Buprenorphine deaths confirmed by toxicology reveal a low proportion of opioid agonist treatment before death in Finland.

We studied opioid agonist treatment (OAT) status before buprenorphine-related death in Finland, where buprenorphine is the principal OAT medicine and also the most misused opioid, through a retrospective population-based study using medico-legal cause-of-death investigation and OAT patient records. The study included all death cases (N = 570) between 2018 and 2020 with a buprenorphine or norbuprenorphine finding in post-mortem toxicology and with known drug misuse history or concomitant findings of illicit drugs. Of the deceased, 10% had received OAT in the year before death. Less than 1% of individuals < 25 years had received OAT, whereas the proportion in individuals ≥ 25 years was 13% (p < 0.001). There were significantly more females and more fatal poisonings (p < 0.001) among those < 25 years than among those ≥ 25 years. OAT medication at the time of death was sublingual buprenorphine-naloxone in 74% and subcutaneous buprenorphine in 23%. Except for significantly fewer benzodiazepine findings among those receiving OAT, minimal differences were found in terms of age, gender, cause and manner of death, or concomitant substance use between the deceased in and outside of OAT. Concomitant misuse of benzodiazepines, psychostimulants, alcohol, and gabapentinoids was frequent both in and outside of OAT and likely contributed to the death. These results suggest that access to OAT especially for young people and treatment of multiple addictions should be improved. Comprehensive information from medico-legal cause-of-death investigation as a starting point, combined with subsequent ante-mortem patient records, proved to be a successful approach to shed light on the Finnish scene of buprenorphine mortality.

Comparison of poisoning deaths with wastewater-based consumption estimates and assessment of fatal toxicity for amphetamine-type stimulant drugs.

Among several established indicators that are used to monitor the illicit drug scene, drug-related deaths and wastewater-based epidemiology (WBE) stand out for population-level coverage. In this study, we aimed to compare temporal trends with respect to amphetamine, methamphetamine and methylenedioxymethamphetamine (MDMA) revealed by these indicators and explore the differences in fatal toxicity between the stimulants. All deaths in which poisoning caused by amphetamine, methamphetamine or MDMA was either the underlying or contributing cause of death in Finland in 2012, 2014, 2016, 2018 and 2020 were included in the study. Consumption of the studied drugs was measured by WBE in the same years. There was a significant correlation between poisoning and drug consumption for all three stimulants, and for amphetamine and MDMA, these figures increased over the study period. The highest fatal toxicity, as expressed by the number of deaths per million doses, was obtained for methamphetamine at an estimated dose of 50 mg, followed by MDMA (100 mg dose) and with amphetamine (50 mg dose). The fatal toxicity found here for the stimulants was close to that previously reported for many prescription opioids and tricyclic antidepressants. Our study is the first to quantitatively investigate the fatal toxicity of amphetamine-type stimulants by comparing deaths with consumption estimates derived from WBE. It shows that amphetamine, methamphetamine and MDMA possess a quite similar capacity to cause death. This new approach adds to the earlier methods of estimating drug-related harm.

Fatal concentrations of antidepressant and antipsychotic drugs in postmortem femoral blood.

Antidepressants and antipsychotics are both an important class of prescription drugs within postmortem (PM) toxicology because most of the substances are toxic in overdose and the mental disorders being treated may be associated with suicidality. A wide range of antidepressants and antipsychotics are currently included in up-to-date PM toxicology analysis protocols. However, apart from case studies, few reports on fatal concentrations based on large number of cases have been published in the literature. Based on PM investigations in Finland between 2000 and 2020, this study provides fatal reference concentrations in poisonings due to an antidepressant or an antipsychotic drug assigned as the principal intoxicant. Summary statistics for drug concentrations in PM femoral blood (min, max, mean, 10th, 25th, 50th, 75th, 90th percentile) were calculated for 17 antidepressant (N = 2,007) and for 12 antipsychotic drugs (N = 1,161). The proportion of suicide, accident and undetermined manner of death is indicated for each drug. Further, the fatal concentrations obtained in this study were evaluated by comparison with fatal and "normal" PM concentrations reported by two previously published approaches, the grouped causes of death approach and the all causes of death approach, respectively. This study shows that, despite the well-known variation in PM drug concentrations, competently generated fatal concentration results for the drugs studied are consistent to such an extent that they can be used as a reference in the interpretation process.

Ethylene glycol poisoning may be associated with elevated post-mortem vitreous glucose level.

Ethylene glycol (EG) is a toxic chemical that is sometimes used as ethanol substitute. Besides the desired intoxicating effects, the intake of EG may often lead to death unless timely treatment measures are provided by medical professionals. We examined 17 fatal EG poisonings between 2016 and March 2022 in Finland in terms of forensic toxicology and biochemistry results and demographic information. Most of the deceased were male and the median (range) age was 47 (20-77) years. Of the cases, 6 were suicides, 5 accidents and in 7 cases the intent remained undetermined. In all cases, vitreous humour (VH) glucose was above the limit of quantitation 0.35 mmol/L (mean: 5.2 mmol/L; range 0.52-19.5 mmol/L). Other markers of the glycaemic balance were within the normal range in all except one case. As EG is not routinely screened for in most laboratories but only analysed in cases where the intake of EG is suspected, some fatal EG poisonings may remain unrecognised in post-mortem (PM) investigations. Although various conditions may induce hyperglycaemia, it is worthwhile keeping in mind that elevated PM VH glucose levels that cannot be otherwise explained may suggest intake of ethanol substitutes.

Postmortem concentrations of ropivacaine, bupivacaine, and lidocaine in femoral venous blood after hip fracture surgery.

Pain relief in hip fracture patients may be sought by injecting local anesthetic such as ropivacaine, bupivacaine, and lidocaine to the femoral area. As femoral veins are a routine sampling site for postmortem blood, this short report aimed to describe the levels of local anesthetics in ipsilateral (i.e., side of surgery) and contralateral (i.e., opposite side) femoral blood in ten medico-legal autopsy cases that had undergone a hip fracture surgery within 7 days before death. Postmortem blood samples were systematically collected from the ipsilateral and contralateral femoral veins, and toxicological analysis was performed in an accredited laboratory. The sample comprised six female and four male decedents who died at the age of 71-96 years. Median postoperative survival was 0 days and median postmortem interval 11 days. Strikingly, ropivacaine concentration was a median of 24.0 (range 1.4-28.4) times higher on the ipsilateral than contralateral side. The median ipsilateral concentration of ropivacaine clearly exceeded the 97.5th reference percentile measured in this laboratory for ropivacaine in postmortem cases representing all causes of death. The remaining drugs did not show high concentrations or notable differences between the sides. Our data clearly advise against performing postmortem toxicology on femoral blood from the operated side; the contralateral side may constitute a better sampling site. Toxicology reports that are based on blood collected from the operated area should be interpreted with caution. Larger studies are needed to confirm the findings, with accurate records of the dosage and administration route of local anesthetics.

Post-mortem oxycodone blood concentrations of hospitalized cancer and surgery patients compared with fatal poisonings.

Oxycodone is a strong opioid drug commonly used to treat acute, cancer, and chronic non-malignant pain. In this study, all oxycodone-related medico-legal cases where death had occurred in a hospital or nursing home in Finland were investigated to determine the range of post-mortem (PM) oxycodone blood concentrations in a therapeutic setting. All toxicology cases in which oxycodone was detected in PM femoral blood during the 4-year period of 2016-2019 in Finland were retrieved from the national PM toxicology database. In this material, the 365 deceased hospital patient cases that met the study inclusion criteria were divided into four groups according to the cause and manner of death. The reference group of 121 fatal oxycodone poisoning cases comprised two groups: those with verified associated drug abuse and those without drug abuse. The median oxycodone concentration in PM blood was significantly higher in cancer patients (0.10 mg/L) than in patients with recent surgery (0.07 mg/L) or other disease (0.06 mg/L) (p < 0.05). In addition, the median oxycodone concentration was significantly lower in all hospital patient groups than in the poisoning groups, the latter displaying 0.38 mg/L (abuse) and 0.64 mg/L (no abuse) (p < 0.001). This study shows that half of the subjects in the cancer patient group had PM blood oxycodone concentrations above the typical clinical therapeutic plasma concentration range (0.005-0.10 mg/L). Appropriate medication of hospitalized surgery and cancer patients can result in concentrations of up to 0.2 and 0.6 mg/L, respectively, while higher concentrations are exceptional.

Investigation of buprenorphine-related deaths using urinary metabolite concentrations.

Quantitative analysis of postmortem urine, instead of blood, for buprenorphine and metabolites may provide additional evidence for the diagnosis of fatal buprenorphine poisoning. In this study, 247 autopsy urine samples, previously testing positive for buprenorphine or norbuprenorphine, were quantitatively reanalysed with a recently developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for unconjugated buprenorphine (BUP), norbuprenorphine (NBUP), naloxone (NAL), and their respective conjugated metabolites, buprenorphine glucuronide (BUPG), norbuprenorphine glucuronide (NBUPG), and naloxone glucuronide (NALG). The cases were divided, according to medical examiners' decision, to buprenorphine poisonings and other causes of death. The groups were compared for urinary concentrations and metabolite concentration ratios of the six analytes. All median concentrations were higher in the buprenorphine poisoning group. The median concentration of BUPG was significantly higher and the median metabolite ratios NBUP/BUP, NBUPG/BUPG, and NBUPtotal/BUPtotal were significantly lower in poisonings than in other causes of death. Naloxone-related concentrations and ratios were not significantly different between the groups.

Propranolol and metoprolol: Two comparable drugs with very different post-mortem toxicological profiles.

Propranolol is a widely used beta-blocker mainly prescribed for the treatment of hypertension and other cardiac conditions. This medicine is also a frequent finding in drug screens, but little is known about its post-mortem toxicological profile. Our aim was to examine all post-mortem toxicology cases positive for propranolol in a three-year period, between 2016 and 2018 in Finland, and to compare these cases to those positive for metoprolol, another beta-blocker commonly used to treat cardiac diseases. There were 179 cases positive for propranolol and 416 for metoprolol in the study period. In the majority of propranolol cases (53%), the drug concentration in the blood was above the typical therapeutic range, but among the metoprolol cases this proportion was 18%. Propranolol was significantly more common than metoprolol in fatal poisonings, suicides and in cases with a history of drug abuse. Alcohol, benzodiazepines, antipsychotics and antidepressants were significantly more often detected in propranolol cases than in metoprolol cases. The deceased positive for propranolol were significantly younger than those positive for metoprolol. Cardiovascular diseases as the underlying cause of death were significantly more common among the metoprolol cases than among the propranolol cases. Our results showed significant differences between the propranolol group and the metoprolol group in post-mortem toxicology cases. The two drugs were used by two very different groups of people, with propranolol use being associated with psychiatric conditions.

Pregabalin and gabapentin in non-opioid poisoning deaths.

Post-mortem findings of gabapentinoids have often been connected to drug abuse and especially opioid use. We aimed to investigate whether gabapentinoids have been implicated in the cause of death without the presence of opioids. In a three-year study period from 2016 to 2018, a total of 907 Finnish post-mortem cases positive for pregabalin or gabapentin were found. In nearly half of the pregabalin cases and in a third of the gabapentin cases, the blood concentration was above the typical therapeutic range of the drug. Of the cases in which pregabalin was detected, in 35% the drug was implicated in a fatal poisoning with or without other drugs or alcohol. For gabapentin, the percentage was 22%. In most of the fatal gabapentinoid poisonings, opioids or other central nervous system depressants were additionally detected in relevant concentrations. There were eight non-opioid gabapentinoid poisonings, in which no relevant other drugs were detected. Many of these cases were unintentional poisonings with a relatively high gabapentinoid concentration in the blood. In all but one, the manner of death was accidental, or the intent was undetermined. This study confirmed the previous findings that gabapentinoids are mostly implicated in fatal poisoning together with opioids. Half of the non-opioid cases were related to drug abuse but in the other half the death was presumably caused by overuse of a prescribed drug or suicide. While the use of gabapentinoids is a well-known problem among people who use drugs, it is important to note other groups of users who may be at risk of overdose by gabapentinoids.