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BACKGROUND AND AIMS: Current laboratory methods for opioid detection involve an initial screening with immunoassays which offers efficient but non-specific results and a subsequent liquid chromatography-tandem mass spectrometry (LC-MS/MS) confirmation which offers accurate results but requires extensive sample preparation and turnaround time. Direct Analysis in Real Time (DART) tandem mass spectrometry is evaluated as an alternative approach for accurate opioid detection with efficient sample preparation and turnaround time. MATERIALS AND METHODS: DART-MS/MS was optimized by testing the method with varying temperatures, operation modes, extraction methods, hydrolysis times, and vortex times. The method was evaluated for 12 opioids by testing the analytical measurement range, percent carryover, precision studies, stability, and method-to-method comparison with LC-MS/MS. RESULTS: DART-MS/MS shows high sensitivity and specificity for the detection of 6-acetylmorphine, codeine, hydromorphone, oxymorphone, hydrocodone, naloxone, buprenorphine, norfentanyl, and fentanyl in urine samples. However, its performance was suboptimal for norbuprenorphine, morphine and oxycodone. CONCLUSION: In this proof-of-concept study, DART-MS/MS is evaluated for its rapid quantitative definitive testing of opioids drugs in urine. Further research is needed to expand its application to other areas of drug testing.

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Background: Switching from methadone to buprenorphine in patients receiving opioid maintenance therapy often requires inpatient care with a gradual tapering of methadone and an opioid-free day with challenging withdrawal symptoms. This case report describes and discusses a gentle outpatient approach without the opioid-free day. Case presentation: A patient with a 15-year history of opioid maintenance therapy reduced his methadone dose from 80 mg to 50 mg due to concurrent use of other sedative substances and a significant risk of overdose. A week-long switch to buprenorphine 16 mg subcutaneous depot formulation was then undertaken using a microinduction approach in the outpatient setting. Interpretation: In line with earlier reports on microinduction, the switch from methadone to buprenorphine was carried out with no opioid withdrawal symptoms or complications. Microinduction offers a smooth and more patient-friendly approach to switching from full opioid agonists to partial agonists. Randomised controlled trials are, however, needed for a systematic evaluation of this method.

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BACKGROUND: Opioids are commonly used to provide analgesia during and after congenital heart surgery. The effects of exposure to opioids on neurodevelopment in neonates and infants are not well understood. OBJECTIVES: This study sought to evaluate the associations between cumulative opioid exposure (measured in morphine mg equivalent) over the first year of life and 2-year neurodevelopmental outcomes (Bayley Scales of Infant and Toddler Development-Third/Fourth Edition [Bayley-III/IV] cognitive, language, and motor scores). METHODS: A single-center retrospective cohort study of infants undergoing congenital heart surgery was performed. Adjustment for measurable confounders was performed through multivariable linear regression. RESULTS: A total of 526 subjects were studied, of whom 32% underwent Society for Thoracic Surgeons-European Association for Cardio-Thoracic Surgery category 4 or 5 operations. In unadjusted analyses, higher total exposure to opioids was associated with worse scores across all 3 Bayley-III/IV domain scores (all P < 0.05). After adjustment for measured confounders, greater opioid exposure was associated with lower Bayley-III/IV scores (cognitive: ß = -1.0 per log-transformed morphine mg equivalents, P = 0.04; language: ß = -1.2, P = 0.04; and motor: ß = -1.1, P = 0.02). Total hospital length of stay, prematurity, genetic syndromes, and worse neighborhood socioeconomic status (represented either by Social Vulnerability Index or Childhood Opportunity Index) were all associated with worse Bayley-III/IV scores across all domains (all P < 0.05). CONCLUSIONS: Greater postnatal exposure to opioids was associated with worse neurodevelopmental outcomes across cognitive, language, and motor domains, independent of other less modifiable factors. This finding should motivate research and efforts to explore reduction in opioid exposure while preserving quality cardiac intensive care.

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We examined a natural history of opioid overdose deaths from 1999-2021 in the United States to describe state-level spatio-temporal heterogeneity in the waves of the epidemic. We obtained overdose death counts by state from 1999-2021, categorized as involving prescription opioids, heroin, synthetic opioids, or unspecified drugs. We developed a Bayesian multivariate multiple change point model to flexibly estimate the timing and magnitude of state-specific changes in death rates involving each drug type. We found substantial variability around the timing and severity of each wave across states. The first wave of prescription-involved deaths started between 1999 and 2005, the second wave of heroin-involved deaths started between 2010 and 2014, and the third wave of synthetic opioid-involved deaths started between 2014 and 2021. The severity of the second and third waves was greater in states in the eastern half of the country. Our study highlights state-level variation in the timing and severity of the waves of the opioid epidemic by presenting a 23-year natural history of opioid overdose mortality in the United States. While reinforcing the general notion of three waves, we find that states did not uniformly experience the impacts of each wave.

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BACKGROUND: Breakthrough cancer pain (BTcP) has a negative impact on patients' quality of life, general activities, and is related to worse clinical outcomes. Fentanyl inhalant is a hand-held combination drug-device delivery system providing rapid, multi-dose (25µg/dose) administration of fentanyl via inhalation of a thermally generated aerosol. This multicenter, randomized, placebo-controlled, multiple-crossover, double-blind study evaluated the efficacy, safety, and tolerability of fentanyl inhalant in treating BTcP in opioid-tolerant patients. METHODS: The trial was conducted in opioid-tolerant cancer patients with 1 ~ 4 BTcP outbursts per day. Each patient was treated and observed for 6 episodes of BTcP (4 with fentanyl inhalant, 2 with placebo). During each episode of targeted BTcP, patients were allowed up to six inhalations, with an interval of at least 4 min between doses. Primary outcome was the time-weighted sum of PID (pain intensity difference) scores at 30 min (SPID30). RESULTS: A total of 335 BTcP episodes in 59 patients were treated. The mean SPID30 was -97.4 ± 48.43 for fentanyl inhalant-treated episodes, and -64.6 ± 40.25 for placebo-treated episodes (p < 0.001). Significant differences in PID for episodes treated with fentanyl inhalant versus placebo was seen as early as 4 min and maintained for up to 60 min. The percentage of episodes reported PI (pain intensity) scores ≤ 3, a ≥ 33% or ≥ 50% reduction in PI scores at 30 min, PR30 (pain relief scores at 30 min) and SPID60 favored fentanyl inhalant over placebo. Only 4.4% of BTcP episodes required rescue medication in fentanyl inhalant group. Most AEs were of mild or moderate severity and typical of opioid drugs. CONCLUSION: Treatment with fentanyl inhalant was shown to be a promising therapeutic option for BTcP, with significant pain relief starting very soon after dosing. Confirmation of effectiveness requires a larger phase III trial. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05531422 registered on 6 September 2022 after major amendment, NCT04713189 registered on 14 January 2021.

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BACKGROUND: Overdose deaths remain high for opioid use disorder, emphasizing the need to pursue innovative therapeutics. Classic psychedelic drugs that engage many monoamine receptors mitigate opioid use. Here, we tested the hypothesis that the preferential serotonin 5-HT2AR agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI) could reduce the demand for fentanyl in a preclinical model of fentanyl self-administration. METHODS: Male and female Sprague-Dawley rats (n = 25-29) were implanted with indwelling jugular catheters and allowed to self-administer fentanyl (3.2µg/kg/infusion). Rats progressed to a novel low price twice within-session threshold procedure where rats sampled the lowest price twice before decreasing the dose of fentanyl by a » log every 10minutes across 11 doses. Once stable, rats were pretreated with saline or DOI (0.01, 0.03, 1mg/kg). Fentanyl consumption was analyzed using an exponentiated demand function to extract the dependent variables, Q0 and α. RESULTS: Male and female rats acquired fentanyl self-administration in the lowest price twice within-session threshold procedure. DOI dose-dependently altered fentanyl intake such that 5-HT2AR activation decreased Q0 in female rats but increased Q0 in male rats. For demand elasticity, DOI increased α in male rats but did not alter α in female rats. DOI did not alter inactive lever presses or latency. CONCLUSION: DOI reduces consumption at minimally constrained costs but did not affect the reinforcement value of fentanyl in female rats. Alternatively, DOI significantly reduced the reinforcement value of fentanyl in male rats. Biological sex alters the therapeutic efficacy of DOI and 5-HT2AR activation sex-dependently alters opioid reinforcement.

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BACKGROUND: Medications for opioid use disorder (MOUD) are the gold standard. However, significant barriers limit their use in the primary care setting, including limited knowledge of the medications and stigmatizing attitudes. In this study, we assess knowledge levels among primary care-aligned professionals (PCPs) currently in practice, and whether knowledge of MOUD is associated with stigma and treatment attitudes. PARTICIPANTS AND METHODS: Using rosters from the state of Ohio licensing boards, we surveyed 403 physicians, nurse practitioners, and physician associates in 2022, on the mechanism of different MOUD, as well as stigma and treatment attitudes. To assess MOUD knowledge, we employed descriptive and bivariate statistics. We fit four linear regression models, which controlled for empathy towards patients with OUD and provider demographics to assess the relationship between MOUD knowledge and four endpoints: stigma, perceived controllability of opioid use, perceived vulnerability to opioid use disorder, and support for abstinence-only treatment. RESULTS: 43% of participants correctly identified the mechanism of all 3 medications whereas 13% of participants did not identify the mechanism of any MOUD correctly. MOUD knowledge was higher among physicians as compared to nurse practitioners and physician associates. Lower MOUD knowledge was associated with more negative attitudes towards patients with OUD and MOUD treatment. CONCLUSION: Expanding access to MOUD treatment requires a trained and willing health-care professional (HCP) workforce. Our findings highlight considerable variation in clinician knowledge of MOUD and suggest that knowledge levels are also related to negative attitudes towards patients with OUD and MOUD. Training interventions that increase knowledge, as well as focus on stigma reduction, are critical for reducing the longstanding treatment gap for opioid use disorder.

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Importance: With the implementation of Measure 110 (M110) in 2021, Oregon became the first US state to decriminalize small amounts of any drug for personal use. To date, no analysis of the association of this law with overdose mortality has fully accounted for the introduction of fentanyl-a substance that is known to drive fatal overdose-to Oregon's unregulated drug market. Objective: To evaluate whether the decriminalization of drug possession in Oregon was associated with changes in fatal drug overdose rates after accounting for the rapid spread of fentanyl in Oregon's unregulated drug market. Design, Setting, and Participants: In this cohort study, the association between fatal overdose and enactment of M110 was analyzed using a matrix completion synthetic control method. The control group consisted of the 48 US states and Washington, DC, all of which did not decriminalize drugs. The rapid spread of fentanyl in unregulated drug markets was determined using the state-level percentage of all samples reported to the National Forensic Laboratory Information System that were identified as fentanyl or its analogues. Mortality data were obtained from the Centers for Disease Control and Prevention for January 1, 2008, to December 31, 2022. Data analysis was performed from fall 2023 through spring 2024. Exposures: Measure 110 took effect in Oregon on February 1, 2021. Main Outcomes and Measures: The primary outcome assessed was fatal drug overdose rates per half-year. A changepoint analysis also determined when each state experienced a rapid escalation of fentanyl in its unregulated drug market. Results: In this analysis, rapid spread of fentanyl in Oregon's unregulated drug supply occurred in the first half of 2021, contemporaneous with enactment of M110. A positive crude association was found between drug decriminalization and fatal overdose rate per 100 000 per half year (estimate [SE], 1.83 [0.47]; P < .001). After adjusting for the spread of fentanyl as a confounder, the effect size changed signs (estimate [SE], -0.51 [0.61]; P = .41) and there was no longer an association between decriminalization and overdose mortality in Oregon. Sensitivity analyses were consistent with this result. Conclusions and Relevance: In this cohort study of fatal drug overdose and the spread of fentanyl through Oregon's unregulated drug market, no association between M110 and fatal overdose rates was observed. Future evaluations of the health effects of drug policies should account for changes in the composition of unregulated drug markets.

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BACKGROUND: Every year, many opioid users undergo surgery, experiencing increased postoperative complications, inadequate pain control, and opioid-related adverse effects. This overview aims to summarise and critically assess the systematic reviews about perioperative pain management interventions, identify the knowledge gaps, and potentially provide high-quality recommendations to improve postoperative analgesia and surgical outcomes. METHODS: A systematic search was conducted from the following databases, PubMed, Cochrane Database of Systematic Reviews, Embase, APA PsycINFO, CINAHL, AMED, Scopus, PROSPERO, ProQuest, and Epistemonikos, in June 2023. Additionally, reference lists were reviewed. The identified studies were assessed based on eligibility criteria and data extracted by a self-designed form and two independent reviewers. Qualitative data were synthesised, and all included studies were assessed by The Assessment of Multiple Systematic Reviews 2 (AMSTAR 2) checklist. RESULTS: Nine studies were included. The methodological quality of the studies was mostly critically low. Various interventions were identified, including perioperative management of buprenorphine, ketamine administration, multimodal analgesia, higher doses of medications, patient education, and interprofessional collaboration. The level of certainty of the evidence ranged from very low to high. One high-quality study showed that ketamine administration may improve perioperative analgesia supported with moderate to very low-quality evidence, and low and critically low studies indicated the efficacy of perioperative continuation of buprenorphine with low to very low-quality evidence. CONCLUSION: Perioperative continuation of buprenorphine and ketamine administration as a multimodal analgesia approach, with moderate to very low-quality evidence, improves pain management in opioid users and decreases opioid-related adverse effects. However, high-quality systematic reviews are required to fill the identified gaps in knowledge.

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INTRODUCTION: surgical pain is managed with multi-modal anesthesia in total knee arthroplasty (TKA). It is dubious whether including local infiltrative anaesthesia (LIA) before wound closure provides adequate pain control and decreases morbidity. MATERIAL AND METHODS: this was a retrospective conducted to assess postoperative pain control, morbidity index, and opioid consumption in 116 patients who underwent TKA and were divided into two groups based on LIA (Modified Ranawat Regimen) or normal saline infiltration in the wound. RESULTS: the mean NRS score was significantly lower in LIA group (3.2) as compared to the control group (3.9) in the first 24 hours. Functional milestones were relatively achieved earlier in LIA group but the values were not significant. Tramadol consumption was remarkably higher in the control group as compared to LIA group on day 1 and 2. As per the morbidity index the mean score on day one was 16.18 and 23.40 which decreased to 6.37 and 9.21 by day three in LIA and control group respectively indicating morbidity has decreased but more so in LIA group. CONCLUSION: our study concludes that use of modified cocktail regimen in the knee effectively decreased morbidity with excellent to good results, declining NRS score, minimal rescue analgesia requirement, early ambulation with better safety.

INTRODUCCIÓN: el dolor quirúrgico se trata con anestesia multimodal en la artroplastia total de rodilla (ATR). Es dudoso que incluir anestesia local infiltrativa (LIA) antes del cierre de la herida proporcione un control adecuado del dolor y disminuya la morbilidad. MATERIAL Y MÉTODOS: se realizó una retrospectiva para evaluar el control del dolor posoperatorio, el índice de morbilidad y el consumo de opioides en 116 pacientes sometidos a ATR y se dividieron en dos grupos según el LIA (régimen de Ranawat modificado) o la infiltración de solución salina normal en la herida. RESULTADOS: la puntuación media NRS fue significativamente menor en el grupo LIA (3.2) en comparación con el grupo control (3.9) en las primeras 24 horas. Los hitos funcionales se alcanzaron relativamente antes en el grupo LIA, pero los valores no fueron significativos. El consumo de tramadol fue notablemente mayor en el grupo de control en comparación con el grupo de LIA los días 1 y 2. Según el índice de morbilidad, la puntuación media el día uno fue 16.18 y 23.40, que disminuyó a 6.37 y 9.21 en el día tres en el grupo de LIA y control, respectivamente, lo que indica que la morbilidad ha disminuido, pero más en el grupo LIA. CONCLUSIÓN: nuestro estudio concluye que el uso de un régimen de cóctel modificado en la rodilla disminuyó efectivamente la morbilidad con resultados excelentes a buenos, una disminución de la puntuación NRS, un requisito mínimo de analgesia de rescate y una deambulación temprana con mayor seguridad.

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BACKGROUND: Persistent opioid use is a common occurrence after surgery and prolonged exposure to opioids may result in escalation and dependence. The objective of this study was to develop machine-learning-based predictive models for persistent opioid use after major spine surgery. METHODS: Five classification models were evaluated to predict persistent opioid use: logistic regression, random forest, neural network, balanced random forest, and balanced bagging. Synthetic Minority Oversampling Technique was used to improve class balance. The primary outcome was persistent opioid use, defined as patient reporting to use opioids after 3 months postoperatively. The data were split into a training and test set. Performance metrics were evaluated on the test set and included the F1 score and the area under the receiver operating characteristics curve (AUC). Feature importance was ranked based on SHapley Additive exPlanations (SHAP). RESULTS: After exclusion (patients with missing follow-up data), 2611 patients were included in the analysis, of which 1209 (46.3%) continued to use opioids 3 months after surgery. The balanced random forest classifiers had the highest AUC (0.877, 95% confidence interval [CI], 0.834-0.894) compared to neural networks (0.729, 95% CI, 0.672-0.787), logistic regression (0.709, 95% CI, 0.652-0.767), balanced bagging classifier (0.859, 95% CI, 0.814-0.905), and random forest classifier (0.855, 95% CI, 0.813-0.897). The balanced random forest classifier had the highest F1 (0.758, 95% CI, 0.677-0.839). Furthermore, the specificity, sensitivity, precision, and accuracy were 0.883, 0.700, 0.836, and 0.780, respectively. The features based on SHAP analysis with the highest impact on model performance were age, preoperative opioid use, preoperative pain scores, and body mass index. CONCLUSIONS: The balanced random forest classifier was found to be the most effective model for identifying persistent opioid use after spine surgery.

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