Fentanyl and xylazine crisis:Crafting coherent strategies for opioid overdose prevention

The United States is in the throes of a severe opioid overdose epidemic,primarily fueled by the pervasive use of fentanyl and the emerging threat of xylazine,a veterinary sedative often mixed with fentanyl.The high potency and long duration of fentanyl is compounded by the added risks from xylazine,heightening the lethal danger faced by opioid users.Measures such as enhanced surveillance,public awareness campaigns,and the distribution of fentanylxylazine test kits,and naloxone have been undertaken to mitigate this crisis.Fentanyl-related overdose deaths persist despite these efforts,partly due to inconsistent policies across states and resistance towards adopting harm reduction strategies.A multifaceted approach is imperative in effectively combating the opioid overdose epidemic.This approach should include expansion of treatment access,broadening the availability of medications for opioid use disorder,implementation of harm reduction strategies,and enaction of legislative reforms and diminishing stigma associated with opioid use disorder.

Manner of Death and Fentanyl Related Drug Overdose Trends in Marion County, Indiana, US from 2018 to 2021

The purpose of this research was to investigate the manner of deaths in Marion County, throughout the years of 2018 to 2021 to see if there were any correlative increases in homicide, suicide, natural, accidental, or drug overdose related deaths. We surveyed the incidence of all deaths that occurred from 2018 through 2021 which came through the Marion County Coroner’s Office, Indiana. The data was then divided into two halves. According to the data, the leading manner of death in the first half and second half was accidental. This study revealed a total of 8732 cases: 3817 of them were observed to be accidental, 3092 natural, 956 homicide, 689 suicide, and 178 were undetermined. There were initially 318 drug overdose related deaths in 2018 and they increased to 2163 by 2021. In 2018, the number of deaths due to fentanyl related overdoses increased from 195 to 799 in 2021. This research will contribute to the forensic science field by providing information about the manner of death and fentanyl trends in Marion County over the last four years.

Commentary: “Ockham’s Razor” Doesn’t Apply to “Opioid” Overdose Death

Polysubstance Abuse (PSA) greatly complicates an attempt to implicate a single drug as sole cause of an overdose death. Since PSA now occurs in the majority of cases of drug overdoses, many or most overdose deaths are polysubstance overdose deaths. And since many of the substances involved in a polysubstance Overdose Death (POD) are Central Nervous System (CNS) depressants, many of which can cause overdose death themselves, or synergistically with opioids, it is somewhat puzzling that prescription opioids have been singled out as the cause of these deaths—without reference to PSA. This is particularly puzzling in light of the fact that the issues of PSA and POD have been recognized and discussed in the literature since at least the 1960’s and before. We therefore here consider the question: are we facing an “opioid” crisis or, instead, a “polysubstance crisis”? And we wonder if the issue has been over-simplified, to the detriment of the individuals affected, and to society more broadly. There is a need for an “agnostic” respiratory stimulant that can reverse polysubstance-induced respiratory depression.

Polysubstance Use and Overdose Visualized via Maps: Opioids

Polysubstance (combinations of substances) abuse and overdose deaths now surpass mono-substance abuse and overdose deaths. Several international and governmental organizations such as the WHO (World Health Organization), CDC (Centers for Disease Control and Prevention), several of the Institutes of the NIH (National Institutes of Health), Regulators, and Enforcement Agencies, among others, track and provide a valuable source of statistical information about drug (prescription and illicit) (mis)use and overdose. The information is disseminated free to stakeholders and the general public for use. Although the numeric presentations of the data are helpful and adequate for professionals, the non-expert and the visual learner often find visual representation more clear and more compelling. With this in mind, the aim of this study was to present polysubstance use and overdose using visual maps of the available data. This article considers the opioids.

Delayed post-hypoxic leukoencephalopathy following barbiturate overdose: A case report

Rationale:Delayed post-hypoxic leukoencephalopathy(DPHL)is usually an overlooked condition,which arises as a result of a multitude of reversible and irreversible conditions.Patient’s Concern:A 50-year-old female with a history of epilepsy,who developed DPHL 12 days after respiratory failure secondary to barbiturate toxicity.Diagnosis:DPHL on magnetic resonance imaging of the brain.Interventions:Mechanical ventilation was initiated for respiratory failure and hemodialysis for barbiturate toxicity.Outcomes:The patient developed akinetic mutism due to infirmity and had a residual disability,which led to permanent dependency.Lessons:The diagnosis of DPHL is often delayed or missed,given the rarity of this condition and its inconsistent clinical symptomatology.Diagnostic delay can be avoided by early recognition of the classical“delayed onset”symptoms.

A Lazarus effect： A case report of Bupropion overdose mimicking brain death

Dear editor,We report a case of a 47-year-old female who presented with a toxic bupropion ingestion leading to cardiac arrest.She initially exhibited a loss of brainstem reflexes in conjunction with burst-suppression pattern on EEG.Burst suppression is an EEG waveform pattern of alternating isoelectric suppressions and high voltage bursts.^([1])

Potentially life-threatening intravenous acetaminophen overdose in a 3-month-old (40 weeks’ post-menstrual age), 2.3 kg baby girl

A case is presented of a serious, potentially life-threatening intravenous acetaminophen overdose in a 3-month-old (40 weeks’ post menstrual age),2.3 kgbaby girl. The neonate was scheduled for urgent laser therapy for retinopathy of prematurity. Instead of an intended intravenous Hartmann’s solution bolus of 10 ml·kgˉ1, the neonate received a 17 ml bolus of correctly labelled intravenous 1% acetaminophen. The National Poisons Bureau was immediately contacted for advice and in the absence of data suggested a treatment with N-acetylcysteine for a 24-hour period. Baseline blood samples for clotting, liver function, urea and electrolytes, full blood count and plasma acetaminophen concentration were taken 30 min, 8.25 h, 12.5 h, 18.5 h and 120 h after the overdose. Acetaminophen concentration was 78 mg·Lˉ1 at 30 min, but it was undetectable at any other time. Using a recent and complete PK-PD dataset we are able to show that the measured plasma acetaminophen concentration fits well on PK estimates for acetaminophen in this neonate. The non-detectable (low) plasma acetaminophen concentration at >8 h is also consistent with this model, especially if clearance is slightly increased in the premature nursery graduate. Medical errors are rarely the fault of an individual and they are often due to a combination of factors. Contributing factors, in this case, are described under the following headings: Catalyst event, system fault, loss of situational awareness, and human error.

Compartment Syndrome of the Leg Requiring Emergent Fasciotomy Resulting from Multi-Drug Overdose

A paucity of literature exists linking acute extremity compartment syndrome associated with cocaine or olanzapine overdose. LJ, a 38-year male, was initially seen at an outside hospital for acute encephalopathy and left lower extremity swelling shortly after cocaine and suspected olanzapine overdose. On presentation, totalcreatinine kinase levels were >1000 units/liter but quickly rose to 23,000 units/liter after 12 hours. He was transferred to a tertiary care center for surgical evaluation. Upon the exam, it was quickly determined that he had compartment syndrome and he was urgently taken to the operating room for a four-compartment lower extremity fasciotomy. Acute compartment syndrome is a limb threatening condition generally diagnosed clinically. Cocaine, a potent vasoconstrictor, is widely reported to cause rhabdomyolysis from ischemia of skeletal muscle tissue and direct toxicity to myocytes resulting in leakage of creatinine kinase. Other complications including cardiovascular, respiratory, neurological, and gastrointestinal disturbances have also been well documented. Olanzapine, an atypical antipsychotic, has also been reported to cause rhabdomyolysis. However, myositis with lower extremity compartment syndrome is a rare occurrence and requires quick diagnosis and aggressive treatment in order to achieve limb salvage. The potential causality of compartment syndrome from either cocaine, olanzapine, or both will be examined in this case report.

Iron Overdose during Pregnancy: Case and Treatment Review

A 22-year-old pregnant female was transferred to the emergency department having ingested a bottle of iron-containing prenatal vitamins, ondansetron (Zofran?) tablets and alcohol. The patient was hemodynamically stable but suffered from intense bouts of brown, sandy emesis for the first few hours. Investigation revealed the patient ingested 13.57 mg/kg of elemental iron. Due to the initial iron level, history and presentation time whole bowel irrigation was initiated with polyethylene glycol solution. Acute iron toxicity in pregnancy is a medical emergency that can result in multisystem organ failure leading to maternal death and potential fetal demise. High maternal serum iron loads do not affect the developing fetus and are not associated with fetal malformations;however advanced poisoning can lead to maternal death, spontaneous abortions or preterm emergency deliveries. Initial treatment strategies may include whole bowel irrigation using polyethylene glycol electrolyte lavage solution and deferoxamine treatment along with necessary supportive care management. Despite concerns of teratogenicity deferoxamine does not cross the placenta and is regarded as safe for use during pregnancy. Maternal resuscitation must always be the primary objective in acute iron overdoses and, therefore such concern should not delay clinically indicated maternal treatment.

Altered Mental Status and Hyperammonemia after Overdose of Valproic Acid with Therapeutic Valproic Acid Concentrations

Valproic acid is used in the treatment of multiple disorders. Adverse effects from valproic acid include hepatotoxicity, hypotension, metabolic acidosis, and decreased mental status. Valproic acid also causes hyperammonemia. Many physicians assume that this is due to a supratherapeutic valproic acid concentration;when in fact, it can occur with therapeutic valproic acid concentrations. This is because the hyperammonemia may be related to carnitine deficiency and disruption of the urea cycle, which can both occur with therapeutic valproic acid concentrations. We report a patient presented to the emergency department with alteration of mental status after ingesting valproic acid for recreational purposes, who developed hyperammonemia with a therapeutic valproic acid concentration.

Overdose of Venlafaxine with Mild Outcome

The antidepressant venlafaxine in overdose can lead to serotonin syndrome, seizures, QTc interval prolongation and can increase the risk of cardiac arrhythmias. It has been reported to be more toxic in overdose than other new antidepressants. We report a case of venlafaxine intoxication with a venlafaxine/O-desmethylvenlafaxine serum level of 2861/2670 ng/mL 22 h after ingestion. This is one of the so far highest survived venlafaxin serum levels. In contrast to other reported survived venlafaxin overdoses with high serum levels no clinical signs of intoxication were observed in our case. So venlafaxine overdose not necessarily leads to life-threatening signs of intoxication.

Paediatric amitriptyline overdose

We report a near fatal case of paediatric amitriptyline overdose including a series of ECGs demonstrating the effects of sodium bicarbonate therapy on cardio-toxicity. We briefly discuss the role of sodium to counteract the sodium channel blockade of tricyclic antidepressants and discuss the possible utility of lipid emulsion therapy in such cases.

Commentary: New Complications Make Treatment of “Opioid” Overdose Challenging

The “opioid crisis” has had a tremendous impact not only on its victims, but also on the practice of medicine, pain patients, and society in general. Unfortunately, efforts to “stem the tide” have not been successful at reducing overdose deaths. Counterbalancing the many ardent efforts to eliminate overdose deaths (such as the current widespread availability and use of opioid-receptor antagonists such as naloxone) is influx of the illicit fentanoids (i.e., fentanyl and analogs). In addition to their high-potency, the fentanoids differ in surprising ways from more “traditional” opioids such as morphine and heroin. This uniqueness contributes to a reduced effectiveness of opioid receptor antagonists in the treatment of opioid overdose. Further greatly complicating overdose treatment is polysubstance abuse (e.g., an opioid plus a benzodiazepine). The non-opioid in the combination is not responsive to an opioid-recep- tor antagonist, which imparts additional challenges. Thus, the new reality introduces complications that negatively impact efforts to reverse “opioid” overdose. New approaches to improve outcomes in individuals who experience respiratory depression due to fentanoid-induced or polysubstance-induced over- dose are needed. Approaches that harmonize with the new reality, perhaps something like a non-opioid “agnostic” pharmacologic ventilatory stimulant, would provide a welcome addition to the current choices.

Polysubstance Use and Overdose Visualized via Maps: Amphetamines and Cocaine

Abuse of drug substances and resultant overdose deaths are no longer very straightforward—viz., attributable to a single chemical entity of known purity. The reality is that most overdose deaths involve polysubstance use (i.e., the use of combinations of substances). Further, the combinations are often of unknown purity, and even of unknown composition. Overdose deaths are at all-time highs. The depressing statistics are monitored and reported by several international and governmental organizations such as the WHO (World Health Organization), CDC (Centers for Disease Control and Prevention), several Institutes of the NIH (National Institutes of Health), Regulators, and Enforcement Agencies (e.g., DEA). The information is disseminated for free for review and use. But it is our observation that although numeric presentation is helpful and adequate for professionals, the non-expert and the visual learner often find a visual representation clearer and compelling. With this in mind, we present the “gestalt” of polysubstance use and overdose using available maps of the data. The previous article in the series considered the opioids. This one considers amphetamines and cocaine, and places the rise in opioid-associated overdose deaths in the context of other abused drugs.

Characteristics and Outcomes of Acetaminophen Overdose and Hepatotoxicity in Thailand

Background and Aims:Acetaminophen(APAP)is the leading cause of drug overdose and hepatotoxicity worldwide,including in Thailand.Patterns of overdose and hospital management are known to have significant impacts on the outcomes of APAP overdose,and these factors vary from country to country.Therefore,this study aimed to analyze clinical characteristics of Thai patients with APAP overdose in terms of overdose patterns,clinical presentation,treatment and outcomes.Methods:In this retrospective analytical study,medical records of adult patients hospitalized with a diagnosis of APAP overdose at Rajavithi Hospital,Bangkok,between January 2013 and December 2017 were reviewed.Results:A total of 184 patients diagnosed with APAP overdose were included.The median age was 22(15–76)years and the majority were female(79.9%).Most overdoses were intended self-poisoning ingestion(90.8%)with a median dose of 10.5 g(4.5–50).A total of 121 patients were treated with N-acetylcysteine with a median visit-to-N-acetylcysteine time of 2(0.5–15)h.Overall,15.6%developed mild hepatotoxicity(aspartate aminotransferase or alanine aminotransferase>3 times the upper limit of normal),6.4%developed severe hepatotoxicity(aspartate aminotransferase or alanine aminotransferase>10 times the upper limit of normal and international normalized ratio>2.0)and 3 patients developed acute liver failure(1 patient resolved spontaneously and 2 patients,neither of whom had a liver transplant,died).Significant predictors for hepatotoxicity included older age,chronic alcohol drinking,repeated taking of medication for more than 8 h(staggered ingestion),long duration between ingestion and hospital visit,alcohol coingestion,abdominal pain symptoms,and acute kidney injury.Conclusions:Most cases of APAP overdose in Thailand appear to be young women with intentional ingestion.With prompt management,most patients(76.4%)did not develop significant hepatotoxicity;nevertheless,despite N-acetylcysteine therapy,hepatotoxicity including acute liver failure was observed in a small proportion of patients,particularly those with unintentional overdose and chronic alcohol drinking.

Successful Treatment with Integrated Chinese and Western Medicine for Severe Overdose of Amlodipine:A Case Report

Introduction Amlodipine is a dihydropyridine calcium channel blocker （CCB） that inhibits calcium influx into cardiac, vascular smooth muscle cells, and pancreatic beta cells, leading to dilation of arteries and arterioles and reduction in insulin secretion. Oral administration of amlodipine is absorbed slowly but almost completely, with a hiah oral bioavailabilitv up to 60%-80%.

Paroxetine overdose during pregnancy

Paroxetine is a selective serotonin reuptake inhibitor(SSRI)used in the treatment of depression and anxiety disorders.In some epidemiological studies,slightly increased risks of major malformations and cardiac malformations have been reported following paroxetine exposure in the first trimester of pregnancy.However,such findings have been inconsistent.There is only one report of any overdose of an SSRI during pregnancy,and that involved escitalopram.The aim of this case report was to describe the impact of a paroxetine overdose in the first trimester of pregnancy on the health of the foetus.A 21-year-old mother of one child who was pregnant with a second child was prescribed 20 mg/day paroxetine hydrochloride for the treatment of anxiety/depression.The patient ingested 15 or 1620-mg tablets of paroxetine hydrochloride(300-320 mg)during the 5th week of pregnancy as a suicide attempt.Within 15 min of ingestion,she was admitted to hospital and treated for intoxication.No evidence of maternal SSRI intoxication was observed after treatment.The patient consulted our teratology information service for further risk assessment regarding possible major congenital malformations following the paroxetine overdose.We were unable to find previous reports of paroxetine overdose during pregnancy in the literature.The timely administration of the overdose treatment and the lack of maternal intoxication symptoms were considered positive for the foetal well-being,and the patient was referred for perinatology and psychiatry follow-ups.A healthy,3500-g male infant was born at 38 weeks’gestation,and his development at the age of 2 years was normal.This is the first reported case of paroxetine overdose during pregnancy.Comprehensive studies are needed to evaluate pregnancy outcomes after SSRI overdose.

Lipid profile and atherogenic predictor indices of albino rabbits administered coconut water as antidote to paracetamol overdose

Objective:To investigate the effects of coconut water intake on lipid profile and atherogenic predictor indices of albino rabbits overdosed with paracetamol using standard methods.Methods:Thirty-five albino rabbits weighing between 800-1200 g and aged between 2 and 3 months,were divided into 7 groups(I-VII)of 5 animals each.Groups I,II and III were orally administered distilled water(20 mL/kg body weight),coconut water(20 mL/kg body weight)and paracetamol(1000 mg/kg body weight)respectively,for 7 days.Groups IV and V were administered coconut water(20 mL/kg body weight)and silymarin(35 mg/kg body weight),respectively,for 6 days,then paracetamol(1000 mg/kg body weight)on the 7th day.Groups VI and VII were administered distilled water for 6 days,paracetamol on the 7th day,then coconut water and silymarin,respectively,after 3 h.Results:The results showed that paracetamol overdose significantly reduced(P<0.05)the mean body weight of the animals,increased the concentrations of serum total cholesterol,triacylglycerol,very low density lipoprotein cholesterol,low density lipoprotein cholesterol and the atherogenic predictor indices but reduced the serum high density lipoprotein cholesterol concentration of the animals relative to the control.The observed changes in the lipid profile and atherogenic predictor indices were countered more by post-than pre-treatment with coconut water and silymarin.Conclusions:The results indicated that coconut water acted as an effective antidote to paracetamol overdose-induced lipid abnormality in animals.

Fatal Overdoses Involving Carfentanil:A Case Series

Carfentanil,an ultrapotent analog of fentanyl,has invaded the street drug market,unbeknownst to many heroin users.About 10,000 times more potent than morphine,it was initially suspected that 20μg of the substance was lethal.In this case series,we present 17 confirmed carfentanil overdoses in Michigan,with a primary focus on the concentration levels.Through a retrospective review,each public death reported in Oakland County,Michigan,with a subsequent toxicology report was investigated for suspected carfentanil use.To characterize each fatality,the autopsy results were collected,including the postmortem findings at scene and the decedent’s medical and social history.Carfentanil levels were measured through liquid chromatography and tandem mass spectrometry(LC-MS-MS)by National Medical Services(NMS)Laboratories.Our case series found postmortem carfentanil concentrations as low as 10 ng/mL,with a mean concentration of 0.387 ng/mL.Ultimately,there are implications on law enforcement,first responders,and health care providers when dealing with this emerging illicit substance,and there is an alarmingly high mortality rate associated with the abuse of carfentanil.

Characteristics of Suicides Caused by Drug Overdose in the State of Maryland

Suicidal drug overdose is a major public health issue.In the United States,every year more than 33,000 people commit suicides.Our study focused on the characteristics of suicide victims in the state of Maryland.Material and methods:This study was a retrospective review of autopsy cases of all suicide deaths caused by drug(s)or drug(s)with alcohol intoxication investigated by the OCME in Maryland over a 7-year period from January 2004 to December 2011.All deaths investigated by the OCME that require autopsy examination are subject to comprehensive toxicology testing for drugs and alcohol.The screen tests were performed using gas chromatography(GC)and radioimmunoassay techniques.All detected drugs and/or metabolites were confirmed using GC-mass spectrometry(GC-MS).Results:From 2004 to 2011,434 deaths were certified as suicide.Of the 434 suicidal overdose deaths,84%were white,11%were African-American,and about 5%were either Hispanic or Asian.The male and female ratio was almost equal.Their ages ranged 15-82 years.Of the 434 suicidal drug overdose deaths,277 victims(63.8%)consumed a single drug type and 157(36.2%)consumed more than one type of drug.Of the 277 single-drug overdose cases,71.1%suicides were due to prescription drugs,23.5%due to over-the-counter drugs,and 5.4%due to street/recreational drugs.Among single-type prescription drugs,analgesic(N=76),antidepressant(N=45),and neuroleptic(N=35)classes were the three leading type of drugs used in suicidal deaths.Oxycodone,morphine,quetiapine,and amitriptyline were the most common prescription drugs in suicidal overdose.Diphenhydramine was the leading over-the-counter drug.Of the 157 victims who consumed more than one drug,combined prescription drugs were present in 54.1%,mixed prescription and overthe-counter drugs in 29.3%,and prescription drugs/over-the-counter drugs and street drugs in 16.6%of cases.Of the multiple-drug overdose suicides,66.2%cases involved antidepressants.Discussion:Suicide is found in every age,racial,and ethnic group.In the USA,poisoning is thethird-leading method of suicide,following firearm injuries and hanging/strangulation.Our study indicates that prescription drugs,such as those in the opioid analgesic,neuroleptic,and antidepressant class(e.g.,oxycodone,morphine,quetiapine,amitriptyline,doxepin,and citalopram),are of special concern in the context of suicidal overdose deaths in the state of Maryland.Therefore,addressing the problems of intentional drug overdose in our society is worthy of public attention.