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72 records · Page 4
All sourcesNASA NTRSDOE OSTI
DOE OSTI2025

Environmental life cycle of fentanyl: From the cradle to an unknown grave

The lack of available information on the presence and persistence of fentanyl in the environment is a significant gap in the technical literature. Although the origins of the opioid in the environment are well-known because they follow the same pathways of other drug-related environmental contaminants, the downstream effects of fentanyl in the water supply and its retention in soil are less understood. The characterization of fentanyl and its potential degradation products in complex environmental samples such as soil is severely understudied. Very few articles are available that work to identify fentanyl and its degradation products in complex samples or name the possible hazards that may result from environmental exposure and degradation. Therefore, the objectives were to identify available articles focused on environmental fentanyl and its pathways and highlight quantifiable research or results that included specific degradation products or downstream effects. Research articles focused on fentanyl between 2000 and 2024 were identified and reviewed and then filtered using Boolean search terms for environmental parameters. Various studies have determined that trace levels of fentanyl can be found in a variety of environments, and additional data suggest preferential partitioning into soils from water and long-term persistence. Despite this knowledge, very little data exists on the long-term downstream effects of fentanyl or its analogs. As the chronic effects from low-level fentanyl exposure are currently unknown, this lack of insight brings to the forefront the need for further research to improve our understanding of fentanyl persistence, degradation, and toxicity within the environment.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2025

Evaluation of dried blood spot sampling for verification of exposure to chemical threat agents

Abstract Purpose Exposure to chemical threat agents (CTAs), including nerve agents, the vesicating agent sulfur mustard, and opioids, remains a significant threat to warfighter and civilian populations. Definitive analytical methods to verify exposure to CTAs require shipping refrigerated or frozen biomedical samples to reference laboratories for analysis. Logistical and financial burdens arise as the transport of biomedical samples is subject to strict restrictions and complex packaging, which, if done incorrectly, can lead to sample deterioration. The use of dried blood spot (DBS) sampling could provide operational improvements for collecting, storing, and shipping important forensic samples. Therefore, this effort focuses on developing DBS techniques with Mitra® 30-µL volumetric absorptive microsampling (VAMS®) devices for use in CTA exposure verification. Methods VAMS® devices were loaded and dried with human whole blood that was exposed to the metabolites pinacolyl methylphosphonic acid (PMPA), ethyl methylphosphonic acid (EMPA), 1,1’sulfonylbis[2-(methylsulfinyl)ethane] (SBMSE), norfentanyl, norcarfentanil, norsufentanil, and norlofentanil. Following extraction from the VAMS® devices, metabolites were detected using liquid chromatography-tandem mass spectrometry (LC–MS/MS). The methods were validated for performance by assessing sensitivity, precision, accuracy, and recovery. Results These methods were sensitive to 1 ng/mL for SBMSE, 0.5 ng/mL for PMPA, EMPA, and norfentanyl; 0.1 ng/mL for norlofentanil, and 0.05 ng/mL for norsufentanil and norcarfentanil. All methods met acceptable precision and accuracy criteria with favorable recovery. Conclusions These results demonstrated the utility of VAMS® in stabilizing human whole blood and show promise as an improved collection method for verification of exposure to various CTAs.

Toxicology↗
DOE OSTI2025

Nanoparticle-mediated antagonism of sustained endosomal signaling of the calcitonin receptor-like receptor provides enhanced and persistent relief of oral cancer pain

By improving the delivery and tumor retention of chemotherapeutics, nanomedicines hold potential for cancer treatment. The usefulness of nanoparticle (NP)-encapsulated analgesics for the cancer pain treatment is comparatively unexplored. We investigated whether NPs encapsulating olcegepant (OCP), an antagonist of the calcitonin receptor-like receptor (CLR) for the calcitonin gene-related peptide (CGRP), effectively relieved oral cancer pain in mice. Because persistent endosomal CLR signaling in Schwann cells mediates craniofacial pain, we reasoned that the predisposition of NPs to accumulate in endosomes could be leveraged to effectively relieve oral cancer pain. By expressing biosensors for activated CLR, Gα proteins and β-arrestins in HEK293T and Schwann cells, we found that CGRP activates CLR signaling first at the plasma membrane and then in early, late and recycling endosomes and the cis- and trans-Golgi apparatus. We synthesized biocompatible NPs encapsulating OCP and fluorophores by integrating hydrophobic ion pairing nanoformulation with Flash NanoPrecipitation. NPs slowly released OCP and accumulated in early endosomes, leading to sustained inhibition of endosomal CLR signaling in HEK293T and Schwann cells. Oral cancers were established in mice, which led to heightened pain-like responses. After intra-tumoral injection, NPs were retained in tumors for at least one week. OCP-loaded NPs almost completely reversed allodynia and hyperalgesia for a prolonged period, whereas unencapsulated OCP had small and transient effects. The NP accumulation in endosomal sites of pain signaling, the sustained release of antagonist, and the retention of NPs in tumors explain their beneficial actions. Thus, NP-encapsulation holds promise for the relief of painful cancers that are inadequately treated by opioids.

Calcitonin gene-related peptide↗
DOE OSTI2022

Randomized Phase 3, Double-blind, Placebo-controlled Study of Prophylactic Gabapentin for the Reduction of Oral Mucositis Pain During the Treatment of Oropharyngeal Squamous Cell Carcinoma

The purpose of this paper is to determine whether prophylactic gabapentin usage in patients undergoing definitive concurrent chemotherapy and radiation therapy (chemoRT) for oropharyngeal cancer (OPC) improves treatment-related oral mucositis pain, opioid use, and feeding tube (FT) placement.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2020

Structural and antibacterial properties of NSAID-loaded ultra-high molecular weight polyethylene

Peri-articular delivery of pain medication in joint arthroplasty has the potential to address post-operative pain and decrease the use of systemic opioids. Additionally, the sustained release from a delivery vehicle may be especially impactful in the initial post-operative period when pain is most severe. We recently described a novel approach for the sustained intra-articular delivery of an analgesic (bupivacaine) from an ultra-high molecular weight polyethylene (UHMWPE) bearing surface. A secondary but very significant effect of incorporating bupivacaine in UHMWPE was its antibacterial effect against Staphylococcal species, which are associated with the majority of periprosthetic joint infections. Here, we report on the structure, properties, elution characteristics and antibacterial properties of UHMWPE loaded with the non-steroidal anti-inflammatory drug (NSAID) — tolfenamic acid. We showed that 6 wt% drug loading was optimal for eluting clinically relevant intra-articular and systemic concentrations, for maintaining mechanical properties at a clinically relevant level, and for providing anti-colonization potential against low risk (planktonic) and high risk (biofilm forming) Staphylococcal species. We determined the osteoblast response to the tolfenamic acid-loaded UHMWPE to evaluate the cytotoxicity profile of this novel material. Tolfenamic acid-loaded UHMWPE has the potential to be used as a part of multimodal pain management therapy following arthroplasty and may provide prophylaxis for periprosthetic infection.

36 MATERIALS SCIENCE↗
DOE OSTI2020

Evaluating Exposures of Bay Mussels (Mytilus trossulus) to Contaminants of Emerging Concern through Environmental Sampling and Hydrodynamic Modeling.

Bay mussels (Mytilus trossulus) were transplanted to 18 locations representing a range of potential exposures throughout Puget Sound, WA. Tissues were analyzed for over 200 organic contaminants. Results indicated the widespread exposure of marine organisms to trace levels of organic contaminants including the synthetic opioid oxycodone, present at three urban sites, and the chemotherapy drug melphalan, present at nine locations, at levels that may be of biological concern. Land-use and wastewater outfalls were evaluated as potential sources of CECs to the nearshore. Exposure to alkylphenol ethoxylates was associated with increased impervious surfaces in upland watersheds. A hydrodynamic simulation was performed using the Salish Sea Model to integrate inputs from 99 wastewater sources to Puget Sound. Predictions were consistent with concentrations of several wastewater-associated contaminants and d15N enrichment. These results support the notion that Puget Sound nearshore biota suffer chronic exposures to a suite of contaminants from multiple sources and provide critical to focus future monitoring and management.

toxic contamination, Salish Sea, Sish Sea Model, m↗
DOE OSTI2020

The 1 H T 1 dispersion curve of fentanyl citrate to identify NQR parameters

We report the 1 H T 1 dispersion curve between 0 and 5 MHz for the synthetic opioid fentanyl citrate (C 28 H 36 N 2 O 8 ). The structures in the curve can be used to estimate the 14 N nuclear quadrupole resonance (NQR) frequencies of the material. Density functional theory predictions of the NQR parameters of several fentanyl citrate compounds are also reported. The predictions for the aniline nitrogen are consistent with structures in the observed T 1 data. To help interpret the fentanyl citrate results the T 1 dispersion curve for the explosive ammonium nitrate is also presented.

73 NUCLEAR PHYSICS AND RADIATION PHYSICS↗
DOE OSTI2020

Electrochemical Detection of Oxycodone and Its Main Metabolites with Nafion-Coated Single-Walled Carbon Nanotube Electrodes

Oxycodone is a strong opioid frequently used as an analgesic. Although proven efficacious in the management of moderate to severe acute pain and cancer pain, use of oxycodone imposes a risk of adverse effects such as addiction, overdose, and death. Fast and accurate determination of oxycodone blood concentration would enable personalized dosing and monitoring of the analgesic as well as quick diagnostics of possible overdose in emergency care. However, in addition to the parent drug, several metabolites are always present in the blood after a dose of oxycodone, and to date, there is no electrochemical data available on any of these metabolites. In this paper, a single-walled carbon nanotube (SWCNT) electrode and a Nafion-coated SWCNT electrode were used, for the first time, to study the electrochemical behavior of oxycodone and its two main metabolites, noroxycodone and oxymorphone. Both electrode types could selectively detect oxycodone in the presence of noroxycodone and oxymorphone. However, we have previously shown that addition of a Nafion coating on top of the SWCNT electrode is essential for direct measurements in complex biological matrices. Therefore, in this work, the Nafion/SWCNT electrode was further characterized and used for measuring clinically relevant concentrations of oxycodone in buffer solution. The limit of detection for oxycodone with the Nafion/SWCNT sensor was 85 nM, and the linear range was 0.5–10 μM in buffer solution. Furthermore, this study shows that the fabricated Nafion/SWCNT sensor has potential to be applied in clinical concentration measurements.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2024

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 uniquely 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. In conclusion, our new observations on the IM and MS/MS properties of fentanyls can be exploited to positively identify them as fentanyls without requiring reference libraries and will hopefully assist first responders and law enforcement in combating new and emerging fentanyls.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2024

Distinct binding conformations of epinephrine with α- and β-adrenergic receptors

Abstract Agonists targeting α 2 -adrenergic receptors (ARs) are used to treat diverse conditions, including hypertension, attention-deficit/hyperactivity disorder, pain, panic disorders, opioid and alcohol withdrawal symptoms, and cigarette cravings. These receptors transduce signals through heterotrimeric Gi proteins. Here, we elucidated cryo-EM structures that depict α 2A -AR in complex with Gi proteins, along with the endogenous agonist epinephrine or the synthetic agonist dexmedetomidine. Molecular dynamics simulations and functional studies reinforce the results of the structural revelations. Our investigation revealed that epinephrine exhibits different conformations when engaging with α-ARs and β-ARs. Furthermore, α 2A -AR and β 1 -AR (primarily coupled to Gs, with secondary associations to Gi) were compared and found to exhibit different interactions with Gi proteins. Notably, the stability of the epinephrine–α 2A -AR–Gi complex is greater than that of the dexmedetomidine–α 2A -AR–Gi complex. These findings substantiate and improve our knowledge on the intricate signaling mechanisms orchestrated by ARs and concurrently shed light on the regulation of α-ARs and β-ARs by epinephrine.

Biochemistry & Molecular Biology↗
DOE OSTI2023

Non-invasive authentication of mail packages using nuclear quadrupole resonance spectroscopy

The international postal network is one of the most widely used methods for correspondence throughout the world. Most postal traffic across the globe consists of legitimate interpersonal, business-consumer, and business-business communications. However, the global postal system is also utilized for criminal activity. In particular, it is often utilized to ship and distribute contraband, including illegal psychoactive drugs such as fentanyl and heroin, to consumers. Existing technological solutions are capable of identifying synthetic opioids and other illegal drugs within packages, but are accompanied by several disadvantages that make them unsuitable for large-scale authentication of international mail traffic. This paper presents a novel method for non-invasive authentication of mail packages that overcomes these challenges. The approach uses nuclear quadrupole resonance (NQR) spectroscopy to detect and quantify the presence of known active pharmaceutical ingredients (APIs) within the package. It has been experimentally demonstrated using a bench top prototype. Test results from a variety of package types demonstrate the effectiveness of the proposed authentication approach.

42 ENGINEERING↗
DOE OSTI2022

Vapor detection and vapor pressure measurements of fentanyl and fentanyl hydrochloride salt at ambient temperatures

There is a need for non-contact, real-time vapor detection of drugs to combat illicit transportation and help curb the opioid epidemic. The low-volatility of drugs, like fentanyl, makes room temperature vapor detection of illicit drugs challenging, but feasible by atmospheric flow tube-mass spectrometry (AFT-MS). AFT-MS is a non-contact vapor detection approach capable of ultra-trace detection of drugs, including fentanyl and its analogs at low parts-per-quadrillion (ppqv) levels. The determination of vapor pressure values of fentanyl is necessary to understand potential vapor concentrations that may be available for detection. In this paper, vapor pressures of fentanyl free base and fentanyl hydrochloride salt (a common form of the illicit drug) were measured as a function of temperature at or near ambient conditions using the transpiration (gas saturation) method and AFT-MS. Based on our measurements, the vapor pressure of fentanyl at 25 °C is 9.0 × 10-14 atm (90 ppqv), and the vapor pressure of fentanyl hydrochloride at 25 °C is 1.8 x 10-17 atm (0.018 ppqv). We also demonstrate non-contact, real-time vapor detection of fentanyl. Preconcentration of vapors can further extend the detection capabilities. The collection, desorption, and detection of fentanyl vapors at ambient conditions was demonstrated for sampling times of seconds to an hour resulting in increased signal. AFT-MS is a viable detection method of fentanyl and other drugs for screening of packages and cargo.

atmospheric flow tube-mass spectrometry (AFT-MS), ↗
DOE OSTI2023

Energetics of high temperature degradation of fentanyl into primary and secondary products

Fentanyl is a synthetic opioid used for managing chronic pain. Due to its higher potency (50–100×) than morphine, fentanyl is also an abused drug. A sensor that could detect illicit fentanyl by identifying its thermally degraded fragments would be helpful to law enforcement. While experimental studies have probed the thermal degradation of fentanyl, little theoretical work has been done to understand the mechanism. Here, we studied the thermal degradation pathways of fentanyl using extensive ab initio molecular dynamics simulations combined with enhanced sampling via multiple-walker metadynamics. We calculated the free energy profile for each bond suggested earlier as a potential degradation point to map the thermodynamic driving forces. In conclusion, we also estimated the forward attempt rate of each bond degradation reaction to gain information about degradation kinetics.

Poudel, Bharat↗
DOE OSTI2026

Association of short-term ambient environmental exposures with suicide and drug overdose deaths among U.S. Veterans

This study examined associations between short-term ambient environmental exposures and suicide (n = 3210) and overdose mortality (n = 4293; 2226 opioid-related) among U.S. Veterans from 2018 to 2019. Daily exposure to 24-hour maximum temperature, average atmospheric pressure, average fine particulate matter (PM 2.5 ), 1-hour maximum nitrogen dioxide (NO 2 ), and 8-hour maximum ozone (O 3 ) was assessed at the decedent's county of residence on the day of death and up to 6 days prior. A national bi-directional, time-stratified case-crossover design was applied. Conditional logistic regression models estimated associations between each exposure and suicide or overdose deaths, overall, and stratified by season, region, elevation, and urbanicity. Over lag days 0-1, an interquartile range increase in maximum temperature was associated with increased suicide (19%) and overdose (27%) mortality, with stronger summer effects for suicide (55%) and overdose (71%). In winter, interquartile range increases in atmospheric pressure, PM 2.5 , and NO 2 were associated with 104%, 15%, and 19% increases in suicide mortality. Maximum temperature was associated with a 22% increase in suicide risk in metropolitan areas and 57% in the Western U.S., while NO 2 was associated with a 26% increase in overdose mortality in nonmetropolitan areas. Findings suggest environmental stressors contribute to suicide and overdose mortality among Veterans, supporting environmentally informed prevention efforts.

air pollution↗
DOE OSTI2023

Detection and confirmation of fentanyls in high clay‐content soil by electron ionization gas chromatography‐mass spectrometry

Abstract Detection of illicit drugs in the environment, particularly in soils, often suggests the present or past location of a clandestine production center for these substances. Thus, development of efficient methods for the analysis and detection of these chemicals is of paramount importance in the field of chemical forensics. In this work, a method involving the extraction and retrospective confirmation of fentanyl, acetylfentanyl, thiofentanyl, and acetylthiofentanyl using trichloroethoxycarbonylation chemistry in a high clay‐content soil is presented. The soil was spiked separately with each fentanyl at two concentrations (1 and 10 μg/g) and their extraction accomplished using ethyl acetate and aqueous NH 4 OH (pH ~ 11.4) with extraction recoveries ranging from ~56% to 82% for the high‐concentration (10 μg/g) samples while ranging from ~68% to 83% for the low‐concentration (1 μg/g) samples. After their extraction, residues containing each fentanyl were reacted with 2,2,2‐trichloroethoxycarbonyl chloride (Troc‐Cl) to generate two unique and predictable products from each opioid that can be used to retrospectively confirm their presence and identity using EI‐GC‐MS. The method's limit of detection (MDL/LOD) for Troc‐norfentanyl and Troc‐noracetylfentanyl were estimated to be 29.4 and 31.8 ng/mL in the organic extracts. In addition, the method's limit of quantitation for Troc‐norfentanyl and Troc‐noracetylfentanyl were determined to be 88.2 and 95.5 ng/mL, respectively. Collectively, the results presented herein strengthen the use of chloroformate chemistry as an additional chemical tool to confirm the presence of these highly toxic and lethal substances in the environment.

Valdez, Carlos A.↗
DOE OSTI2022

People who inject drugs in metropolitan Chicago: A meta-analysis of data from 1997-2017 to inform interventions and computational modeling toward hepatitis C microelimination

Progress toward hepatitis C virus (HCV) elimination in the United States is not on track to meet targets set by the World Health Organization, as the opioid crisis continues to drive both injection drug use and increasing HCV incidence. A pragmatic approach to achieving this is using a microelimination approach of focusing on high-risk populations such as people who inject drugs (PWID). Computational models are useful in understanding the complex interplay of individual, social, and structural level factors that might alter HCV incidence, prevalence, transmission, and treatment uptake to achieve HCV microelimination. However, these models need to be informed with realistic sociodemographic, risk behavior and network estimates on PWID. We conducted a meta-analysis of research studies spanning 20 years of research and interventions with PWID in metropolitan Chicago to produce parameters for a synthetic population for realistic computational models (e.g., agent-based models). We then fit an exponential random graph model (ERGM) using the network estimates from the meta-analysis in order to develop the network component of the synthetic population.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Enhancing Docking Accuracy with PECAN2, a 3D Atomic Neural Network Trained without Co-Complex Crystal Structures

Decades of drug development research have explored a vast chemical space for highly active compounds. The exponential growth of virtual libraries enables easy access to billions of synthesizable molecules. Computational modeling, particularly molecular docking, utilizes physics-based calculations to prioritize molecules for synthesis and testing. Nevertheless, the molecular docking process often yields docking poses with favorable scores that prove to be inaccurate with experimental testing. To address these issues, several approaches using machine learning (ML) have been proposed to filter incorrect poses based on the crystal structures. However, most of the methods are limited by the availability of structure data. Here, we propose a new pose classification approach, PECAN2 (Pose Classification with 3D Atomic Network 2), without the need for crystal structures, based on a 3D atomic neural network with Point Cloud Network (PCN). The new approach uses the correlation between docking scores and experimental data to assign labels, instead of relying on the crystal structures. We validate the proposed classifier on multiple datasets including human mu, delta, and kappa opioid receptors and SARS-CoV-2 Mpro. Our results demonstrate that leveraging the correlation between docking scores and experimental data alone enhances molecular docking performance by filtering out false positives and false negatives.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2021

National variability in Americans’ COVID-19 protective behaviors: Implications for vaccine roll-out

Protective behaviors such as mask wearing and physical distancing are critical to slow the spread of COVID-19, even in the context of vaccine scale-up. Understanding the variation in self-reported COVID-19 protective behaviors is critical to developing public health messaging. The purpose of the study is to provide nationally representative estimates of five self-reported COVID-19 protective behaviors and correlates of such behaviors. In this cross-sectional survey study of US adults, surveys were administered via internet and telephone. Adults were surveyed from April 30-May 4, 2020, a time of peaking COVID-19 incidence within the US. Participants were recruited from the probability-based AmeriSpeak® national panel. Brief surveys were completed by 994 adults, with 73.0% of respondents reported mask wearing, 82.7% reported physical distancing, 75.1% reported crowd avoidance, 89.8% reported increased hand-washing, and 7.7% reported having prior COVID-19 testing. Multivariate analysis (p critical value .05) indicates that women were more likely to report protective behaviors than men, as were those over age 60. Respondents who self-identified as having low incomes, histories of criminal justice involvement, and Republican Party affiliation, were less likely to report four protective behaviors, though Republicans and individuals with criminal justice histories were more likely to report having received COVID-19 testing. The majority of Americans engaged in COVID-19 protective behaviors, with low-income Americans, those with histories of criminal justice involvement, and self-identified Republicans less likely to engage in these preventive behaviors. Culturally competent public health messaging and interventions might focus on these latter groups to prevent future infections. These findings will remain highly relevant even with vaccines widely available, given the complementarities between vaccines and protective behaviors, as well as the many challenges in delivering vaccines.

60 APPLIED LIFE SCIENCES↗