Background and aims
Wastewater‐based epidemiology is an additional indicator of drug use that is gaining reliability to complement the current established panel of indicators. The aims of this study ...were to: (i) assess spatial and temporal trends of population‐normalized mass loads of benzoylecgonine, amphetamine, methamphetamine and 3,4‐methylenedioxymethamphetamine (MDMA) in raw wastewater over 7 years (2011–17); (ii) address overall drug use by estimating the average number of combined doses consumed per day in each city; and (iii) compare these with existing prevalence and seizure data.
Design
Analysis of daily raw wastewater composite samples collected over 1 week per year from 2011 to 2017.
Setting and Participants
Catchment areas of 143 wastewater treatment plants in 120 cities in 37 countries.
Measurements
Parent substances (amphetamine, methamphetamine and MDMA) and the metabolites of cocaine (benzoylecgonine) and of Δ9‐tetrahydrocannabinol (11‐nor‐9‐carboxy‐Δ9‐tetrahydrocannabinol) were measured in wastewater using liquid chromatography–tandem mass spectrometry. Daily mass loads (mg/day) were normalized to catchment population (mg/1000 people/day) and converted to the number of combined doses consumed per day. Spatial differences were assessed world‐wide, and temporal trends were discerned at European level by comparing 2011–13 drug loads versus 2014–17 loads.
Findings
Benzoylecgonine was the stimulant metabolite detected at higher loads in southern and western Europe, and amphetamine, MDMA and methamphetamine in East and North–Central Europe. In other continents, methamphetamine showed the highest levels in the United States and Australia and benzoylecgonine in South America. During the reporting period, benzoylecgonine loads increased in general across Europe, amphetamine and methamphetamine levels fluctuated and MDMA underwent an intermittent upsurge.
Conclusions
The analysis of wastewater to quantify drug loads provides near real‐time drug use estimates that globally correspond to prevalence and seizure data.
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 toxicity of amphetamine‐type stimulants is quantitatively investigated by comparing deaths with consumption estimates derived from wastewater‐based epidemiology.
Introduction
Epidural hydromorphone could be useful in obstetric analgesia as there is a need for a more water-soluble opioid than sufentanil or fentanyl with prolonged analgesic effect. To our ...knowledge, the pharmacokinetics of epidural hydromorphone has not been evaluated in parturients.
Materials and methods
In this pilot study, seven healthy parturients were given a single epidural dose of hydromorphone for labour pain. One parturient received 1.5 mg, two 0.75 mg and four 0.5 mg of hydromorphone hydrochloride. Dose was decreased due to nausea and pruritus. Hydromorphone’s effect, adverse effects and plasma concentrations were evaluated. Neonatal drug exposure was evaluated by umbilical vein and artery opioid concentration at birth. Neonatal outcomes were assessed using Apgar and the Neurologic Adaptive Capacity Score (NACS).
Results
All patients received additional levobupivacaine doses on parturients’ requests. The first dose was requested at a median of 163 min (range 19–303 min) after hydromorphone administration. A total of 12 opioid related expected adverse events were reported by seven parturients. All newborn outcomes were uneventful. Hydromorphone’s distribution and elimination after single epidural dose seem similar to that reported for non-pregnant subjects after intravenous hydromorphone administration, but further research is required to confirm this observation.
Conclusions
The optimal dose of hydromorphone in labour pain warrants further evaluation.
Background: We analysed illicit stimulant use in Finland by comparing three separate datasets collected at the same time. Methods: The data used were wastewater analysis (2014 and 2018), ...population-based drug surveys (2014 and 2018) and European Web Survey on Drugs (2018, Finnish data). Proportions, prevalence levels and trends of stimulant use as well as their consumption were measured. Factors associated with stimulant use were assessed for past-year stimulant or amphetamine use as an outcome measure in regression analyses. Results: Both population-based drug survey and wastewater data showed that stimulant use has increased in Finland between 2014 and 2018. Disadvantaged socio-demographic background and other substance use were associated with past-year stimulant use, with no geographical variation in Finland. The socio-demographics of those reporting amphetamine use differed between population-based drug survey and web survey. In the web survey, infrequent and occasional users of amphetamine were quite alike, whereas frequent users were more likely to be unemployed or use injection as the route of administration. Conclusion: Analysis of three different data revealed findings that would have been missed and conclusions that could not have been made by using only one dataset. Putting findings from different methods into dialogue raises new questions and opens new interpretations. This analysis emphasises the importance of the prevention of frequent use and associated harm, as well as the impact of versatile drug treatment and harm reduction services on it.
Abstract Context Measuring opioid concentrations in pain treatment is warranted in situations where optimal opioid analgesia is difficult to reach. Objectives To assess the usefulness of oral fluid ...(OFL) as an alternative to plasma in opioid concentration monitoring in cancer patients on chronic opioid therapy. Methods We collected OFL and plasma samples from 64 cancer patients on controlled-release (CR) oral morphine, CR oral oxycodone, or transdermal (TD) fentanyl for pain. Samples were obtained on up to five separate days. Results A total of 213 OFL and plasma samples were evaluable. All patients had detectable amounts of the CR or TD opioid in both plasma and OFL samples. The plasma concentrations of oxycodone and fentanyl (determination coefficient R2 = 0.628 and 0.700, respectively), but not morphine ( R2 = 0.292), were moderately well correlated to the daily opioid doses. In contrast to morphine and fentanyl (mean OFL/plasma ratio 2.0 and 3.0, respectively), the OFL oxycodone concentrations were significantly higher than the respective plasma concentrations (mean OFL/plasma ratio 14.9). An active transporter could explain the much higher OFL vs. plasma concentrations of oxycodone compared with morphine and fentanyl. Conclusion OFL analysis is well suited for detecting the studied opioids. For morphine and fentanyl, an approximation of the plasma opioid concentrations is obtainable, whereas for oxycodone, the OFL/plasma concentration relationship is too variable for reliable approximation results.
In this study, 2 different methods for determining strictly conservative confidence intervals for expected values in the case of heteroscedastic errors are presented. A conservative confidence ...interval means that a given false positive error rate is not exceeded. The novelty in both approaches is in carrying out the required approximations in such a way that this property holds. The other method is based on variance stabilizing transformations and given as 2 variants, Transformation Models I and II. For variant II, a rigorous proof is given to show that a given false positive error rate is not exceeded if the underlying distributional assumptions are valid. The second method is based on modeling the variance as a function of the expected value, and this is also given as 2 variants, Variance Models I and II. In all cases, only random errors are considered. The methods were tested and compared by applying them to a real case of breath alcohol concentration measurements performed by the Finnish law enforcement authorities, and also by simulation studies. The methods compared were studied by simulating a sample that had the same distributional properties as the real data. These studies showed that Variance Model I is overly conservative, and Variance Model II doesn't quite satisfy the set rate. Both transformation models give too many false positives at concentrations levels exceeding the prosecution limits, but in the range of prosecution limits they could be used.
Two different methods for determining strictly conservative confidence intervals for expected values in the case of heteroscedastic errors are presented, one based on variance stabilizing transformations, the other based on modelling the variance as a function of the expected value. The methods are compared by applying them to a large set of breath alcohol concentration measurements and also tested by simulation. It is shown that both approaches can be used, but the transformation approach has both some theoretical advantages.
Laboratory methods for differentiating intravenous substance abuse from medical oral or sublingual use are lacking. The disaccharides lactose and sucrose are common excipients in both medical ...preparations and illicit drugs. If substances are abused intravenously, the disaccharides are excreted unchanged in urine. This study evaluated whether urine lactose indicates recent intravenous abuse of substances with special reference to buprenorphine (BPN). Samples were attained from 21 patients in assessment for opioid maintenance treatment (OMT) and from 29 patients already enrolled in OMT. Patients were divided in two groups. Group 1 patients reported intravenous abuse of BPN within 48 hours and Group 2 more than 48 hours since the last injection. The urine samples were assayed for lactose using an enzymatic method. To verify intravenous abuse, examination of needle marks and mass spectrometric analysis of abused substances was performed. Urine lactose concentration was significantly higher in Group 1 (86 mg/L) than in Group 2 (24 mg/L). All samples with lactose concentration more than 140 mg/L were given by the Group 1 patients, who all had recent injection marks. A significant inverse correlation was found between the time from last injection and the urine lactose concentration within the 48‐hour post‐injection period. Elevated lactose concentrations in urine could indicate intravenous abuse of substances containing lactose. The co‐occurrence of higher than 140 mg/L of lactose in urine by means of enzymatic assay verified by fresh puncture sites is a potential indicator of recent intravenous abuse of BPN.
Urine samples were analyzed for lactose to investigate if elevated lactose concentrations indicate recent (< 48 hours) intravenous abuse of substances containing lactose as an excipient. Elevated lactose levels were found in samples given by patients who had recently injected substances intravenously, verified by fresh injection marks. Urine lactose assay can support clinical and toxicological findings when assessing substance abuse.
A comprehensively validated procedure is presented for simultaneous semiquantitative/quantitative screening of 51 drugs of abuse or drugs potentially hazardous for traffic safety in serum, plasma or ...whole blood. Benzodiazepines (12), cannabinoids (3), opioids (8), cocaine, antidepressants (13), antipsychotics (5) and antiepileptics (2) as well as zolpidem, zaleplon, zopiclone, meprobamate, carisoprodol, tizanidine and orphenadrine and internal standard flurazepam, were isolated by high-yield liquid-liquid extraction (LLE). The dried extracts were derivatized by two-step silylation and analyzed by the combination of two different gas chromatographic (GC) separations with both electron capture detection (ECD) and mass spectrometry (MS) operating in a selected ion-monitoring (SIM) mode. Quantitative or semiquantitative results were obtained for each substance based on four-point calibration. In the validation tests, accuracy, reproducibility, linearity, limit of detection (LOD) and limit of quantitation (LOQ), selectivity, as well as extraction efficiency and stability of standard stock solutions were tested, and derivatization was optimized in detail. Intra- and inter-day precisions were within 2.5–21.8 and 6.0–22.5%, and square of correlation coefficients of linearity ranged from 0.9896 to 0.9999. The limit of quantitation (LOQ) varied from 2 to 2000
ng/ml due to a variety of the relevant concentrations of the analyzed substances in blood. The method is feasible for highly sensitive, reliable and possibly routinely performed clinical and forensic toxicological analyses.
The most common commercially available silylating reagents, N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA), N,O-bis-(trimethylsilyl)trifluoroacetamide+1% trimethylchlorosilane (BSTFA+1% TMCS) ...and N-methyl-N-(tert-butyldimethylsilyl)trifluoroacetamide (MTBSTFA) were evaluated to achieve optimal derivatization conditions for analyzing various benzodiazepines based on gas chromatography-electron impact ionization-mass spectrometry (GC-EI-MS). Sensitivity, repeatability, retention times and stability of the derivatives, as well as specificity of mass fragmentation, were studied in detail. Also other parameters affecting the derivatization chemistry of benzodiazepines are discussed. tert-Butyldimethylsilyl (TBDMS) derivatives proved to be more stable, reproducible and sensitive than corresponding trimethylsilyl (TMS) derivatives for the GC-EI-MS analysis of benzodiazepines. Based on the TBDMS derivatives, a rapid, reliable, sensitive and quantitative GC-MS method was developed for the determination of 14 benzodiazepines and two hydroxy metabolites, as well as two non-benzodiazepine hypnotic agents, zolpidem and zaleplon, using 50 microl of whole blood. The method was completely validated in terms of accuracy, intra- and interday precision, limit of detection (LOD), limit of quantitation (LOQ), linearity, selectivity and extraction efficiency; these were all within the required limits, except for the accuracy of nitrazepam at a medium concentration level.
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