Trends in hydrocodone combination product exposures reported to California Poison Control System (CPCS) following DEA rescheduling.

CONTEXT: On October 6, 2014, the United States Drug Enforcement Administration (DEA) implemented a regulatory change for hydrocodone combination products (HCPs), moving them from Schedule III to II, in an effort to decrease drug overdoses. Existing research suggests this regulatory action reduced HCP prescribing and dispensing; however, there is limited research assessing its possible effects on overdoses and accidental exposures. OBJECTIVE: To analyze the changes in opioid exposures reported to the California Poison Control System (CPCS) before and after DEA rescheduling of HCPs. METHODS: We collected monthly exposure data reported to CPCS from 2012 to 2019 and conducted interrupted time series analyses to assess changes in exposures after rescheduling for HCPs, tramadol, oxycodone, morphine, codeine, fentanyl, and heroin. Additional analyses were done to assess any changes in exposures resulting in severe outcomes (moderate or major health effects). For HCPs, we also conducted logistic regressions to identify characteristics of exposures resulting in severe outcomes before and after rescheduling. RESULTS: Overall monthly opioid exposures reported to CPCS decreased after DEA rescheduling of HCPs. These decreases were significant for HCP, tramadol, and morphine (p < 0.001). Exposures significantly increased for heroin and fentanyl (p < 0.001). There were no significant changes in the share of severe outcomes attributed to HCP exposures after rescheduling. DISCUSSION: The DEA rescheduling of HCPs was associated with a significant decrease in HCP exposures and prescription opioid exposures overall, but was associated with increased fentanyl and heroin exposures. While other initiatives may have contributed to this decrease, our findings suggest that rescheduling may be a useful regulatory strategy to reduce drug exposures. CONCLUSION: DEA rescheduling of HCPs was associated with a significant reduction in prescription opioid exposures, suggesting that rescheduling high-risk drugs may be an effective strategy to improve public health.

Opioid Deaths in Milwaukee County, Wisconsin 2013-2017: The Primacy of Heroin and Fentanyl.

Heroin and fentanyl are the overwhelming and increasing cause of opioid deaths in Milwaukee County, Wisconsin. We reviewed all drug and opioid deaths from 2013 to 2017 to delineate the specific opioid drugs involved and changes in their incidence. From 2013 to 2017, 980 deaths were due to opioids, rising from 184 in 2013 to 337 in 2017. In 2017, opioid deaths exceeded combined non-natural deaths from homicide and suicide. Illicit heroin and fentanyl/analogs caused 84% of opioid deaths and 80% of drug deaths, with no increase in deaths due to oral prescription drugs such as oxycodone and hydrocodone. Any approach to decreasing this dramatic increase in opioid deaths should first focus on interdicting the supply and cheap availability of these illicit opioids. Fentanyl and its analogs represent the most deadly opioids and the greatest threat to human life in our population.

Fatal Fentanyl: One Pill Can Kill.

OBJECTIVE: The current national opioid epidemic is a public health emergency. We have identified an outbreak of exaggerated opioid toxicity caused by fentanyl adulterated tablets purchased on the street as hydrocodone/acetaminophen. METHODS: Over an 8-day period in late March 2016, a total of 18 patients presented to our institution with exaggerated opioid toxicity. The patients provided a similar history: ingesting their "normal dose" of hydrocodone/acetaminophen tablets but with more pronounced symptoms. Toxicology testing and analysis was performed on serum, urine, and surrendered pills. RESULTS: One of the 18 patients died in hospital. Five patients underwent cardiopulmonary resuscitation, one required extracorporeal life support, three required intubation, and two received bag-valve-mask ventilation. One patient had recurrence of toxicity after 8 hours after naloxone discontinuation. Seventeen of 18 patients required boluses of naloxone, and four required prolonged naloxone infusions (26-39 hours). All 18 patients tested positive for fentanyl in the serum. Quantitative assays conducted in 13 of the sera revealed fentanyl concentrations of 7.9 to 162 ng/mL (mean = 52.9 ng/mL). Pill analysis revealed fentanyl amounts of 600-6,900 µg/pill. The pills are virtually indistinguishable from authentic hydrocodone/acetaminophen tablets and are similar in weight. To date, our county has reported 56 cases of fentanyl opioid toxicity, with 15 fatalities. In our institution, the outbreak has stressed the capabilities and resources of the emergency department and intensive care units. CONCLUSIONS: A serious outbreak of exaggerated opioid toxicity caused by fentanyl-adulterated tablets purchased on the street as hydrocodone/acetaminophen is under way in California. These patients required higher dosing and prolonged infusions of naloxone. Additionally, observation periods off naloxone were extended due to delayed, recurrent toxicity. The outbreak has serious ramifications for public health and safety, law enforcement, and healthcare facilities and resources.

Trends in analgesic exposures reported to Texas Poison Centers following increased regulation of hydrocodone.

CONTEXT: In October 2014, the Drug Enforcement Administration reclassified hydrocodone to schedule II, increasing regulations on use. The impact of rescheduling hydrocodone on opioid exposures is unclear, especially in states with special restrictions required for prescribing schedule II agents. OBJECTIVE: To assess whether changes in exposures to prescription opioid analgesics and heroin as reported to poison centers occurred in the 6 months after hydrocodone rescheduling. We hypothesized that hydrocodone exposures would decrease, while less tightly regulated opioids, such as codeine and tramadol, would increase. MATERIALS AND METHODS: This study compares opioid analgesic exposures reported to Texas Poison Centers before and after this change in a state that requires special prescription pads for Schedule II agents. Cases included all opioid analgesic exposures reported to a statewide poison center network, comparing exposures from 6 months before to 6 months after heightened regulations. Specific opioids with large changes in reported exposures were further characterized by patient age and exposure intent. RESULTS: Hydrocodone exposures decreased from 1567 to 1135 (28%, p = 0.00017), decreasing for all ages. Codeine exposures increased significantly from 189 to 522 (176%, p = 0.00014), including a 263% increase for age >20 years. Codeine misuse increased 443% and adverse drug events 327%. Oxycodone exposures increased from 134 to 189 (39%, p = 0.0143), increasing only among patients age >20 years. Reported heroin exposures increased from 156 to 179 (15%, p = 0.2286) and tramadol from 666 to 708 (6%, p = 0.0193). Other opioid exposures changed little or had limited reports. DISCUSSION: The increased regulation of hydrocodone was followed temporally by a decrease in reported hydrocodone exposures, but also increases in codeine, oxycodone and tramadol exposures. This may reflect a shift in prescribing practices, changes in street availability of hydrocodone or decreased drug diversion. CONCLUSION: The increased regulation was temporally associated with decreased hydrocodone exposures reported to Texas Poison Centers.

A case of moderate liver enzyme elevation after acute acetaminophen overdose despite undetectable acetaminophen level and normal initial liver enzymes.

Liver function test (LFT) increase is an early sign of acetaminophen (APAP) toxicity. Typically, when an acute overdose patient is evaluated and has an initial undetectable APAP level and normal liver enzymes, the patient is not treated with N-acetylcysteine, and liver enzymes are not expected to increase later. We report a case of moderate LFT increase despite normal LFTs and an undetectable APAP level after delayed presentation of an APAP ingestion. A 22-year-old male with no medical history ingested 15-25 hydrocodone/APAP tablets (5 mg/500 mg). His suicide note and his bunkmate corroborated the overdose time. He arrived at the emergency department 16 hours after ingestion. At that time, his APAP level was <10 µg/mL, and his liver enzymes were normal [aspartate transaminase (AST) 31 U/L and alanine transaminase (ALT) 34 U/L]. Twenty-nine hours after ingestion, the psychiatry team obtained LFTs (AST 45, ALT 61). He had persistent nausea and diffuse abdominal pain. On repeat analysis, the APAP level at 36 hours was found to be <10 µg/mL, AST 150, and ALT 204. After 2 more days of increasing LFTs and persistent abdominal pain and nausea, the toxicology department was consulted, the patient was transferred to the medicine department, and intravenous N-acetylcysteine was started 66 hours after ingestion. He was treated for 16 hours and had a significant decline in LFTs and symptom resolution. His prothrombin time, bilirubin, lactate, creatinine, and mental status were normal throughout the admission. Other cases of LFT increase were excluded. Our case report illustrates that a moderate increase in liver transaminase may occur despite an initial undetectable APAP level and normal transaminases after a delayed presentation. In our case, no serious clinical effects were reported.

Sodium channel blockade with QRS widening after an escitalopram overdose.

INTRODUCTION: Escitalopram is rarely associated with prolongation of the QTc interval; however, there are no reported cases of QRS complex widening associated with escitalopram overdose. We report a case of a patient who presented with both QRS complex widening and QTc interval prolongation after an escitalopram overdose. CASE: A 16-year-old girl presented to the emergency department after ingestion of escitalopram, tramadol/acetaminophen, and hydrocodone/acetaminophen. Laboratory results were significant for 4-hour acetaminophen 21.1 µg/mL. Serum electrolytes including potassium, magnesium, and calcium were all normal. Initial electrocardiogram (ECG) revealed a widened QRS with an incomplete right bundle branch pattern. After administration of 100-mEq sodium bicarbonate, a repeat ECG revealed narrowing of the QRS complex and a prolonged QTc interval. Magnesium sulfate 2 g intravenous and sodium bicarbonate drip were initiated. A repeat ECG, 1 hour after the second, revealed normalization of the QRS complex and QTc interval. DISCUSSION: Prolongation of the QTc interval is an expected effect of escitalopram. Both escitalopram and citalopram are metabolized to the cardiotoxic metabolite S-didesmethylcitalopram and didesmethylcitalopram, respectively, which have been implicated in numerous cardiac abnormalities including widening of the QRS complex. Although never previously described with escitalopram, this mechanism provides a reasonable explanation for the QRS complex widening and incomplete right bundle branch block that occurred in our patient. CONCLUSIONS: Both QRS complex widening and QTc interval prolongation should be monitored in cases of escitalopram and citalopram overdoses.

Clinical characteristics of cough mixture abusers referred to three substance abuse clinics in Hong Kong: a retrospective study.

OBJECTIVES. Cough mixture is the third most commonly abused substance in patients attending the Prince of Wales Hospital Substance Abuse Clinic. The content of the local cough mixture is not well researched. Paranoid psychosis manifesting as persecutory delusions and derogatory hallucination, as well as mood symptoms, is common in these patients. The natural history and outcome of such psychoses associated with cough mixture abuse are not well known. This study aimed to address these questions. METHODS. This was a retrospective study of cough mixture abuse in Hong Kong. Case records of cough mixture abusers currently receiving treatment at the 3 substance abuse clinics at the Prince of Wales Hospital, Alice Ho Miu Ling Nethersole Hospital, and the North District Hospital were retrieved for data collection. The patients' demographic data, duration and intake pattern of cough mixture, and use of any other drugs were documented. The presenting psychopathology, first urine toxicology results, diagnosis, treatment, number of hospitalizations, and course of the illness were also recorded. RESULTS. A total of 63 patients with the diagnosis of cough mixture abuse were identified in the database; 89% were male. The mean +/- SD age of the patients was 34.4 +/- 6.2 years; 67% were single and 83% were unemployed. The mean +/- SD age of onset of cough mixture abuse was 20 +/- 5 years. Psychiatric symptoms developed a mean +/- SD of 7.6 +/- 6.0 years after onset of abuse. According to the ICD-10 Mental and Behavioural Disorders criteria, the top psychiatric diagnoses were substance-induced psychotic disorder (67%), schizophrenia (19%), depressive disorder (11%), and dysthymia (10%). The most common ingredients in the urine sample at first presentation were promethazine (75%), pseudoephedrine (67%), codeine (60%), ephedrine (57%), zopiclone (17%), and hydrocodone (16%). Additionally, 16% of patients were in the priority follow-up group. The mean +/- SD follow-up period was 6.2 +/- 7.1 years during which there were 3.2 +/- 3.7 episodes of hospitalizations, with a mean +/- SD length of stay in each admission of 25.0 +/- 40.9 days. CONCLUSIONS. Promethazine, ephedrine, pseudoephedrine, codeine, and hydrocodone are the most common ingredients of cough mixture abused in this locality. Psychotic disorders are the most frequent psychiatric diagnosis associated with cough mixture abuse.

Overdose deaths demand a new paradigm for opioid rotation.

OBJECTIVE: An increasing number of deaths have been inferred to be associated with current opioid rotation practices and evidence is mounting that the use of widely accepted protocols for opioid rotation is an important contributing factor. Based on the findings of a literature review published in conjunction with this article, we propose a new paradigm for a potentially safer method of opioid rotation and present a case study illustrating the paradigm. This new paradigm suggests three easy-to-remember steps in opioid rotation and obviates the need to use a conversion table. DESIGN: Report of a clinical case of a patient undergoing opioid rotation using this new paradigm. SUMMARY: The patient was successfully rotated from extended-release oxycodone to extended-release hydromorphone. The dose of oxycodone was slowly decreased, while the hydromorphone dose was slowly titrated. A critical element to this approach involved providing sufficient immediate-release opioid to treat breakthrough pain and to reverse acute abstinence signs and symptoms if the dosing changes prove insufficient. CONCLUSION: A safer new paradigm for opioid rotation may provide an important incremental step forward in reducing adverse public health consequences of inappropriate opioid dosing.

Ingestions of hydrocodone, carisoprodol, and alprazolam in combination reported to Texas poison centers.

The combination of hydrocodone, carisoprodol, and alprazolam is subject to abuse. Ingestions of this drug combination reported to Texas poison centers during 1998-2009 were identified (totaling 1,295 cases) and the distribution of ingestions by selected factors was determined. The number of cases increased from 0 in 1998 to 200 in 2007, and then decreased to 132 in 2009. The counties in eastern and southeastern Texas accounted for 80.9% of the cases. Of the patients, 57.3% were women and 94.6% were age 20 or older. Suspected attempted suicide accounted for 59.3% of the cases and intentional misuse or abuse for 27.3%.

What is the lethal concentration of hydrocodone?: a comparison of postmortem hydrocodone concentrations in lethal and incidental intoxications.

Hydrocodone is a semisynthetic opioid medication that is widely used as an analgesic and antitussive. Since 2004 it has been the most commonly prescribed drug in the United States and is often misused as a drug of abuse. Hydrocodone is frequently encountered in the postmortem setting, both as a cause of death and incidentally. Unfortunately, information regarding the concentrations of hydrocodone found with chronic high-dose use is lacking, and interpretation of postmortem concentrations can be difficult. A retrospective review of postmortem and "Driving under the Influence" (DUI) cases in Bexar County Texas in which hydrocodone was present was conducted. The cases were included in the study if they fit the criteria of belonging to 1 of 3 categories: the hydrocodone either caused or was the main contributor to death; the hydrocodone was incidental and definitively did not cause or contribute to death; and the DUI cases. The average hydrocodone concentration in the cases where the hydrocodone caused death was 0.47 mg/L (median, 0.38 mg/L). The average hydrocodone concentration in cases where it was incidental to death was 0.15 mg/L (median, 0.08 mg/L). The average hydrocodone concentration in the DUI cases was 0.09 mg/L (median, 0.08 mg/L). Analysis showed the possibility of postmortem redistribution as well as significant overlap of the concentrations noted in the different groups. Given that no definitive lethal concentration could be delineated, it is recommended that each hydrocodone case encountered be assessed individually to include a thorough medical record review to accurately interpret hydrocodone concentrations. It has also been shown that concentrations as high as 0.3 mg/L peripherally and 1.4 mg/L centrally can be present and not result in death. In addition, further research into hydrocodone concentrations with chronic use and hydrocodone metabolism is necessary.

Fatal hydrocodone overdose in a child: pharmacogenetics and drug interactions.

Fatal opioid toxicity occurred in a developmentally delayed child aged 5 years 9 months who was inadvertently administered high doses of hydrocodone for a respiratory tract infection. The concentration of hydrocodone in postmortem blood was in the range associated with fatality; however, hydromorphone, a major metabolite catalyzed by cytochrome P450 2D6 (CYP2D6), was not detected when using mass spectrometry. Genetic analysis revealed that the child had a reduced capability to metabolize the drug via the CYP2D6 pathway (CYP2D6*2A/*41). Coadministration of clarithromycin (a potent cytochrome P450 3A4 inhibitor) for an ear infection and valproic acid for seizures since birth further prevented drug elimination from the body. This case highlights the interplay between pharmacogenetic factors, drug-drug interactions, and dose-related toxicity in a child.

Profile of medication identification requests managed by a U.S.-certified regional poison information center.

INTRODUCTION: According to the American Association of Poison Control Centers, the number of medication identification requests (MIR) to poison centers has increased dramatically. In 2003, there were 617,414 calls compared to 1,070,537 in 2007. The purpose of this investigation was to characterize the nature of the most common requests to a poison center for medication identification. METHODS: To profile the MIR to a poison information center, the data from 2003 to 2007 were analyzed to identify all requests for medication identification. The subset of MIR data was extracted and analyzed to profile the requests by the specific medication and category. Descriptive statistics were used to characterize the data. RESULTS: MIR were responsible for 193,006 calls: 24,643 in 2003, increasing to 55,473 in 2007. In 2003, there were inquiries about 1,261 different medications and in 2007 that increased to 3,165. During all but two of the five years, substances with known substance abuse potential accounted for 24 of the 25 most common MIR. Acetaminophen in combination with either hydrocodone or oxycodone dominated the requests. The most common identification request each year was for the brand-specific product Mallinckrodt 512 (acetaminophen/oxycodone). DISCUSSION: The most frequent MIR involved medications with substance abuse potential, primarily opioids. CONCLUSIONS: Poison center MIR data can provide important information to officials about substance abuse trends.

Alleged breaches of "standards of medical care" in a patient overdose death possibly related to chronic opioid analgesic therapy, application of the controlled substances model guidelines: case report.

OBJECTIVES: The objectives of this medicolegal case report are the following: 1) to present details of a chronic pain patient (CPP) who was placed on chronic opioid analgesic therapy (COAT), and subsequently overdosed on multiple drugs, some of which were not prescribed by his COAT physician; 2) to present both the plaintiff's and defendant's (the COAT prescriber) expert witnesses' opinions as to the allegation that COAT prescribing was the cause of death; and 3) based on these opinions, to develop some recommendations on how pain physicians can utilize the use of Controlled Substances Model Guidelines in order to protect the patient and themselves from such an occurrence. METHODS: This is a case report of a CPP treated by a pain physician. RESULTS: Differences between the plaintiff's and defendant's expert's opinions are explained utilizing the Controlled Substances Model Guidelines. CONCLUSIONS: Some CPPs may withhold information critical to their COAT treatment. Application of the Controlled Substances Model Guidelines and the newer Federation of State Medical Boards' policy on opioid prescribing can be helpful in improving patient care and may be helpful in protecting the physician medicolegally.