The Risk of Overdose With Concomitant Use of Z-Drugs and Prescription Opioids: A Population-Based Cohort Study.

OBJECTIVE: The Z-drugs (zolpidem, zopiclone, zaleplon) are widely used to treat insomnia in patients receiving prescription opioids, and the risk of overdose resulting from this coprescription has not been explored. The authors compared the rates of overdose among patients using opioids plus Z-drugs and patients using opioids alone. METHODS: All individuals 15 to 85 years of age receiving prescription opioids, regardless of underlying indication and without evidence of cancer, were identified in the IBM MarketScan database (2004-2017). Patients with concomitant exposure to Z-drugs were matched 1:1 to patients with exposure to prescription opioids alone based on opioid prescribed, morphine equivalents, number of days' supply, and hospitalization within the past 30 days. The primary outcome was any hospitalization or emergency department visit due to an overdose within 30 days, using an intention-to-treat approach. Fine stratification on the propensity score was used to control for confounding. RESULTS: A total of 510,529 exposed patients and an equal number of matched reference patients were analyzed. There were 217 overdose events among the exposed patients (52.5 events per 10,000 person-years) and 57 events among the reference patients (14.4 events per 10,000 person-years), corresponding to an unadjusted hazard ratio of 3.67 (95% CI=2.75, 4.90). Using fine stratification on the propensity score (c-statistic: 0.66), the adjusted hazard ratio was 2.29 (95% CI=1.79, 2.91). Results were consistent across sensitivity analyses. CONCLUSIONS: Among patients receiving prescription opioids, after controlling for all confounding factors, concomitant treatment with Z-drugs was associated with a substantial relative increase in the risk of overdose. The potential implications are significant given the large number of opioid-treated patients receiving Z-drugs.

Acute bone marrow suppression and gastrointestinal toxicity following acute oral methotrexate overdose.

OBJECTIVE: Acute methotrexate overdose rarely causes systemic toxicity due to saturable absorption and rapid renal elimination. We present a case of methotrexate toxicity following acute overdose. CASE REPORT: A 56-year-old female presented soon after an overdose of 1250 mg of methotrexate, zopiclone and tramadol. The methotrexate was initially under-reported (500 mg) and folinic acid was not provided. Despite normal renal function, the patient developed toxicity. She represented 5 days following the overdose with mucositis, bone marrow suppression and prolonged febrile neutropenia. Treatment included folinic acid, broad-spectrum antibiotics, filgrastim, red cell and platelet transfusion. Her bone marrow began to recover 12 days following the overdose. She was discharged home on Day 17. DISCUSSION: Severe toxicity following an acute ingestion of a large amount of methotrexate is rarely reported. The development of toxicity was unexpected in this case given methotrexate's pharmacokinetics and the patient's normal renal function. The serum methotrexate concentrations were below the treatment threshold of the folinic acid rescue therapy nomogram suggesting that the nomogram should not be relied on in acute ingestions. Large acute oral methotrexate poisoning can result in systemic toxicity and folinic acid therapy should be provided in ingestions >1000 mg.

Two fatalities associated with synthetic opioids: AH-7921 and MT-45.

In this study, two fatalities associated with the synthetic opioids AH-7921 and MT-45 are reported. Within the last few years, both compounds have emerged on the recreational drug market and are sold as "research chemicals" on the internet. In the first case, a 22-year-old woman was found dead in the bedroom of her apartment by two of her friends. A plastic bag labeled "AH-7921" was found in the apartment and the two friends stated that the deceased had consumed AH-7921 prior to her death. The woman was a known drug addict. In the second case, a 24-year-old man was found dead in his room by his mother. The deceased was sitting on a chair in front of his desk slumped over. Several bags of white powder labeled "MT-45", "Methoxmetamine" and "Methoxphenidine" were found in his room. Toxicological analyses of femoral blood, heart blood, liver, pericardial fluid, urine, vitreous humor and stomach content of the deceased were performed using liquid chromatography-quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS). Time-of-flight mass spectrometry was carried out on an LC-Triple TOF 5600 system (AB Sciex) with electrospray ionization operated in positive mode. In the first case, additional hair analysis was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and LC-QTOF-MS. In both cases, the relevant synthetic opioid could be detected in all analyzed samples. The concentration of AH-7921 was determined to be 450µg/L in femoral blood. MT-45 was present at a concentration of 2900µg/L in femoral blood. Besides methoxmetamine which could qualitatively be detected in femoral blood, urine and stomach content no methoxphenidine was found. In summary, deaths of the young individuals could be, by exclusion of other causes of death, attributed to the consumption of an overdose of AH-7921 and MT-45, respectively.

Propolis protective role against morphological, hormonal biochemical and histological alterations induced by sildenafil overdoses / Rol protector del propóleo contra las alteraciones morfológicas, hormonales, bioquímicas e histológicas inducidas por sobredosis de sildenafil

Sildenafil is widely used for the treatment of erectile dysfunction with few studies are available on the protective role of propolis against its reproductive toxicity. The present study aims to investigate the hormonal biochemical and histomorphometric alterations induced in the testicular tissues by sildenafil overdoses. Four groups of rabbits were exposed to sildenafil with or without propolis as follows: Group I received the formulated vehicle, Group II received sildenafil (3 mg/kg), Group III received propolis (50 mg/kg), Group IV received sildenafil plus propolis. Sildenafil lowered body weight gain, testosterone and follicular stimulating hormone concentration but increased testis index while luteinizing hormone was almost not affected. Moreover, sildenafil treated rabbits showed degenerative seminiferous tubules and disturbance of spermatogenesis together with spermatocytes sloughing and nuclear alterations. Exposure to sildenafil plus propolis ameliorated tubular alterations, spermatogenesis disturbances, hormonal levels changes and partially protected spermatocytes from morphological nuclear alterations but could not ameliorate the effect on the body weight gain and testis index. The findings of the present work may indicate that propolis can ameliorate partially the reproductive toxicity induced by sildenafil overdoses with more need for further studies on the adverse effect of these doses on the other vital organs.

El sildenafil es un medicamento ampliamente utilizado para el tratamiento de la disfunción eréctil y existen pocos estudios disponibles referente a la función protectora del propóleo contra su toxicidad reproductiva. El objetivo fue investigar las alteraciones hormonales, bioquímicas e histomorfométricas, inducidas en los tejidos testiculares por sobredosis de sildenafil. Cuatro grupos de conejos fueron expuestos a sildenafil con o sin propóleo de la siguiente manera: grupo I recibió el sildenafil formulado, grupo II recibió sildenafil (3 mg/kg), grupo III recibió propóleo (50 mg/kg) y el grupo IV recibió sildenafil más propóleo. El sildenafil redujo el peso corporal, la testosterona y la concentración de la hormona foliculoestimulante, sin embargo, se observó un aumento del índice testicular mientras que la hormona luteinizante casi no se vio afectada. Por otra parte, los conejos tratados con sildenafil mostraron degeneración de los túbulos seminíferos, trastornos de la espermatogénesis y alteraciones nucleares de los espermatocitos. Con el uso de sildenafil más propóleo fue posible disminuir las alteraciones de los túbulos seminíferos, los trastornos de la espermatogénesis y los niveles de cambios hormonales; los espermatocitos fueron protegidos parcialmente de alteraciones nucleares morfológicas, pero no pudo mejorar el efecto de aumento de peso corporal e índice testicular. Los resultados indican que el propóleo puede aliviar, en parte, la toxicidad en la reproducción inducida por sobredosis de sildenafil. No obstante, existe la necesidad de realizar más estudios sobre los efectos adversos de estas dosis en otros órganos vitales.

Novel psychoactive substances. / Nye psykoaktive stoffer.

There has been a significant increase in the number of new intoxicants on the illegal drugs market globally, also in Norway. The substances are given the name NPS: Novel Psychoactive Substances, and are mainly sold over the Internet. Uncertain dosage of potent substances entails a risk of accidental overdose, and therefore serious intoxication and death. In this article we provide an overview of current knowledge with regard to these substances.

Analysis of MT-45, a Novel Synthetic Opioid, in Human Whole Blood by LC-MS-MS and its Identification in a Drug-Related Death.

MT-45 (1-cyclohexyl-4-(1,2-diphenylethyl)piperazine) is just one of the many novel psychoactive substances (NPS) to have reached the recreational drug market in the twenty-first century; it is however, one of the first designer opioids to achieve some degree of popularity, in a market currently dominated by synthetic cannabinoids and designer stimulants. A single fatality involving MT-45 and etizolam is described. A method for the quantitation of MT-45 in whole blood using liquid chromatography-tandem mass spectrometry was developed and validated. The linear range was determined to be 1.0-100 ng/mL with a detection limit of 1.0 ng/mL, and the method met the requirements for acceptable linearity, precision and accuracy. After analyzing the sample on dilution and by standard addition, the concentration of MT-45 in the decedent's blood was determined to be 520 ng/mL, consistent with other concentrations of MT-45 reported in drug-related fatalities. Etizolam was present at a concentration of 35 ng/mL. This case illustrates the importance of considering non-traditional drugs in unexplained apparent drug-related deaths.

[Acute cutaneous symptom complex with subsequent cataract. The internet drug MT-45 may be the cause]. / Akut kutant symtomkomplex med efterföljande katarakt - Nätdrogen MT-45 kan vara orsaken.

The number of new psychoactive substances (¼NPS«) sold by online drug vendors (¼Internet drugs«) shows a steady increase. Over a short time period in 2013-2014, three Swedish men aged 23-34 years with suspected drug use experienced similar but unusual clinical symptoms including loss and depigmentation of hair, widespread folliculitis and dermatitis, painful intertriginous dermatitis, dryness of eyes, and elevated liver enzymes. Two also had lines of discoloration across the nails (¼Mees' lines«) of the fingers and toes. The symptoms gradually disappeared over time. However, two of them subsequently developed severe bilateral secondary cataracts requiring surgery. Blood tests for NPS performed within the Swedish STRIDA project demonstrated intake of the synthetic opioid MT-45, a piperazine derivative originally synthesized as a therapeutic drug candidate in the 1970s, in all three patients, suggesting this as a possible common causative agent. These clinical cases highlight the importance for physicians to consider the increasing number of untested recreational drugs as a potential cause of unusual clinical symptoms.

Características generales de los principales grupos de Drogas Emergentes: catinonas, piperacinas y spices / General characteristics of the main groups of Emerging Drugs: cathinones, piperazines and spices

Introducción: el extenso, cambiante y muy diverso grupo de las drogas emergentes, de variado origen, composición y efectos de naturaleza diversa, ha invadido al mundo entero en el siglo XXI, y como una pandemia se extiende y devora al hombre, a su familia y a la comunidad, donde los más vulnerables continúan siendo los más jóvenes. Objetivo: aumentar el conocimiento de los principales grupos de drogas emergentes: catinonas, piperacinas y spices, surgidas en los últimos cinco años. Método: para ello se realizaron búsquedas en la Biblioteca Cochrane Plus, MEDLINE, EMBASE, PsyclNFO, EBsCO, HINARI, Dissertation Abstracts y en los artículos identificados en sus bibliografías, además de las búsquedas individuales en MEDLINE de autores que han reportado información relacionada con el consumo de drogas emergentes en los últimos cinco años. Conclusiones: la gravedad del fenómeno las drogas emergentes radica en que de ellas no escapa casi ningún país. Son sustancias que pues se encuentran en plena y continua evolución al obtenerse a través de sofisticados procesos de síntesis que, en la mayor parte de los casos, constituyen un enigma. La información obtenida, es habitualmente pseudo científica que con frecuencia se utiliza como justificación para la promoción del uso desde muchas páginas web. La naturaleza virtual y globalizada de internet, dificulta aplicar medidas restrictivas legales y, su relativo anonimato favorece el comercio y la distribución. Su proliferación deviene en una alerta para las comunidades modernas porque amenazan la vida y la estabilidad del planeta tierra(AU)

Introduction: the vast, changing and diverse group of emerging drugs, of varied origin, composition and effects of various kinds, has invaded the whole world in the twenty-first century, and as a pandemic spreads and devours the man, his family and the community, where the most vulnerable are still younger. Objective: To increase awareness of the main groups of emerging drugs: cathinones, piperazines and spices emerged in the last five years. Method: for it searched the Cochrane Library, MEDLINE, EMBASE, PsyclNFO, EBSCO, HINARI, Dissertation Abstracts and articles identified in their bibliographies, in addition to individual searches of MEDLINE of authors who have reported information regarding the emerging drug consumption in the last five years. Conclusions: The severity of the emerging drug phenomenon is that of them not escape almost any country. They are therefore substances are in full and continuous evolution to sophisticated obtained by synthesis processes which, in most cases, an enigma. The information obtained is usually pseudo science that is often used as a justification for promoting the use from many websites. The virtual and globalized nature of the Internet makes it difficult to apply restrictive legal measures and their relative anonymity favors trade and distribution. Their proliferation becomes an alert for modern communities that threaten life and stability of the planet earth(AU)

[Research Progress on Forensic Toxicology of Z-drugs].

The Z-drugs (zolpidem, zopiclone, and zaleplon), as the innovative hypnotics, have an improvement over the traditional benzodiazepines in the management of insomnia. Z-drugs have significant hypnotic effects by reducing sleep latency and improving sleep quality, though duration of sleep may not be significantly increased. As benzodiazepines, Z-drugs exert their effects through increasing the transmission of γ-aminobutyric acid. Z-drugs overdose are less likely to be fatal, more likely would result in poisoning. Z-drugs can be detected in blood, urine, saliva, and other postmortem specimens through liquid chromatography-mass spectrometry techniques. Zolpidem and zaleplon exhibit significant postmortem redistribution. Z-drugs have improved pharmacokinetic profiles, but incidence of neuropsychiatric sequelae, poisoning, and death may prove to be similar to the other hypnotics. This review focuses on the pharmacology and toxicology of Z-drugs with respect to their adverse effect profile and toxicity and toxicology data in the field of forensic medicine.

Multi-drug intoxication fatality involving atorvastatin: A case report.

Mixed antihypertensive drug intoxication poses a significant risk for patient mortality. In tandem to antihypertensives, hypolipidemic medicines (especially statins) are often prescribed. Among their well-known adverse effects belongs rhabdomyolysis. We report a case of fatal multi-drug overdose in a 65-year-old female alcoholic. The patient was unconscious at admission. Empty blister packs indicated the abuse of 250 tablets of urapidil, 42 tablets of verapamil/trandolapril, 50 tablets of moxonidin, 80 tablets of atorvastatin and 80 tablets of diacerein. Standard measures (gastric lavage, activated charcoal, mechanical ventilation, massive doses of vasopressors, volume expansion, diuretics and alkalinization) failed to provide sufficient drug elimination and hemodynamic support and the sufferer deceased on the fourth day. Dramatic elevations of serum myoglobin (34,020 µg/L) and creatine kinase (219 µkat/L) were accompanied by rise in cardiac troponin I and creatinine. Gas chromatography revealed ethanol 1.17 g/kg (blood) and 2.81 g/kg (urine). Thin layer chromatography and gas chromatography of gastric content and urine verified verapamil, moxonidin and urapidil fragment (diacerein method was unavailable). Atorvastatin and trandolapril concentrations (LC-MS(n)) equaled 277.7 µg/L and 57.5 µg/L, resp. (serum) and 8.15 µg/L and 602.3 µg/L, resp. (urine). Histology confirmed precipitates of myoglobin with acute necrosis of proximal renal tubules in association with striated muscle rhabdomyolysis and myocardial dystrophy. Cardiogenic-distributive shock in conjunction with acute renal failure due to the combined self-poisoning with vasoactive agents and atorvastatin were determined to be this decedent's immediate cause of death. The manner of death was assigned to be suicidal.

Research Progress on Forensic Toxicology of Z-drugs / 法医学杂志

The Z-drugs (zolpidem, zopiclone, and zaleplon), as the innovative hypnotics, have an improvement over the traditional benzodiazepines in the management of insomnia. Z-drugs have significant hypnotic effects by reducing sleep latency and improving sleep quality, though duration of sleep may not be significantly increased. As benzodiazepines, Z-drugs exert their effects through increasing the transmission of γ-aminobutyric acid. Z-drugs overdose are less likely to be fatal, more likely would result in poisoning. Z-drugs can be detected in blood, urine, saliva, and other postmortem specimens through liquid chromatography-mass spectrometry techniques. Zolpidem and zaleplon exhibit significant postmortem redistribution. Z-drugs have improved pharmacokinetic profiles, but incidence of neuropsychiatric sequelae, poisoning, and death may prove to be similar to the other hypnotics. This review focuses on the pharmacology and toxicology of Z-drugs with respect to their adverse effect profile and toxicity and toxicology data in the field of forensic medicine.

[MT-45--a dangerous and potentially ototoxic internet drug]. / MT-45 - en livsfarlig och potentiellt ototoxisk internetdrog.

During the last years several synthetic opioids have been introduced on Internet sites selling new psychoactive substances (NPS). One of these, called MT-45, a piperazine derivative originally synthesized as a therapeutic drug candidate in the 1970s, has recently been detected in 21 deaths, according to unpublished data from the Swedish National Board of Forensic Medicine. We present clinical data from 12 analytically confirmed hospital cases of MT-45 poisoning. The cases demonstrate that MT-45, like other opioids, can induce potentially life threatening respiratory depression and loss of consciousness in users and that symptoms are usually reversed by standard doses of the opioid receptor antagonist naloxone. Significant auditory symptoms with transient tinnitus and hearing loss occurred in two cases and a pronounced sensorineural hearing loss still present at two weeks follow-up in one case. This indicates that MT-45 may be an ototoxic substance, illustrating the ubiquitous risk of unintended adverse effects NPSs pose to users.

MT-45, a new psychoactive substance associated with hearing loss and unconsciousness.

BACKGROUND: MT-45 (1-cyclohexyl-4-(1,2-diphenylethyl)piperazine) is an opioid analgesic drug candidate developed in the 1970s that has recently been introduced as a new psychoactive substance (NPS) on the "recreational" drug market. We describe a case series of non-fatal intoxications associated with MT-45 within the Swedish STRIDA project. STUDY DESIGN: Observational case series of consecutive patients with admitted or suspected intake of NPS presenting to hospitals in Sweden from November 2013 to February 2014. PATIENTS AND METHODS: Blood and urine samples were collected from intoxicated patients presenting to emergency departments and intensive care units over the country. NPS analysis was performed by an LC-MS/MS multi-component method. Clinical data were collected when caregivers consulted the Poisons Information Centre and also retrieved from medical records. CASE SERIES. Among nine intoxications where MT-45 was detected in the biological samples, four cases were indicated to only involve MT-45, while one or several psychoactive substances were found along with MT-45 in the others. All patients were men aged 17-32 years and they commonly presented with opioid-like adverse symptoms, such as unconsciousness and respiratory depression. Naloxone appeared to have utility in the treatment of MT-45 intoxication in several cases. Three patients complained of bilateral hearing loss that in one case persisted after two weeks. CONCLUSION: MT-45 should be added to the growing list of harmful NPS causing life-threatening poisonings, and rapid actions taken to make it a controlled substance.

Forensic imaging for causal investigation of death.

A 63-year-old man was found in the street after overrun by a car. Postmortem CT revealed multiple bone fractures, but surprisingly all without any relevant hemorrhage which would have been expected under such circumstances. A round radiopaque formation was found in the duodenum, which was reminiscent of ingested tablets. The toxicological analysis revealed high concentrations of zopiclone and alcohol. By combining radiologic and forensic results, zopiclone and alcohol intoxication were concluded as the cause of death, followed by a postmortem overrun accident.

The clinical and forensic toxicology of Z-drugs.

The Z-drugs zolpidem, zopiclone, and zaleplon were hailed as the innovative hypnotics of the new millennium, an improvement to traditional benzodiazepines in the management of insomnia. Increasing reports of adverse events including bizarre behavior and falls in the elderly have prompted calls for caution and regulation. Z-drugs have significant hypnotic effects by reducing sleep latency and improving sleep quality, though duration of sleep may not be significantly increased. Z-drugs exert their effects through increased γ-aminobutyric acid (GABA) transmission at the same GABA-type A receptor as benzodiazepines. Their pharmacokinetics approach those of the ideal hypnotic with rapid onset within 30 min and short half-life (1-7 h). Zopiclone with the longest duration of action has the greatest residual effect, similar to short-acting benzodiazepines. Neuropsychiatric adverse events have been reported with zolpidem including hallucinations, amnesia, and parasomnia. Poisoning with Z-drugs involves predominantly sedation and coma with supportive management being adequate in the majority. Flumazenil has been reported to reverse sedation from all three Z-drugs. Deaths from Z-drugs are rare and more likely to occur with polydrug overdose. Z-drugs can be detected in blood, urine, oral fluid, and postmortem specimens, predominantly with liquid chromatography-mass spectrometry techniques. Zolpidem and zaleplon exhibit significant postmortem redistribution. Zaleplon with its ultra-short half-life has been detected in few clinical or forensic cases possibly due to assay unavailability, low frequency of use, and short window of detection. Though Z-drugs have improved pharmacokinetic profiles, their adverse effects, neuropsychiatric sequelae, and incidence of poisoning and death may prove to be similar to older hypnotics.

Poisoning with illicit substances: toxicology for the anaesthetist.

The consumption of illicit substances represents a considerable threat to the health and wellbeing of particular sectors of our communities. Hospitalisation is sometimes required for the treatment of the direct toxic effects of the drugs as well as for injuries sustained while under their influence. Although poisoning with 'traditional' substances of abuse such as opioids, cocaine and cannabis still predominate in terms of numbers, the availability and use of new psychoactive substances are on the rise. These latter agents, some of which began life as failed pharmaceutical products, have enjoyed renewed status as recreational stimulants, entactogens or hallucinogens, properties that originally precluded them from legitimate use. These drugs may act by enhancing endogenous release of neurotransmitters, inhibiting their reuptake back into neurons or having direct effects on receptors, and may involve adrenergic, dopaminergic or serotonergic systems. The use of intravenous lipid emulsion for the symptomatic treatment of drug overdose has become a fertile ground for research and may hold promise as a non-specific treatment for poisoning with illicit substances. Dexmedetomidine, an α(2)-receptor agonist with a central sympatholytic effect, may be able to counteract the cardiovascular and central nervous system overstimulation that may accompany stimulant toxicity.

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.