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Abstract INTRODUCTION:
Over a decade ago, illicit fentanyl emerged in the drug supply and continues to be the major driver of the ongoing opioid epidemic. Fentanyl is commonly monitored in clinical laboratories using immunoassays or targeted mass spectrometry methods. However, the drug supply is ever-changing, with new emerging threats such as fentanyl analogs, other novel synthetic opioids, and drug adulterants. These constant changes in the unstable drug supply pose continual challenges for clinical labs providing analytical testing services. The true extent of the synthetic opioid epidemic is likely underappreciated due to the lack of routine diagnostic monitoring of all possible exposures. In the acute care setting, there is often insufficient information available to clinicians to aid in understanding complex clinical presentations in the setting of multi-drug use/exposure. The unstable drug supply and changes in illicit drug co-use patterns also make treatment of substance use disorders challenging. In 2023, local concerns in SF about new fentanyl contaminants and changing co-use patterns prompted the initiation of real-time surveillance of the drug supply utilizing urine from patients at a hospital-based opioid treatment program. This bio-surveillance program utilizes untargeted liquid chromatography high-resolution mass spectrometry to provide toxicological analysis of de-identified urine aliquots from an at-risk patient population.
OBJECTIVE:
The objective of this abstract is to review the results of the SF bio-surveillance program and highlight trends observed in Y1-Y2.
METHODS:
Urine drug testing is ordered clinically for every patient presenting for treatment at SF General Hospital’s Opiate Treatment Outpatient Program (OTOP). Under a UCSF IRB-approved protocol, a de-identified aliquot of each urine sample is analyzed using a clinically validated comprehensive drug test by untargeted LC-HRMS. Briefly, for sample preparation urine samples are diluted 1:5 with mobile phase. Chromatographic separation is performed using a C18-column with a 10-minute gradient from 2%-100% organic. Data is collected on a SCIEX XenoTOF 7600 operating in positive-ion mode using a TOF MS survey scan with information dependent acquisition triggered collection of high-resolution product ion spectra. Data is analyzed using a library containing >5000 small molecules. Retention times and limits of detection have been validated for approximately 500 of these compounds, including common pharmaceutical drugs/metabolites, illicit drugs, fentanyl analogs, novel psychoactive substances (nitazenes, non-FDA approved benzodiazepines, synthetic cannabinoids, etc.), common drug adulterants, and toxic natural products. Aggregate results are communicated weekly to OTOP clinicians via an interactive dashboard. A one-page factsheet presenting weekly aggregated results is generated for use as patient education material.
RESULTS:
For Y1-Y2 (03/2023-02/2025), 1362 samples were tested with a higher number of samples analyzed in Y2 (n=732) compared to Y1 (n=630), representing an increase in patients presenting for intake at the OTOP clinic. Fentanyl and precursors/metabolites were identified in 83%, with the remaining samples testing positive for “other opioids” such as methadone in the case of patients transferring from the hospital to OTOP. Heroin and metabolites were only detected in 70 (5%) samples. Of the fentanyl-positive samples, 95% were also positive for methamphetamine and 70% for cocaine, supporting ongoing self-report of a high degree of fentanyl and stimulant co-use. During Y1, 115 (18%) samples tested positive for fentanyl analogs increasing to 208 (28%) in Y2. A total of 11 unique fentanyl analogs were detected, with fluoro fentanyl (n=303, 22%), methoxy furanyl fentanyl (n=117, 9%), and methoxy tetrahydrofuran fentanyl (n=44, 3%) being predominant.
Xylazine, a non-opioid sedative used in veterinary medicine, emerged in April 2023, reaching a peak prevalence of 36% in May 2023 and then leveling off to an average 17%/month. All xylazine-positive samples were also positive for fentanyl and/or associated compounds. Prevalence continues to remain significantly lower than estimates from other geographic regions in the United States. In June 2024, a drug-checking program reported the emergence of Bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate (BTMPS), a hindered amine light stabilizer commonly used in plastics with the potential for significant cardiovascular and neuromuscular toxicity, in the fentanyl drug supply. Similarly, BTMPS and predicted metabolites were first detected in our study in June 2024 through retrospective data analysis. From June to October 2024, 24 (7%) samples tested positive for BTMPS; however, since that time, no additional positives have been detected. All BTMPS-positive samples were also positive for fentanyl, norfentanyl, and 4-ANPP, with 83% positive for xylazine. This is the first study to detect BTMPS in biological samples and identify predicted metabolites.
During Y1, there were 4 samples (<1%) positive for bromazolam, a non-FDA approved benzodiazepine. This increased to 19 samples (3%) in Y2. These samples have been evaluated to understand bromazolam metabolism which has not been well characterized in biological samples to date.
To date, no samples have been positive for nitazenes, a class of highly potent synthetic opioids, despite reports of nitazene drug products being sold. Low concentrations are expected in urine due to the high degree of potency, therefore a highly sensitive targeted method is now being used for monitoring.
CONCLUSION:
This real-time information on the state of the local substance supply and illicit drug co-use patterns informs clinicians, patients, and the SF DPH. These findings provide a critical foundation for understanding the prevalence of drug contaminants and emerging synthetic drugs and informing public health responses to mitigate their potential impact.
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= Discovery stage. (53.14%, 2025)
= Translation stage. (22.33%, 2025)
= Clinically available. (24.53%, 2025)
