IMPORTANCE Drug 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. OBJECTIVE To 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 PARTICIPANTS This 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. EXPOSURES Medically 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 MEASURES Rates of nonprescribed fentanyl positivity among cocaine-or methamphetamine-positive UDT results, quantified through time. RESULTS In 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).

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IMPORTANCE Polysubstance use is a concern for patients treated for opioid use disorder (OUD).While buprenorphine can curtail harmful opioid use, co-occurring use of nonprescribed substances, such as cocaine, methamphetamine, and other opioids, may negatively affect treatment outcomes.OBJECTIVE To characterize factors associated with urine drug positivity for nonprescribed substances among patients prescribed buprenorphine. DESIGN, SETTING, AND PARTICIPANTSThis cross-sectional study included patients who had been prescribed buprenorphine and who provided urine specimens for urine drug testing (UDT), as ordered by clinicians in primary care or behavioral health or at substance use disorder treatment centers, from 2013 to 2019. Specimens were analyzed by liquid chromatography-tandem mass spectrometry to assess positivity for several commonly used substances. EXPOSURES Buprenorphine prescription. MAIN OUTCOMES AND MEASURESPositivity for buprenorphine and several nonprescribed substances. Unadjusted trends in positivity for each nonprescribed substance were compared between specimens that did and did not test positive for buprenorphine. Multivariable logistic regression was used to examine factors associated with positivity; factors included patient age, sex, setting of care, payer, collection year, and census division. RESULTSThe study included first UDT specimens from 150 000 patients, of whom 82 107 (54.74%) were men and 77 300 (51.53%) were aged 18 to 34 years. Across all specimens, 128 240 (85.49%) were positive for buprenorphine, and 71 373 (47.58%) were positive for 1 or more nonprescribed substances. From 2013 to 2019, positivity rates increased for most substances (eg, fentanyl: from 131 of 21 412 [0.61%] to 1464 of 13 597 [10.77%]). Factors associated with positivity varied widely by substance; for example, fentanyl positivity was highest for men (OR, 1.13; 95% CI, 1.06-1.21), patients aged 18 to 24 years (OR for patients Ն55 years, 0.46; 95% CI, 0.39-0.54), patients living in New

Key Points Question Do urine drug test (UDT) results correlate with overdose mortality rates? Findings In this cross-sectional study of 500 000 unique urine specimens collected from substance use disorder treatment practices, UDT results for 5 drug categories were correlated with overdose mortality rates at national, state, and county levels. Correlation was strongest for synthetic opioids and methamphetamine, and multivariate regression analysis using state-level data revealed that synthetic opioid and methamphetamine UDT positivity rates were significantly associated with overdose deaths. Meaning This study’s findings suggest that UDT is a valuable data source that is capable of informing real-time surveillance efforts.

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