patients administered 4 g of APAP per day for 14 days or longer with blood samples obtained at 0 (baseline), 4, 7, 10, 13 and 16 days. We used the highest ALT as the clinical outcome to be predicted in our integrated analysis. We used penalized regression to model the relationship between genetic variants and day 0 metabolite level, and then performed a metabolite-wide colocalization scan to associate the genetically regulated component of metabolite expression with ALT elevation. Genome-wide association study (GWAS) analyses were conducted for ALT elevation and metabolite level using linear regression, with age, sex, and the first five principal components included as covariates. Colocalization was tested via a weighted sum test. RESULTS: Out of the 164 metabolites modeled, 120 met the criteria for predictive accuracy and were retained for genetic analyses. After genomic examination, eight metabolites were found to be under genetic control and predictive of ALT elevation due to therapeutic acetaminophen. The metabolites were: 3-oxalomalate, allantoate, diphosphate, L-carnitine, L-proline, maltose, and ornithine. These genes are important in the tricarboxylic acid cycle (TCA), urea breakdown pathway, glutathione production, mitochondrial energy production, and maltose metabolism. CONCLUSIONS: This multi'omic approach can be used to integrate metabolomic and genomic data allowing identification of genes that control downstream metabolites. These findings confirm prior work that have identified mitochondrial energy production as critical to APAP induced liver injury and have confirmed our prior work that demonstrate the importance of the urea cycle in therapeutic APAP liver injury.

Genetic variants associated with ALT elevation from therapeutic acetaminophen.

BACKGROUND: Several studies have suggested genetic variants associated with acetaminophen induced liver injury (DILI) following overdose. Genetic variation associated with acetaminophen-induced alanine aminotransferase elevation during therapeutic dosing has not been examined. METHODS: We performed genetic analyses on patients that ingested therapeutic doses of 4 grams of acetaminophen for up to 16 days. We examined 20 genes previously implicated in the metabolism of acetaminophen or the development of immune-mediated DILI using the Illumina Multi-Ethnic Global Array 2. Autosomes were aligned and imputed using TOPMed. A candidate gene region analysis was performed by testing each gene individually using linkage disequilibrium (LD) pruned variants with the adaptive sum of powered scores (aSPU) test from the aSPU R package. The highest measured ALT during therapy, the maximum ALT, was used as the outcome. RESULTS: 192 subjects taking therapeutic APAP were included in the genetic analysis. 136 (70.8%) were female, 133 (69.2%) were Caucasian race, and the median age was 34 years (IQR: 26, 46). Age > 50 years was the only clinical factor associated with maximum ALT increase. Variants in SULT1E1, the gene responsible for Sulfotransferase Family 1E Member 1 enzyme production, were associated with maximum ALT. No single variant drove this association, but rather the association was due to the additive effects of numerous variants within the gene. No other genes were associated with maximum ALT increase in this cohort. CONCLUSION: Acetaminophen induced ALT elevation at therapeutic doses was not associated with variation in most genes associated with acetaminophen metabolism or immune-induced DILI in this cohort. The role of SULT1E1 polymorphism in acetaminophen-induced elevated ALT needs further examination.

Metabolomic markers predictive of hepatic adaptation to therapeutic dosing of acetaminophen.

BACKGROUND: Drug induced liver injury (DILI) remains a prominent global issue and acetaminophen (APAP) overdose represents a common cause of hepatic injury and DILI. Transient alanine aminotransferase (ALT) elevations have been documented while adhering to recommended daily dosing. However, no metabolites have been identified in pre-treatment samples predicting which patients will develop these transient increases. METHODS: This was a secondary analysis of samples collected from a parent study describing the course of ALT levels in subjects receiving therapeutic APAP dosing. Two hundred and four subjects recruited from Denver, Colorado received 4 g APAP/daily for at least 16 days. Subjects were grouped by ALT at any monitored time point above 60 units/L (n = 25) vs. no increase (n = 179). Serum samples from days 0, 7, 16, and 31 were run on ultra-high performance liquid chromatography mass spectrometry. We report the metabolomic results of samples analyzed prior to APAP administration and over time. Significant changes in metabolite and demographic variable expressions were explored using t-tests with false discovery rate correction, chi square, and partial least squares discriminant analyses. RESULTS: Within pre-treatment day 0 samples, allantoate and ornithine were significantly elevated in subjects of the ALT elevation group (p = .032). Baseline ALT (p = .011) and alkaline phosphatase (p = .006) were also significant. These metabolites were significant independent of race, ethnicity, gender, or BMI. CONCLUSIONS: Allantoate and ornithine are directly involved in pathways related to nitrogen release and urea production. Further investigation into alterations in the glutathione metabolism and urea cycle pathways may lead to a greater understanding of the mechanisms associated with hepatic adaptation for a variety of pharmaceuticals.

The Genomics of Elevated ALT and Adducts in Therapeutic Acetaminophen Treatment: a Pilot Study.

INTRODUCTION: Therapeutic acetaminophen (APAP) ingestion causes asymptomatic drug-induced liver injury in some patients. In most cases, elevations in alanine aminotransferase (ALT) are transient and return to the normal range, even with continued APAP ingestion, though ALT elevation persists in some patients unpredictably. The etiology of this liver injury or adaption is unclear. Our objective was to identify new pharmacogenomic variants associated with elevated ALT or elevated protein adduct concentrations in patients receiving therapeutic acetaminophen. METHODS: We performed genome-wide sequencing analysis on eight patients using leftover blood samples from an observational study that administered four grams of acetaminophen for up to 16 days to all patients. Two patients with ALT elevations > two times the upper limit of normal, two patients with no adduct formation, and four control patients were sequenced. The genomes were aligned with the GRCh38 reference sequence, and variants with predicted low, moderate, or high impact on the subsequent proteins were first manually curated for biologic plausibility, then organized and examined in the REACTOME pathway analysis program. RESULTS: We found 394 variants in 107 genes associated with elevated ALT. Variants associated with ALT elevation predominantly involved genes in the immune system (MHC class II complex genes), endoplasmic reticulum stress response (SEC23B and XBP1), oxidative phosphorylation (NDUFB9), and WNT/beta-catenin signaling (FZD5). Variants associated with elevated adducts were primarily in signal transduction (MUC20) and DNA repair mechanisms (P53). CONCLUSIONS: While underpowered, genetic variants in immune system genes may be associated with drug-induced liver injury at therapeutic doses of acetaminophen.

The In Vivo Net Energy Content of Resistant Starch and Its Effect on Macronutrient Oxidation in Healthy Adults.

The in vivo net energy content of resistant starch (RS) has not been measured in humans so it has not been possible to account for the contribution of RS to dietary energy intake. We aimed to determine the in vivo net energy content of RS and examine its effect on macronutrient oxidation. This was a randomized, double-blind cross-over study. Eighteen healthy adults spent 24 h in a whole room indirect calorimeter to measure total energy expenditure (TEE), substrate oxidation, and postprandial metabolites in response to three diets: 1) digestible starch (DS), 2) RS (33% dietary fiber; RS), or 3) RS with high fiber (RSF, 56% fiber). The in vivo net energy content of RS and RSF are 2.74 ± 0.41 and 3.16 ± 0.27 kcal/g, respectively. There was no difference in TEE or protein oxidation between DS, RS, and RSF. However, RS and RSF consumption caused a 32% increase in fat oxidation (p = 0.04) with a concomitant 18% decrease in carbohydrate oxidation (p = 0.03) versus DS. Insulin responses were unaltered after breakfast but lower in RS and RSF after lunch, at equivalent glucose concentrations, indicating improved insulin sensitivity. The average in vivo net energy content of RS is 2.95 kcal/g, regardless of dietary fiber content. RS and RSF consumption increase fat and decrease carbohydrate oxidation with postprandial insulin responses lowered after lunch, suggesting improved insulin sensitivity at subsequent meals.

Hands-Only Cardiopulmonary Resuscitation Education: A Comparison of On-Screen With Compression Feedback, Classroom, and Video Education.

STUDY OBJECTIVE: We compare 3 methods of hands-only cardiopulmonary resuscitation (CPR) education, using performance scores. A paucity of research exists on the comparative effectiveness of different types of hands-only CPR education. This study also includes a novel kiosk approach that has not previously been studied, to our knowledge. METHODS: A randomized, controlled study compared participant scores on 4 hands-only CPR outcome measures after education with a 25- to 45-minute practice-while-watching classroom session (classroom), 4-minute on-screen feedback and practice session (kiosk), and 1-minute video viewing (video only). Participants took a 30-second compression test after initial training and again after 3 months. RESULTS: After the initial education session, the video-only group had a lower total score (compressions correct on hand placement, rate, and depth) (-9.7; 95% confidence interval [CI] -16.5 to -3.0) than the classroom group. There were no significant differences on total score between classroom and kiosk participants. Additional outcome scores help explain which components negatively affect total score for each education method. The video-only group had lower compression depth scores (-9.9; 95% CI -14.0 to -5.7) than the classroom group. The kiosk group outperformed the classroom group on hand position score (4.9; 95% CI 1.3 to 8.6) but scored lower on compression depth score (-5.6; 95% CI -9.5 to -1.8). The change in 4 outcome variables was not significantly different across education type at 3-month follow-up. CONCLUSION: Participants exposed to the kiosk session and those exposed to classroom education performed hands-only CPR similarly, and both groups showed skill performance superior to that of participants watching only a video. With regular retraining to prevent skills decay, the efficient and free hands-only CPR training kiosk has the potential to increase bystander intervention and improve survival from out-of-hospital cardiac arrest.

Medication organizers (pill minders) increase the risk for unintentional pediatric ingestions.

OBJECTIVE: Medication organizers may help improve medication compliance; however, they may increase the risk of having an unintentional pediatric exposure. The objective of this study was to measure the association between a pediatric emergency department (ED) visit for an unintentional pharmaceutical ingestion and the use of a medication organizer in the household. METHODS: This was a cross-sectional case control study at a tertiary care children's hospital ED. Cases included subjects <6 years of age who were evaluated in the ED for an unintentional pharmaceutical ingestion. The control group presented to the ED for a non-injury complaint and was matched using age and sex. RESULTS: The unadjusted odds ratio (OR) of risk for unintentional pharmaceutical ingestion with use of a medication organizer was 2.0 (95% CI, 1.3, 2.9). After adjusting for the presence of prescription medications in the home, the OR of risk for ingestion remained statistically significant at 1.8 (95% CI, 1.1, 2.7). The child obtained the exposure medication from the medication organizer in 63% of cases where a medication organizer was present in the home. Cases were more likely to have knowledge of, and previous contact with poison control centers (PCC) than non-injury controls. Overall, a large number of caregivers (36%) did not have any knowledge of PCC. There were also differences in smoking and use of seat belts between cases and controls. CONCLUSIONS: The use of medication organizers may be a risk factor for unintentional pediatric pharmaceutical ingestions, even when controlling for the use of prescription medications in the home. Further research is needed to evaluate the specific role of medication organizers, and subsequently, improve prevention strategies.

Opioid prescription fill rates after emergency department discharge.

PURPOSE: Opioid prescription fill rates and the time to fill after emergency department (ED) discharge were studied. METHODS: Data were evaluated for all patients discharged from the ED between September 1, 2011, who were February 1, 2012, who were diagnosed with one of the following: dental pain, jaw pain, flank pain, abdominal pain, pelvic pain, back pain, neck pain, knee pain, headache, fracture, or sprain. Clinical information was abstracted via computer algorithm, and prescription filling within 100 days of prescription writing was determined by cross-referencing patient demographics with the state prescription drug monitoring program. Logistic regression analysis and a Cox proportional hazards model were used to determine if any clinical and demographic characteristics were associated with fill rates or the time to fill, respectively. RESULTS: Of the 2243 patients who received an opioid prescription at ED discharge, 1775 (79%) filled it, with a median time to fill of 0 days. On adjusted analysis, characteristics associated with filling the opioid prescriptions included Caucasian race, being insured by the federal government or through a state indigent assistance program, a chief complaint of back pain, and a history of filling an opioid prescription within the past year. No characteristics were predictive of a prolonged time to filling. CONCLUSION: One in five patients who received an opioid prescription at discharge from an urban academic ED did not fill it. Several factors may be associated with a greater likelihood of filling, such as insurance status and history of filling an opioid prescription within the past year.

Acute hepatotoxicity associated with therapeutic doses of intravenous acetaminophen.

BACKGROUND: IV acetaminophen at 4 g per day is considered safe, producing no hepatic failure in more than 1400 cases. Oxidation of acetaminophen forms a reactive intermediate that binds to cellular proteins resulting in acetaminophen-protein adducts (APAP-CYS). Serum concentrations of APAP-CYS have been found to correlate with acetaminophen-induced hepatotoxicity. We report a case of hepatotoxicity associated with therapeutic doses of IV acetaminophen, with elevated serum APAP-CYS. CASE DETAILS: The patient was a 92-year-old, 68 kg woman without known hepatic disease or ethanol abuse. On hospital day 3 she underwent laparoscopic reduction of internal hernias under general anesthesia. Surgery was uncomplicated and postoperatively she was treated with subcutaneous heparin and IV acetaminophen, 1 g every 6 h for almost 4 days (total dose = 13 g). At the start of therapy, transaminases were normal. On hospital day 5, she was noted to have marked transaminase elevations (AST: 4698 IU/L; ALT: 3914 IU/L) with increases in INR (1.68), ammonia (60 mcg/dL), and total bilirubin (1.8 mg/dL). Serum acetaminophen concentration was 15.3 mcg/mL 26 h after her last dose. Acetaminophen was discontinued and IV acetylcysteine was given and continued at the second maintenance dose rate for a second 16-hour infusion, at which time transaminases, INR, ammonia and total bilirubin were all improving. The patient was discharged 2 days later. Serum APAP-CYS concentrations in serum samples obtained during her hospitalization were elevated (peak = 4.81 µM on hospital day 5; expected range for therapeutic dosing <1.1 µM). CASE DISCUSSION: We have identified a case of acute liver injury associated with therapeutic dosing of IV acetaminophen. The serum APAP-CYS concentrations are consistent with that seen in cases of hepatotoxicity following repeated supratherapeutic acetaminophen ingestion. Several factors that likely contributed to her susceptibility included advanced age, post-operative status, a likely catabolic state and multiple acetaminophen doses over several days. These uncommon circumstances limit the generalizability of risk. We believe the findings are most consistent with acetaminophen-induced liver injury. CONCLUSION: This case illustrates a potential hazard of IV acetaminophen and demonstrates the potential utility of APAP-CYS adducts in evaluating causality in acute liver injury.

Clinically Inconsequential Alerts: The Characteristics of Opioid Drug Alerts and Their Utility in Preventing Adverse Drug Events in the Emergency Department.

STUDY OBJECTIVE: We examine the characteristics of clinical decision support alerts triggered when opioids are prescribed, including alert type, override rates, adverse drug events associated with opioids, and preventable adverse drug events. METHODS: This was a retrospective chart review study assessing adverse drug event occurrences for emergency department (ED) visits in a large urban academic medical center using a commercial electronic health record system with clinical decision support. Participants include those aged 18 to 89 years who arrived to the ED every fifth day between September 2012 and January 2013. The main outcome was characteristics of opioid drug alerts, including alert type, override rates, opioid-related adverse drug events, and adverse drug event preventability by clinical decision support. RESULTS: Opioid drug alerts were more likely to be overridden than nonopioid alerts (relative risk 1.35; 95% confidence interval [CI] 1.21 to 1.50). Opioid drug-allergy alerts were twice as likely to be overridden (relative risk 2.24; 95% CI 1.74 to 2.89). Opioid duplicate therapy alerts were 1.57 times as likely to be overridden (95% CI 1.30 to 1.89). Fourteen of 4,581 patients experienced an adverse drug event (0.31%; 95% CI 0.15% to 0.47%), and 8 were due to opioids (57.1%). None of the adverse drug events were preventable by clinical decision support. However, 46 alerts were accepted for 38 patients that averted a potential adverse drug event. Overall, 98.9% of opioid alerts did not result in an actual or averted adverse drug event, and 96.3% of opioid alerts were overridden. CONCLUSION: Overridden opioid alerts did not result in adverse drug events. Clinical decision support successfully prevented adverse drug events at the expense of generating a large volume of inconsequential alerts. To prevent 1 adverse drug event, providers dealt with more than 123 unnecessary alerts. It is essential to refine clinical decision support alerting systems to eliminate inconsequential alerts to prevent alert fatigue and maintain patient safety.

Cyclic vomiting presentations following marijuana liberalization in Colorado.

OBJECTIVES: Case reports have described a syndrome of cyclic vomiting associated with chronic marijuana use, termed cannabinoid hyperemesis syndrome. The primary objective was to determine the prevalence of patients presenting with cyclic vomiting before and after the liberalization of medical marijuana in Colorado in 2009. The secondary objective was to describe the odds of marijuana use among cyclic vomiting visits in these same time periods. METHODS: This was a cross-sectional study of cyclic vomiting visits to the emergency department (ED) before and after marijuana liberalization. ED visits with International Classification of Diseases, ninth revision, coding for cyclic vomiting or that met diagnostic criteria for cyclic vomiting by the Rome III criteria were included. RESULTS: The authors reviewed 2,574 visits and identified 36 patients diagnosed with cyclic vomiting over 128 visits. The prevalence of cyclic vomiting visits increased from 41 per 113,262 ED visits to 87 per 125,095 ED visits after marijuana liberalization, corresponding to a prevalence ratio of 1.92 (95% confidence interval [CI] = 1.33 to 2.79). Patients with cyclic vomiting in the postliberalization period were more likely to have marijuana use documented than patients in the preliberalization period (odds ratio = 3.59, 95% CI = 1.44 to 9.00). CONCLUSIONS: The prevalence of cyclic vomiting presentations nearly doubled after the liberalization of medical marijuana. Patients presenting with cyclic vomiting in the postliberalization period were more likely to endorse marijuana use, although it is unclear whether this was secondary to increased marijuana use, more accurate marijuana reporting, or both.

Confirming the Causative Role of Acetaminophen in Indeterminate Acute Liver Failure Using Acetaminophen-Cysteine Adducts.

INTRODUCTION: Acetaminophen-cysteine adducts (APAP-CYS) are a serum biomarker of acetaminophen exposure, formed when the oxidative metabolite of acetaminophen binds to cysteine residues of hepatic proteins. APAP-CYS adducts become elevated in cases of acute liver failure following acetaminophen overdose and have been proposed as a diagnostic tool to identify acetaminophen-induced acute liver failure when standard testing is inconclusive. CASE REPORT: A 26-year-old female with history of unexplained, severe hepatitis presented with a second episode of severe hepatitis including coagulopathy and transaminase levels >10,000 U/L. The patient reported ingesting "only a couple" of acetaminophen tablets several days prior to her presentation. An acetaminophen concentration of 14 mcg/mL at presentation aroused suspicion that acetaminophen might have caused the patient's liver failure, despite her adamant denial of overdose. APAP-CYS adduct levels measured from serum obtained 4 days after her presentation and in two consecutive serum samples are reported alongside previously reported APAP-CYS levels. DISCUSSION: The patient's APAP-CYS adduct levels were consistent with those seen in acute liver injury due to acetaminophen toxicity, even up to 1 week following presentation, and allowed for confirmation of acetaminophen toxicity as the cause of the her hepatitis. Overall, this case demonstrates the real-time application of APAP-CYS adducts as a biomarker to diagnose acetaminophen toxicity in patients with indeterminate acute liver failure.

Accuracy of Electronic Medical Record Medication Reconciliation in Emergency Department Patients.

BACKGROUND: Medication history discrepancies have the potential to cause significant adverse clinical effects for patients. More than 40% of medication errors can be traced to inadequate reconciliation. OBJECTIVE: The objective of this study was to determine the accuracy of electronic medical record (EMR)-reconciled medication lists obtained in an academic emergency department (ED). METHODS: Comprehensive research medication ingestion histories for the 48 h preceding ED visit were performed and compared to reconciled EMR medication lists in a convenience sample of ED patients. The reconciled EMR list of prescription, nonprescription, vitamins, herbals, and supplement medications were compared against a structured research medication history tool. We measured the accuracy of the reconciled EMR list vs. the research history for all classes of medications as the primary outcome. RESULTS: Five hundred and two subjects were enrolled. The overall accuracy of EMR-recorded ingestion histories in the preceding 48 h was poor. The EMR was accurate in only 21.9% of cases. Neither age ≥ 65 years (odds ratio [OR] = 1.3; 95% confidence interval [CI] 0.6-2.6) nor sex (female vs. male: OR = 1.5; 95% CI 0.9-2.5) were predictors of accurate EMR history. In the inaccurate EMRs, prescription lists were more likely to include medications that the subject did not report using (78.9%), while the EMR was more likely not to capture nonprescriptions (76.1%), vitamins (73.0%), supplements (67.3%), and herbals (89.1%) that the subject reported using. CONCLUSIONS: Medication ingestion histories procured through triage EMR reconciliation are often inaccurate, and additional strategies are needed to obtain an accurate list.

Initiation of a medical toxicology consult service at a tertiary care children's hospital.

Currently, only 10% of board-certified medical toxicologists are pediatricians. Yet over half of poison center calls involve children < 6 years, poisoning continues to be a common pediatric diagnosis and bedside toxicology consultation is not common at children's hospitals. In collaboration with executive staff from Department of Pediatrics and Emergency Medicine, regional poison center, and our toxicology fellowship, we established a toxicology consulting service at our tertiary-care children's hospital. There were 139 consultations, and the service generated 13 consultations in the first month; median of 11 consultations per month thereafter (range 8-16). The service increased pediatric cases seen by the fellowship program from 30 to 94. The transition to a consult service required a culture change. Historically, call center advice was the mainstay of consulting practice and the medical staff was not accustomed to the availability of bedside medical toxicology consultations. However, after promotion of the service and full attending and fellowship coverage, consultations increased. In collaboration with toxicologists from different departments, a consultation service can be rapidly established. The service filled a clinical need that was disproportionately utilized for high acuity patients, immediately utilized by the medical staff and provided a robust pediatric population for the toxicology fellowship.

The accuracy of self-reported drug ingestion histories in emergency department patients.

Inaccuracies in self-reports may lead to duplication of therapy, failure to appreciate non-compliance leading to exacerbation of chronic medical conditions, or inaccurate research conclusions. Our objective is to determine the accuracy of self-reported drug ingestion histories in patients presenting to an urban academic emergency department (ED). We conducted a prospective cohort study in ED patients presenting for pain or nausea. We obtained a structured drug ingestion history including all prescription drugs, over-the-counter medication (OTC) drugs, and illicit drugs for the 48 hours prior to ED presentation. We obtained urine comprehensive drug screens (CDS) and determined self-report/CDS concordance. Fifty-five patients were enrolled. Self-reported drug ingestion histories were poor in these patients; only 17 (30.9%) of histories were concordant with the CDS. For the individual drug classes, prescription drug-CDS was concordant in 32 (58.2%), OTC-CDS was concordant in 33 (60%), and illicit drug-CDS was concordant in 45 (81.8%) of subjects. No demographic factors predicted an accurate self-reported drug history. Sixteen patients had drugs detected by CDS that were unreported by history. Nine of these 16 included an unreported opioid. In conclusion, self-reported drug ingestion histories are often inaccurate and resources are needed to confirm compliance and ensure unreported drugs are not overlooked.

The effect of CYP2D6 drug-drug interactions on hydrocodone effectiveness.

OBJECTIVES: The hepatic cytochrome 2D6 (CYP2D6) is a saturable enzyme responsible for metabolism of approximately 25% of known pharmaceuticals. CYP interactions can alter the efficacy of prescribed medications. Hydrocodone is largely dependent on CYP2D6 metabolism for analgesia, ondansetron is inactivated by CYP2D6, and oxycodone analgesia is largely independent of CYP2D6. The objective was to determine if CYP2D6 medication coingestion decreases the effectiveness of hydrocodone. METHODS: This was a prospective observational study conducted in an academic U.S. emergency department (ED). Subjects were included if they had self-reported pain or nausea and were excluded if they were unable to speak English, were less than 18 years of age, had liver or renal failure, or carried diagnoses of chronic pain or cyclic vomiting. Detailed drug ingestion histories for the preceding 48 hours prior to the ED visit were obtained. The patient's pain and nausea were quantified using a 100-mm visual analog scale (VAS) at baseline prior to drug administration and following doses of hydrocodone, oxycodone, or ondansetron. We used a mixed model with random subject effect to determine the interaction between CYP2D6 drug ingestion and study drug effectiveness. Odds ratios (ORs) were calculated to compare clinically significant VAS changes between CYP2D6 users and nonusers. RESULTS: A total of 250 (49.8%) of the 502 subjects enrolled had taken at least one CYP2D6 substrate, inhibitor, or inducing pharmaceutical, supplement, or illicit drug in the 48 hours prior to ED presentation. CYP2D6 drug users were one-third as likely to respond to hydrocodone (OR = 0.33, 95% confidence interval [CI] = 0.1 to 0.8) and more than three times as likely as nonusers to respond to ondansetron (OR = 3.4, 95% CI = 1.3 to 9.1). There was no significant difference in oxycodone effectiveness between CYP2D6 users and nonusers (OR = 0.53, 95% CI = 0.3 to 1.1). CONCLUSIONS: CYP2D6 drug-drug interactions appear to change effectiveness of commonly prescribed drugs in the ED. Drug-drug interaction should be considered prior to prescribing CYP2D6 drugs.