Timely toxicology testing remains vital to patient treatment, but the challenge is staying ahead of emerging illicit drugs.

By Ann H. Carlson

Although clinical drug testing decreased by more than 50% during the height of stay-at-home orders in the spring of 2020, the drug abuse epidemic within the COVID-19 pandemic raged on behind closed doors in the United States1.

“The pandemic decreased drug screening, although the need increased dramatically,” says Steve Noel, PhD, DABCC, senior clinical consultant for Siemens Healthineers, Malvern, Pa.

Overdose deaths reached an all-time high during the COVID-19 pandemic. According to provisional data from the Centers for Disease Control and Prevention (CDC), there were 95,133 reported overdose deaths in the 12-month period ending in February 20212. In December 2020, the CDC identified three primary drivers for overdose deaths: 1) synthetic opioids (mainly fentanyl), 2) cocaine (usually in combination with heroin or fentanyl), and 3) psychostimulants (such as methamphetamine)3.

“Nationwide, we’re seeing a big  increase in methamphetamine and cocaine use and overdoses,” says Vonda McAllister, director of cardiometabolic marketing for Quidel, San Diego, who adds that, and more often, unbeknownst to the user, these street drugs are  cut with fentanyl. “Users may also be combining  opioids with cocaine or methamphetamine to extend the affects or to stave off opioid withdrawal Opioid withdrawals are excruciating and an opioid dependent user, not able to obtain their opioid prescription, will try multiple substances including  heroin to avoid it.  Many resort to street versions of opioids that appear to be legitimate but are actually fentanyl, again, with deadly results.   

Drug positivity rates in the U.S. general workforce also remained high last year, according to the 2021 Quest Diagnostic Drug Testing Index, which reported a 4.4% positivity rate based on a sample size of 7 million urine drug tests4. By comparison, drug positivity rates reached a 16-year high of 4.5% in 2019, from a sample size of 14 million urine drug tests5.

A drug screening is often the first critical step in providing help and treatment for individuals with drug addiction issues. Although the pandemic saw dramatic drops in routine drug screenings, testing numbers have started to increase in recent months.

“We’ve seen a pretty significant rebound in the screening interest and activity on the behavioral health/toxicology side, the physician office laboratory segment, as well as the hospital segment,” says Doug Harris, business development director for Horiba, a Kyoto, Japan-based company with U.S. headquarters in Irvine, Calif. “There seems to be a significant increase in better monitoring those patients who are on pain medications as well.”

Screening Process

Toxicology screenings are required for a variety of reasons, including employment testing, medical testing, and the growing segment of pain management testing to monitor the use of potentially addictive prescription medications.

Because it’s non-invasive and easy to collect, a urine drug screening is the most common method. Generally, the sample is tested with toxicology cups or dip sticks, or using an immunoassay on an automated instrument. This first step provides a same-day qualitative result.

“It is imperative that the collection process is somehow monitored to avoid the possibility of tampering with the specimen,” Noel says. “In addition to monitoring collection, laboratories can test for tampering by performing specimen validity testing.”

It is also important to watch out for false positives. “Although most screening tests are evaluated for cross reaction with commonly prescribed or abused drugs, there is always the chance for a false positive due to another substance when using an immunoassay drug screen,” says Mary Mayo, PhD, BCLD, DABCC, FAACC, MT(ASCP), senior manager of medical safety at Beckman Coulter, which is headquartered in Brea, Calif. “It is important for the laboratory to know which drug the test targets; i.e., what is the positive calibrator. For instance, opiate screens are usually targeted to morphine. Some immunoassays will target the most commonly excreted metabolite. An example of this is norfentanyl, which is the major metabolite in urine of fentanyl. Since urine drug screens indicate past usage or exposure, not current indication of what is in the patient’s system, it is important to clarify what is actually in the tests when clinicians inquire.” 

If a sample comes back positive, it is then usually sent out to a reference laboratory for confirmation performed by liquid chromatography–mass spectrometry (LC-MS) or gas chromatography–mass spectrometry (GC-MS). These methods help rule out false positives by giving a more precise breakdown of the substances detected. This provides a quantitative result, usually within 72 hours.

In general, turn-around times for all testing technologies have improved over the years, Noel says. “Typically for point-of-care and automated screening, results are available within minutes,” he adds. “Although with COVID restraints, turn-around time has decreased due to staffing shortages and demand for testing.”

Identifying Designer Drugs

In emergency departments, McAllister notes, running a routine drug panel is common practice to rule out a possible overdose or other patient presentation that may be influenced by drug use or misuse.  This is especially true for patients who present with altered mental status and prior to admittance to psychiatric care,“ she says. “A drug screen is one of many diagnostic tools that can assist the physician in determining the correct path of treatment for that patient.”

Today’s drug screening technology can identify an impressive number of substances. However, new synthetic drugs created on the street or coming in from other countries can easily stump existing toxicology tests—often by design. These “designer drugs” include synthetic opioids and cannabinoids as well as other psychoactive substances.

“Many drug addicts know what kind of testing is done in a lab and ensure they are negative for those analytes by using alternate drugs to give them a high,” says Elizabeth Skowronek Andrien, senior global product manager for Thermo Fisher Scientific, Fremont, Calif. “If a physician suspects drug use, and the traditional immunoassay screening test is negative, it is encouraged that the toxicology testing be performed using LC/MS to pick up designer drugs.”

Even after advanced screenings, however, the source of an overdose can remain a mystery.

“Designer drugs are a moving target,” says Sumandeep Rana, PhD, director of scientific assessment and market access in Lake County, Ill.-based Abbott’s rapid and molecular diagnostic business. “It is difficult for the labs to constantly keep updating their testing methods to include the newly appearing drugs. Lack of timely availability of immunoassay-based screening for the newer drugs results in a testing approach that requires broad spectrum screening via expensive and complex mass spectrometry-based analytical techniques.”

The challenge is not only identifying new synthetics, but also ramping up testing capabilities to screen for these new substances. “That’s a very real problem because developing the screening product that would go on a chemistry analyzer or in that cup takes years,” Harris says. “It’s not an overnight kind of thing.”

Still, there has been hopeful progress, especially in response to the opioid crisis. “In the past few years, more options for screening for drugs such as buprenorphine, 6-monoacetylmorphine, fentanyl, and oxycodone have emerged for use on clinical chemistry analyzers,” Mayo says. “These drugs were not detected well by the opiate screening tests.”

One of the challenges in developing a test for fentanyl, for example, is how quickly the drug metabolizes, Harris says. “Depending on when you get the sample collected, there may not be enough fentanyl in the urine sample for the screening methodology to identify it,” he says. “But there are screening methods that have been built to detect raw fentanyl in the urine as well as the norfentanyl metabolite. If you’ve got both of those, you’re more likely to capture whether this patient has had this drug.”

The skyrocketing number of fentanyl overdoses has driven these technological breakthroughs. “The opioid crisis, especially the uptick of fentanyl use and abuse, has caused manufacturers to come out with FDA-cleared fentanyl tests,” says Peter van der Lugt, regional marketing manager for Thermo Fisher Scientific, Fremont, Calif. “As some drugs became unavailable during 2020 due to the lockdown, other substances such as fentanyl’s abuse increased.”

In the case of an overdose, every second matters. Even when the exact substance is unknown, emergency department physicians will likely administer an antidote such as Naloxone (Narcan), commonly used to treat opioid overdoses, right away, says McAllister.  Waiting for a drug screen result is not an option.  Especially in the case of fentanyl, they will revive the patient and get them stabilized.  Lab results may inform and support additional course of treatment and if opioid cessation therapy is recommended.

“Fentanyl is such a serious overdose that a physician is not going to wait for a test result before they treat that individual,” she says. “They are going to revive them and get them stable. Once the results come back from the lab, then they’ll discuss treatment.”

These tests are crucial in determining the correct path for the patient going forward. “As with all laboratory testing, sensitivity and specificity are very important, especially when differentiating between the many different opioid tests,” Andrien says. “For patients suspected of an unknown drug overdose, speed and number of analytes detected are also important for the physician to appropriately treat the patient.”

Another class of drugs to watch for are benzodiazepines, according to McAllister. In March 2020, prescriptions for the anti-anxiety medication rose to 9.7 million—a 10.2% increase from March 2019. Some see parallels with this trend and the overprescribing of opioids in recent years6. Designer benzodiazepine versions could potentially elude the currently available screening panels as well.

Tracking trends like these are crucial for clinical laboratories going forward. “It is best for laboratorians to stay abreast of the ever-changing landscape of illicit drug use,” Noel says. “Assays must conform to testing the most popular agents, especially those causing significant numbers of overdose and death. It is also imperative that the drug is detected and monitored for individuals in treatment. Having a quality assay that is accurate and reliable is also very important to obtain trusted test results.”

Growing Spaces

Point-of-care drug testing—whether in a hospital setting or in a physician’s office—continues to be a huge growth sector.

“Point-of-care testing offers the convenience of having these screens being done at treatment centers or physician offices without laboratories,” Mayo says. “Some of these point-of-care tests offer screening for adulterants as well.”

As with all near-patient technologies, sometimes there are trade-offs. “Point-of-care testing is becoming more requested, as treatment may be determined by drug levels for some prescription drugs,” Andrien says. “Unfortunately, there are not a lot of rapid solutions available, and the most common point-of-care tests are the toxicology test cups and dip sticks. The drawback of these tests is that they may not be as sensitive or specific as immunoassay or LC-MS testing for the drugs that physicians are looking for. On a positive note, some rapid urine cup test manufacturers are able to react quickly and offer testing for new drugs of abuse, i.e., designer drugs.”

Still, newer technologies for this space are emerging. “Historically, point-of-care testing utilized urine as the matrix; but, in the last couple of years, the use of oral fluid has been growing as a sample collection matrix,” Rana says. “The oral fluid sample collection process is also simpler and gender neutral, and the drugs in oral fluid show a good correlation to plasma drug concentrations. Positive oral fluid screens are also reflective of recent drug use, which is more meaningful in most clinical settings compared to a urine screen that may indicate drug use several days ago.”

Both addiction therapy and pain management are helping to drive point-of-care drug screening. According to the U.S. Department of Health and Human Services, there are more than 14,000 substance abuse facilities in the United States, and more than 1.27 million Americans are receiving medication-assisted treatment7

“This has resulted in an increase in monitoring compliance by both private toxicology and routine clinical laboratories,” Mayo says.

Recent regulations require pain management physicians to screen patients who are taking certain prescribed drugs, such as those that contain opioids. The cut-off thresholds for these tests are usually lower to help physicians ensure that their patients are complying with their prescribed medication and not supplementing with other illicit drugs. In these cases, physicians expect a positive result—a negative result could indicate either noncompliance or even that a patient is selling unused doses illegally elsewhere.

“Pain management continues to drive the evolution of drug screen panels,” McAllister says. “Physicians need an accurate and reliable test that includes commonly prescribed medications in addition to the standard drug panel to enable patient monitoring and to ensure compliance through their treatment process.”

The role of clinical laboratories in toxicology will also continue to evolve to address reimbursement and staffing challenges. “Cost pressure will continue long after the pandemic. Countries and healthcare facilities have been financially impacted by COVID-19 and will take time to rebound,” says van der Lugt, who adds that the staffing shortage in clinical laboratories will expedite the need for automation across the board. “It will be important for manufacturers to be agile and develop new assays as trends in drug abuse change.”

Ultimately, clinical laboratories may begin to play a larger role in community health and wellness, especially when it comes to drug screening and treatment. “Laboratories and laboratory personnel will need to work on transforming the lab’s focus from just releasing results to improving health outcomes in general,” Mayo says.

Ann H. Carlson is a contributor to CLP.


1. “Pandemic Brings Drop in Testing, Increase in Illicit Drugs.” Quest Diagnostics. 2021. https://www.questdrugmonitoring.com/blog/2020/pandemic-brings-drop-in-testing–increase-in-dangerous-illicit-d

2. “Provisional Drug Overdose Death Counts.” National Center for Health Statistics. October 13, 2021. https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm#COD_classification_definition_drug_deaths

3. “Overdose Deaths Accelerating During COVID-19.” Centers for Disease Control and Prevention. December 17, 2020. https://www.cdc.gov/media/releases/2020/p1218-overdose-deaths-covid-19.html

4. “Marijuana Workforce Drug Test Positivity Continues Double-Digit Increases to Keep Overall Drug Positivity Rates at Historically High Levels, Finds Latest Quest Diagnostics Drug Testing Index Analysis.” Quest Diagnostics. May 26, 2021. https://newsroom.questdiagnostics.com/2021-05-26-Marijuana-Workforce-Drug-Test-Positivity-Continues-Double-Digit-Increases-to-Keep-Overall-Drug-Positivity-Rates-at-Historically-High-Levels,-Finds-Latest-Quest-Diagnostics-Drug-Testing-Index-TM-Analysis

5. “Industry-specific workplace drug testing data.” Quest Diagnostics. 2019. http://www.employer-solutions-resources.com/whitepaper/quest-industry-drug-testing-data

6. “More People Are Taking Drugs for Anxiety and Insomnia, and Doctors Are Worried.” Petersen, Andrea. The Wall Street Journal. May 25, 2020. https://www.wsj.com/articles/more-people-are-taking-drugs-for-anxiety-and-insomnia-and-doctors-are-worried-11590411600

7. “Opioid Crisis Statistics.” U.S. Department of Health and Human Services. February 12, 2021. https://www.hhs.gov/opioids/about-the-epidemic/opioid-crisis-statistics/index.html]