Scaling Up Point-of-Care Fentanyl Testing — A Step Forward

Whereas the first two waves of the U.S. opioid epidemic were driven by prescription opioids and heroin, a fundamental shift occurred around 2013. This third wave has been marked by the rise of illicitly manufactured synthetic opioids, which are much more potent and cheaper than their predecessors. In 2016, these illicit opioids, primarily fentanyl and its ultrapotent analogues, surpassed prescription opioids as the leading cause of overdose-related deaths.

The increased lethality of fentanyl, as compared with other opioids, appears to be multifactorial. People who use fentanyl are unable to discern by visual inspection alone whether a dose may be lethal. They may also require higher doses of naloxone for overdose reversal than the doses required for those using other opioids; they may be more likely, after overdose reversal, to experience “renarcotization” (recurrent opioid overdose due to persistence of the drug in the body); and they are at increased risk for chest-wall rigidity (“wooden chest syndrome”) during overdose.

Although fentanyl is now the dominant driver of the opioid epidemic, our health care system has struggled to adapt toxicology screening practices to this reality. Routine fentanyl immunoassay screening has not been fully adopted in clinical practice, in part because of the costs of implementation and maintenance of laboratory instrumentation, as well as interpretation challenges related to false positive results from “designer fentanyls” and cutting agents. There is also no reliable Food and Drug Administration (FDA)–approved self-testing kit that people who use drugs can deploy for harm-reduction purposes.

Some health care facilities may not have fentanyl immunoassays available. For those that do, turnaround times may be long, and given the varying chemical structures of illicit fentanyls, results may be difficult to interpret in the clinical context. Though hospitals can create their own point-of-care (POC) fentanyl tests to reduce turnaround time, such laboratory-developed tests are classified as “high complexity” under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), the federal standards that govern testing of specimens from humans for purposes of clinical care. Such tests must therefore be processed in laboratories whose technologists can perform high-complexity testing, which severely limits feasibility for many facilities. The tests are also unavailable for people with opioid use disorder (OUD), for whom self-testing for fentanyl might guide safe use and prevent overdose.

Fortunately, there is some recent progress on this front. In December 2022 — a decade after the emergence of illicit fentanyl — the FDA cleared a qualitative POC instrument (manufactured by Shenzhen Superbio Technology¹) for testing urine for fentanyl with high sensitivity and specificity, which may enable scaling up of POC fentanyl testing in our health care system.

From the perspective of public health surveillance, the dearth of POC fentanyl testing has hindered efforts to better characterize patterns and correlates of fentanyl use. Such information is important, since many people are unintentionally exposed to fentanyl, which is used to adulterate not only street supplies of heroin, but also cocaine, methamphetamine, and counterfeit tablets marketed as various drugs. In a 2020 study involving 76 patients presenting with overdose, 83% tested positive for fentanyl, though only 5% were aware of having been exposed to it.² Strikingly, of the 39 patients who underwent both a standard urine drug screen and a fentanyl screen, 56% tested positive for fentanyl on the latter but negative for opiates on the former: standard urine drug screening tests are immunoassays that contain antibodies only for naturally occurring opioids such as morphine, to which fentanyl, a synthetic opioid, has no structural homology.

The lack of POC fentanyl testing is also hamstringing clinicians’ efforts to effectively manage fentanyl exposures. Opportunities to give patients potentially lifesaving information about unintentional exposures are routinely missed, as are chances to provide treatment resources and harm-reduction strategies to people with OUD whose condition may not come to light because a urine drug screen cannot detect fentanyl. A study of 315,467 emergency department visits for overdose between 2018 and 2022 found that 49% of visits involved a test for opiates, as compared with only 5% for fentanyl, though the fentanyl positivity rate increased from 33% to 42% over the study period.³ Furthermore, since payers frequently will not cover opioid detoxification or residential treatment for OUD without a positive opioid test, patients may be declined treatment coverage if their clinician has not ordered a separate fentanyl screen. Even if one has been ordered, patients may still abandon efforts to obtain treatment if doing so requires a long wait for test results in order to secure coverage.

Fentanyl has resulted in additional challenges for clinicians prescribing buprenorphine for the management of opioid withdrawal. Buprenorphine is a high-affinity partial agonist at the mu-opioid receptor, so to avoid precipitating opioid withdrawal, guidelines recommend waiting for the onset of mild opioid-withdrawal symptoms (usually 12 to 16 hours after heroin use) before initiating buprenorphine treatment. Although fentanyl is a short-acting opioid, when it is used long term, the body requires substantially more time to clear both fentanyl and its primary metabolite, norfentanyl, probably because of their high lipophilicity. In a 2020 study involving 12 patients in residential treatment who had been exposed to fentanyl, the mean (±SD) clearance times for fentanyl and norfentanyl were 7.3±4.9 days and 13.3±6.9 days, respectively.⁴ This slow clearance may explain increasing reports of patients having precipitated withdrawal after induction of buprenorphine treatment despite waiting 72 hours or more after their last fentanyl use. Such a reaction causes some patients to abandon buprenorphine treatment and request discharge — or leave against medical advice — because of severe discomfort. Low-dose (“microdosing”) and high-dose (“macrodosing”) buprenorphine inductions are promising approaches that may reduce the risk of precipitated withdrawal, but more research is needed. Scaling up POC fentanyl testing therefore remains an important intervention for informing clinical decisions about the timing and safety of buprenorphine induction.

Although Shenzhen’s POC fentanyl test has been cleared by the FDA, it is instrument-based and categorized under CLIA as “moderate complexity.” Sites using it must therefore be CLIA-certified, submit to routine laboratory inspections, and meet personnel-training and other requirements. These regulatory demands, along with the cost of the instrument, preclude implementation in many health care settings, such as community hospitals and syringe services programs, as well as distribution for home use.

Though they have not been FDA-cleared, urine fentanyl test strips that are read visually are an attractive alternative in settings where use of the POC test is infeasible. For example, one brand of low-cost test strips approved for diagnostic testing in Canada has a fentanyl-detection sensitivity of 96.8% and specificity of 100%. These strips are commercially available in the United States, typically being sold for testing street-acquired drugs for the presence of fentanyl and its analogues; in a 2020 study, they outperformed two spectrometer-based tests for this purpose.⁵ In jurisdictions where the use of drug-testing strips is legal, deployment of such test strips in health care facilities could provide an opportunity for distributing them to patients for testing their drug supplies.

The FDA could expand access to POC fentanyl testing for patients and less-resourced health care settings by working with manufacturers of urine test strips and, where applicable, other POC fentanyl tests to classify these tests as “CLIA-waivered.” Examples of CLIA-waivered tests include urine pregnancy tests and fingerstick blood glucose monitoring. To qualify for a CLIA waiver, a test must be simple to administer, use unprocessed specimens, and have an insignificant risk of inaccurate results — standards that many POC fentanyl tests probably already meet.

With the advent of the first FDA-cleared POC fentanyl test, a long-overdue, potentially lifesaving tool is now available to many health care facilities. This development will not solve all our fentanyl testing needs, but we hope it will catalyze efforts by regulators and manufacturers to expand access to less resource-intensive types of POC testing for fentanyl and other adulterants. And given the new trend toward adulteration of street opioid supplies with xylazine, for which there is no FDA-cleared POC test or self-testing kit, we must already begin applying the lessons of our decade-long struggle for a POC fentanyl test to a new scourge.