Enhanced autopsy triage (EA-Triage) in drug-related deaths: integrating quick toxicological analysis and postmortem computed tomography.

The objective was to assess the diagnostic accuracy of an enhanced autopsy triage (EA-Triage) setup consisting of postmortem computed tomography (PMCT), simulated quick toxicological analysis (sQTA), external examination, and case information in determining cause of death (COD) in persons with past or current use of illegal drugs (drug-related deaths). Information on drug-related deaths selected for medico-legal autopsy in 2020-2021 at the Department of Forensic Medicine, Aarhus University, Denmark, was analyzed retrospectively. The included cases underwent conventional autopsy, PMCT, and systematic toxicological analysis. A board-certified forensic pathologist, who was blinded to the internal examination and COD from the medico-legal autopsy, determined COD based on the EA-Triage setup. 154 cases with a median age of 40.6 years (range 17-70 years, 82% males) were included. The COD determined by medico-legal autopsy and that determined by EA-Triage matched in 113 cases (73%), including those with an unknown COD. EA-Triage and medico-legal autopsy determined unknown COD in 45 (29%) and 5 cases (3%), respectively. Excluding cases with an unknown COD, EA-Triage predicted COD in 109 cases (71%); of those, 72 (66%) had no unexplained case circumstances or suspicion of a criminal act. In these 72 cases, the CODs determined by EA-Triage and medico-legal autopsy matched in 71 cases (99%), and the sensitivity and specificity for detecting lethal intoxication were 100% and 90%, respectively. EA-Triage showed strong diagnostic accuracy for determining COD in drug-related deaths. This method may be suitable for enhancing preautopsy triage and guiding police investigations at an early stage.

Exploring death scenes and circumstances in fatal opioid poisonings: Insights for preventive strategies using forensic autopsy cases in Western Denmark.

INTRODUCTION: Fatal opioid poisoning is a growing global issue. This study aims to describe circumstances surrounding fatal opioid poisonings by examining death scenes, demographics, and information from bystanders with the goal of informing prevention efforts. METHODS: We extracted data from the autopsy reports of 327 forensic autopsy cases with fatal poisoning involving methadone and/or morphine from 2013-2020. RESULTS: Fatal opioid poisonings occurred in both rural and urban areas. Death scene was the decedent's own home and a relative's or friend's home in 62% and 21%, respectively. The decedent died alone in 64% of the cases while other people were staying at the same address while death occurred in 30%. Decedents aged 15-34 years were more likely to die with other people staying at the same address than persons aged > 44 years (OR±SD: 2.3 ± 0.9, p = 0.005), and had lower postmortem blood methadone concentrations compared to persons > 34 years (Median [interquartile range]: 0.36 [0.23-0.62] vs 0.63 [0.28-1.2] mg/kg, p = 0.002). Female sex was more prevalent, and persons using illegal drugs were less prevalent in decedents aged > 44 years compared to those with age 15-44 years (29% vs 20%, p = 0.05% and 67% vs 89%, p < 0.001, respectively). Other psychoactive drugs were detected in 97% of decedents, mainly benzodiazepines (80%). CONCLUSIONS: Preventive strategies based on our findings include the need for harm reduction initiatives in both urban and rural areas, recognizing symptoms of fatal poisoning, and awareness of low tolerance among younger age groups. Urgent attention should be given to avoiding opioid use alone, particularly among older individuals, including women using prescribed opioids. Conveying the risks of polydrug use to all age groups is essential, especially co-use of sedative drugs.

Combined in vivo metabolic effects of quetiapine and methadone in brain and blood of rats.

Changes in pharmacokinetics and endogenous metabolites may underlie additive biological effects of concomitant use of antipsychotics and opioids. In this study, we employed untargeted metabolomics analysis and targeted analysis to examine the changes in drug metabolites and endogenous metabolites in the prefrontal cortex (PFC), midbrain, and blood of rats following acute co-administration of quetiapine and methadone. Rats were divided into four groups and received cumulative increasing doses of quetiapine (QTP), methadone (MTD), quetiapine + methadone (QTP + MTD), or vehicle (control). All samples were analyzed using liquid chromatography-mass spectrometry (LC-MS). Our findings revealed increased levels of the quetiapine metabolites: Norquetiapine, O-dealkylquetiapine, 7-hydroxyquetiapine, and quetiapine sulfoxide, in the blood and brain when methadone was present. Our study also demonstrated a decrease in methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in the rat brain when quetiapine was present. Despite these findings, there were only small differences in the levels of 225-296 measured endogenous metabolites due to co-administration compared to single administrations. For example, N-methylglutamic acid, glutaric acid, p-hydroxyphenyllactic acid, and corticosterone levels were significantly decreased in the brain of rats treated with both compounds. Accumulation of serotonin in the midbrain was additionally observed in the MTD group, but not in the QTP + MTD group. In conclusion, this study in rats suggests a few but important additive metabolic effects when quetiapine and methadone are co-administered.

Combined effects of methadone and quetiapine on respiratory rate, haemodynamic variables, and temperature in conscious rats.

Fatal poisonings where both methadone and quetiapine are detected post-mortem occurs frequently in legal autopsy cases. It is unclear whether quetiapine increases the risk of fatal methadone poisoning or if it is merely detected due to widespread use. We hypothesized that methadone and quetiapine would have additive toxic effects on respiratory rate, blood pressure, and the QTc-interval. To investigate this hypothesis, we used telemetry implants for measurements of respiratory rate, haemodynamic variables, the velocity of blood pressure changes, temperature, and movement in conscious, freely moving male Wistar rats aged 12-13 weeks. The combined effects of three accumulative i.p. doses of methadone (2.5, 10, 15 mg/kg) and quetiapine (3, 10, 30 mg/kg) were compared to rats treated with the same doses of each drug alone, and a vehicle-treated group in a randomized investigator blinded study. No additive effects of quetiapine and methadone on respiratory rate, haemodynamic variables, or movement were observed. However, body temperature was significantly lower by approximately 1.5°C on average in the group treated with both methadone and quetiapine (15 + 30 mg/kg) compared to the other groups. This indicates a synergistic effect of quetiapine and methadone on thermoregulation, which may increase the risk of fatal poisoning. We suggest studying this finding further in human settings.

Municipal offers and principles for substitution treatment for abuse and addiction to opioids.

Opioid use disorders can be treated with psychosocial interventions which aim to increase quality of life and minimize problems maintaining drug use. In addition, pharmacological treatment with opioid maintenance therapy (OMT) can help minimize morbidity and mortality. The principle for OMT is substituting to another opioid with a more favourable pharmacological profile, primarily buprenorphine or methadone. The first choice is buprenorphine in combination with naloxone. The aim of this review is to summarize current principles for handling patients in OMT.

Clinical characteristics of hospitalized patients with paracetamol poisoning before and after restrictions of over-the-counter sale of paracetamol.

INTRODUCTION: Paracetamol poisoning is a frequent cause of hospitalization in Denmark. On 30 September 2013, the Danish authorities restricted packages available without a prescription in pharmacy outlets to contain a maximum of 10 g of paracetamol. We aimed to investigate the effects of this regulation. METHODS: This was a cross-sectional study of two groups of patients admitted consecutively to a Danish University Hospital due to poisoning with paracetamol in 365 days in 2012-13 before 30 September 2013, and a corresponding 365-day period in 2017-18. Data were extracted from patient records. RESULTS: In 2012-2013 and 2017-18, 156 and 92 admissions in 127 and 78 unique patients, respectively, were identified. Ingestion of more than 20 g paracetamol occurred in a significantly higher proportion of cases in 2012-13 compared to 2017-18 (29% vs 13%, P < 0.01). In accordance, there were no cases of international normalized ratio >1.5 or alanine aminotransferase activity >1000 U/L in the post-legislation period, and seven and five cases in the pre-legislation period, respectively. Females accounted for 80% and 78% of patients in the two periods, respectively, and were considerably younger than males (median [interquartile range]: 22 [17-40] vs. 47 [30-56], P < 0.01 in 2012-13, and 23 [18-46] vs. 43 [27-49] years, P = 0.02 in 2017-18). Furthermore, in 2012-13, intentional poisonings occurred in a higher proportion of females than males 2012-13 (97% vs 85%, P < 0.01). CONCLUSIONS: The present study demonstrated a lower number of paracetamol poisonings, a decreased proportion of poisonings involving ingestion of more than 20 g of paracetamol, and a lower occurrence of hepatotoxicity after the regulation. However, circumstances other than pack size restrictions, such as increased public awareness of the danger of paracetamol poisonings, may affect these associations. Furthermore, the study showed that females and males constitute two distinct groups in terms of age and intentional poisoning.

Combined effects of quetiapine and opioids: A study of autopsy cases, drug users and sedation in rats.

Fatal opioid poisonings often involve methadone or morphine. This study aimed to elucidate if quetiapine, a widely used sedative antipsychotic medication, may increase the risk of fatal opioid poisoning by additive inhibitory effects on the central nervous system. We used data from 323 cases of fatal methadone or/and morphine poisonings autopsied from 2013 to 2020, a survey of 34 drug users, and performed blinded placebo-controlled studies in 75 Flinders Resistant Line rats receiving three cumulative intraperitoneal doses of vehicle, methadone (2.5, 10 and 15 mg/kg), morphine (3.75, 15 and 22.5 mg/kg), quetiapine (3, 10 and 30 mg/kg) or quetiapine combined with methadone or morphine. Quetiapine was detected in 20.4% of fatal opioid poisonings with a significantly increased frequency over time, primarily in low or therapeutic concentrations, and was not associated with methadone or morphine concentrations. Use of quetiapine, most commonly in low-to-moderate doses to obtain a sleep-inducing or tranquillizing effect, was reported by 67.6% of survey respondents. In the animal studies, a significant impairment of sedation score, performance on the rotarod and open field mobility was observed in all treatment groups compared with vehicle. However, the effect of quetiapine plus the opioid was not significantly different from that of the opioid alone. Thus, no additive sedative effects were observed in rats. Our results suggest that quetiapine is more often an innocent bystander than a contributor to fatal opioid poisoning. However, the combined effects on other parameters, including blood pressure, cardiac rhythm and respiratory rate, need investigation.

Acute drug poisonings leading to hospitalization.

Knowledge about current trends and epidemiology in poisonings is important to maintain quality in diagnostics, treatment and prevention. We performed a cross-sectional study of all cases (n = 261) admitted with drug poisoning to Aalborg University Hospital during 1 year in 2017-2018. Median age was 30 (22-49) years, and 58% were female. Fifty percent were suicide attempts. In most cases, involved drugs were identified by history taking; blood analysis barely revealed any additional paracetamol and salicylicate poisonings. Drugs prescribed to the patient or available over the counter were involved in nearly two thirds of cases. Weak analgesics dominated by paracetamol (n = 91, 35%) was the most frequently involved group of drugs followed by opioids and benzodiazepines. Gender differences were observed with respect to involvement of weak analgesics and central stimulants. A higher prevalence of unidentified involved drugs was observed in 26 cases (10%) in which the length of admission exceeded 2 days and/or intensive care was needed. No deaths, cardiac arrhythmias or physical complications occurred. Thus, current handling of the acute poisoning seems effective in most cases. However, a more tailored use of blood analyses including a toxicological screen in selected cases may represent an opportunity for improvement.

Purity of street-level cocaine across Denmark from 2006 to 2019: Analysis of seized cocaine.

Cocaine-related emergency department admissions are increasing, and cocaine seizures are at an all-time high in Europe. Our aim was to investigate the trends in purity and adulterants over time in cocaine available to cocaine users at street level in Denmark. We used a representative sample of cocaine seized at street level and analyzed by the national departments of forensic medicine between 2006 and 2019 (n = 1460). Latent profile analysis was used to classify the samples based on cocaine, levamisole, and phenacetin content. Low purity cocaine comprised most of the cocaine seizures in early years, but its share began to decline in 2013, and from 2016 to 2019, the high purity profile was dominant. While the total number of samples containing adulterants decreased, levamisole remained a common and dangerous adulterant. The findings underline the need to inform the public, medical doctors, and service providers for people with drug use disorders about the higher potency of street cocaine.

[Tardive akathisia after long-term metoclopramide treatment].

This case report describes a 57-year-old male with symptoms of tardive akathisia after long-term metoclopramide treatment. As metoclopramide is a dopamine receptor antagonist, it has the potential to cause drug-induced movement disorders, including akathisia, which is characterised by an inner restlessness resulting in a need for constant movement. Tardive akathisia, in contrast to acute akathisia, evolves after prolonged exposure to the triggering medication and can be a permanent condition. Treatment duration of metoclopramide should be restricted, and awareness of neurological side effects is important.

Quetiapine and other antipsychotics combined with opioids in legal autopsy cases: A random finding or cause of fatal outcome?

Opioid poisoning is a frequent cause of death in drug addicts and occurs with opioid treatment. Quetiapine is often found in forensic autopsies and may increase the risk of fatal opioid poisoning by enhancing sedation, respiratory depression, hypotension and QT prolongation. We systematically searched for studies of acute toxicity of quetiapine or other antipsychotics combined with morphine or methadone. Case reports describing toxicity of quetiapine combined with morphine or methadone were also included. We retrieved one human study that observed pharmacokinetic interaction between quetiapine and methadone, and 16 other human studies. Fourteen investigated the combination of droperidol and morphine in treatment doses, and some indicated an additive sedative effect. Five animal studies with acepromazine in combination with morphine or methadone were located and indicated an additive effect on sedation and hypotension. Six forensic case reports in which death could have been caused solely by quetiapine, the opioid, or other drugs were found. Thus, acute toxicity of quetiapine combined with morphine or methadone has not been studied. Because of quetiapine's effects on alpha-adrenoceptors, muscarinic and histamine receptors, human ether-a-go-go-channels and methadone kinetics, we suggest further research to clarify if the indicated additive effects of opioids and droperidol or acepromazine are also true for quetiapine.

Palliation of chronic breathlessness with morphine in patients with fibrotic interstitial lung disease - a randomised placebo-controlled trial.

BACKGROUND: Patients suffering from fibrotic interstitial lung diseases (fILD) have a poor prognosis and a high symptom burden. Palliative treatment includes relief of symptoms such as breathlessness. There is no evidence-based treatment for chronic breathlessness but opioids are often used despite concerns due to the hypothetical risk of respiratory depression. This study investigated the effect of oral morphine drops in patients with fILD on chronic breathlessness and safety. METHODS: In a double-blinded placebo-controlled study, 36 patients with fILD were randomised to either four daily doses of 5 mg of oral morphine drops or placebo for 1 week. Endpoints and safety parameters were obtained at baseline, at follow-up after 1 h and 1 week. RESULTS: The primary endpoint, the visual analogue score (VAS) of dyspnea was reduced by 1.1 ± 0.33 cm in the morphine group at follow-up compared to baseline (P < 0.01), whereas the reduction was 0.35 ± 0.47 cm in the placebo group. However, the difference between the two groups was not statistically significant (p = 0.2). Oral morphine drops did not affect respiratory frequency, pulse rate, blood pressure, peripheral saturation or the 6-min walk test. More patients treated with morphine reported constipation, nausea and confusion. CONCLUSION: Oral administration of morphine drops, 20 mg a day, in patients with fILD did not significantly reduce dyspnea VAS score during 1 week compared to placebo. Oral morphine did not induce respiratory depression, but was related to an increased risk of constipation, nausea and confusion. TRIAL REGISTRATION: The trial is registered in clinicaltrials.gov (Identifier: NCT02622022 ). Registered 4 December 2015.

The risk of osteoporosis in patients with asthma.

It is well-known that use of continuous systemic corticosteroids (SG) affects bone metabolism, bone mineral density (BMD), and ultimately increases the risk of osteoporosis. In patients with asthma, on the other hand, the effects of long-term high-dose inhaled corticosteroids (ICS) on BMD and risk of osteoporotic fractures is controversial. The reasons for this inconsistency could be explained by the fact that only few long-term studies investigating the effect of ICS in patients with asthma exist. The studies are characterized by different study designs and duration of ICS exposure, small study populations, and differences between the used ICS. The aim of this article is to unravel which factors, if any, that contribute to an increased risk of osteoporosis in patients with asthma and to summarize the evidence regarding adverse effects of ICS on bone metabolism, BMD and osteoporotic fractures in patients with asthma.

Prevalence of medication-related falls in 200 consecutive elderly patients with hip fractures: a cross-sectional study.

BACKGROUND: Hip fractures constitute a major health problem in elderly people and are often fall-related. Several factors can contribute to a fall episode leading to hip fracture, including fall-risk-increasing drugs (FRIDs), which are often used by elderly people. We aimed to investigate the prevalence of medication-related falls and to assess the role of FRIDs and potentially inappropriate medications (PIMs) in a population of elderly patients hospitalized for a hip fracture. METHODS: We reviewed the patient records of 200 consecutive patients, aged ≥65 years, who were admitted for a hip fracture and evaluated whether medications were likely to have contributed to the fall episode. PIMs were identified using the Screening Tool of Older Persons' Prescriptions version 2 (STOPP) and by evaluating indications, contra-indications and interactions of the prescribed medications for each patient. RESULTS: FRIDs were used by 175 patients (87.5%). Medications were considered a likely contributor to the fall in 82 patients (41%). These were most often psychotropic medications alone or in combination with antihypertensives and/or diuretics. The 82 patients with suspected medication-related falls used more medications, FRIDs and PIMs than the rest of the patients, and in 74 (90%) of the 82 patients, at least one medication considered to be a contributor to the fall was also a PIM. CONCLUSIONS: The prevalence of suspected medication-related falls was 41%. It seems likely that a medication review could have reduced, though not eliminated, the risk of falling in this group of patients.

Fatal poisoning among drug users in Denmark in 2017.

INTRODUCTION: Knowledge of trends of illegal drug use is vital for planning initiatives to reduce accidents and deaths among drug users. The aim of this study was to describe the cause of death, abuse pattern and geographic differences in fatal poisonings among drug users in Denmark in 2017. METHODS: All fatal poisonings among drug users examined at the three institutes of forensic medicine in Denmark in 2017 were included in the study. RESULTS: Overall, fatal poisonings declined from a maximum of 226 in 2007 to 162 in 2017. Methadone (52%) was the most common cause of death, followed by heroin/morphine (25%). A marked increase in deaths was due to stimulants (13%), especially cocaine. The abuse pattern has changed since 2012. Methadone remained the most frequently detected drug, but clonazepam and cocaine surpassed heroin/morphine, diazepam and tetrahydrocannabinol as the second-most frequently detected drugs. Ketobemidone had disappeared, whereas buprenorphine, oxycodone, fentanyl, pregabalin and gabapentin had increased. Antidepressants/antipsychotics were detected in half (47%) of the cases. Cocaine was more frequent in the areas covered by Copenhagen and Aarhus, whereas heroin/morphine was most frequently detected in the area covered by Odense. Amphetamine was more frequent in the Aarhus area. CONCLUSIONS: Methadone and heroin/morphine still account for most fatal poisonings. However, deaths due to stimulants, especially cocaine, have increased. The abuse pattern has changed and geographical differences have emerged. FUNDING: none. TRIAL REGISTRATION: not relevant.

Macular oedema and changes in macular thickness in multiple sclerosis patients treated with fingolimod.

Macular oedema is a known side effect to fingolimod, but changes in specific areas of the retina are only sparsely described. Our aim was to investigate the prevalence of macular oedema and characterize macular changes after initiation of fingolimod based on routine ophthalmological examinations in all consecutive patients treated at our hospital. We evaluated macular thickness change from baseline to 3-4 months after initiation of treatment. Central retinal thickness, total macular volume, total macular thickness, average thickness and inner-/outer macular thickness were automatically measured using optical coherence tomography (OCT). A total of 190 eyes completed the study, and none of those developed visible macular oedema. All macular areas showed a small, but statistically significant increase in thickness. Total macular volume increased by a mean of 0.05 mm3 (P = <.001). Mean best-corrected visual acuity only changed by .03 (P = .074). We observed a minimal change in macular thickness and no clinically relevant affection on visual acuity after 3-4 months of fingolimod treatment. Thus, our results do not underpin the need for routine screening for macular oedema in asymptomatic MS patients without diabetes or uveitis receiving 0.5 mg fingolimod daily.

[Examination for osteoporosis in patients with chronic obstructive pulmonary disease].

Patients with chronic obstructive pulmonary disease (COPD) are at risk of developing osteoporosis, as the COPD in itself as well as continued smoking and treatment with systemic corticosteroid all increase the risk of developing osteoporosis. Other risk factors for osteoporosis are low vitamin D levels, malnutrition and physical inactivity. All patients who have risk factors in the form of severe COPD, and all patients with COPD in active treatment with systemic corticosteroid and/or other risk factors should be examined with a DEXA-scan. Treatment of osteoporosis in patients with COPD does not differ from general recommendations.

Opioids: an unexplored option for treatment of dyspnea in IPF.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common among the idiopathic interstitial pneumonias and has the worst prognosis, with a median survival of 3-5 years. The most common symptom in IPF is dyspnea, impacting on the patient's quality of life and life expectancy. Morphine in the treatment of dyspnea has been investigated but with conflicting results. This review aims to clarify the role of opioids in the treatment of dyspnea in patients with IPF. METHODS: A literature search was performed using the MeSH and PubMed databases. As only very few studies included patients with IPF, studies conducted primarily with patients with chronic obstructive pulmonary disease were also included. In total, 14 articles were found. RESULTS: Seven studies reported use of systemic morphine and seven studies of inhaled morphine. Five of the seven studies investigating systemic administration detected an improvement in either dyspnea or exercise capacity, whereas no beneficial effect on dyspnea was detected in any study using inhaled morphine. No severe adverse effects such as respiratory depression were reported in any study, although constipation was reported as a notable adverse effect. CONCLUSIONS: Results were inconsistent, but in some studies systemic morphine administration showed a significant improvement in the dyspnea score on a visual analog scale without observation of severe side effects. Nebulized morphine had no effect on dyspnea.