Search Results (170)

Background: Patients with malignant diseases receiving chronic opioid therapy are particularly susceptible to drug–drug interactions because of extensive polypharmacy, multimodal anticancer treatment, supportive care, and comorbidities. This study aimed to determine the prevalence of potentially clinically relevant drug–drug interactions and to identify factors associated with their occurrence. Methods: This exploratory observational cross-sectional pilot study included 49 adult oncology patients receiving chronic opioid therapy. Complete medication regimens were screened using the Medscape Drug Interaction Checker and Lexicomp. Lexicomp category D and X interactions were analysed descriptively. Because category D interactions were nearly universal and category X interactions were rare, the presence of at least one Medscape “Serious—Use Alternative” interaction was used pragmatically as the binary outcome for regression modelling. Potential predictors were assessed using univariable binary logistic regression and a parsimonious adjusted model with covariates selected using a clinically informed approach. Because of quasi-complete separation, Firth’s penalized-likelihood logistic regression was used as the primary adjusted analysis. Results: Lexicomp category D interactions were identified in 48 of 49 patients (98.0%), whereas category X interactions were present in 2 patients (4.1%). Medscape serious interactions were detected in 33 patients (67.3%). In the Firth-adjusted model, female sex was associated with lower odds of a Medscape serious interaction (adjusted OR 0.12, 95% CI 0.02–0.52), while cardiovascular disease was associated with higher odds (adjusted OR 5.16, 95% CI 1.27–26.31). Stage IV disease showed a positive but statistically non-significant association, and total medication count was not independently associated with the outcome in sensitivity analysis. Because of the small pilot sample and the resulting wide confidence intervals, these findings should be interpreted as exploratory and hypothesis-generating. Conclusions: Oncology patients receiving chronic opioid therapy had a high burden of potentially clinically relevant drug–drug interactions, predominantly Lexicomp category D interactions, warranting consideration of therapy modification and individualized monitoring rather than absolute avoidance. Regular medication review, use of complementary interaction databases, and individualized clinical assessment may improve pharmacotherapy safety in this vulnerable population. Full article

Cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger downstream of G protein-coupled receptors (GPCRs) and a central regulator of cellular signaling. Genetically encoded exchange proteins directly activated by cAMP (Epac)-based Förster resonance energy transfer (FRET) biosensors enable real-time monitoring of cAMP dynamics in living cells, but commonly used cyan/yellow FRET pairs require short-wavelength excitation, limiting compatibility with multiplex imaging and blue-light optogenetic tools such as bacterial photoactivated adenylyl cyclases (bPACs). Here, we engineered and systematically characterized four red-shifted Epac-based single-chain FRET cAMP sensors combining yellow or orange FRET donors with red fluorescent FRET acceptors. Using ratiometric live-cell imaging, we quantified stimulus-evoked FRET responses and identified Epac_red4 as the best-performing variant, showing an approximately 55% decrease in normalized FRET after forskolin stimulation. Epac_red4 also reliably detected G_i/o-mediated decreases in cAMP following μ-opioid receptor activation. Brief 405 nm light pulses induced graded and reversible cAMP elevations using the low dark-activity variant bPAC-F198Y. Furthermore, Epac_red4 enabled analysis of cAMP recovery kinetics during phosphodiesterase inhibition and multiplex imaging of cAMP and intracellular Ca²⁺ using Fura-2 with minimal spectral and pH-related interference under physiological imaging conditions. Together, Epac_red4 represents a robust red-shifted cAMP sensor for optogenetic and multiplex signaling studies. Full article

Background: Online communities such as Reddit can reveal critical information needs (CINs) among people who discuss opioid use for chronic or acute pain under conditions of stigma and uncertainty. Methods: We used a mixed-method design to analyze 3428 unique Reddit posts from 1 January to 31 December 2022. Sentence-BERT embeddings and K-means clustering identified eight dominant themes, followed by qualitative analysis of a random subsample of 400 posts. Results: The most prevalent theme was seeking alternatives to opioids for pain relief (28.00%), followed by medications for chronic pain (19.84%) and kratom use experiences (14.64%). Qualitative findings showed recurrent concerns about addiction, stigma in clinical encounters, withdrawal, treatment access, and peer-to-peer discussion of kratom, tianeptine, cannabis, and other substitute substances. Conclusions: The study suggests an unmet need for accessible, nonstigmatizing, and clinically grounded information on pain management, tapering, and lower-risk alternatives to opioid use. These results have implications for addiction prevention, harm reduction, and patient-facing communication strategies for clinical practice and community health. Full article

The ongoing emergence of New Psychoactive Substances represents a growing threat to public health, as newly synthesized compounds continuously enter the illicit drug market, evading standard detection methods and challenging regulatory frameworks. Among New Psychoactive Substances, nitazenes are potent non-fentanyl opioids associated with severe cases of intoxication. This study evaluated the genotoxic potential of metodesnitazene and etodesnitazene in the human TK6 cell line. Cells were exposed to increasing concentrations of studied compounds, with and without S9 metabolic activation system. Preliminary assessments and micronuclei frequency analyses were performed by flow cytometry in at least three independent experiments. Metodesnitazene induced an increase in micronuclei frequency starting from 12.5 μM (p < 0.05), whereas etodesnitazene induced an effect only at 50 μM. Metabolic activation increases micronuclei formation at higher concentrations of metodesnitazene 25 μM, but did not substantially affect the response to etodesnitazene. Both compounds also induced intracellular reactive oxygen species production, measured through a chemiluminescent-based bioassay, suggesting oxidative stress as a potential contributing mechanism. These findings highlight the need for compound-specific toxicological profiling to better anticipate the acute and long-term risks associated with nitazene consumption. Full article

Background: Oxycodone is a widely prescribed semi-synthetic opioid central to pain management. However, establishing its role in death when detected in postmortem toxicology is challenging. Quantitative evidence to support forensic interpretation remains limited. Methods: A systematic review and meta-analysis was conducted following PRISMA 2020 guidelines. PubMed and Scopus were searched through 3 March 2026, for studies reporting quantitative postmortem oxycodone concentrations in human biological matrices. Peripheral blood was predefined as the primary matrix for quantitative synthesis. Random-effects meta-analysis with restricted maximum likelihood estimation was performed on logarithmically transformed concentrations to compare fatal intoxications versus non-intoxication deaths and mono- versus mixed-intoxication cases. Pooled estimates were reported as geometric mean concentrations with 95% confidence and prediction intervals. Secondary analyses evaluated metabolite-to-parent ratios, alternative matrices, and postmortem interval (PMI). Results: Twenty-three studies comprising 4335 oxycodone-positive decedents were included in the qualitative synthesis, and 14 studies in the quantitative meta-analysis. Fatal intoxication cases (n = 1555) showed a pooled geometric mean peripheral blood oxycodone concentration of 0.37 mg/L (95% CI: 0.24–0.58; I² = 93.5%), compared with 0.08 mg/L (95% CI: 0.04–0.15; I² = 98.5%) in non-intoxication deaths (n = 1409). Mono-intoxication cases (n = 135) exhibited higher concentrations (0.52 mg/L; 95% CI: 0.22–1.21; I² = 82.3%) than mixed-drug fatalities (n = 511; 0.29 mg/L; 95% CI: 0.13–0.65; I² = 93.1%). Metabolite data indicated that noroxycodone and oxymorphone patterns may assist in distinguishing acute intake and metabolic variability. Alternative matrices, particularly vitreous humor and solid tissues provided complementary interpretative information, while PMI contributed concentration variability. Conclusions: The key quantitative findings of this meta-analysis indicate higher peripheral blood oxycodone levels in fatal intoxications than in non-intoxication deaths. However, substantial heterogeneity precludes the definition of absolute concentration cut-offs, emphasizing the need to approach postmortem oxycodone interpretation within a probabilistic forensic framework integrating circumstantial evidence, sampling time, metabolite ratios, and data from alternative biological matrices. Full article

Background: The 2-benzylbenzimidazoles or nitazenes are an evolving class of highly potent mu-opioid receptor agonists. Nitazenes were originally developed in the late 1950s for pharmaceutical use as analgesics; however, due to their extreme potency and the risk of adverse health outcomes, pharmaceutical research was discontinued. Since 2019, nitazenes have emerged as illicit drugs of abuse, causing significant concern. From 2021, they have been detected in both coronial and clinical casework in Victoria, Australia. This study examined nitazene-related coronial casework in Victoria from 2021 to 2025 to explore the trends and characteristics of nitazene-related deaths. Methods: Relevant cases were identified from the Victorian Institute of Forensic Medicine’s (VIFM’s) case management system. Data were collated and analysed from all coronial cases where a nitazene was detected by a toxicological analysis between 1 January 2021 and 31 December 2025. Trend comparisons were made with nitazene detections reported in other countries. Results: Nitazenes were detected in 23 deaths from a total of approximately 33,108 coronial cases admitted to the VIFM for investigation over the time period. The age range was 17–45 years, with a median of 32 and with 87% of the deaths being male. The nitazenes detected were protonitazene (n = 14), metonitazene (n = 5), isotonitazene (n = 2), N-pyrrolidino etonitazene (n = 2), N-desethyl isotonitazene (n = 1), methylenedioxynitazene (n = 1) and etodesnitazene (n = 1). Two cases contained more than one nitazene; both involved protonitazene, one involved metonitazene, and the other involved N-desethyl isotonitazene and methylenedioxynitazene. The timeline of detection of these nitazenes displays similarities with emergence trends in other countries. The nitazene concentrations ranged from 0.1 to 33 ng/mL. Broad polydrug usage was evident in all cases, with other drugs co-detected in the blood including stimulants (particularly, methylamphetamine (48%) and cocaine (44%)) as well as pharmaceutical benzodiazepines (43%) and pharmaceutical opioids (22%), and 13% had 6-monoacetylmorphine detected in either blood or urine. Novel benzodiazepines (39%) were also common, including bromazolam, which was co-detected in 35% of cases. Nineteen deaths were attributed solely to nitazene-related mixed-drug toxicity, while the remaining four cases were attributed to cardiac- and pulmonary-related disease, with polydrug use deemed a contributing factor. Conclusions: This novel case series adds comprehensive toxicological information to the body of evidence reinforcing the high risk of harm associated with the use of nitazenes. It is imperative that toxicology services continue to monitor for nitazenes to promote community awareness against nitazene-related harm. Full article

Background/Objectives: major open abdominal surgery remains associated with clinically important postoperative pain, delayed gastrointestinal recovery, opioid exposure, and prolonged length of stay. Intravenous lidocaine infusion (IVLI) has biologically plausible analgesic, anti-hyperalgesic, anti-inflammatory, and opioid-sparing effects, but prior evidence syntheses have often combined open and minimally invasive procedures. This systematic review evaluated evidence for perioperative IVLI in adult patients undergoing major open abdominal surgery. Methods: the review was structured according to PRISMA 2020. The final search was run on 15 January 2026 and covered PubMed/MEDLINE, Embase, Cochrane CENTRAL, Scopus, Web of Science Core Collection, ClinicalTrials.gov, and WHO ICTRP from database inception to that date, without language restrictions at the search stage. Eligible studies enrolled adults undergoing elective open abdominal surgery and compared systemic IVLI with placebo, usual care, or active epidural analgesic comparators. Primary outcomes were postoperative opioid consumption and pain intensity. Secondary outcomes included gastrointestinal recovery, postoperative ileus, length of hospital stay, postoperative nausea and vomiting, inflammatory/stress biomarkers, and adverse events. Results: ten randomized trials involving 658 participants were included. Placebo/usual-care trials and active-comparator trials were synthesized separately because they address different clinical questions. IVLI generally reduced opioid consumption compared with placebo, with extractable effects including a 55.9 mg reduction in 72 h morphine use in one abdominal surgery trial and a 13.9 mg reduction in 24 h morphine use after radical prostatectomy. Gastrointestinal recovery favored IVLI in most placebo-controlled studies; for example, first flatus occurred 12.5 h earlier and first bowel movement 28.4 h earlier in one trial. Active-comparator trials suggested comparable early dynamic pain outcomes versus thoracic epidural analgesia in selected settings, although opioid consumption findings were less consistent. No serious lidocaine-related toxicity was reported, but the included trials were underpowered to detect rare local anesthetic systemic toxicity events and did not consistently capture subclinical neurologic symptoms such as perioral numbness or visual disturbance. Conclusions: in adult open abdominal surgery, perioperative IVLI may provide opioid-sparing and recovery benefits, particularly when infusion continues beyond the intraoperative period. However, the certainty of evidence remains limited. Full article

β-Casein A1 and A2 (β-CN-A1 and β-CN-A2) are the two predominant β-CN proteoforms in bovine milk. β-CN-A1 has been associated with a greater propensity to release opioid peptides, such as β-casomorphin-7 (β-CM-7) and β-casomorphin-5 (β-CM-5), during gastrointestinal (GI) digestion, which may have adverse biological effects. This has stimulated growing interest in milk from cows carrying the β-CN A2A2 genotype (A2 milk), which requires reliable characterization methods. In this work, we developed a rapid, selective, and sensitive capillary electrophoresis–mass spectrometry (CE-MS) method for the accurate identification and quantification of β-CM-7 and β-CM-5 in milk hydrolysates from in vitro GI digestion of bovine milk. The method showed good linearity (R² > 0.99, over 0.5–100 mg/L for β-CM-7 and 0.25–100 mg/L for β-CM-5), limits of detection (0.25 and 0.10 mg/L), and repeatability (<0.2% for times and <1.4% for areas), and tandem mass spectrometry (MS/MS) allowed confirmation. The method was applied to A1A1 and A2A2 milk digested using the standardized INFOGEST protocol, followed by solid-phase extraction. β-CM-7 was detected and quantified only in A1A1 digests (0.98 mg/L), whereas β-CM-5 was not detected (<0.10 mg/L). These results indicate a differential release of β-CMs from A1 and A2 milk and support the method’s suitability for β-CM profiling, which may help assess A2 milk quality control and β-CM health impact. Full article

Peripheral nerve blocks can effectively reduce the use of general anesthesia and opioids in situations where robust pain management is critical, such as severe extremity trauma and hip, femur, and knee surgeries. Despite these benefits, nerve blocks are underutilized due to the high skill required to accurately insert a needle and safely deliver local anesthetic. To overcome this challenge, ultrasound image guidance enabled by artificial intelligence (AI) offers a semi-automated solution for regional anesthesia delivery by non-specialists. As a first step towards realizing an integrated platform for AI-guided nerve blocks, the main objective of this study is to develop and characterize deep learning algorithms to interpret anatomical landmarks on ultrasound images in real time and identify aimpoints for needle placement. Our AI system was trained on over 55,000 images from 20 porcine models and demonstrated an average area under the precision–recall curve of 0.92 (SD = 0.03) for in vivo landmark detection in the femoral nerve region. In prospective live animal testing, aimpoint identification had a 98.3% success rate with an average time of 40.5 s (SD = 33.5). Future work will focus on integrated testing with handheld robotics towards a more accessible method for delivering regional anesthesia in settings from point of injury to medical transport to hospitals. Full article

Background/Objectives: This study aimed to evaluate the frequency and predictors of adverse drug events (ADEs) related to medication abuse, misuse, and dependence, along with serious adverse events (SAEs), and to develop machine learning models to detect serious abuse, misuse, and dependence cases. Methods: This study included 455,415 ADE reports involving medications with high dependence potential reported to the Korea Adverse Event Reporting System (KIDS KAERS DB) between 2013 and 2022. Multivariate logistic regression was used to identify predictors. Three machine learning algorithms, random forest (RF), support vector machine, and eXtreme Gradient Boosting, were developed and evaluated. Results: Higher reporting likelihood of abuse-, misuse-, and dependence-related ADEs was observed with concomitant use of acetaminophen (OR 3.60, 95% CI 2.40–5.39), antidepressants (OR 1.75, 95% CI 1.17–2.61), antipsychotics (OR 4.97, 95% CI 3.21–7.17), and anticonvulsants (OR 3.42, 95% CI 2.42–4.81). Reports from the general public were associated with higher odds of abuse, misuse, and dependence than those from healthcare professionals (OR 4.59, 95% CI 3.04–6.94). Ketamine (ROR 14.03) and bromazepam (ROR 13.02) showed the highest likelihood of being classified as SAEs. Cardiovascular (ROR 30.36) and respiratory disorders (ROR 17.03) demonstrated the highest SAE reporting likelihood. RF model demonstrated the best predictive performance (AUC-ROC 0.928; accuracy 94.4%), with reporter type identified as a key feature. Conclusions: RF model demonstrated optimal predictive performance, with reporter type as the most important feature for detecting serious cases. This study emphasizes the importance of incorporating patient-reported data and polypharmacy surveillance to facilitate early detection of serious cases. Full article

Background/objectives: Chronic kidney disease (CKD) affects approximately 800 million individuals worldwide and poses a growing health challenge. To support safer prescribing practices, our research group developed a renal risk medication quick guide (RRMQG), which provides recommendations for the 50 most prevalent renal risk medications (RRMs). This study explored the usefulness of implementing the RRMQG in Danish hospital settings. Methods: In this multicenter pilot study conducted across six Danish hospitals, 28 clinical pharmacists applied the RRMQG during medication reviews of frail, geriatric patients with renal impairment from May to October 2023. Useability was explored through structured surveys completed by the pharmacists. Results: Among 182 patients, 378 RRMs were detected, and 14% of these were associated with potential drug-related problems (DRPs). The RRMs were distributed across 35 of the 50 from the RRMQG, and patients received an average of two RRMs each. Most pharmacists found the RRMQG manageable for implementation in practice. Conclusions: The RRMQG was useful and manageable for implementation in practice in Danish hospitals, particularly due to its medication-specific recommendations. However, adjustments to the RRMQG may be beneficial by, for example, adding opioids or context-relevant medications to meet individual needs. Full article

The ongoing substance use crisis in the United States involves a broad range of illicit and prescription drugs, including opioids, stimulants, sedatives, and various psychoactive and non-psychoactive compounds. Traditional surveillance methods rely on self-reported data, which could lead to bias and recall inconsistencies. Wastewater-based epidemiology has emerged as a powerful, non-invasive tool for monitoring community-level drug use, offering near real-time estimates and the potential to serve as an early warning system. However, challenges such as analyte degradation, wastewater variability, and matrix effects can affect data quality and comparability across regions. This study presents a standardized, practical workflow for multi-drug (n = 52) detection in wastewater, aiming to minimize analyte loss and improve reproducibility. Composite samples were collected from multiple U.S. cities, transported on ice, and extracted using solid-phase extraction. Extraction efficiencies were compared using Oasis Hydrophilic-Lipophilic-Balanced and Mixed-mode Cation-Exchange (MCX) cartridges, with the MCX sorbent providing complementary reversed-phase and cation-exchange interactions that enabled the retention of chemically diverse compounds across multiple drug classes. Analysis was performed with an Ultra-High-Performance Liquid Chromatography system coupled to a triple quadrupole mass spectrometer, in which the instrument parameters and critical methodological considerations, including sample handling, transport, column selection, and method validation, are detailed. This work contributes to the development of a robust, scalable protocol for multi-drug surveillance in wastewater, supporting timely, data-driven public health responses and informing national drug policy efforts. Full article

The continuous emergence of New Psychoactive Substances (NPS) poses a significant challenge to public health and forensic toxicology due to their unpredictable pharmacology and rapid turnover on the illicit market. This study describes the development and validation of a high-resolution screening method for the simultaneous detection of 90 NPS in oral fluid (OF), a matrix of choice for non-invasive sampling and roadside testing. The analytical workflow utilizes a “dilute-and-shoot” approach (1:2 v/v dilution) followed by ultra-high-performance liquid chromatography coupled with a quadrupole-Orbitrap hybrid mass spectrometer (UHPLC-HRMS/MS). Chromatographic separation was achieved in 11 min using a biphenyl column and a gradient elution. The method was validated according to ANSI/ASB Standard 036 guidelines, covering 90 substances including synthetic cannabinoids (e.g., HHC, MDMB-4en-PINACA), synthetic cathinones, and high-risk synthetic opioids such as nitazenes and fentanyl analogues. Results showed high sensitivity, with limits of identification (LOI) reaching 1 ng/mL for 44.4% of the analytes and 5 ng/mL for 37.8%, while the remaining compounds showed higher LOIs ranging from 10 to 100 ng/mL. No significant matrix interference or carryover was observed. The method was successfully applied to real samples from external quality control programs and forensic cases. This robust and versatile screening tool is suitable for clinical and forensic applications, supporting the monitoring of emerging NPS trends. Full article

Background/Objectives: The opioid crisis is an ongoing problem in the United States, and fentanyl analogs play a major role in the issue, as novel fentanyl analogs are constantly being developed. Substitutions and additions to the fentanyl scaffold impact the potency of the substances and can sometimes influence the biotransformation of the drugs. This study aimed to determine whether one or more common metabolites could be detected among a group of five methoxylated fentanyl analogs, for the purpose of eventually providing a more rapid detection method for new and unknown fentanyl-related compounds in toxicological samples. Methods: In vitro metabolism via pooled human liver microsomes (HLMs) was performed for five methoxylated fentanyl analogs (para-methoxyfentanyl, ortho- and para-methoxy butyryl fentanyl, and ortho- and para-methoxy furanyl fentanyl) to generate metabolites. Assays were analyzed via liquid chromatography–tandem mass spectrometry. Results: Nine metabolites were detected. A common metabolite was observed between fentanyl analogs that were methoxylated at the para-position. Conclusions: Similarities between metabolites of five methoxylated fentanyl analogs were noted. It appeared that the major pathway of metabolism for methoxylated fentanyl analogs is largely consistent, regardless of the location of the methoxy substituent so long as the piperidine nitrogen is unobstructed and is available for N-dealkylation. This research provides valuable insight to potentially find new ways for toxicologists to identify novel methoxylated fentanyl analogs in biological matrices. Full article

High-resolution mass spectrometry (HRMS) enables non-targeted detection of drugs and metabolites in complex matrices. Phase II metabolites—especially glucuronides—are often the only detectable biomarkers in late or postmortem samples but are underrepresented in commercial libraries. This work pursued the prediction of phase II-glucuronide conjugates in diluted urine samples by non-targeted/targeted LC-HRMS workflows. A simply “dilute-and-shoot” qualitative UHPLC-HRMS/MS method (Q Exactive HF, ddMS²) was integrated with Compound Discoverer^® software for data processing. The workflow incorporated predictive strategies such as exact mass suspect lists, Structured Query Language (SQL)-based filters, compound-class and diagnostic neutral-loss rules (including the characteristic loss of 176.0321 Da for glucuronides) and MS/MS confirmation using both in-house and public spectral libraries. An additional part of the application’s performance assessment involved its validation for diluted urine sample. A qualitative validated method for more than two hundred drugs in urine samples was performed, including the method’s selectivity/specificity, limit of identification, matrix effects, and potential carryover. Most analytes fulfilled the qualitative acceptance criteria, with more than 60% successfully identified at a concentration of at least 2.5 ng/mL. Matrix effects were within acceptable limits for most compounds, and no severe ion suppression was observed. A non-targeted workflow was applied to real forensic samples (n = 16), allowing a reduction of approximately 66,800 detected features to 225 glucuronide candidates, while a targeted workflow based on exact mass lists yielded 31 high-confidence identifications. Characteristic neutral losses and diagnostic fragment ions led to the tentative identification of some glucuronide phase II metabolites such as mirtazapine–glucuronide, morphine-6–glucuronide, and glucuronide conjugates of benzodiazepines and synthetic opioids. In conclusion, the integration of biotransformation knowledge with HRMS-based predictive filtering allows for the efficient and hydrolysis-free detection of glucuronide metabolites, thereby extending detection windows and enhancing toxicological interpretation in complex forensic scenarios. This adaptable and library-independent workflow also facilitates retrospective data mining, making it suitable for the identification of emerging substances and newly characterized metabolites. Full article