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Background: Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses need to be better examined. The purpose of this study was to describe daily dosages, measured blood concentrations, and clinical responses in critically ill patients. The purpose was also to contribute to establishing whole blood concentration reference values of the drugs investigated., Methods: A descriptive study of prospectively collected data from 302 admissions to a general intensive care unit (ICU) at a university hospital. Ten drugs (clonidine, fentanyl, morphine, dexmedetomidine, ketamine, ketobemidone, midazolam, paracetamol, propofol, and thiopental) were investigated, and daily dosages recorded. Blood samples were collected twice daily, and drug concentrations were measured. Clinical responses were registered using Richmond agitation-sedation scale (RASS) and Numeric rating scale (NRS)., Results: Drug dosages were within recommended dose ranges. Blood concentrations for all 10 drugs showed a wide variation within the cohort, but only 3% were above therapeutic interval where clonidine (57 of 122) and midazolam (38 of 122) dominated. RASS and NRS were not correlated to drug concentrations., Conclusion: Using recommended dose intervals for analgesic and sedative drugs in the ICU setting combined with regular monitoring of clinical responses such as RASS and NRS leads to 97% of concentrations being below the upper limit in the therapeutic interval. This study contributes to whole blood drug concentration reference values regarding these 10 drugs., Competing Interests: The authors report no conflict of interest., (© 2024 The Author(s).)

At the Swedish national forensic toxicology laboratory, a measured testosterone/epitestosterone (T/E) ratio ≥ 12 together with testosterone/luteinizing hormone (T/LH) in urine > 400 nmol/IU is considered as a proof of exogenous testosterone administration. However, according to the rules of the World Anti-Doping Agency (WADA), samples with T/E ratio > 4 are considered suspicious and shall be further analysed by gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS) to confirm the origin of testosterone and its metabolites. The aim of this study was to investigate the possibility of false negative results and to estimate the frequency of negative results using the current criteria for detection of abuse of testosterone in forensic investigations. Urine and serum samples were collected by the police at suspected infringement of the doping law in Sweden. Fifty-eight male subjects were included in the study. Urinary testosterone was determined by gas chromatography-mass spectrometry (GC-MS), serum testosterone and LH-by immunoassay. The origin of testosterone and its metabolites was confirmed by means of GC-C-IRMS. Twenty-six of the 57 analysed subjects tested positive for exogenous testosterone using the criteria T/E ≥ 12 combined with T/LH > 400 nmol/IU. The IRMS analyses confirmed 47 positives; thus, 21 were considered false negatives. Negative predictive value was 32% (95% confidence interval [CI]: 16%-50%) and sensitivity 55%. No false positive subjects were found. The number of false negative cases using the current criteria for the detection of testosterone abuse and hence the low sensitivity indicates a need to discuss introduction of new strategies in forensic doping investigations., (© 2021 John Wiley & Sons, Ltd.)

Purpose: We endeavored to investigate whether previous findings of an association between antemortem exposure to selective serotonin re-uptake inhibitors (SSRI) and method of suicide could be replicated., Methods: Using the Swedish National Board of Forensic Medicine's toxicology database and the Swedish National Board of Health and Welfare's national registries of causes of death and prescriptions, 10,002 incidents of suicide were retrieved. Risks of violent suicide conferred by SSRIs, expressed as odds ratios (ORs) with 95% confidence intervals (CIs), were estimated using logistic regression. In accordance with previous work, suicide by violent means-cases-were defined as death attributable to causes designated by ICD-10 codes X70-X83 and Y20-Y33; and suicide by non-violent means-controls-by codes X60-X69 and Y10-Y19., Results: Our results imply that SSRI exposure confers a risk of violent suicide for shorter treatment durations; and that antemortem exposure to other substances (including illegal drugs) confounds estimates of risk. After adjustment for age, sex, and other substances, SSRIs treatment not exceeding 28 days conferred an almost fourfold risk of violent suicide (OR 3.6 [95% CI 1.9-6.8]), a finding partly in line with a recent Swedish study that employed a case-crossover design., Conclusions: Although risks associated with shorter treatment duration may reflect latencies to onset of therapeutic effect, it is unclear how latencies would influence the choice of suicide method, unless conditions for which SSRIs are prescribed are themselves associated with violent suicide. Finally, in the total dataset, SSRIs were not associated with an increased risk of violent suicide; however, by adjusting for other substances, we avoided the spurious conclusion that the effect of medications in this regard is protective.

Background and Objectives: Oxycodone is frequently prescribed as well as detected in postmortem cases. Concurrent use of pharmacodynamically or pharmacokinetically interacting drugs can cause adverse effects or even fatal intoxication. The aims of this study were to investigate differences in prescriptions for and toxicological findings of pharmacodynamically and pharmacokinetically interacting drugs in fatal oxycodone-related intoxications and other causes of death. We also aimed to investigate the differences in prevalence of oxycodone prescriptions, and the detected postmortem oxycodone concentrations between fatal oxycodone-related intoxications and other causes of death., Methods: Forensic autopsy cases (2012-2018) where oxycodone was identified in femoral blood (n = 1236) were included. Medical history and prescription data were retrieved from national databases and linked to the forensic toxicology findings., Results: Oxycodone-related deaths were found to have higher blood concentrations of oxycodone (median 0.30 µg/g vs. 0.05 µg/g) and were less likely to have a prescription for oxycodone (OR 0.62) compared to nonintoxication deaths. Pharmacodynamically interacting drugs were prescribed in 79% and found in blood in 81% of the cases. Pharmacokinetically interacting drugs were rarely prescribed (1%). Oxycodone-related deaths were more likely to have prescriptions for a pharmacodynamically interacting drug (OR 1.7) and more often have co-findings of one or multiple pharmacodynamically interacting drugs (OR 5.6)., Conclusion: The results suggest that combined use of oxycodone and pharmacodynamically interacting drugs is associated with oxycodone-related death and that non-medical use of oxycodone is a potential risk factor for oxycodone-related intoxication., (© 2022. The Author(s).)

Amphetamine is frequently detected in forensic toxicological cases. Differentiating between the two isomers of amphetamine (d-amphetamine and l-amphetamine) and determining their relative proportion are fundamental to correctly interpret the results of toxicological analyses. The aim of this study was to examine the profile of amphetamine as well as storage stability of the isomers in authentic samples from patients chronically treated with lisdexamfetamine (LDX), the most prescribed medical amphetamine product in Sweden. Blood and urine samples were collected from 18 patients. The samples were analyzed with an achiral (racemate) method for quantification of amphetamine and with a chiral method to determine the proportion of each isomer of amphetamine. The median daily dose of LDX was 40 mg (range, 20-70 mg). The median amphetamine concentration was 0.06 µg/g (range, 0.02-0.15 µg/g) in blood and 6 µg/mL (range, 1-22 µg/mL) in urine. Only d-amphetamine was found in the blood and urine samples from the included patients. Furthermore, no formation of l-amphetamine occurred during the storage for 3 months at 4°C, 9 months at -20°C and three freeze-thaw cycles. The results from this study may be helpful in the interpretation of whether the source of identified amphetamine in biological samples is from LDX drug intake or not., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Although beta-hydroxybutyrate (BHB) analysis has proved its importance in forensic pathology, its effects on cause-of-death diagnostics are unaddressed. Therefore, this study aims at evaluating the effects of BHB analysis on the number of deaths by DKA (diabetes ketoacidosis), AKA (alcoholic ketoacidosis), HHS (hyperosmolar hyperglycaemic state), hypothermia, diabetes, alcoholism, and acidosis NOS (not otherwise specified). All 2900 deaths from 2013 through 2019 in which BHB was analysed at the National Board of Forensic Medicine, and 1069 DKA, AKA, HHS, hypothermia, diabetes, alcoholism, and acidosis cases without BHB analysis were included. The prevalence of BHB-positive cases for each cause of death, and trends and proportions of different BHB concentrations, were investigated. The number of BHB analyses/year increased from 13 to 1417. AKA increased from three to 66 and acidosis from one to 20. The deaths from alcoholism, DKA, and hypothermia remained stable. It is unclear why death from alcoholism remained stable while AKA increased. The increase in unspecific acidosis deaths raises the question why a more specific diagnosis had not been used. In conclusion, BHB analysis is instrumental in detecting AKA and acidosis. The scientific basis for the diagnosis of DKA and hypothermia improved, but the number of cases did not change.

A highly sensitive and accurate electrospray liquid chromatography tandem-mass spectrometry (ESI-LC-MS/MS) method for determination of testosterone in human serum and saliva was developed and validated. Accurate quantification of testosterone in human matrices is essential in diagnosis and management of androgen status in men, women and children, and in forensic investigations of suspected abuse of anabolic androgenic steroids. Chromatography was performed on an HSS-T3 C18 column with a total run-time of 5.5 min. The tandem mass spectrometry was operated in positive electrospray ionization mode with multiple reaction monitoring. Serum and saliva samples of 200 μL, were prepared by solid-phase extraction using a 96-well plate following precipitation with 200 μL methanol. 13 C labeled testosterone was used as internal standard for quantification. The standard curve was linear within the range of 4-1000 pg/mL and the limit of quantification of both serum and salivary testosterone was 4 pg/mL. Accuracy were 99-101 % and 93-95 % with between-run imprecision in serum and saliva, respectively, and inter- and intra-assay coefficients of variation were less than 9.2 %. The method proved to be applicable for determination of testosterone over a wide range of concentrations in serum and saliva samples from clinical patients with various androgen disorders, healthy male and female adults as well as from forensic cases., Competing Interests: Declaration of competing interest No competing interest is declared for all authors., (Copyright © 2020 Elsevier B.V. All rights reserved.)

This review summarizes current evidence on the abuse and misuse of the gabapentinoids pregabalin and gabapentin. Pharmacovigilance studies, register-based studies, surveys, clinical toxicology studies, and forensic toxicology studies were identified and scrutinized with the goal to define the problem, identify risk factors, and discuss possible methods to reduce the potential for abuse and misuse. Studies found that gabapentinoids are abused and misused and that individuals with a history of psychiatric disorders or substance use disorder seem to be at high risk. Moreover, some evidence supports the notion that patients with opioid use disorders may be at an increased risk of abusing gabapentinoids. Available evidence also suggests that abuse and misuse are more frequent in users of pregabalin compared with users of gabapentin. Health professionals and prescribers should be aware of the risk for misuse of pregabalin and gabapentin, which eventually could lead to abuse, substance dependence, and intoxications. Prescribing to patients belonging to risk populations such as those with psychiatric disorders or substance use disorder should be avoided if possible and, if prescribed, signs of misuse and abuse should be monitored.

Context: Amlodipine is the most common calcium channel blocker (CCB) on the Swedish market, and poison center (PC) consultations for amlodipine overdoses are increasing. The clinical picture is dominated by vasodilation with relative preservation of cardiac function. CCBs selectively dilate vessels on the afferent side of the capillary network which, in states of preserved or increased blood flow may lead to edema formation, including non-cardiogenic pulmonary edema (NCPE). This complication has been considered rare in CCB poisoning. In this cohort study of nineteen amlodipine poisonings with high amlodipine blood levels, the incidence and clinical significance of NCPE in severe amlodipine poisoning are explored. Methods: During 2017-2018 the Swedish PC prospectively encouraged the gathering of blood samples in amlodipine poisonings with symptoms requiring treatment with inotropes or vasopressors. Samples were sent by mail to the Forensic Toxicology Division at the Swedish National Board of Forensic Medicine for screening and quantification of relevant toxicants. Patients with blood amlodipine levels >0.25 µg/mL were included in a cohort whose case details were gathered from medical records and PC-case notes with a special focus on signs of NCPE. Results: Nineteen patients met the blood amlodipine inclusion criteria. Four (21%) died and one patient was treated with VA-ECMO. Nine patients developed NCPE defined as a need for positive pressure ventilation (PPV) while having an echocardiographically normal left ventricular function. Conclusion: In this prospective cohort study of consecutive and analytically confirmed significant amlodipine poisonings NCPE was a common finding occurring in 47% of the whole cohort and in 64% of patients who did not go on to develop complete hemodynamic collapse.

Objective: To compare the assessments of 10-year probability by patients and their physicians of cardiovascular complications of hypertension with actual outcomes. Design: Patients with uncomplicated hypertension treated with at least one antihypertensive drug at inclusion were followed for 10 years through mandatory national health registers. Setting: 55 primary health care centres, 11 hospital outpatient clinics in Sweden Patients: 848 patient, 212 physicians. Main outcome measures: Patients and physicians estimated the probability of hypertension-related complications with treatment (death, heart failure, acute myocardial infarction/AMI, and stroke) for each patient in 848 pairs. Estimates were compared with the clinical outcomes 10 years later using data from the Mortality Register and the National Patient Register. Results: Patients were significantly better ( p  < 0.001) than their physicians in estimating the average probability of heart failure compared with actual outcome data (14% vs. 24%, outcome 15%), AMI (16% vs. 26%, outcome 8%), and stroke (15% vs. 25%, outcome 11%). Patients were significantly worse ( p  < 0.001) at estimating the average probability of death (10% vs. 18%, actual outcome 20%). Neither the patients nor the physicians were able to distinguish reliably between low-risk and high-risk patients after adjustment for age and sex. Conclusions: Patients were better than their physicians in estimating the average probability of morbidity due to hypertension. Both the patients and their attending physicians had difficulty in estimating the individual patient's risk of complications. The results support the use of evidence-based tools in consultations for assessing the risk of cardiovascular complications associated with hypertension.Key points • Shared decision making relies on a common understanding of risks and benefits. Tools for risk assessment of hypertension have been introduced in the last two decades. • Without tools for risk assessment, both patients and physicians had difficulties in estimating the individual patient's risk of cardiovascular morbidity. • Patients were better than physicians in estimating actual average cardiovascular morbidity due to hypertension during a follow-up of 10 years. • The results support the use of evidence-based tools in consultations for assessing the risk of cardiovascular complications associated with hypertension.

Background: Approximately 1% of Sweden's 90 000 annual deaths were reported caused by poisoning. In this study, we aim to describe this poisoning population's characteristics, autopsy frequency and results of toxicology testing., Method: A national cohort study based on Swedish national registers. All deceased subjects older than 18 years with poisoning as the cause of death registered between 1 January 2000 and 31 December 2021 were included. Causes of death according to primary ICD-10 code were analysed along with the substances found in forensic chemistry testing., Results: There were 27 057 poisonous deaths during the study periods 2 018 495 adult deaths. Subjects deceased due to poisoning had a median age of 53 years, and 18 838 (70%) were men. A private home was the most reported location of death (52%). In total, 23 260 (87%) did undergo some sort post-mortem examination. Drugs (synthetic narcotics, opioids, heroin) caused 12 448 (46%) deaths, and alcohols explained 9056 cases (33%). Positive toxicological tests were found in 22 550 (83%) of the subjects. The most common separate substances were ethanol, zopiclone and nordazepam., Conclusion: Poisoning caused 1.3% of Swedish deaths. Men in their 50s were the most common victims, and their deaths were often cause by synthetic narcotics, other opioids or alcohol. The autopsy frequency was lower than expected for poisonous deaths., (© 2024 The Author(s). Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background & Objectives: To improve the interpretation of fatal intoxications by establishing fatal and non-fatal reference concentrations of metformin in postmortem femoral blood and to further evaluate risk factors associated with fatal metformin intoxication., Methods: All forensic autopsies in Sweden where metformin was detected in femoral blood 2011-2016 were identified in the National Board of Forensic Medicine databases (NFMD). The cases were classified as single substance intoxications, A (n = 22), multiple substance intoxications, B (N = 7) and postmortem controls, C (N = 13). The control group consisted of cases where metformin was detected, but the cause of death excluded the incapacitation by metformin or other substances. Strict inclusion criteria were used, and all postmortem cases were assessed by two independent reviewers. All other cases where the inclusion criteria of groups A-C where not met formed group O (N = 78). The forensic findings logged in the NFMD where linked to national registers whereby information on comorbidities, dispensed drugs and clinical data could be obtained., Results: The mean age was 66 ± 10 years in the total study population and did not differ between the groups. The proportion of men was 64% in group A, 71% in B, 77% in C and 74% in group O. The median values of metformin in group A (48.5 μg/g; range 13.0-210 μg/g) and B (21.0 μg/g; range 4.40-95.0 μg/g) were significantly (p < 0.001 and p = 0.015 respectively) higher than those of the control group C (2.30 μg/g ; range 0.70-21.0 μg/g). The median concentration of metformin in group A and B was also significantly higher than in group O (4.60 μg/g; range 0.64-54.0 μg/g) (p < 0.001 and p = 0.040 respectively). The results suggest that intoxication with metformin as a cause of death should be considered when the postmortem femoral blood level exceeds about 10 μg/g, although higher levels may be seen in postmortem in cases without incapacitation. The metformin intoxication was confirmed to be intentional in 23% (n = 5) of the single intoxications. Underlying factors identified as important for the remaining fatal metformin intoxications included living alone, any contraindication for the use of metformin, known alcohol abuse and a history of stroke or cardiovascular disease., Conclusions: The reported post mortem femoral blood concentrations of metformin can hopefully contribute to a better interpretation of results in suspected poisonings and obscure cases. Living in a single household, history of cardiovascular disease and contraindications, predominantly alcohol abuse, were associated with fatal metformin intoxication., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Driving under the influence of alcohol is a major problem for traffic-safety and a popular defence argument is alleged consumption after driving, commonly referred to as the hip-flask defence. Forensic toxicologists are often called as expert witnesses in drinking and driving cases where the suspect has claimed the hip-flask defence, to assess the credibility of the explanation. Several approaches to help the expert have been introduced but the scientific data used to support or challenge this is solely based on data from controlled single doses of ethanol administered during a short time and in abstinent subjects. In reality, we believe that even in drinking after driving cases, the subject many times has alcohol on board at time of the hip-flask drink. This questions the applicability of the data used as basis to investigate the hip-flask defence. To fill this knowledge gap, we aimed to investigate how blood and urine ethanol kinetics vary after an initial drinking session of beer and then a subsequent hip-flask drink of three different doses of whiskey. Fifteen subjects participated in the study and each provided 10 urine samples and 17 blood samples over 7h. The initial drink was 0.51g ethanol/kg and the second was either 0.25, 0.51, or 0.85g/kg. Our data suggested that the difference between the ethanol concentrations in two consecutive urine samples is a more sensitive parameter than the ratio between urine and blood alcohol to detect a recent intake when ethanol from previous intakes are already present in the body. Twelve subjects presented results that fully supported a recent intake using the criteria developed from a single intake of ethanol. Three subjects showed unexpected results that did not fully support a recent intake. We conclude that data from one blood sample and two urine samples provide good evidence for investigating the hip-flask defence even if alcohol was on board at the time of the hip-flask drink., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Menopausal hormone therapy (MHT) is an effective treatment for menopause-related symptoms. Menopause management guidelines recommend a personalized approach to menopause care, including MHT use. Decision-making around menopause care is a complex, iterative process influenced by multiple factors framed by perspectives from both women and healthcare providers (HCPs). This narrative review aims to summarize evidence around factors affecting decision-making regarding menopause-related care. For HCPs, the provision of individualized risk estimates is challenging in practice given the number of potential benefits and risks to consider, and the complexity of the data available, especially within time-limited consultations. Women seeking menopause care have the difficult task of making sense of the benefit versus risk profiles to make choices in line with their decisional needs influenced by sociocultural/economic, educational, demographic, and personal characteristics. The press, social media, and influential celebrities also impact the perception of menopause and decision-making around it. Understanding these factors can lead to improved participation in shared decision-making, satisfaction with the decision and decision-making process, adherence to treatment, reduced decisional regret, efficient use of resources, and ultimately long-term satisfaction with care., (© 2024 The Author(s). Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of The New York Academy of Sciences.)

Purpose: The most commonly associated substance found in Ecstasy tablets is MDMA (3,4-methylenedioxymethamphetamine). In our study, we showed how the composition of psychoactive ingredients in Ecstasy tablets seized on the drug market in Poland has changed in the years 2005-2020., Methods: The study material consisted of nearly 20,000 single Ecstasy tablets seized by representatives of law enforcement (the police, prosecutors) from 2005 to 2020 and analysed by the Institute of Forensic Research, Krakow, Poland. The analysis of the tablets was carried out by gas chromatography-mass spectrometry (GC-MS), high-performance liquid chromatography with diode array detection (HPLC-DAD) and ultra-high-performance liquid chromatography with photodiode array detection (UHPLC-PDA)., Results: Currently, new types of MDMA tablets are introduced onto the market, available in various colours and shapes. Our study showed that tablets sold on the street as Ecstasy have variable purity and sometimes contain little or no MDMA. The mean content of MDMA in one tablet seized in 2005-2011 decreased from 90 to 50 mg. In 2013, Ecstasy tablets with a very high MDMA content (average 195 mg per tablet) appeared on the market, but in the next 2 years, the MDMA content decreased again. From 2016, the average MDMA content began to rise again, ranging from 60 to 280 mg., Conclusion: Tablets sold as Ecstasy also contained completely different psychoactive substances, including new psychoactive substances (NPS) (found in almost 20% of all examined tablets sold as Ecstasy) belonging to different chemical groups or their dangerous combinations (i.e. phenylethylamines, piperazines, tryptamines, cathinones, arylalkylamines, arylcyclohexylamines and piperidines). Such a large variety of psychoactive substances in Ecstasy tablets is associated with a high risk for users unaware of their composition., (© 2024. The Author(s), under exclusive licence to Japanese Association of Forensic Toxicology.)

Background It is important for the physician and the patient to have a mutual understanding of the possible consequences of different treatment alternatives in order to achieve a partnership in decision-making. Objective The aim of this study was to explore to which degree first-time consultations for discussion of climacteric discomfort achieved shared understanding of the risks and benefits associated with hormone therapy in the menopausal transition. Methods Analysis of structure and content of transcribed consultations (n = 20), and follow-up interviews of the women (n = 19 pairs of consultations and interviews), from first-time visits for discussion of climacteric discomfort and/or HT with five physicians at three different outpatient clinics of gynecology in Sweden. Results Four distinctively different interpretations of risk, depending on whether or not benefits were discussed in the same context, emerged from the analysis. On average, five advantages (range 0-11) and two (0-3) disadvantages were mentioned during the consultations. In the interviews, the women expressed on average four advantages (0-7) and one disadvantage (0-3). There were major variations between advantages and disadvantages expressed in the consultation and the following interview. Conclusion Even though the consultations scored high in patient involvement, the information in most consultations was not structured in a way that made it possible to achieve a shared or an informed decision-taking. [ABSTRACT FROM AUTHOR]

Objective: Many commonly used pharmaceuticals, such as antidepressants and neuroleptics as well as some illegal drugs, are metabolised by the cytochrome P 450 enzyme debrisoquine 4-hydroxylase (CYP2D6). Of Caucasians, 7-10% lack this enzyme, which can, upon administration of drugs in normal therapeutic doses, lead to adverse reactions and unexpected intoxication, leading in turn even to a fatal outcome in some cases. Methods: Individuals (n = 242) who had died due to intoxication by pharmaceuticals were genotyped for CYP2D6 and CYP2C19 and compared with a reference group of 281 blood donors. A single nucleotide polymorphism (SNP) method was used to identify five CYP2D6 alleles: *1 (wt), *2, *3, *4 and *6. The allele *5, a complete gene deletion, was identified by a multiplex amplification of long DNA fragments. Four CYP2C19 alleles *1 (wt), *2, *3 and *4 were also identified by SNP analysis. Results: The prevalence of the CYP2D6 poor metaboliser (PM) genotypes in individuals with fatal intoxication was lower (4.7%) than expected from the frequencies of these genotypes in the blood donors (8.5%). A significantly lower frequency Pc 0.005 (0.03 with correction according to Bonferroni) was found for the CYP2D6*4 allele among the fatal intoxication cases. The CYP2C19 genotype analyses showed the same results for the fatal intoxication cases and for the blood donors. Conclusions: The findings in this study confirm our earlier observations of a lower frequency of CYP2D6 PM genotypes in cases of fatal intoxication. To our knowledge, it has not been shown previously that intoxication victims might have a lower frequency of PMs than the general population. [ABSTRACT FROM AUTHOR]