During the first year of the COVID pandemic, ending April 2021, the Centers for Disease Control and Prevention reported a record 100,306 drug overdose deaths, an increase of 28.5% from the 78,056 deaths reported during the same period the year before.
Of this number, overdose deaths from opioids increased to 75,673, up from 56,064 the year before. This includes deaths from synthetic opioids (primarily fentanyl) and psychostimulants such as methamphetamine; as well as cocaine; and deaths from natural and semi-synthetic opioids (such as prescription pain medication)1 .
The adverse effects of these abused drugs on individuals, families, society, and health care costs are monumental. This public health crisis is recognized and well publicized, with Federal and state governments investing billions of dollars in an attempt to end the opioid epidemic.
The opioid epidemic evolved rapidly in recent years, starting with an increase during the 1990s in opioid prescriptions to treat chronic pain. Since then, the drug addiction and opioid overdose epidemics have been steadily growing in the United States, with no signs of reversing course.
How did we get to this point?
The rise in opioid overdose deaths can be outlined in three distinct waves 2 :
I. The first wave began in 1991 when deaths involving opioids began to rise following a sharp increase in the prescribing of opioid and opioid-combination medications for the treatment of pain. The increase in opioid prescriptions was influenced by reassurances given to prescribers by pharmaceutical companies and medical societies claiming that the risk of addiction to prescription opioids was very low. During this time, pharmaceutical companies also began to promote the use of opioids in patients with non-cancer related pain even though there was a lack of data regarding the risks and benefits in these patients.
By 1999, 86% of patients using opioids were using them for non-cancer pain. Communities where opioids were readily available and prescribed liberally were the first places to experience increased opioid abuse.
II. The second wave of the opioid epidemic started around 2010 with a rapid increase in deaths from heroin abuse. As early efforts to decrease opioid prescribing began to take effect, making prescription opioids harder to obtain, the focus turned to heroin, a cheap, widely available, and potent illegal opioid. Deaths due to heroin-related overdose increased by 286% from 2002 to 2013, and approximately 80% of heroin users admitted to misusing prescription opioids before turning to heroin.
III. The third wave began in 2013, with significant increases in overdose deaths involving synthetic opioids, particularly those involving illicitly manufactured fentanyl (IMF).
The sharpest rise in drug-related deaths occurred in 2016 with over 20,000 deaths from fentanyl and related drugs. The increase in fentanyl deaths has been linked to illicitly manufactured fentanyl used to replace or adulterate other drugs of abuse.
The Need to Monitor Drug Therapy
While in many scenarios opioids remain the most effective treatment for severe pain, its use creates one of the greatest challenges as well: identifying which patients may be potentially at risk of addiction prior to the initiation of opioid therapy, and identifying which patients develop an addiction during therapy. In fact, recent data has shown that greater than 40% of patients receiving opioid therapy may develop “opioid use disorder.” 3
In order to do this, patients in pain management programs are often assessed before treatment and monitored while they are receiving treatment.
Various strategies are available to monitor pain management, and multicomponent interventions are often used. Many settings require patients to sign a contract before they are given a prescription for opioids. The contracts generally involve obtaining patients’ agreement on behaviors they will engage in during the treatment period (e.g., taking medication as prescribed) and not engage in (e.g., selling prescribed medication and/or obtaining additional prescriptions from other physicians).
Confirming whether patients follow these behavioral guidelines can be a challenge. An essential tool of this assessment of the potential for opioid abuse by patients is drug testing.
This testing is used to determine if a patient is taking opioids or other pain medications as prescribed, or to determine if a patient is abusing other substances; these tests also monitor continued drug therapy, and adjustments to dosage as needed.
Laboratory Drug Testing Programs
Basically, an effective drug-testing program involves a two-step process: the initial screen, usually utilizing urine as the preferred specimen (immunoassay) tests; and then the confirmatory Mass Spectrometry (MS) testing.
The immunoassay (EMIT, ELISA and RIA are the most common) is performed first and used as a screening method. If the immunoassay is negative, no further action is required, and the results are reported as negative.
If the sample is positive, an additional confirmatory MS analysis is performed on a separate portion of the biological sample. The more specific MS is used as a confirmatory test to identify individual drug substances or metabolites and quantify the amount of the substance.
Confirmatory tests, such as MS should be utilized prior to reporting positive drug test results.
False positive samples from the screening test will almost always be negative on the confirmation test. Samples testing positive during both screening and confirmation tests are reported as positive to the entity that ordered the test.
These laboratory procedures are the methods most commonly utilized to test for drugs. Using a combination of both allows a high level of sensitivity and specificity, ensuring an extremely low chance for false positives or false negatives 4 .
Urine Drug Screens (UDS): Immunoassay Testing (Qualitative/Presumptive/Screens) 5
These tests can be performed either in a laboratory or at point of care (POC). Immunoassay tests are based on the principle of competitive binding and use antibodies to detect a particular drug, drug class or drug metabolite in a urine sample. Immunoassays generally have a rapid turnaround time, within minutes for onsite tests and 1 to 4 hours for laboratory-based tests.
Immunoassay tests vary in the type of compounds they can detect. Some detect specific drugs and may fail to recognize similarly structured drugs within the same class. Other immunoassays identify only classes of drugs and thus results cannot be used to determine a specific drug a patient is taking.
Immunoassay findings are generally reported qualitatively as either positive (drug level above a pre-specified threshold) or negative (drug level below a pre-specified threshold). Raising or lowering the threshold thus changes the proportion of positive tests. A negative test is interpreted as a level below the threshold and does not necessarily mean that the drug or metabolite is absent.
1. Urine is the preferred specimen for drug abuse testing primarily because it is non-invasive;
2. Ample volume available
3. Drugs and drug metabolites found in urine are usually stable
4. Drug levels in blood only reflect the presence of a drug at a given point in time, and levels may be high enough to be detected only for a relatively short period; detectable in urine for relatively long period of time.
5. Drugs and their metabolites are often present in higher concentrations in urine than in other biological materials
6. Readily preserved by refrigeration or freezing
7. Analysis relatively simple because of absence of proteins and cellular material in urine
8. Wide availability of commercial reagents and analytical systems
1. Does not provide quantitative results;
2. Reliance on the presence of an antibody; but not all drugs elicit an antibody response, limiting the number of drugs detected. For example, some opioids, such as fentanyl, buprenorphine, tapentadol, and tramadol, are not routinely detected;
3. Can produce false positive results due to cross-reactivity with structurally related and other compounds from prescriptions, herbal compounds and over-the-counter drugs, or false negative results due to lack of cross-reactivity with newer, emerging novel psychoactive substances, all of which can result in poor quality patient care.
4. Drug levels may vary widely, depending on fluid intake, voiding pattern, and time lapse since drug intake
5. Urine drug excretion continues after physiologic effect of the drug ceases, resulting in lack of correlation of drug level with intoxication
6. Urine specimens are easily substituted, diluted, or adulterated
7. Direct observation of urine collection may be an invasion of privacy
Mass Spectrometry: Confirmatory Testing
Mass Spectrometry testing is usually conducted in full service toxicology laboratories; distinct from the initial point-of-care urine drug screening that is conducted in non-specialized laboratories or in a doctor’s or health care provider’s office. The more comprehensive laboratory data from MS testing is invaluable for epidemiological studies to target prevention efforts, detect and track emerging synthetic drugs, and direct policy changes.
Mass spectrometry-based tests overcome the limitations of the current frontline screening method, the immunoassay, which is useful but can produce a high rate of incorrect results and sometimes only reveals what general drug class is present in a patient's urine rather than the specific drug.
1. Provides qualitative and quantitative results with highly specific and sensitive results;
2. Guarantees the use of quality assessment controls and requires trained laboratory personnel to perform and interpret the test results;
3. Produces accurate and high-quality data that can improve treatment and prevention efforts;
4. Detects a wide range of drugs and differentiates between classes of drugs, providing specific data to clinicians, public health agencies, and law enforcement;
5. Produces data reflecting medication compliance or lack thereof;
6. Effectively monitors emerging synthetic drugs, providing information to public health and safety agencies about the factors driving the drug abuse epidemic;
7. Accurately identifies potentially dangerous drug interactions, such as benzodiazepines and alcohol that can lead to an overdose or death, so that health care providers can intervene.
Building Strategic Partnerships 9
Success in combating the opioid epidemic requires a multifaceted, collaborative approach, of which toxicology test data is a critical component. These include strategic partnerships with federal agencies, state and local health agencies, associations, law enforcement officials, health care providers and others to leverage the data collected by clinical laboratories to use for treatment and prevention efforts.
Toxicology laboratories, in particular, have the ability to work in conjunction with health care providers and state and local agencies to design specific methods and patterns of testing that are often geographically focused and based on the observed and reported abuse in that specific region.
Additionally, these laboratories have the ability to assist health care providers in developing and managing individualized patient risk protocols and implementing testing policies that reduce cost, utilization and frequency while simultaneously improving patient care and outcomes.
CAP Position Statement on the Opioid Epidemic 10
The CAP understands that the opioid epidemic continues to rip apart families and communities across the country,” said R. Bruce Williams, MD, FCAP, CAP president. “A variety of approaches is needed to control this crisis requiring collaboration across the entire health care spectrum.”
“It is imperative that pathologists work together with other clinicians to improve the way opioids are prescribed and monitored to ensure patients have access to safer and more effective chronic pain treatment while also reducing the risk of opioid use disorder, overdose, and death.”
1 Drug Overdose Deaths in the U.S. Top 100,000 Annually. CDC Press Release November 17 2021.
2 Centers for Disease Control and Prevention. CDC-Info. Opioid Overdose. Three Waves of Opioid Overdose
Deaths. Dec. 19, 2018 https://www.cdc.gov/drugoverdose/epidemic/index.html#three-waves
3 H Heit, and D Gourlay. Philosophy of Urine Drug Testing in Pain Management. Prescribe Responsibly. July 2,
4 Drugs.com. Drug testing FAQs. https://www.drugs.com/article/drug-testing.html
6 Urine Drug Testing: Approaches to Screening and Confirmation Testing. Gifford Lum, MD and Barry Mushlin, MA.
Laboratory Medicine. June 2004. No.6 V. 35.
8 Curbing Drug Addiction and the Opiod Crisis. The Role of Toxicology Laboratories in Diagnosis, Treatment, and
Prevention. National Independent Laboratory Association (NILA). https://www.nila-usa.org/images/Opioid%20TF%20White%20Paper%20FINAL2.pdf
10 Pathologists Confront the Opioid Crisis. College of American Pathologists Press Release. September 5 2018.