Troponin, A Predictor of Mortality in Methadone Exposure: An Observational Prospective Study.

Background Methadone poisoning/overdose is a global public health problem. We aimed to determine whether methadone poisoning increased cardiac troponin and whether high-sensitivity cardiac troponin I (hs-cTnI) levels predicted the need for intensive care unit admission, intubation, and mortality. Methods and Results This observational, prospective single-center study was done at Loghman-Hakim Hospital (Tehran, Iran) from June 2018 until February 2019. Patients aged >14 years admitted with a diagnosis of methadone exposure were included. Patients were excluded if they had coexisting conditions associated with elevated hs-cTnI levels. An ECG and hs-cTnI levels were obtained on emergency department presentation. Patients were followed up on their need for intubation, intensive care unit admission, and in-hospital mortality. Of 245 included patients (186 [75.9%] men; median age, 33 years), most referred to loss of consciousness (210 cases, 89%). Nineteen (7.7%) patients had hs-cTnI levels of >0.1 ng/mL (positive), and 41 (16.7%) had borderline levels of 0.019 to 0.1 ng/mL. Twenty-three (9.3%) cases were admitted to the intensive care unit, 21 (8.5%) needed intubation, and 5 (2%) died during hospitalization. An hs-cTnI cutoff value of 0.019 ng/mL independently predicted mortality. For optimal concomitant sensitivity and specificity, receiver operating characteristic curve analysis was conducted and showed that hs-cTnI had an independent significant association with mortality, with a cutoff value of 0.0365 ng/mL (odds ratio, 38.1; 95% CI, 2.3-641.9; P<0.001). Conclusions Methadone exposure/toxicity is a newly identified cause of elevated hs-cTnI. Values >0.019 ng/mL, and particularly >0.0365 ng/mL, of hs-cTnI predicted mortality in our sample. Future studies should measure troponin levels in methadone maintenance treatment clients to assess the risk of myocardial injury from long-term exposure.

Forensic pathological study of methadone-related deaths in the Genoa (Italy) district: A six-year study.

Methadone is a synthetic opioid, a pure agonist of the µ receptor. It is used for opioid maintenance therapy in heroin addiction. In recent years, Italian studies of incidence and prevalence have indicated an increase in the illegal sales of methadone and, consequently, an increase in deaths due to acute methadone intoxication as well. The present review is a prospective-observational study regarding epidemiological and toxicological analyses of methadone-related deaths recorded in the district of Genoa (Italy) from 2013 to 2018. The study includes a list of twenty-six people that have died from methadone toxicity: twenty-two males and four females. The concentration of methadone in the blood samples ranged from 181 to 4058.53 ng/mL, with an average of 964.29 ng/mL. Six subjects tested positive for methadone alone; twenty cases, however, presented drugs or substances in different concentrations in the blood samples. Illegal sales and consumption of methadone have a negative impact on the self-administration therapy of opioid addiction, inducing patients to increase their dosage or sell methadone in order to purchase illegal drugs. As shown in our study, this behaviour is associated with an increase in methadone-related deaths. Accordingly, careful monitoring of dosage administrated to patients is required in order to render the system safer.

Intravenous methadone causes acute toxic and delayed inflammatory encephalopathy with persistent neurocognitive impairments.

BACKGROUND: The mu-opioid agonist methadone is administered orally and used in opioid detoxification and in the treatment of moderate-to-severe pain. Acute oral methadone-use and -abuse have been associated with inflammatory and toxic central nervous system (CNS) damage in some cases and cognitive deficits can develop in long-term methadone users. In contrast, reports of intravenous methadone adverse effects are rare. CASE PRESENTATION: Here, we report a patient who developed acute bilateral hearing loss, ataxia and paraparesis subsequently to intravenous methadone-abuse. While the patient gradually recovered from these deficits, widespread magnetic resonance imaging changes progressed and delayed-onset encephalopathy with signs of cortical dysfunction persisted. This was associated with changes in the composition of monocyte and natural killer cell subsets in the cerebrospinal fluid. CONCLUSION: This case suggests a potential bi-phasic primary toxic and secondary inflammatory CNS damage induced by intravenous methadone.

Unintentional buprenorphine and methadone poisoning in children: a matched observational study.

OBJECTIVE: To compare accidental pediatric poisoning from methadone vs. buprenorphine in terms of clinical indicators and in-hospital morbidity. METHODS: A matched observational study conducted on children aged ≤12 years admitted to our center between March 2018 and March 2019 with acute poisoning from methadone or buprenorphine. Data were extracted from the electronic patient files of the pediatric methadone poisoning cases, and buprenorphine poisoning cases were followed from ED, during the study period. Cases were compared regarding rates of bradypnea/apnea (primary outcome), the need for antidote therapy and intubation, duration of hospital stay, miosis, loss of consciousness, blood gas analyses, and mortality (secondary outcomes). RESULTS: A total of 90 methadone- and 30 buprenorphine-poisoned children were evaluated. Methadone cases had significantly higher rates of apnea (20/90 methadone vs. 0/30 buprenorphine; OR = 17.7, 95% CI 1.1, 302.8; p = 0.047), but there was no group difference in bradypnea (39/90 methadone vs. 10/30 buprenorphine; p = ns). 28 (31%) methadone and 3 buprenorphine (10%) cases had been referred to as fully awake (p = 0.013). Methadone cases required higher median naloxone doses for initial bolus (0.4 vs. 0.02 mg; p = 0.014) and maintenance infusion (14.4 vs. 2.4 mg; p < 0.001). 20 apnea cases (all from the methadone group) had miotic pupils, and miotic pupils were seen in 44 (90%) cases with bradypnea (OR = 3.2, 95% CI 1.1, 9.3; p = 0.026). Intubation was needed in only 5 methadone cases (5.5%; p = ns). All patients survived. CONCLUSION: Compared to children poisoned with methadone, buprenorphine cases had higher rates of loss of consciousness on admission but subsequently experienced fewer complications during hospital treatment, which is likely due to the buprenorphine partial antagonist effect. Our findings suggest that methadone exposure is more toxic than buprenorphine in pediatric populations.

Methadone-related deaths among youth and young adults in Sweden 2006-15.

AIMS: To identify methadone-related deaths and determine the prevalence among youth and young adults in Sweden 2006-15. DESIGN, SETTING AND PARTICIPANTS: National retrospective registry study comparing data from all forensic autopsy examinations and toxicology cases involving methadone during 2006-15 in individuals aged 15-29 years with police records, previous pharmaceutical prescriptions and health-care episodes. MEASUREMENTS: Multinomial logistic regression. To assess the factors contributing to the deaths, we compared individuals with and without previous substance use treatment and opioid use-related diagnoses with regard to previous opioid agonist treatment (OAT), psychiatric care and previous pain medication. To assess the circumstances of deaths, we analyzed the presence of other drugs and other factors at time of death. FINDINGS: We identified 269 methadone-related deaths, and the rate increased during the study period. Seventy-two (27%) cases had not previously received substance use treatment, 112 (42%) had received treatment but had no opioid use-related diagnosis and 85 (32%) had received treatment and had an opioid use-related diagnosis. In total, only 10 individuals had been prescribed methadone during the year before death. Prescriptions of benzodiazepines (60%), antidepressants (62%) and opioids for pain (22%) the year before death were common. Most deaths occurred during sleep with a time lag from ingestion of methadone. CONCLUSION: Prescription opioid- and methadone-related deaths increased in the group aged 15-29 years in Sweden between 2006 and 2015. Exposure to non-prescribed methadone and prescribed benzodiazepines, antidepressants and opioids for pain appears to be common in drug-related deaths in youth and young adults in Sweden.

A study of the effectiveness of naltrexone in preventing recurrence of methadone poisoning in opioid-naive children.

BACKGROUND: The prevalence of poisoning from methadone and prescription opioids is increasing in pediatric populations. Naloxone is the main antidote for treatment. Long-acting opioid toxicity may need close observation in the intensive care unit (ICU). In our previous study, naltrexone prevented re-narcotization in methadone-poisoned adults. Here, we aim to share our experience with the use of oral naltrexone for preventing recurrence of toxicity in opioid-naïve children. METHODS: In a single-center, retrospective case series, children (age ≤12 years) admitted to a poison center in Tehran (Iran) between March 2014-March 2016 were included if they presented with methadone poisoning and received naltrexone treatment in hospital. Naltrexone (1 mg/kg) was administrated orally after initial administration of 0.1 mg/kg naloxone intravenously. Children were monitored for level of consciousness, cyanosis, respiratory rate, VBG results, and O2 saturation for ≥48 h during their hospitalization. RESULTS: Eighty patients with methadone poisoning were enrolled, with median age of three years (range: 0.2-12.0). None involved polysubstance poisoning. Following naltrexone treatment, none experienced recurrent opioid toxicity during hospitalization, and hospital records indicated no readmission within 72-h post-discharge. CONCLUSION: Oral naltrexone could be a potential substitute for continuous naloxone infusion in methadone-poisoned children and reduce the need for ICU care.

Aspiration in lethal drug abuse-a consequence of opioid intoxication.

AIMS: The primary objective of this study was to investigate whether the fatalities of opioid abuse are not only related to respiratory depression but also as a result of other side effects such as emesis, delayed gastric emptying, a reduction of the cough reflex, and impaired consciousness leading to the aspiration of gastric contents, a finding regularly observed in drug-related deaths. DESIGN: A retrospective exploratory study analyzing heroin/morphine/methadone-related deaths submitted to court-ordered autopsy. SETTING: Center for Forensic Medicine, Medical University of Vienna, Austria (2010-2015). PARTICIPANTS: Two hundred thirty-four autopsy cases were included in the study: morphine (n = 200), heroin (n = 11), and methadone (n = 23) intoxication. FINDINGS: Analyses revealed that 41.88% of all deceased showed aspiration of gastric contents with equal gender distribution (p = 0.59). Aspiration was more frequent in younger deceased (χ2 = 8.7936; p = 0.012) and in deceased with higher body mass index (BMI) (χ2 = 6.2441; p = 0.044). Blood opioid concentration was lower in deceased with signs of aspiration than in non-aspirators (p = 0.013). Toxicological evaluation revealed a high degree of concomitant substance abuse (91%)-benzodiazepines (61.6%) and/or alcohol (21.8%). CONCLUSIONS: There are lower opioid concentrations in deceased with signs of aspiration, a fact which strongly points to aspiration as alternative cause of death in opioid-related fatalities. Furthermore, this study highlights the common abuse of slow-release oral morphine in Vienna and discusses alternative medications in substitution programs (buprenorphine/naloxone or tamper-resistant slow-release oral morphine preparations), as they might reduce intravenous abuse and opioid-related deaths.

Clinical characteristics and time trends of hospitalized methadone exposures in the United States based on the Toxicology Investigators Consortium (ToxIC) case registry: 2010-2017.

BACKGROUND: Methadone is well known for its long duration of action and propensity for mortality after an overdose. The present research was aimed at evaluating the clinical manifestations and time trends of methadone exposure in patients in US hospitals. METHODS: We queried the American College of Medical Toxicology's Toxicology Investigators Consortium case registry for all cases of methadone exposure between January 1, 2010, and December 31, 2017. The collected information included demographic features, clinical presentations, therapeutic interventions, poisoning type (acute, chronic, or acute on chronic), and the reason(s) for exposure. Descriptive data and relative frequencies were used to investigate the participants' characteristics. Our data analysis was performed using SPSS version 19 and Prism software. The trends and clinical manifestations of methadone poisoning over the time period of the study were specifically investigated. RESULTS: Nine hundred and seventy-three patients who met our inclusion criteria, with a mean age of 41.9 ± 16.6 years (range: 11 months-78 years) were analyzed. Five hundred eighty-two (60.2%) were male. The highest rate of methadone poisoning was observed in 2013. There was an increasing rate of methadone exposures in 2010-2013, followed by a decline in 2014-2017. The most common clinical manifestations in methadone-poisoned patients were coma (48.6%) and respiratory depression (33.6%). The in-hospital mortality rate of methadone poisoning was 1.4%. CONCLUSION: ToxIC Registry data showed that inpatient methadone exposures enhanced from 2010 to 2013, after which a reduction occurred in the years 2014 to 2017.

The impact of the prescription opioid epidemic on young children: Trends and mortality.

BACKGROUND: Our objective was to describe trends and deaths in young children associated with opioid analgesics. METHODS: Analysis of pediatric exposures using the RADARS System Poison Center Program from July 1, 2010 through December 31, 2018. Cases involving a child < 6 years, with an exposure to one or more opioids: buprenorphine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tramadol. Poisson regression was used to model the shape of the time response curve. RESULTS: 48,560 cases were identified, median age 2 years (IQR 1.4, 2.0), 52.4 % male. The most commonly involved opioid was hydrocodone (32.5 %); buprenorphine and methadone had the highest exposure rates when adjusted for dispensed prescriptions (0.84 and 0.73 per 10,000 prescriptions). There were 28 deaths, methadone being the most commonly involved opioid (16). Exposures decreased significantly accounting for population (from 8.39 to 4.19 exposures per 100,000 children) and per prescription (from 0.33 to 0.25 exposures per 10,000 prescriptions). After adjustment for prescriptions, the exposure rate for hydromorphone and fentanyl increased over the study period, while buprenorphine had the greatest decrease in exposure rate. Among 28 deaths, 11 (39 %) were known or suspected to have been exposed, but medical care was not sought or was delayed. CONCLUSION: Pediatric opioid exposure rates by prescription and population decreased from July 2010 through December 2018. However, with over 48,000 exposures and 28 deaths, the opioid epidemic continues to impact young children. Many exposures including deaths were preventable. Continued improvements in prevention require a multifaceted approach.

Buprenorphine to reverse respiratory depression from methadone overdose in opioid-dependent patients: a prospective randomized trial.

BACKGROUND: Naloxone is the usual drug used in opioid-induced respiratory depression but it has a short half-life, precipitates withdrawal in dependent patients, and thus for persistent reversal of long-acting opioids has to be given by titrated doses and infusions. The partial agonist buprenorphine has a much longer duration of action and causes less severe withdrawal, but still should largely reverse respiratory depression induced by full agonist opioids. We aimed to compare the efficacy/safety of buprenorphine and naloxone in reversing respiratory depression in methadone-poisoned opioid-dependent patients. METHODS: Patients with methadone-induced respiratory depression were randomized to receive naloxone (titrated doses), or lower or higher doses of buprenorphine (10 µg/kg or 15 µg/kg). The primary outcome was immediate reversal of respiratory depression. We also recorded acute opioid withdrawal, need for intubation/recurrent apnea, repeated doses of opioid antagonists, length of hospital stay, other morbidity, and mortality. The study was registered with the Iranian Registry of Clinical Trials (Trial ID: 18265; Approval code: IRCT2015011020624N1). RESULTS: Eighty-five patients were randomized; 55/56 patients who received buprenorphine had rapid reversal of respiratory depression, which persisted for at least 12 h. Naloxone was effective in 28/29 patients, but often required very high titrated doses (thus delaying time to respond) and prolonged infusions. Intubation (8/29 vs 5/56) and opioid withdrawal (15/29 vs 7/56) were less common with buprenorphine. There were no serious complications or deaths in those receiving buprenorphine. The 15-µg/kg buprenorphine dose appeared to provide a longer duration of action, but precipitated withdrawal more frequently than the 10-µg/kg dose. CONCLUSION: Buprenorphine appears to be a safe and effective substitute for naloxone in overdosed opioid-dependent patients. Further studies are warranted to explore the optimal dosing strategy for buprenorphine to consistently maintain reversal of respiratory depression but not precipitate withdrawal. TRIAL REGISTRATION NUMBER: IRCT2015011020624N1. Registered 30 September 2015.

Epidemiology of pediatric buprenorphine and methadone exposures reported to the poison centers.

BACKGROUND: Buprenorphine prescriptions have increased dramatically within the United States, whereas methadone continues to be used widely. We investigated the trends and characteristics of buprenorphine and methadone exposures in the pediatric population. METHODS: We identified pediatric exposures to buprenorphine and methadone using the National Poison Data System from 2013 to 2016. We descriptively assessed characteristics of the exposures. Trends in exposures were evaluated using generalized linear mixed models. RESULTS: Pediatric buprenorphine exposures increased from 2013 (1097) to 2016 (1226) while methadone calls decreased (486 to 396). After adjusting for the random effects of the geographical region, the mean number of pediatric buprenorphine exposures (per 100,000 pediatric population) increased from 1.3 to 1.5 (P = .05). Conversely, the mean number of methadone exposures decreased from 0.6 to 0.4 (P = .03). Children aged ≤3 years constituted the highest percentage of both exposures. Unintentional exposures accounted for most of the buprenorphine (86.9%) and methadone (62.4%) exposures. Major clinical effects were demonstrated in 2.3% of buprenorphine exposures and were more frequent with methadone (13%). West Virginia and Maryland demonstrated the highest incidence of buprenorphine and methadone exposures, respectively. CONCLUSIONS: Pediatric buprenorphine exposures increased but demonstrated less severe effects compared to methadone exposures, which decreased during the study period.

Investigating opioid-related fatalities in southern Sweden: contact with care-providing authorities and comparison of substances.

BACKGROUND: Opioid-related deaths have increased in Western countries over recent decades. Despite numerous studies investigating opioid-related mortality, only a few have focused on the lives of the deceased individuals prior to their deaths, specifically regarding contact with care-providing authorities such as health, social and correctional services. Furthermore, a change has been noted in the last two decades as to which opioids cause most deaths, from heroin to prescription opioids. However, studies comparing fatalities caused by different substances are rare. The aim of this study was to investigate contact with care-providing authorities during the year prior to death among individuals who died as a result of opioid intoxication and to analyse differences relating to which opioids caused their deaths. METHODS: The study is based on retrospective register data and includes 180 individuals with a history of illicit drug use, who died from opioid intoxication in Skåne, Sweden, between 1 January 2012 to 31 December 2013 and 1 July 2014 to 30 June 2016. Intoxications caused by heroin, methadone, buprenorphine and fentanyl were included. Data were collected from the National Board of Forensic Medicine, regional health care services, municipal social services and the Prison and Probation Service. Statistical testing was performed using Pearson's chi-square test, Fisher's exact test and the Mann-Whitney U test to analyse group differences. RESULTS: A total of 89% of the deceased individuals had been in contact with one or more of the care-providing authorities during the year prior to death; 75% had been in contact with health care, 69% with the social services, 28% with the Prison and Probation Service, and 23% had been enrolled in opioid substitution treatment at some point during their final year of life. Few differences appeared between the substance groups with regard to which opioid contributed to the death. In addition to opioids, sedatives were present in more than 80% of the cases. Individuals whose deaths were buprenorphine-related had been in contact with the social services to a significantly lesser extent during the year prior to death. CONCLUSIONS: The studied population is characterised by extensive contact with care-providing authorities, thus providing numerous opportunities for authorities to reach this group with preventive and other interventions. Few differences emerged between groups with regard to which opioid had contributed to the death.

Potential undercounting of overdose deaths caused by specific drugs in vital statistics data: An analysis of Florida.

INTRODUCTION: Due largely to ambiguous or incomplete information provided on death certificates, the widely cited Multiple Cause of Death (MCOD) data reported by the U.S. Centers for Disease Control and Prevention has been shown to undercount the number of fatal overdoses caused by specific drugs. However, the extent of the undercounts is unclear. METHODS: We obtained the number of fatal overdoses from 2003 to 2017 in Florida caused by the three drug groups (amphetamines, benzodiazepines, and opioids) and three drugs (methadone, cocaine, and heroin) that we could map across the MCOD data and data reported by the Florida Medical Examiners Commission (FMEC). The FMEC data are based on state-mandated reporting of the causal drugs in overdose deaths. We analyzed the differences across all deaths and by gender, age group, and race. RESULTS: Depending on the drug, the numbers of deaths across all individuals reported in the FMEC data ranged from 19 %-39 % higher than the counts in the MCOD data. The differences varied over time and by some demographic factors. CONCLUSIONS: The MCOD data appear to undercount the number of fatal overdoses caused by the drugs we investigated. Our analysis did not identify a cause or pattern to explain the differences. Efforts to improve the reporting of fatal overdoses may enhance our understanding of and subsequently may improve the response to the drug overdose epidemic.

Methadone poisonings: a seven-year retrospective study of the French poison center network focusing on suicide attempts vs. misuses.

Methadone has been prescribed in France as opioid substitution therapy as a syrup formulation since 1995 and as capsules since 2008. Following two publications showing on a national scale the high risk of methadone poisoning in children and the lack of difference in poisoning severity between both methadone formulations, French health authorities chose to benefit from the experience acquired by the network of French poison centres concerning poisoning by this substitution medication. The aim of this study was to identify and compare the main circumstances of methadone exposure collected by a poison centre on a national scale over a period of 7 years. Retrospective descriptive study of cases of methadone exposure was compiled by the network of French poison centres between 15 October 2010 and 15 October 2017. Analysis of 1415 files revealed two major circumstances: 47% misuse and 41% suicide attempts. Severity scores evaluated according to the PSS were higher for misuse than for suicidal behaviour, despite the supposed ingested dose being statistically higher in the latter. The results also confirmed the lack of significant difference in methadone exposure between both of the formulations (syrup and capsules). This series of methadone exposure on a national scale is one of the largest compiled series in international medical literature. On the one hand, it highlights the severity of methadone poisoning (in suicidal behaviour and even more so in misuse behaviour), and on the other hand, it confirms that the capsule formulation does not seem to represent a higher risk than the syrup formulation.

Opioid Toxidrome Following Grapefruit Juice Consumption in the Setting of Methadone Maintenance.

BACKGROUND: Methadone is a synthetic mu-opioid receptor agonist used in the treatment of chronic pain and opioid dependence. Methadone is metabolized by several cytochrome P450 isoenzymes; primarily CYP3A4, CYP2B6, and CYP2D6 before renal and fecal elimination. Exposure to substances like grapefruit juice, that inhibit these isoenzymes may result in increased blood levels of methadone, and thus may manifest clinically as unexpected opioid toxicity. CASE: A 51-year-old male was found unresponsive. He was hypoxic and bradypneic with pinpoint pupils. Multiple boluses followed by infusion of naloxone were required before improvement of respiratory status. Upon awakening, the patient reported participating in an opioid treatment program where he is administered 90 mg of oral methadone daily and denied any other substance use. On further questioning, he admitted to drinking grapefruit juice (estimated to be approximately 500 mL/day) every day for 3 consecutive days before presentation. The patient was discharged home after being counseled to stop drinking grapefruit juice. DISCUSSION: Grapefruit juice is known to be an inhibitor of the CYP3A4 isoenzyme. Various studies demonstrate that through CYP3A4 inhibition, grapefruit juice increases serum levels of opioids, such as methadone, though no clinically significant effects have been reported. CONCLUSIONS: Grapefruit juice inhibits the metabolism of methadone, raising its serum levels. To our knowledge, this is the first reported case in which the interaction between grapefruit juice and methadone was significant enough to cause an opioid toxidrome. It is, therefore, recommended that opioid treatment programs (OTPs) advise patients about this interaction before administering methadone.

Methadone associated long term hearing loss and nephrotoxicity; a case report and literature review.

BACKGROUND: Methadone is a long-acting opioid receptor agonist. Reported adverse effects of methadone include constipation, respiratory depression, dizziness, nausea, vomiting, itching, sweating, rhabdomyolysis, QT prolongation, and orthostatic hypotension. Hearing loss has been rarely reported following methadone use, and when reported, long term follow-up is rare. Herein we report a case of methadone poisoning with rhabdomyolysis, acute kidney injury, and persistent hearing loss documented by a 2 year follow up. CASE PRESENTATION: The patient was a 34 years old male who presented with a reduced level of consciousness and acute hearing loss after suicidal ingestion of 40 mg of methadone while experiencing family-related stresses. He had no prior history of methadone use, abuse, or addiction. Initial laboratory testing was significant for a serum creatinine concentration of 4.1 mg/dl, a mixed metabolic and respiratory acidosis, thrombocytopenia, abnormal hepatic transaminases, and coagulation tests. The patient then developed severe rhabdomyolysis. Also, audiometry showed a bilateral sensorineural hearing loss. The patient required hemodialysis for 11 days while his metabolic abnormalities gradually resolved. However, his hearing loss was persistent, as demonstrated by 2 years of follow up. CONCLUSION: Our patient simultaneously had kidney failure, rhabdomyolysis, and permanent hearing loss following methadone poisoning. Although rare, ototoxicity and permanent hearing loss may happen in cases of methadone poisoning. While opioid-induced hearing loss is uncommon, methadone toxicity should be taken into account for any previously healthy patient presenting with acute hearing loss with or without rhabdomyolysis.

Methadone-induced Toxic Encephalopathy In Pediatric Patients: Two Case Reports.

Toxic encephalopathy is a wide spectrum of encephalopathy secondary to insult from toxic substances, with variable clinical presentations from minor cognitive impairment to severe neurological dysfunction and death. Methadone-induced toxic encephalopathy is an extremely rare form of toxic encephalopathy which typically demonstrates abnormal imaging findings in the dentate nuclei or cerebellum. This is a report of methadone-induced toxic encephalopathy in two toddlers secondary to accidental ingestion. They were brought in unconscious to the emergency department of a tertiary hospital and were found to be cyanotic and pulseless, requiring cardiopulmonary resuscitation and mechanical ventilation. Magnetic resonance imaging (MRI) of the brain of both patients showed similar findings of symmetrical hyperintense foci in bilateral cerebellar hemispheres on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences. These areas also demonstrated diffusion restriction on diffusion weighted imaging (DWI). Blood and urine toxicology results confirmed the presence of methadone in both patients. As the exact substance of accidental ingestion may not be known at the time of presentation, early radiological diagnosis of methadone-induced encephalopathy may prompt early initiation of treatment to prevent further life-threatening complications, particularly in vulnerable pediatric population.

Deaths by poisoning in New Zealand, 2008-2013.

Introduction: While a number of developed countries have witnessed a decline in carbon monoxide (CO) deaths and increasing numbers of opioid-related fatalities, it is not known whether these or other trends have occurred in New Zealand. The aim of this study was, therefore, to review deaths due to poisoning in New Zealand, describe the causative substances, and identify any trends. Methods: Retrospective study reviewing New Zealand's poison-related death findings recorded in the National Coronial Information System (NCIS) database over the 6-year period 2008-2013. Results: We identified 1402 poisoning-related deaths recorded in the NCIS database representing a mortality rate of 5.4 deaths/100,000 population per year. The mortality rate due to poisoning was higher in males (6.96/100,000) than females (3.83/100,000). Fatalities peaked in the 40-50-year age group with the highest proportion of intentional deaths occurring in people aged 80-90 years. Pharmaceuticals accounted for 731 fatalities (52%) and chemicals 431 (31%), with multiple exposures occurring in 399 cases (28.5%). While CO was the leading cause of death throughout the period (n = 303, 21.6%), there was a significant reduction in the rate of CO fatalities from 1.69/100,000 population in 2008 to 0.94/100,000 in 2013 (IRR (95% CI) 2013/2008 0.56 (0.37-0.83)). There was, however, no statistically significant change in either the opioid-related death rate or the total number of deaths. Methadone was the leading pharmaceutical cause of fatality and the third most common cause overall, followed by morphine and codeine, with zopiclone and clozapine equally ranked as the sixth most common cause. Conclusion: While New Zealand has not suffered an "opioid epidemic" and has experienced a significant decline in CO deaths, the overall death rate due to poisoning has remained high. The development of accessible, timely, and relevant toxicovigilance systems would support the early implementation of interventions to reduce the leading causes of fatal poisoning.

Reversal of Pediatric Opioid Toxicity with Take-Home Naloxone: a Case Report.

BACKGROUND: Take-home naloxone, an opioid antagonist, has become part of a multimodal approach to curbing opioid-related mortality. However, there is little information about the utility of take-home naloxone in pediatric patients. We report a case of opioid toxicity after exposure to methadone in a pediatric patient, which was successfully reversed with take-home naloxone. CASE: A previously healthy 22-month-old girl ingested an unknown amount of liquid methadone. The child became progressively somnolent. The mother administered intranasal naloxone at home with reversal of somnolence. The patient presented to the emergency department and had recurrence of symptoms. The patient was placed on a naloxone infusion and discharged from a tertiary care facility, uneventfully, 2 days after ingestion. RESULTS: To our knowledge, we report the first case of pediatric opioid toxicity reversed by take-home naloxone. In the setting of rising opioid-related mortality, providers and public health officials should consider expanding access of take-home naloxone for children at high risk for opioid overdose.

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.