Mixed Drug Toxicity Research Articles

Causes, Nature and Toxicology of Fentanyl-Associated Deaths: A Systematic Review of Deaths Reported in Peer-Reviewed Literature.

PurposeFentanyl poisoning has been widely reported, yet there is a lack of systematic evaluation of the nature and toxicology of associated deaths in the published literature. This article aims to systematically review the nature, causes, routes of administration and toxicology of fentanyl-associated deaths using case studies and case series in peer-reviewed published literature.MethodsFour electronic databases including Embase, Medline (via Ovid), Scopus and Google Scholar were searched from inception until October 2019 to identify the studies reporting fentanyl related deaths. Two independent reviewers screened and selected the titles and then evaluated the full texts. Only case studies and case series were included. A structured data extraction tool was used to extract data on the number of deaths, routes of administration, concomitant drug use and toxicological data. The Joanna Briggs Institute quality assessment tool was used to evaluate the quality of included studies. Data were synthesized narratively.ResultsOf 1251 articles identified during initial search, 8 case reports and 9 case series met the inclusion criteria. A total of 1969 deaths were reported in the included studies. Deaths were concentrated in the north American region (n = 1946) and the Nordic region (n = 22). Reported causes of death included fentanyl overdose (n = 321, 56.4%), mixed drug toxicity (n = 196, 34.5%), natural (n = 28, 4.9%), other drug toxicity (n = 10, 1.8%), fentanyl and ethanol intoxication (n = 8, 1.4%), incidental (n = 5, <1%) and aspiration (n = 1). Most common routes of use were intravenous (70.5%) and transdermal routes (23.0%). Deaths came swiftly via the intravenous route. Mean level of blood fentanyl amongst all reported deaths was 0.024 µg/mL.ConclusionLiterature related to fentanyl-associated deaths predominantly come from North America. Deaths are comparatively lower or not reported in peer-reviewed publications from the rest of the world. Abuse through intravenous administration, mixed drug toxicities and self-treatment of breakthrough pain are mainly responsible for majority of the reported deaths.

The Management of a Difficult Case: A Suicide Attempt by the Ingestion of Multiple Drugs by a Pregnant Woman with Epilepsy

The Management of a Difficult Case: A Suicide Attempt by the Ingestion of Multiple Drugs by a Pregnant Woman with Epilepsy

Pregabalin and Its Involvement in Coronial Cases.

Pregabalin is an anticonvulsant and analgesic designed to treat neuropathic pain and partial seizure disorders and has been available in Australia as a prescription medication since 2005. Studies have found high rates of polydrug use associated with pregabalin and it is reportedly used recreationally for its euphoric and relaxing effects as well as to self-manage opioid withdrawal symptoms. A robust analytical method for the analysis of pregabalin using protein precipitation and LC/MS/MS was developed, validated and employed in routine case work. In recent years a substantial increase in pregabalin detections in coronial case submissions had been noted. This study examines the case characteristics and outcomes of 332 coronial cases submitted to the laboratory and analyzed for pregabalin between 2015 and 2017. Pregabalin was identified in approximately 5% of all coronial cases submitted during this time. A high rate of concurrent drug use with pregabalin was evident with the predominant classes being opioids, benzodiazepines and anti-depressants. Post-mortem blood pregabalin concentrations ranged from <0.05 to 140 mg/kg (median 5.5 mg/kg); however, limited interpretation of levels could be achieved as the drug was rarely identified in the absence of other drugs. Cause of death (COD) was found to be drug related in 58% of all cases, with mixed drug toxicity specifically mentioned as related to COD in 40% of cases.

Correction to: Post-mortem distribution of the synthetic cannabinoid MDMB-CHMICA and its metabolites in a case of combined drug intoxication.

The following clarification to the content of Table 3 (MDMB-CHMICA data from previously published cases of acute (non-fatal) and fatal drug intoxications) of the named manuscript needs to be brought to the readership's attention.

Analysis of psychotropic drug-related deaths in south Osaka.

ObjectiveThe aim of this study was to investigate the occurrence of deaths due to psychotropic drugs in south Osaka during a 10-year period and discuss societal factors from a medical viewpoint.MethodsPsychotropic drug-related deaths were retrospectively investigated based on the forensic postmortem data of 1,746 decedents in 2005–2014, and we excluded cases in which stimulant drugs were detected. Of these, 133 cases (7.6%) were found to be psychotropic drug-related deaths and were analyzed.ResultsPsychotropic drug-related deaths occurred in 78 males (59%; age range, 14–95 years) and 55 females (41%; 20–84 years). The direct cause of death was acute drug intoxication in many cases, and of these, acute combined drug intoxication due to the use of multiple drugs accounted for 76% of the deaths. Most of these victims were found to have gastrointestinal and cardiovascular diseases. Cases of psychotropic drug-related deaths had especially poor medical conditions. In addition, tests were positive for blood alcohol in 23% of the cases.ConclusionThe descriptive results revealed several factors that may be related to psychotropic drug-related deaths. To prevent drug abuse, several factors were deemed to be important, including improvements in the medical state of an individual, the avoidance of social isolation, and from a medical standpoint, the management of prescription drugs by medical personnel.

A Case Study Involving U-47700, Diclazepam and Flubromazepam-Application of Retrospective Analysis of HRMS Data.

The number of new psychoactive substances (NPS) available is constantly increasing, making it difficult for toxicology laboratories to keep screening methods up to date. Full scan high-resolution mass spectrometry (HRMS) is a versatile technique which allows for progressive updating of spectral databases to increase the scope of screening. It also allows for retrospective screening of data-specifically, reprocessing of data files using an updated spectral database without the need for re-extraction or reanalysis.The coronial case reported here illustrates the application of retrospective processing of HRMS data in the detection of emerging NPS. A 28-year-old male with a history of illicit drug use was found deceased at home. Initial routine screening of the post-mortem peripheral blood identified only methylamphetamine, amphetamine and trace amounts of lorazepam. A compound with an accurate mass and isotope ratio consistent with the opioid AH-7921 was also detected in the liquid chromatography (LC)-HRMS screen; however; the retention time and mass spectrum did not match the library. Further investigation confirmed the compound to be U-47700, another opioid and structural isomer of AH-7921. Several months later, after additional NPS had been added to the in-house HRMS database, retrospective screening of the HRMS data was performed, revealing the presence of designer benzodiazepines, diclazepam and flubromazepam as well as the psychedelic drug 2,5-dimethoxy-4-chloroamphetamine (DOC). Quantitative analysis gave the following results in peripheral post-mortem blood: U-47700 (330 μg/L), diclazepam (70 μg/L), flubromazepam (10 μg/L), methylamphetamine (290 μg/L) and amphetamine (150 μg/L) (DOC not quantitated). These substances, along with lorazepam and etizolam, were also confirmed in the post-mortem urine and an investigation into blood and urinary metabolites was carried out. All analyses were performed using the same LC-quadrupole-time of flight method. The cause of death was aspiration (of gastric content into airways and lungs) due to mixed drug toxicity.

Retrospective evaluation of adult poisoning cases admitted to emergency department of a University Hospital in Turkey.

We aimed to evaluate demographic, etiological, clinical features, and prognosis of poisoning cases applied to a tertiary emergency department retrospectively. The recordings of poisoning cases aged 18 years old and over which applied to the department of emergency medicine between the dates of 2010-2015 were examined. Age, gender, admission date, amount of time passed since exposure to the poisonous substance, application method, cause of poisoning, laboratory findings at arrival, vital signs, type of poisonous substance, the way of taking, treatment method in urgent care, consultation need, and the outcome of cases were recorded. Of the poisoning cases, 437 (52.1%) were female, and 402 (47.9%) were male. The mean age was calculated as 33.50. When the cause of poisonings are examined; 456 patients were found to be poisoned by a suicide attempt, 350 were accidentally poisoned, and 33 were poisoned by treatment complication. As the causing substance of poisoning, medicinal drugs were found in 465 cases (55.4%), carbon monoxide in 205 cases (24.4%), and narcotics in 119 cases (14.2%). Of medicinal drug poisonings, 221 (46.8%) were multiple drug intake. It was seen that 46.6% of the patients were kept under observation with only symptomatic treatment while nasogastric lavage and activated charcoal were applied in 40.2% of them. It can be suggested that poisonings are encountered more commonly in young people, especially in women, with medicinal drugs and for suicidal purposes. Drugs detected at high rates in poisonings, such as painkillers and antidepressants, should be used more cautiously.

Safety and tolerability of inebilizumab (MEDI-551), an anti-CD19 monoclonal antibody, in patients with relapsing forms of multiple sclerosis: Results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study

Background: B cells may be involved in the pathophysiology of multiple sclerosis (MS). Inebilizumab (formerly MEDI-551) binds to and depletes CD19+ B cells. Objectives: To assess safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of inebilizumab in adults with relapsing MS. Methods: This phase 1 trial randomised 28 patients 3:1 (21, inebilizumab; 7, placebo) to inebilizumab (2 intravenous (IV) doses, days 1 and 15: 30, 100 or 600 mg; or single subcutaneous (SC) dose on day 1: 60 or 300 mg) or matching placebo, with follow-up until at least week 24 or return of CD19+ B-cell count to ⩾80 cells/µL. Results: Complete B-cell depletion was observed across all doses. Infusion/injection (grade 1/2) reactions occurred in 6/15 patients receiving inebilizumab IV, 2/5 placebo IV and 1/6 inebilizumab SC. Serious adverse events occurred in three patients receiving inebilizumab: pyrexia, mixed-drug intoxication (unrelated to inebilizumab; resulted in death) and urinary tract infection. Mean number of cumulative new gadolinium-enhancing lesions over 24 weeks was 0.1 with inebilizumab versus 1.3 with placebo; mean numbers of new/newly enlarging T2 lesions were 0.4 and 2.4, respectively. Conclusion: Inebilizumab had an acceptable safety profile in relapsing MS patients and showed a trend in reductions in new/newly enlarging and gadolinium-enhancing lesions.

Heroin-related Deaths from the Hennepin County Medical Examiner's Office from 2004 Through 2015.

Over the past two decades, prescription and illicit opioid use has led to changes in public health policy to address the increasing number of opioid-related deaths. The purpose of this study was to review cases from Hennepin County Medical Examiner's Office between 2004 through 2015 where heroin was listed as a significant contributor or as the cause of death. We identified 322 heroin-related deaths, which were predominantly male (255; 79%). 6-Monoacetylmorphine (6-MAM) median (range) concentrations were as follows: blood (n = 7), 0.010 (0.006-0.078) mg/L; urine (n = 30), 0.359 (0.009-1.75) mg/L; and vitreous humor (n = 31), 0.034 (0.004-0.24) mg/L. Free morphine was measurable in 273 cases and the percent free morphine (range), when grouped by COD, was opioid (n = 124), 28% (2.2%-92%), and mixed drug toxicity (n = 135), 35.3% (1.5%-100%); (p < 0.01). Quantitation of 6-MAM in blood and vitreous humor, along with a free to total morphine ratio >26%, was useful in establishing heroin-related deaths.

PhLeGrA: Graph Analytics in Pharmacology over the Web of Life Sciences Linked Open Data.

Integrated approaches for pharmacology are required for the mechanism-based predictions of adverse drug reactions that manifest due to concomitant intake of multiple drugs. These approaches require the integration and analysis of biomedical data and knowledge from multiple, heterogeneous sources with varying schemas, entity notations, and formats. To tackle these integrative challenges, the Semantic Web community has published and linked several datasets in the Life Sciences Linked Open Data (LSLOD) cloud using established W3C standards. We present the PhLeGrA platform for Linked Graph Analytics in Pharmacology in this paper. Through query federation, we integrate four sources from the LSLOD cloud and extract a drug–reaction network, composed of distinct entities. We represent this graph as a hidden conditional random field (HCRF), a discriminative latent variable model that is used for structured output predictions. We calculate the underlying probability distributions in the drug–reaction HCRF using the datasets from the U.S. Food and Drug Administration’s Adverse Event Reporting System. We predict the occurrence of 146 adverse reactions due to multiple drug intake with an AUROC statistic greater than 0.75. The PhLeGrA platform can be extended to incorporate other sources published using Semantic Web technologies, as well as to discover other types of pharmacological associations.

Risk factor for suicide attempt in a general hospital

IntroductionA major risk factor for suicide is suicide attempts. The aim of the present study was to assess risk factors for nonfatal suicide attempts. Suicide attempt with high lethality have been interacting with certain clinical and demographic factors such as age, sex, psychopathology and adverse events, among others.MethodsObservational, descriptive and retrospective study of people who was admitted to a general hospital after suicide attempt.AimThe aim of this study was to determinate variable associated to high risk of suicide. Describe and analyze demographic and clinical characteristics associated with serious suicide attempts as well as the methods used.ResultsOf a total of 504, 23 patients was admitted after suicide attempt, 61% male, mean age 54.1; 60% required ICU; the most common method consisted of multiple drug intake 40%, 30% associated with toxic, mostly alcohol. Predominant summer and diagnosis of adjustment disorder.ConclusionAs is the case with suicides prevails male and summer. As to the most common method has been from medication, both men and women. We were surprised diagnosis of the most common reactions to stress. We conclude that the findings could guide a progressive change in the presuicidal pathology.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Oral liquid levothyroxine solves the problem of tablet levothyroxine malabsorption due to concomitant intake of multiple drugs

ABSTRACTBackground: Unlike the tablet (TAB) formulation, liquid L-T4 (LIQ) is directly absorbed in the intestine. The aim of this study was to assess whether LIQ was superior to TAB, such that it would overcome the interference induced by co-ingestion of multiple interfering drugs (ID).Methods: In this prospective cohort study, we recruited 11 patients with apparent reduced TAB absorption due to ≥ 2 ID, and switched them to LIQ while maintaining the daily dose and the co-ingestion of the ID. Serum TSH was assayed at least twice every eight weeks.Results: Serum TSH was significantly lower on LIQ compared with TAB (P < 0.0001), in patients who took L-T4 for either replacement (P = 0.002) or TSH-suppression (P < 0.0001). This difference was evident already at the first measurement post-switch (P = 0.008 or P = 0.03). Regardless of the purpose of L-T4 therapy, patients who took two ID had lower serum TSH on LIQ compared with patients who took three ID (P = 0.0006). Interestingly, 2/3 patients who failed to reach target TSH levels while on LIQ took three ID.Conclusions: LIQ overcomes the concurrent interference exerted by the ingestion of multiple ID. In such cases, switching from TAB to LIQ permits patients to reach target TSH within 8 weeks.

Management and Palliative Care in Poisoning and Overdose

The availability of a vast number of drugs and acute poisoning is a common medical emergency in India and any country. Poising and overdose can present with various clinical symptoms, including seizures, tremor, abdominal pain, vomiting, and, cardiac dysrhythmias, respiratory failure and change in mental status. The exact incidence of this problem in India remains uncertain but it is estimated that more than million cases of poisoning are reported every year, of which, more than 50, 000 die. These may be the only clues to diagnosis when the cause of toxicity is unknown at the time of initial assessment of poising and overdose management. In multiple-drug ingestion diagnosis may be complicated. The present review focus on management and palliative care in medical emergencies.

A Complex Case of Suspected Serotonin Syndrome

A Complex Case of Suspected Serotonin Syndrome

Post-mortem levels and tissue distribution of codeine, codeine-6-glucuronide, norcodeine, morphine and morphine glucuronides in a series of codeine-related deaths

This article presents levels and tissue distribution of codeine, codeine-6-glucuronide (C6G), norcodeine, morphine and the morphine metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in post-mortem blood (peripheral and heart blood), vitreous fluid, muscle, fat and brain tissue in a series of 23 codeine-related fatalities. CYP2D6 genotype is also determined and taken into account. Quantification of codeine, C6G, norcodeine, morphine, M3G and M6G was performed with a validated solid phase extraction LC–MS method. The series comprise 19 deaths (83%) attributed to mixed drug intoxication, 4 deaths (17%) attributed to other causes of death, and no cases of unambiguous monointoxication with codeine. The typical peripheral blood concentration pattern in individual cases was C6G≫codeine≫norcodeine>morphine, and M3G>M6G>morphine. In matrices other than blood, the concentration pattern was similar, although in a less systematic fashion. Measured concentrations were generally lower in matrices other than blood, especially in brain and fat, and in particular for the glucuronides (C6G, M3G and M6G) and, to some extent, morphine. In brain tissue, the presumed active moieties morphine and M6G were both below the LLOQ (0.0080mg/L and 0.058mg/L, respectively) in a majority of cases. In general, there was a large variability in both measured concentrations and calculated blood/tissue concentration ratios. There was also a large variability in calculated ratios of morphine to codeine, C6G to codeine and norcodeine to codeine in all matrices, and CYP2D6 genotype was not a reliable predictor of these ratios. The different blood/tissue concentration ratios showed no systematic relationship with the post-mortem interval. No coherent degradation or formation patterns for codeine, morphine, M3G and M6G were observed upon reanalysis in peripheral blood after storage.

Fentanyl-related deaths: A 5-year retrospective study (2010–2014, 81 cases) in the department of forensic medicine, Newcastle, Forensic and Analytical Science Service

Background: Fentanyl is a synthetic opioid developed in the 1960s and is 50–100 times more potent than morphine. Fentanyl is recognised to be abused in the community. The Department of Forensic Medicine Newcastle, Forensic and Analytical Science Service (DOFM, Newcastle) has recently experienced an increase in fentanyl related deaths. This study was carried out to characterise fentanyl related death in DOFM, Newcastle.Method: A retrospective study (5 years, 2010–2014) of deaths related to fentanyl in DOFM, Newcastle, was carried out noting the age, gender, cause of death, toxicological analysis, mode of delivery, and presumed mechanism of death.Result: There was a striking increase in death related to fentanyl from 1 case in 2010 to 38 cases in 2014 (n=81). Most of the fatal cases had a fentanyl blood level between 0.01–0.029 mg/L with the highest level being 0.08 mg/L. The most common cause of death was mixed drug toxicity. The victims were mostly middle aged males and the most common mechanism of death was respiratory depression. Other substances detected apart from fentanyl were benzodiazepine, opioids and alcohol. The most common route of administration was via extracting fentanyl from a patch and injecting it intravenously. Background: Fentanyl is a synthetic opioid developed in the 1960s and is 50–100 times more potent than morphine. Fentanyl is recognised to be abused in the community. The Department of Forensic Medicine Newcastle, Forensic and Analytical Science Service (DOFM, Newcastle) has recently experienced an increase in fentanyl related deaths. This study was carried out to characterise fentanyl related death in DOFM, Newcastle. Method: A retrospective study (5 years, 2010–2014) of deaths related to fentanyl in DOFM, Newcastle, was carried out noting the age, gender, cause of death, toxicological analysis, mode of delivery, and presumed mechanism of death. Result: There was a striking increase in death related to fentanyl from 1 case in 2010 to 38 cases in 2014 (n=81). Most of the fatal cases had a fentanyl blood level between 0.01–0.029 mg/L with the highest level being 0.08 mg/L. The most common cause of death was mixed drug toxicity. The victims were mostly middle aged males and the most common mechanism of death was respiratory depression. Other substances detected apart from fentanyl were benzodiazepine, opioids and alcohol. The most common route of administration was via extracting fentanyl from a patch and injecting it intravenously.

Acute Drug Poisoning in Tunisian Children: About 150 Cases

Background: Acute drug poisoning remains an important public health problem and represents the second most frequent accidental disease in children. In this study, we identified epidemiological and clinical features of children admitted for acute drug poisoning and related factors associated with suicidal poisoning. Methods: We conducted a retrospective study in the Department of Pediatrics, the Military Hospital, Tunis, over a period of 8 years (2008-2014). Children aged less than 16 yr and admitted for acute drug poisoning were included. Cases of drug addiction were excluded. Two groups were compared: accidental poisoning / suicidal poisoning. Results: We collected 150 cases. The ratio male / female was 1:1.2. The mean age was 4.3 yr. Poisoning was due to one drug in 82% of cases. Children were asymptomatic in 39% of cases, had digestive and neurologic symptoms respectively in 30% and 20% of cases, respectively. Psychotropics came in the first place (20%) followed by paracetamol (16%). Two groups were identified: accidental poisoning (74 %) and suicidal poisoning (26%). Four factors were significantly associated with suicidal poisoning: age P< 0.001, OR= 16.25, 95% IC : [6.44-40.95]), female gender (P=0.011, OR= 5.4, 95% IC: [2.09-13.91]), multiple drug intake (P < 0.001, OR= 9.42, 95% IC: [3.05-29.03]) and use of psychotropics (P= 0.003, OR=4.81, 95%IC: [2.06-11.26]) . Conclusion: Two groups had to be distinguished: accidental and suicidal drug poisoning. The identification of their characteristics and their predisposing factors is necessary in order to take appropriate preventive actions.

Seven fatalities associated with ethylphenidate

Ethylphenidate is a stimulant novel psychoactive substance that is an analogue of the prescription drug methylphenidate (Ritalin®). Methylphenidate is used commonly for the treatment of attention deficit hyperactivity disorder. Due to its stimulant effects ethylphenidate is being abused. There is a single case report of a death associated with ethylphenidate in Germany, and a case series of 19 deaths in the East of Scotland, but otherwise, the contribution of ethylphenidate to death is poorly documented. We report the analytical results of 7 cases (between February 2013 and January 2015) in which ethylphenidate was detected and quantitated with a validated liquid chromatography tandem mass spectrometry method (LC–MS/MS). The individuals (all male) ranged in age from 23 to 49 years (median 25 years). The concentration of ethylphenidate in the cases ranged from 0.026mg/L to 2.18mg/L in unpreserved post-mortem femoral blood. Only one case had ethylphenidate present as a sole drug. All other cases had at least 2 other drug classes present (benzodiazepines, heroin, methadone antipsychotics, other new psychoactive compounds). Ethylphenidate toxicity was the sole contribution to the cause of death in one case. Hanging was the cause of death in 2 cases, with the other 4 cases being reported as having occurred due to mixed drug toxicity. These data will further help with the interpretation of post-mortem ethylphenidate levels.

Characteristics of poisoning cases in Adiyaman city

Objective: Aim of this study was to retrospectively evaluate poisoning cases in an intensive care unit (ICU) in order to determine the profile of poisoning cases, update epidemiological data in Adiyaman, and contribute to data about poisoning in our country. Methods: Between 01-01-2012 and 31-12-2013 174 patients (116 males, 58 females) with a mean age of 23.7 years were treated. Demographic characteristics, reasons and ways of poisoning, types of toxic substances, length of their ICU stay and prognosis were evaluated. Results: 2733 patients admitted to the intensive care unit were 174 poisoning cases. Poisoning ways were suicide by drug overdose (n=162, 93.1%), and accidental poisoning (n=12,6.9%).119 patients (66.5%) had single drug intake, thirty-three patients (18.4%) with multiple drug intake, and 16 (8.9%) were poisoned by organic phosphates. The most common drug used for suicide was antidepressants (n=87.5%). 32 patients (18.4%) took analgesics and anti-inflammatory drugs. A total of 152 patients taking the drug, 22 patients were poisoned by other means. The median length of patient stay was 2 days (range 1-20 days). Ninety-nine patients (56.9%) recovered and were discharged.72 patients (41.4%) were admitted to inpatient after intensive care unit. Patients were followed up by asking poisoning suicidal psychiatric consultation.1 patient was followed up for 20 days in intensive care due to alcohol poisoning but was died.2 patients (1.1%) were referred to a center forward. Conclusion: Majority of the patients were females, who took drugs with suicidal intention. Frequent use of antidepressants, which are not subject to control by authorities, to commit suicide was remarkable. Key words: Intensive care unit, poisoning, suicide, antidepressant drugs

Multiple drug poisoning case caused by a pharmacokinetic interaction involving paroxetine

A fatal poisoning case involving multiple psychotropic drugs is presented. Quantitative toxicological analysis showed that the concentrations of diphenhydramine, paroxetine, phenobarbital, diazepam and its metabolites (nordiazepam and temazepam) in the femoral blood were 9.19 µg/ml, 1.02 µg/ml, 19.9 µg/ml, 0.26 µg/ml, 8.55 µg/ml and 2.69 µg/ml, respectively. We concluded that the cause of death was due to multiple drug ingestion. As diphenhydramine metabolism is mediated by CYP2D6, and paroxetine inhibits its enzymatic activity, a pharmacokinetic interaction may have induced the high concentration of diphenhydramine in the present case. Pharmacokinetic drug interactions need to be evaluated in cases involving paroxetine drug overdoses.