Claudia Mariottini

Purpose: Long-acting injectable buprenorphine (LAI BUP) is a novel opioid agonist treatment (OAT) medication with several benefits for patients, OAT units, and society. We present a case series of fatalities in OAT with LAI BUP. Methods: This was an audit of OAT patient records, supplemented with results of post-mortem (PM) investigation. We started with all deaths (N = 604) between 2018 and 2020 in Finland with a buprenorphine or norbuprenorphine finding in PM toxicology and with known substance use history or concomitant findings of illicit drugs. We then examined the patient records of the 43 individuals in OAT at the time of death. We analyzed information on OAT medication, OAT structure, and performance, including concomitant substance use, and PM findings. Results: Ten LAI BUP patients died during the study period, all of them in 2020, out of the 18 patients receiving some OAT that year. Among the LAI BUP patients, four died from buprenorphine poisoning. Eight patients had PM findings of abused drugs, always including unprescribed benzodiazepines. Two patients showed signs of additional buprenorphine use of which their OAT unit was unaware. Three patients were classified as non-compliant with OAT but had received no extra support to tackle their situation. Visits to the OAT clinic had mainly occurred only on injection days. Conclusions: LAI BUP comprised 56% of OAT medication among all deceased OAT patients in 2020. Despite its recognized benefits, LAI BUP treatment was associated with deaths. Psychosocial support among the deceased LAI BUP patients seemed inadequate.

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.

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.

A liquid chromatography–tandem mass spectrometry method for the simultaneous quantification of buprenorphine (BUP), norbuprenorphine (NBUP), naloxone (NAL), and their glucuronide conjugates BUP‐G, NBUP‐G, and NAL‐G in urine samples was developed. The method, omitting a hydrolysis step, involved non‐polar solid‐phase extraction, liquid chromatography on a C18 column, electrospray positive ionization, and mass analysis by multiple reaction monitoring. Quantification was based on the corresponding deuterium‐labelled internal standards for each of the six analytes. The limit of quantification was 0.5 μg/L for BUP and NAL, 1 μg/L for NAL‐G, and 3 μg/L for NBUP, BUP‐G, and NBUP‐G. Using the developed method, 72 urine samples from buprenorphine‐dependent patients were analysed to cover the concentration ranges encountered in a clinical setting. The median (maximum) concentration was 4.2 μg/L (102 μg/L) for BUP, 74.7 μg/L (580 μg/L) for NBUP, 0.9 μg/L (85.5 μg/L) for NAL, 159.5 μg/L (1370 μg/L) for BUP‐G, 307.5 μg/L (1970 μg/L) for NBUP‐G, and 79.6 μg/L (2310 μg/L) for NAL‐G.

Aims: The aims of this study were to estimate the prevalence and predictors of non‐medical substance use, and to assess the association between non‐medical substance use and fatal poisoning or history of drug abuse in Finland.Design and setting: Retrospective cohort study of all medico‐legally investigated death cases in Finland. The postmortem toxicology database was linked together with the register on reimbursed prescription medicines.Participants and cases: All postmortem cases between 2011 and 2013 positive for one or more of the following drugs: oxycodone, fentanyl, tramadol, clonazepam, gabapentin, pregabalin, tizanidine, olanzapine, quetiapine, risperidone, alprazolam, zolpidem, mirtazapine and bupropion, n = 2974.Measurements: Non‐medical use of substance was the outcome variable. Predictors were the following: gender, residence at the time of death, place of death, blood alcohol concentration, age, drug abuse, number of prescriptions of any psychoactive drugs in last year and proportion of prescriptions issued by psychiatrist in last year.Findings: In 50.4% of the studied cases, at least one drug was detected without a prescription. Clonazepam, alprazolam and tramadol were the most prevalent non‐medical findings in these cases (6.6, 6.1 and 5.6%, respectively). The risk of non‐medical use of prescription drugs was especially high in cases with history of drug abuse (88.5%) and in fatal poisonings (71.0%). The proportion of non‐medical use of the studied substances varied between 5.9% [95% confidence interval (CI) = 3.1–10.1%)] for risperidone and 55.7% for fentanyl (95% CI = 44.1–66.9%).Valid prescription for one or more of any psychoactive drug was associated with lower odds for non‐medical use of the studied substances. Additionally, the higher the proportion of psychoactive drugs prescribed by a psychiatrist, the lower the probability of non‐medical use.Conclusions: Non‐prescribed psychoactive drugs are found commonly at postmortem in drug poisoning deaths in Finland, with history of drug abuse being a major contributing factor.

Buprenorphine and methadone are commonly used medications for opioid maintenance treatment (OMT), using sublingual and oral administration, respectively. Although beneficial for OMT, these drugs can also be abused by intravenous administration. In intravenous abuse cases, the adjuvants lactose and sucrose are excreted in urine without hydrolysis to monosaccharides, since there are no disaccharidases in the blood.We validated enzymatic methods for the analysis of lactose and sucrose in urine. The analytical performance of both assays was considered appropriate for detecting intravenous drug abuse. The principle was proven by analyzing 93 postmortem (PM) urine samples for lactose, following comprehensive toxicological drug screening. In addition, 32 clinical urine samples from potential drug abusers were analyzed to assess the effect of PM changes on the assay. The mean level of lactose was low in clinical samples and relatively low in PM samples in which no drugs were found. Markedly elevated levels were seen in many of the buprenorphine positive samples, suggesting intravenous administration.Enzymatic methods could provide a simple and cost effective way to assess the intravenous administration of OMT drugs or drugs of abuse. Very high levels of glucose in urine may interfere with the assays. Furthermore, other causes for elevated urine disaccharides, such as hypolactasia and increased intestinal permeability, need to be considered in the interpretation of the results. Copyright © 2016 John Wiley & Sons, Ltd.