• Leah LaRue, Robert K Twillman, Eric Dawson, Penn Whitley, Melissa A Frasco, Angela Huskey, and Maria G Guevara.
• Millennium Health, San Diego, California.
• JAMA Netw Open. 2019 Apr 5; 2 (4): e192851.

ImportanceDrug overdose deaths continue to increase, despite the leveling off of prescription opioid use and policy changes limiting opioid prescribing. Illicit fentanyl is the leading cause of drug overdose death, and it is important to characterize the emerging combination of other illicit drugs with fentanyl, which increases the risk of overdose.ObjectiveTo determine whether rates of the combination of nonprescribed fentanyl with cocaine or methamphetamine have changed in urine drug test (UDT) results through time.Design, Setting, And ParticipantsThis cross-sectional study of UDT results from January 1, 2013, through September 30, 2018, included patient specimens submitted for UDTs by health care professionals as part of routine care. Patients were selected from health care practices across the United States, including substance use disorder treatment centers, pain management practices, primary care practices, behavioral health practices, obstetrics and gynecology practices, and multispecialty groups. The UDT analysis used liquid chromatography-tandem mass spectrometry to detect benzoylecgonine (cocaine metabolite), methamphetamine, fentanyl, and norfentanyl. Specimens from individuals reported to have been prescribed fentanyl were excluded. A convenience sample approach was used to randomly select 1 million unique patient UDT specimens from Millennium Health's UDT database for further analysis. Each specimen had associated cocaine, methamphetamine, and fentanyl UDT results.ExposuresMedically necessary UDT to detect benzoylecgonine (cocaine metabolite), methamphetamine, fentanyl, and norfentanyl, ordered by a health care professional as part of routine patient care.Main Outcomes And MeasuresRates of nonprescribed fentanyl positivity among cocaine- or methamphetamine-positive UDT results, quantified through time.ResultsIn a sampling of 1 million unique patients' UDT specimens analyzed for cocaine and fentanyl (median [interquartile range] age, 44 [19-69] years; 55.0% women), positivity rates for nonprescribed fentanyl among the cocaine-positive results increased significantly, from 0.9% (n = 84) (95% CI, 0.7%-1.1%) in 2013 to 17.6% (n = 427) (95% CI, 16.1%-19.1%) in 2018, a 1850% increase (τ = 0.78; z = 9.45; P < .001). In the same sampling of 1 million specimens, positivity rates for nonprescribed fentanyl among the methamphetamine-positive results also increased significantly, from 0.9% (n = 29) (95% CI, 0.6%-1.2%) in 2013 to 7.9% (n = 344) (95% CI, 7.1%-8.7%) in 2018, a 798% increase (τ = 0.72; z = 8.75; P < .001).Conclusions And RelevanceAn increasing number of UDT results positive for cocaine or methamphetamine were also positive for nonprescribed fentanyl. This provides additional insight into recently reported increases in cocaine- and methamphetamine-related overdoses. Stimulant users who may be opioid naive are at a heightened risk of overdose when exposed to fentanyl. Clinicians need to be aware that patients presenting for treatment of suspected drug overdose or substance use disorder may have been exposed, knowingly or unknowingly, to multiple substances, including the combination of stimulants and opioids.

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