Using part of the initial analgesic dose as the epidural test dose did not delay the onset of labor analgesia: a randomized controlled clinical trial.

BACKGROUND: Epidural test dose for labor analgesia is controversial and varies widely in clinical practice. It is currently unclear whether using a portion of the initial dose for analgesia as the test dose delays the onset time of analgesia, compared to the traditional test dose. METHODS: One hundred and twenty-six parturients who chose epidural analgesia during labor were randomly assigned to two groups. The first dose in group L was 3 ml 1.5% lidocaine, and in the RF group was 10 ml 0.1% ropivacaine combined with 2 µg/ml fentanyl. After 3 min of observation, both groups received 8 ml 0.1% ropivacaine combined with 2 µg/ml fentanyl. The onset time of analgesia, motor and sensory blockade level, numerical pain rating scale, patient satisfaction score, and side effects were recorded. RESULTS: The onset time of analgesia in group RF was similar to that in group L (group RF vs group L, 7.0 [5.0-9.0] minutes vs 8.0 [5.0-11.0] minutes, p = 0.197). The incidence of foot numbness (group RF vs group L, 34.9% vs 57.1%, p = 0.020) and foot warming (group RF vs group L, 15.9% vs 47.6%, p < 0.001) in group RF was significantly lower than that in group L. There was no difference between the two groups on other outcomes. CONCLUSIONS: Compared with 1.5% lidocaine 3 ml, 0.1% ropivacaine 10 ml combined with 2 µg/ml fentanyl as an epidural test dose did not delay the onset of labor analgesia, and the side effects were slightly reduced. CLINICAL TRIAL REGISTRATION: http://www.chictr.org.cn (ChiCTR2100043071).

Withdrawal during outpatient low dose buprenorphine initiation in people who use fentanyl: a retrospective cohort study.

BACKGROUND: Buprenorphine is an effective treatment for opioid use disorder (OUD); however, buprenorphine initiation can be complicated by withdrawal symptoms including precipitated withdrawal. There has been increasing interest in using low dose initiation (LDI) strategies to reduce this withdrawal risk. As there are limited data on withdrawal symptoms during LDI, we characterize withdrawal symptoms in people with daily fentanyl use who underwent initiation using these strategies as outpatients. METHODS: We conducted a retrospective chart review of patients with OUD using daily fentanyl who were prescribed 7-day or 4-day LDI at 2 substance use disorder treatment clinics in San Francisco. Two addiction medicine experts assessed extracted chart documentation for withdrawal severity and precipitated withdrawal, defined as acute worsening of withdrawal symptoms immediately after taking buprenorphine. A third expert adjudicated disagreements. Data were analyzed using descriptive statistics. RESULTS: There were 175 initiations in 126 patients. The mean age was 37 (SD 10 years). 71% were men, 26% women, and 2% non-binary. 21% identified as Black, 16% Latine, and 52% white. 60% were unstably housed and 75% had Medicaid insurance. Substance co-use included 74% who used amphetamines, 29% cocaine, 22% benzodiazepines, and 19% alcohol. Follow up was available for 118 (67%) initiations. There was deviation from protocol instructions in 22% of these initiations with follow up. 31% had any withdrawal, including 21% with mild symptoms, 8% moderate and 2% severe. Precipitated withdrawal occurred in 10 cases, or 8% of initiations with follow up. Of these, 7 had deviation from protocol instructions; thus, there were 3 cases with follow up (3%) in which precipitated withdrawal occurred without protocol deviation. CONCLUSIONS: Withdrawal was relatively common in our cohort but was mostly mild, and precipitated withdrawal was rare. Deviation from instructions, structural barriers, and varying fentanyl use characteristics may contribute to withdrawal. Clinicians should counsel patients who use fentanyl that mild withdrawal symptoms are likely during LDI, and there is still a low risk for precipitated withdrawal. Future studies should compare withdrawal across initiation types, seek ways to support patients in initiating buprenorphine, and qualitatively elicit patients' withdrawal experiences.

Comparative study between remifentanil (or fentanyl) and dexmedetomidine for the analgesia of rhinoplasty: A meta-analysis of randomized controlled trials.

BACKGROUND: Remifentanil (or fentanyl) and dexmedetomidine may have some potential to improve the analgesia of rhinoplasty, and this meta-analysis aims to compare their efficacy for the analgesia of rhinoplasty. METHODS: PubMed, Embase, Web of Science, EBSCO, and Cochrane Library databases were systematically searched, and we included randomized controlled trials (RCTs) assessing the analgesic effect of remifentanil (or fentanyl) versus dexmedetomidine for rhinoplasty. RESULTS: Four RCTs were finally included in the meta-analysis. In patients undergoing rhinoplasty, remifentanil (or fentanyl) infusion and dexmedetomidine infusion resulted in similar good patient satisfaction (odd ratio [OR] = 2.71; 95% confidence interval [CI] = 0.63 to 11.64; P = .18), good surgeon satisfaction (OR = 1.68; 95% CI = 0.02 to 181.40; P = .83), extubation time (mean difference [MD] = 7.56; 95% CI = -11.00 to 26.12; P = .42), recovery time (MD = -2.25; 95% CI = -23.41 to 18.91; P = .83), additional analgesic requirement (OR = 0.16; 95% CI = 0 to 8.65; P = .37) and adverse events (OR = 8.50; 95% CI = 0.47 to 153.30; P = .15). CONCLUSIONS: Remifentanil (or fentanyl) and dexmedetomidine may have comparable analgesia for patients undergoing rhinoplasty.

Evaluation of Postoperative Pain After Cardiothoracic Surgery in Patients With and Without Significant Preoperative Anxiety: A Prospective Observational Study.

BACKGROUND AND AIMS: Anxiety plays a distressing role in cardiothoracic operations. It may trigger hemodynamic instability, increased morbidity, and very crucially, postoperative pain and analgesic use. Our aim is to look at the association between anxiety, postoperative pain, and analgesic use. MATERIALS AND METHODS: One hundred and twenty-two patients scheduled for cardiothoracic surgeries were asked questions according to the Amsterdam Preoperative Anxiety and Information Scale (APAIS), the evening prior to the surgery. Different factors that could affect anxiety perioperatively were recorded through the patient's hospital records. The visual analog score (VAS) was recorded at arrival in the ICU after surgery. Paracetamol (1 g) and Inj Tramadol (1 mg/kg) were administered as postoperative analgesia. Additional fentanyl boluses (1 mcg/kg) were administered whenever the VAS exceeded 4. Analgesic doses were documented. All the data were then analyzed statistically. RESULTS: Preoperative anxiety was recorded in 63.9% of the 122 subjects included in the study, with younger patients and patients with very low socioeconomic status being the majority. VAS, at 20 and 24 hrs of assessment, was higher in both groups, and there was a statistically significant difference, with patients that were preoperatively anxious, recording higher VAS scores. Postoperative analgesic doses were also significantly higher for patients with anxiety. CONCLUSIONS: This clinical trial demonstrated that greater than 60% of the participants presented with preoperative anxiety, the majority being young participants. Lower socioeconomic status is also a risk factor for preoperative anxiety. Patients who suffered from preoperative anxiety are more likely to have greater pain scores and analgesic needs during postsurgical assessment.

Comparison of patient-controlled analgesia and sedation (PCAS) with remifentanil and propofol versus total intravenous anesthesia (TIVA) with midazolam, fentanyl, and propofol for colonoscopy.

BACKGROUND: Colonoscopy is a commonly performed gastroenterological procedure in patients associated with anxiety and pain. Various approaches have been used to provide sedation and analgesia during colonoscopy, including patient-controlled analgesia and sedation (PCAS). This study aims to evaluate the feasibility and efficiency of PCAS administered with propofol and remifentanil for colonoscopy. METHODS: This randomized controlled trial was performed in an authorized and approved endoscopy center. A total of 80 outpatients were recruited for the colonoscopy studies. Patients were randomly allocated into PCAS and total intravenous anesthesia (TIVA) groups. In the PCAS group, the dose of 0.1 ml/kg/min of the mixture was injected after an initial bolus of 3 ml mixture (1 ml containing 3 mg of propofol and 10 µg of remifentanil). Each 1 ml of bolus was delivered with a lockout time of 1 min. In the TIVA group, patients were administered fentanyl 1 µg/kg, midazolam 0.02 mg/kg, and propofol (dosage titrated). Cardiorespiratory parameters and auditory evoked response index were continuously monitored during the procedure. The recovery from anesthesia was assessed using the Aldrete scale and the Observer's Assessment of Alertness/Sedation Scale. The Visual Analogue Scale was used to assess the satisfaction of patients and endoscopists. RESULTS: No statistical differences were observed in the Visual Analogue Scale scores of the patients (9.58 vs 9.50) and the endoscopist (9.43 vs 9.30). A significant decline in the mean arterial blood pressure, heart rate, and auditory evoked response index parameters was recorded in the TIVA group (P < 0.05). The recovery time was significantly shorter in the PCAS group than in the TIVA group (P = 0.00). CONCLUSION: The combination of remifentanil and propofol could provide sufficient analgesia, better hemodynamic stability, lighter sedation, and faster recovery in the PCAS group of patients compared with the TIVA group.

Substance use patterns, sociodemographics, and health profiles of harm reduction service recipients in Burlington, Vermont.

BACKGROUND: Understanding current substance use practices is critical to reduce and prevent overdose deaths among individuals at increased risk including persons who use and inject drugs. Because individuals participating in harm reduction and syringe service programs are actively using drugs and vary in treatment participation, information on their current drug use and preferred drugs provides a unique window into the drug use ecology of communities that can inform future intervention services and treatment provision. METHODS: Between March and June 2023, 150 participants in a harm reduction program in Burlington, Vermont completed a survey examining sociodemographics; treatment and medication for opioid use disorder (MOUD) status; substance use; injection information; overdose information; and mental health, medical, and health information. Descriptive analyses assessed overall findings. Comparisons between primary drug subgroups (stimulants, opioids, stimulants-opioids) of past-three-month drug use and treatment participation were analyzed using chi-square and Fisher's exact test. RESULTS: Most participants reported being unhoused or unstable housing (80.7%) and unemployed (64.0%) or on disability (21.3%). The drug with the greatest proportion of participants reporting past three-month use was crack cocaine (83.3%). Fentanyl use was reported by 69.3% of participants and xylazine by 38.0% of participants. High rates of stimulant use were reported across all participants independent of whether stimulants were a participant's primary drug. Fentanyl, heroin, and xylazine use was less common in the stimulants subgroup compared to opioid-containing subgroups (p < .001). Current- and past-year MOUD treatment was reported by 58.0% and 77.3% of participants. Emergency rooms were the most common past-year medical treatment location (48.7%; M = 2.72 visits). CONCLUSIONS: Findings indicate high rates of polysubstance use and the underrecognized effects of stimulant use among people who use drugs-including its notable and increasing role in drug-overdose deaths. Crack cocaine was the most used stimulant, a geographical difference from much of the US where methamphetamine is most common. With the increasing prevalence of fentanyl-adulterated stimulants and differences in opioid use observed between subgroups, these findings highlight the importance and necessity of harm reduction interventions (e.g., drug checking services, fentanyl test strips) and effective treatment for individuals using stimulants alongside MOUD treatment.

Physiologically based modeling reveals different risk of respiratory depression after fentanyl overdose between adults and children.

Despite a rapid increase in pediatric mortality rate from prescription and illicit opioids, there is limited research on the dose-dependent impact of opioids on respiratory depression in children, the leading cause of opioid-associated death. In this article, we extend a previously developed translational model to cover pediatric populations by incorporating age-dependent pharmacokinetic, pharmacodynamic, and physiological changes compared to adults. Our model reproduced previous perioperative clinical findings that adults and children have similar risk of respiratory depression at the same plasma fentanyl concentration when specific endpoints (minute ventilation, CO2 tension in the blood) were used. However, our model points to a potential caveat that, in a perioperative setting, routine use of mechanical ventilation and supplemental oxygen maintained the blood and tissue oxygen partial pressures in patients and prevented the use of oxygen-related endpoints to evaluate the consequences of respiratory depression. In a community setting when such oxygenation procedures are not immediately available, our model suggests that the higher oxygen demand and reduced cerebrovascular reactivity could make children more susceptible to severe hypoxemia and brain hypoxia, even with the same plasma fentanyl concentration as adults. Our work indicates that when developing intervention strategies to protect children from opioid overdose in a community setting, these pediatric-specific factors may need to be considered.

L-NAC and L-NAC methyl ester prevent and overcome physical dependence to fentanyl in male rats.

N-acetyl-L-cysteine (L-NAC) is a proposed therapeutic for opioid use disorder. This study determined whether co-injections of L-NAC (500 µmol/kg, IV) or its highly cell-penetrant analogue, L-NAC methyl ester (L-NACme, 500 µmol/kg, IV), prevent acquisition of acute physical dependence induced by twice-daily injections of fentanyl (125 µg/kg, IV), and overcome acquired dependence to these injections in freely-moving male Sprague Dawley rats. The injection of the opioid receptor antagonist, naloxone HCl (NLX; 1.5 mg/kg, IV), elicited a series of withdrawal phenomena (i.e. behavioral and cardiorespiratory responses, hypothermia and body weight loss) in rats that received 5 or 10 injections of fentanyl and similar numbers of vehicle co-injections. With respect to the development of dependence, the NLX-precipitated withdrawal phenomena were reduced in rats that received had co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme. In regard to overcoming established dependence, the NLX-precipitated withdrawal phenomena in rats that had received 10 injections of fentanyl (125 µg/kg, IV) were reduced in rats that had received co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme beginning with injection 6 of fentanyl. This study provides compelling evidence that co-injections of L-NAC and L-NACme prevent the acquisition of physical dependence and overcome acquired dependence to fentanyl in male rats. The higher efficacy of L-NACme is likely due to its greater cell penetrability in brain regions mediating dependence to fentanyl and interaction with intracellular signaling cascades, including redox-dependent processes, responsible for the acquisition of physical dependence to fentanyl.

Accidental substance-related acute toxicity deaths among youth in Canada: a descriptive analysis of a national chart review study of coroner and medical examiner data. / Décès accidentels attribuables à une intoxication aiguë due à une substance chez les jeunes au Canada : analyse descriptive d'une étude nationale portant sur l'examen des dossiers des données de coroners et de médecins légistes.

INTRODUCTION: Substance-related acute toxicity deaths (ATDs) are a public health crisis in Canada. Youth are often at higher risk for substance use due to social, environmental and structural factors. The objectives of this study were to understand the characteristics of youth (aged 12-24 years) dying of accidental acute toxicity in Canada and examine the substances contributing to and circumstances surrounding youth ATDs. METHODS: Data from a national chart review study of coroner and medical examiner data on ATDs that occurred in Canada between 2016 and 2017 were used to conduct descriptive analyses with proportions, mortality rates and proportionate mortality rates. Where possible, youth in the chart review study were compared with youth in the general population and youth who died of all causes, using census data. RESULTS: Of the 732 youth who died of accidental acute toxicity in 2016-2017, most (94%) were aged 18 to 24 years. Youth aged 20 to 24 who were unemployed, unhoused or living in collective housing were overrepresented among accidental ATDs. Many of the youth aged 12 to 24 who died of accidental acute toxicity had a documented history of substance use. Fentanyl, cocaine and methamphetamine were the most common substances contributing to death, and 38% of the deaths were witnessed or potentially witnessed. CONCLUSION: The findings of this study point to the need for early prevention and harm reduction strategies and programs that address mental health, exposure to trauma, unemployment and housing instability to reduce the harms of substance use on Canadian youth.

Accidental substance-related acute toxicity deaths in older adults in 2016 and 2017: a national chart review study. / Décès accidentels liés à une intoxication aiguë due à une substance chez les aînés en 2016 et en 2017 : une étude nationale d'examen des dossiers.

INTRODUCTION: Limited research exists on substance-related acute toxicity deaths (ATDs) in older adults (≥60 years) in Canada. This study aims to examine and describe the sociodemographic characteristics, health histories and circumstances of death for accidental ATDs among older adults. METHODS: Following a retrospective descriptive analysis of all coroner and medical examiner files on accidental substance-related ATDs in older adults in Canada from 2016 to 2017, proportions and mortality rates for coroner and medical examiner data were compared with general population data on older adults from the 2016 Census. Chisquare tests were conducted for categorical variables where possible. RESULTS: From 2016 to 2017, there were 705 documented accidental ATDs in older adults. Multiple substances contributed to 61% of these deaths. Fentanyl, cocaine and ethanol (alcohol) were the most common substances contributing to death. Heart disease (33%), chronic pain (27%) and depression (26%) were commonly documented. Approximately 84% of older adults had contact with health care services in the year preceding their death. Only 14% were confirmed as having their deaths witnessed. CONCLUSIONS: Findings provide insight into the demographic, contextual and medical history factors that may influence substance-related ATDs in older adults and suggest key areas for prevention.

Beyond a spec: assessing heterogeneity in the unregulated opioid supply.

BACKGROUND: Drug checking services aim to provide compositional information for the illicit drug supply and are being employed in public health responses to extreme rates of overdose associated with fentanyl within street opioids. The technologies used within these services range from basic qualitative tests, such as immunoassay test strips, to comprehensive quantitative analyses, such as mass spectrometry. In general, there is concern that heterogeneity of a drug mixture adds significant uncertainty when using drug checking results based on a small subsamples. The presence of hot spots of active drug components in this context is often termed the 'chocolate chip cookie effect'. Establishing the limitations of the service are essential for interpretation of the results. METHODS: This study assesses the consequence of drug heterogeneity and sampling of consumer level opioid purchased in Victoria, British Columbia ( n = 21 , 50-100 mg each) on quantitative fentanyl results determined from testing with paper spray mass spectrometry. RESULTS: Using descriptive statistics, such as relative standard deviation and interquartile range, the results demonstrate varied distributions of fentanyl concentrations within a single drug batch. However, the presence of hot spots, defined as outliers, were relatively rare. CONCLUSIONS: This study found that the variability in fentanyl concentration from drug heterogeneity and sampling is greater than that attributed to the analytical technique. On a practical level, this provides data to help guide communication of limitations of drug checking services, supporting the aim of trust and transparency between services and people who use drugs. However, if drug checking services continue to be restricted from fully engaging with the reality of manufacturing, buying, selling, mixing and dosing practices, the accuracy, usefulness, and impact will always be limited.

Fentanyl abuse proportion in methadone maintenance treatment, and patients' knowledge about its risks.

INTRODUCTION: Fentanyl is not yet routinely monitored among methadone maintenance treatment (MMT) patients in Israel. We aimed 1. to evaluate urine fentanyl proportion changes over 3 years and characterize patients' characteristics 2. To study patients' self-report on fentanyl usage, and compare knowledge about fentanyl risk, before and following brief educational intervention. METHODS: Fentanyl in the urine of all current MMT patients was tested every 3 months year between 2021 and 2023, and patients with positive urine fentanyl were characterized. Current patients were interviewed using a fentanyl knowledge questionnaire (effects, indications, and risks) before and following an explanation session. RESULTS: Proportion of fentanyl ranged between 9.8 and 15.1%, and patients with urine positive for fentanyl (September 2023) were characterized as having positive urine for pregabalin, cocaine, and benzodiazepine (logistic regression). Of the current 260 patients (87% compliance), 78(30%) self-reported of fentanyl lifetime use ("Ever"), and 182 "never" use. The "Ever" group had higher Knowledge scores than the "Never", both groups improved following the explanatory session (repeated measure). The "Ever" group patients were found with urine positive for cannabis and benzodiazepine on admission to MMT, they were younger, did not manage to gain take-home dose privileges and had a higher fentanyl knowledge score (logistic regression). CONCLUSIONS: In the absence of routine fentanyl tests, a high knowledge score, shorter duration in MMT, benzodiazepine usage on admission, and current cannabis usage, may hint of the possibility of fentanyl abuse.

Adulterants present in the San Diego county fentanyl supply: a laboratory analysis of seized law enforcement samples.

BACKGROUND: The opioid overdose crisis is one of the worst public health crises ever to face the US and emerging evidence suggests its effects are compounded by the presence of drug adulterants. Here we report our efforts to characterize the adulterants present within the local fentanyl supply of San Diego County, obtained from undifferentiated drug samples seized by local law enforcement over the calendar year 2021. METHODS: Thirty-two participating local law enforcement agencies across San Diego submitted 4838 unknown individual illicit drug samples (total of 312 kg) to the San Diego County Sheriff's Department Regional Crime Laboratory for identification. RESULTS: Qualitative analysis of these samples via FTIR and GC-MS identified methamphetamine (38.7%), fentanyl (20.8%), diacetylmorphine (heroin) (10.2%), codeine (5.8%) and alprazolam (4.3%) as the most common illicit substances and the presence of 52 unique adulterants. The most common adulterants included 4-methylaminoantipyrine (4-MAAP) (10.9%), mannitol (9%), acetaminophen (8.5%), methamphetamine (4.2%), diacetylmorphine (heroin) (3.6%), tramadol (1.9%), and xylazine (1.7%). Several additional pharmacologically active adulterants and contaminants of interest were also identified. CONCLUSION: This analysis is vital for public health use and harm reduction efforts at the level of the individual consumer. Continued direct surveillance of the drug supply is necessary for the detection of potentially harmful adulterants that may pose serious threats to the public.

Identification of Unique Fragmentation Patterns of Fentanyl Analog Protomers Using Structures for Lossless Ion Manipulations Ion Mobility-Orbitrap Mass Spectrometry.

The opioid crisis in the United States is being fueled by the rapid emergence of new fentanyl analogs and precursors that can elude traditional library-based screening methods, which require data from known reference compounds. Since reference compounds are unavailable for new fentanyl analogs, we examined if fentanyls (fentanyl + fentanyl analogs) could be identified in a reference-free manner using a combination of electrospray ionization (ESI), high-resolution ion mobility (IM) spectrometry, high-resolution mass spectrometry (MS), and higher-energy collision-induced dissociation (MS/MS). We analyzed a mixture containing nine fentanyls and W-15 (a structurally similar molecule) and found that the protonated forms of all fentanyls exhibited two baseline-separated IM distributions that produced different MS/MS patterns. Upon fragmentation, both IM distributions of all fentanyls produced two high intensity fragments, resulting from amine site cleavages. The higher mobility distributions of all fentanyls also produced several low intensity fragments, but surprisingly, these same fragments exhibited much greater intensities in the lower mobility distributions. This observation demonstrates that many fragments of fentanyls predominantly originate from one of two different gas-phase structures (suggestive of protomers). Furthermore, increasing the water concentration in the ESI solution increased the intensity of the lower mobility distribution relative to the higher mobility distribution, which further supports that fentanyls exist as two gas-phase protomers. Our observations on the IM and MS/MS properties of fentanyls can be exploited to positively differentiate fentanyls from other compounds without requiring reference libraries and will hopefully assist first responders and law enforcement in combating new and emerging fentanyls.

Fact vs. fiction: naloxone in the treatment of opioid-induced respiratory depression in the current era of synthetic opioids.

Opioid-induced respiratory depression (OIRD) deaths are ~80,000 a year in the US and are a major public health issue. Approximately 90% of fatal opioid-related deaths are due to synthetic opioids such as fentanyl, most of which is illicitly manufactured and distributed either on its own or as an adulterant to other drugs of abuse such as cocaine or methamphetamine. Other potent opioids such as nitazenes are also increasingly present in the illicit drug supply, and xylazine, a veterinary tranquilizer, is a prevalent additive to opioids and other drugs of abuse. Naloxone is the main treatment used to reverse OIRD and is available as nasal sprays, prefilled naloxone injection devices, and generic naloxone for injection. An overdose needs to be treated as soon as possible to avoid death, and synthetic opioids such as fentanyl are up to 50 times more potent than heroin, so the availability of new, higher-dose, 5-mg prefilled injection or 8-mg intranasal spray naloxone preparations are important additions for emergency treatment of OIRDs, especially by lay people in the community. Higher naloxone doses are expected to reverse a synthetic overdose more rapidly and the current formulations are ideal for use by untrained lay people in the community. There are potential concerns about severe withdrawal symptoms, or pulmonary edema from treatment with high-dose naloxone. However, from the perspective of first responders, the balance of risks would point to administration of naloxone at the dose required to combat the overdose where the risk of death is very high. The presence of xylazines as an adulterant complicates the treatment of OIRDs, as naloxone is probably ineffective, although it will reverse the respiratory depression due to the opioid. For these patients, hospitalization is particularly vital. Education about the benefits of naloxone remains important not only in informing people about how to treat emergency OIRDs but also how to obtain naloxone. A call to emergency services is also essential after administering naloxone because, although the patient may revive, they may overdose again later because of the short half-life of naloxone and the long-lasting potency of fentanyl and its analogs.

[Development of an analytical system for dried blood spots for forensic toxicology: a case study of five common drugs and poisons].

Dried blood spot (DBS) technology is a simple and convenient method for collecting, transporting, and storing blood samples on filter paper, and has numerous applications in the clinical, research, and public health settings. This technique is gaining popularity in the field of forensic science because it facilitates the rapid analysis of prohibited drugs in blood samples and offers significant advantages in toxicology scenarios such as drinking-driving screening, drug abuse detection, and doping detection. However, the lack of a standardized system and the fact that its stability and reliability have not been thoroughly researched and demonstrated limit its application in judicial practice in China. DBS samples can be prepared, stored, and analyzed in various ways, all of which may significantly affect the results. In this study, we developed a method based on ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) that focuses on the preparation, pretreatment, analysis, and storage of DBS samples. A thorough investigation was conducted to examine the optimal preparation conditions, including the blood spot matrix, drying technique, and preprocessing parameters, such as the solvent and extraction method. Moreover, the analytical conditions, such as the mobile phase system and elution gradient, were established to facilitate the quantitative detection of methamphetamine, lidocaine, ketamine, fentanyl, and diazepam in both DBS and whole-blood samples. The impact of storage conditions, such as the temperature, humidity, and sealing, on the analytical results of the DBS and whole-blood samples was also examined. The results showed a strong linear relationship for lidocaine and fentanyl within the range of 0.5-100 ng/mL. Similarly, methamphetamine, ketamine, and diazepam exhibited good linearity within the range of 2-100 ng/mL. The coefficients of determination (r2) ranged from 0.9983 to 0.9997, and the limits of detection ranged from 0.2 to 0.5 ng/mL, indicating a high degree of correlation and sensitivity. Stability tests demonstrated that the five target substances remained stable in the DBS for 60 days, with the measured contents deviating from the nominal values by 15%. Moreover, the measurement results of the DBS samples were highly similar to those of the whole-blood samples, with mean percentage differences of 4.44%, 3.50%, 7.66%, 5.10%, and 5.25% for fentanyl, diazepam, ketamine, lidocaine, and methamphetamine, respectively. Throughout the 60-day storage period, the maintenance of temperatures of -20 and 4 ℃, as well as sealing and dry storage, was not necessary. Room temperature was the most practical storage environment for the DBS samples. The results for each target showed very small concentration differences between the whole-blood and DBS samples, indicating that the DBS samples were suitable for drug and poison analysis in blood. Furthermore, the DBSs exhibited high quantitative consistency with the whole-blood samples, rendering them suitable matrices for preserving blood samples. Because DBS samples are easy to handle and store, they can realize the lightweight preservation of blood samples and provide a novel solution for the analysis and preservation of blood samples in public security practice. We recommend conducting comprehensive validations before utilizing DBS for analysis, particularly in terms of quantification, to ensure the judicial reliability of the results.

The impact of chronic fentanyl administration on the cerebral cortex in mice: Molecular and histological effects.

PURPOSE: Fentanyl, a fully synthetic opioid, is widely used for severe pain management and has a huge abuse potential for its psychostimulant effects. Unlike other opioids, the neurotoxic effects of chronic fentanyl administration are still unclear. In particular, little is known about its effect on the cerebral cortex. The current study aims to test the chronic toxicity of fentanyl in the mice model. METHODS: Adult male Balb/c mice were chronically treated with low (0.05 mg/kg, i.p) and high (0.1 mg/kg, i.p) doses of fentanyl for 5 consecutive weeks, and various neurotoxic parameters, including apoptosis, oxidative stress, and neuroinflammatory response were assessed in the cortex. Potential histological as well as neurochemical changes were also evaluated. RESULTS: The results of this study show that chronic fentanyl administration induced intense levels of apoptosis, oxidative stress, and neuroinflammation in the cerebral cortex. These findings were found to be correlated with histopathological characteristics of neural degeneration and white matter injury. Moreover, fentanyl administration was found to reduce the expression of both NMDA receptor subunits and dopamine receptors and elevate the level of epidermal growth factor (EGF). CONCLUSION: Fentanyl administration induced neurotoxic effects in the mouse cerebral cortex that could be primarily mediated by the evoked oxidative-inflammatory response. The altered expression of NMDA receptors, dopamine receptors, and EGF suggests the pernicious effects of fentanyl addiction that may end in the development of toxic psychosis.

A confirmed case of xylazine-induced skin ulcers in a person who injects drugs in Miami, Florida, USA.

BACKGROUND: Xylazine is an alpha-2 adrenergic receptor agonist that has emerged as a contaminant in the illicit drug supply of fentanyl. Xylazine use may be suspected in naloxone-resistant overdoses and atypical, chronic wounds in people who use drugs (PWUD). This case is unique because it is the first case to our knowledge describing wound care for a xylazine-induced wound with a confirmatory xylazine test strip (XTS) in the setting of a syringe services program (SSP) and in the state of Florida. CASE PRESENTATION: A 43-year-old woman with a past medical history of severe opioid use disorder and stimulant use disorder presented to a student-run clinic at a Miami SSP for wound care. She had multiple ulcerations diffusely over her bilateral forearms with surrounding erythema and warmth. Seven weeks later, she presented to clinic again for wound care because her wounds had progressed. At this visit, a XTS was used to confirm the presence of xylazine in her urine. Wound care management and harm reduction strategies employed at both visits were informed by best clinical judgement due to lack of formal guidelines at the time. Wound outcomes are unknown as the patient has not returned to clinic. CONCLUSIONS: Many PWUD at highest risk for acute and chronic health consequences of xylazine-adulterated fentanyl do not have access to healthcare outside of low barrier clinics and SSPs due to lack of insurance or mistrust of the traditional healthcare system due to stigma. There is an urgent need for access to XTS for PWUD and clinical practice guidelines for the treatment of xylazine-related wounds in outpatient clinics.

Determination of fentanyl contamination on United States paper currency by LC-QQQ-MS.

Previous research has evaluated the extent to which cocaine and other drugs were detectable on currency in the USA. The literature was in agreement that the majority of bills exhibited some degree of contamination. With the increase of fentanyl in the illicit drug supply, this study was designed to evaluate the extent that fentanyl, cocaine, methamphetamine and other substances were present on circulating currency in 2022. A quantitative assay using liquid chromatography-triple quadrupole mass spectrometry was developed and validated to detect six analytes: fentanyl, 4-anilino-N-phenethylpiperidine, acetylfentanyl, benzylfentanyl, cocaine and methamphetamine. One-dollar bills were collected from 13 cities across the country. Sample preparation consisted of soaking the bills in methanol followed by liquid-liquid extraction. Chromatographic separation was achieved using a C18 analytical column and gradient elution with ammonium formate in water (5 mM, pH 3) and 0.1% formic acid in acetonitrile. The quantitative working range for this assay was 0.1 µg to 1.0 µg per bill (equivalent to 1 ng/mL to 100 ng/mL of extract). Fentanyl was detected on the majority (63%) of samples, with 61% of samples having ≥0.1 µg of fentanyl and 4% of samples having ≥1.0 µg. Cocaine and methamphetamine were detected on 100% and 98% of bills, respectively, typically in amounts >1.0 µg. The remaining fentanyl-related substances were detected in 15% of samples in amounts no >0.69 µg per bill and exclusively in the presence of fentanyl. Unsurprisingly, areas of the country with higher incidence of fentanyl use yielded higher frequency of contaminated bills and higher concentrations. Human exposure to drugs on currency is unlikely to have any significant impacts toxicologically or pharmacologically; however, our research findings suggest that paper currency could serve as a useful substrate for surveillance of drug trends regionally, nationally and/or internationally.

Evaluating cross-reactivity of new psychoactive substances (NPS) in human whole blood by enzyme-linked immunosorbent assay (ELISA).

Due to the increase in the use of novel psychoactive substances (NPS) and their overall prevalence, it is important to have effective and reliable screening technologies to detect NPS in biological matrices. Enzyme-linked immunosorbent assays (ELISA) are among the most popular screening methods. To evaluate the effectiveness of ELISA for NPS detection, five subclasses of NPS (novel synthetic opioids, fentanyl analogs, stimulants, benzodiazepines and hallucinogens) were evaluated in whole blood for their cross-reactivity on commercially available ELISA kits. A variety of novel synthetic opioids were tested at concentrations of 1-80 ng/mL and 50-2000 ng/mL and demonstrated no cross-reactivity to a morphine ELISA plate at either concentration range. Fentanyl analogs were tested at concentrations ranging from 0.01 to 1 ng/mL and had cross-reactivities ranging from 8% to 178% on the fentanyl ELISA kit used. Both para-chloro fentanyl (178%) and acryl fentanyl (164%) showed cross-reactivities well above that of fentanyl. Novel stimulants were tested at concentrations of 0.5-40 ng/mL and 20-2,000 ng/mL. 4-Fluoroamphetamine was the only novel stimulant with cross-reactivity (3,354%) to the amphetamine ELISA plate. Novel benzodiazepines were tested at concentrations of 1-40 ng/mL on a benzodiazepine plate. Cross-reactivities ranged from 36.1% to 263%, with desalkylflurazepam having the highest cross-reactivity. Finally, novel hallucinogens were tested at concentrations of 0.5-10 ng/mL on a phencyclidine (PCP) ELISA plate, which produced no cross-reactivity and then with 10-1,000 ng/mL, which gave results from 56.6% to 151%. Both hydroxy-PCP (151%) and chloro-PCP (137%) showed cross-reactivities above that of PCP. This research has demonstrated the utility of using ELISA-based screening for novel benzodiazepines, hallucinogens and for fentanyl analogs; however, there is limited application and risk of false-negative results for the other drug classes due to low or non-existent cross-reactivities.