OBJECTIVES

After completing this chapter, the reader should be able to

  • List the general analytical techniques used in substance abuse and toxicological screening and discuss their limitations

  • Compare the uses of preliminary and confirmatory urine drug tests

  • Discuss the considerations in interpreting a positive and negative drug screen result

  • Discuss why interfering substances can cause false-negative and false-positive results of screening tests

  • Describe how the characteristics of urine, serum, saliva, and hair specimen affect the drug testing process

  • Discuss how toxicologic analyses may be helpful in medicolegal situations, postmortem applications, athletic competition, and substance use disorder

SUBSTANCE ABUSE, POISONING, AND OVERDOSE

When substance abuse, poisoning, or overdose is suspected, the testing of biological specimens is crucial for characterizing usage or exposure, monitoring therapy or abstinence, or aiding in diagnosis or treatment. Millions of Americans are potentially subject to these types of tests. According to the 2018 National Survey on Drug Use and Health (NSDUH), 31.9 million Americans aged 12 years and older (11.7% of the population) reported using an illicit drug in the past month, and 53.2 million (19.4%) reported illicit drug use during the past year (Table 22-1).1

TABLE 22-1.

Americans Aged 12 Years or Older Reporting Use of Illicit Drugs During 2018

PERCENTAGE OF THE TOTAL POPULATION

SUBSTANCE

PAST YEAR (%)

PAST MONTH (%)

Any illicit drug

19.4

11.7

Marijuana and hashish

15.9

10.1

Cocaine

2.0

0.7

Crack cocaine

0.3

0.2

Heroin

0.3

0.1

Hallucinogens

2.0

0.6

 LSD

0.8

0.2

 MDMA, Ecstasy

0.9

0.3

Methamphetamine

0.7

0.4

Inhalants

0.7

0.2

Any illicit drug other than marijuana

8.5

3.2

Nonmedical use of any of the following

 Psychotherapeutic drug

6.2

2.0

 Pain reliever

3.6

1.0

 Tranquilizer

2.1

0.7

 Stimulant

1.9

0.6

 Sedative

0.4

0.1

LSD = lysergic acid diethylamide; MDMA = 3,4-methylenedioxy-N-methamphetamine.

Source: Adapted from Center for Behavioral Health Statistics and Quality. Results from the 2018 national survey on drug use and health: detailed tables. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2019. https://www.samhsa.gov/data/report/2018-nsduh-detailed-tables.

Poison control centers document approximately 2 million unintentional and intentional poison exposures each year, with one-half occurring in children <6 years of age. Ninety percent of cases occur in homes and two-thirds are managed onsite in a non-healthcare facility. Drugs are responsible for approximately 60% of poison exposures (Table 22-2).2

TABLE 22-2.

Ranking of Twelve Most Frequent Poison Exposure Categories Reported to U.S. Poison Control Centers During 2018a,b

ALL EXPOSURES

CHILDREN (<6 YEARS)

ADULTS (>19 YEARS)

Analgesics

Cosmetics, personal care products

Analgesics

Cleaning substances

Cleaning substances

Sedatives, antipsychotics

Cosmetics, personal care products

Analgesics

Antidepressant drugs

Sedatives, antipsychotics

Foreign bodies

Cardiovascular drugs

Antidepressant drugs

Topical medicines

Cleaning substances

Cardiovascular drugs

Antihistamines

Alcohols

Antihistamines

Vitamins

Anticonvulsants

Foreign bodies

Dietary supplements

Stimulants, street drugs

Pesticides

Pesticides

Pesticides

Alcohols

Gastrointestinal drugs

Antihistamines

Stimulants, street drugs

Plants

Hormones and antagonists

Anticonvulsants

Antimicrobial drugs

Cosmetics, personal care products

aIn decreasing order of frequency and based on 2,541,958 substances reported in 2,099,751 cases.

Source: Adapted from Gummin DD, Mowry JB, Spyker DA, et al. 2018 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 36th Annual Report. Clin Toxicol (Phila). 2019;57(12):1220–1413.

In the 2018 NSDUH report, 20.4 million part-time and full-time workers aged ≥18 years reported use of an illicit drug in the past month, and 12.4 million claimed heavy alcohol use (five or more drinks per occasion on ≥5 days) in the past month.1 Based on 9 million urine drug screens performed by a nationwide laboratory service in 2018 for the combined U.S. workforce, 4.4% had positive test results (Table 22-3).3

TABLE 22-3.

Rate of Positive Urine Drug Screens for the Combined U.S. Workforce During 2018 as Reported by a Nationwide Laboratory Service for 9 Million Tests

SUBSTANCE

POSITIVE URINE DRUG SCREENS (%)a

Marijuana

2.30

Amphetamines

1.10

Opiates

0.73

Benzodiazepines

0.52

Oxycodones

0.38

Cocaine

0.28

Barbiturates

0.22

Methadone

0.18

6-acetylmorphine (heroin)

0.02

PCP

0.01

PCP = phencyclidine.

aSome samples had multiple drugs identified.

Source: Adapted with permission from Quest Diagnostics. Drug testing index: employer solutions annual report Spring 2019. Lyndhurst, NJ: Quest Diagnostics Inc; 2019. https://www.questdiagnostics.com/dms/Documents/Employer-Solutions/DTI-2019/quest-drug-testing-index-brochure-2019.pdf.

Driving under the influence of alcohol at least once during the past year was reported by 20.8 million persons (8.0% of people aged ≥16 years) with 12.6 million (4.9%) driving under the influence of illicit drugs. Drugged driving was reported for 28.1 million people (11.0% of people ≥16 years) under the influence of alcohol or selected illicit drugs (marijuana, cocaine, heroin, hallucinogens, inhalants, methamphetamine) in 2018.1

For eighth-grade, tenth-grade, and twelfth-grade students, the lifetime prevalence of the use of illicit drugs during 2018 was 19%, 34%, and 48%, respectively (Table 22-4).4 Substance use disorder involves dependence or abuse of illicit drugs or alcohol. The 2018 NSDUH reported 20.3 million people (7.4% of people ≥12 years) had a substance use disorder in the past year.5

TABLE 22-4.

Categories of Substances Abused as Claimed by High School Seniors During 2018

SUBSTANCE

PERCENTAGE OF SURVEY RESPONDENTS

PAST YEAR (%)

EVER (%)

Alcohol

53.3

58.5

Any illicit drug

38.8

47.8

Marijuana and hashish

35.1

43.6

Any prescription drug

9.9

Sedatives

6.1

4.2

Amphetamines

5.5

8.6

Hallucinogens

4.3

6.6

Tranquilizers

3.9

6.6

Synthetic cannabinoids

3.5

Opioids (excluding heroin)

3.4

6.0

LSD

3.2

5.1

Cocaine

2.3

3.9

3,4-methylenedioxy-N-methamphetamine (MDMA, Ecstasy)

2.2

4.1

Inhalants

1.6

4.4

Androgenic anabolic steroids

1.1

1.6

Ketamine

0.7

Methamphetamine

0.5

0.7

Heroin

0.4

0.8

Source: Adapted with permission from Miech RA, Johnston LD, O’Malley PM, et al. Secondary school students, Vol. I: Monitoring the Future national results on drug use 1975–2018. Ann Arbor, MI: Institute for Social Research, The University of Michigan; 2019. http://monitoringthefuture.org/pubs/monographs/mtf-vol1_2018.pdf.

During 2018, 72,473 people died of poisoning or overdose, with 85 deaths (0.1%) occurring in children <5 years of age.6 Poisoning became the leading cause of injury-related death in the United States in 2008; 93% of these deaths in 2018 were caused by drugs. The rate of drug-related, age-adjusted overdose deaths has increased from 6.2 per 100,000 (n = 17,415) in 2000 to 20.7 per 100,000 (n = 67,367) in 2018—a 236% increase in 19 years.6,7 The 67,367 overdose deaths involved opioids in 69.5% of cases, which included prescription opioids, heroin, illicitly manufactured fentanyl, and fentanyl analogs.8

There is no comprehensive tabulation of all incidents of substance abuse or poisoning, and the available databases have strengths and weaknesses.9 Nevertheless, substance abuse and poisoning are common problems facing healthcare professionals, law enforcement officials, employers, teachers, family members, and individuals throughout society. The detection and management of these incidents often involves laboratory testing and interpretation of the results. On a personal basis, healthcare professionals are asked by family members, acquaintances, and patients about drug testing and the potential impact on their lives. It is often prudent to refer the person to the testing laboratory or physician who ordered the test in question when pertinent facts are not available or when they are unable to be properly assessed. This chapter focuses on urine drug testing and serum drug concentration determinations as a means to aid in the management of substance abuse and poisoning.

URINE DRUG SCREENS

Objectives of Analysis

A drug screen provides a qualitative result based on the presence of a specific substance or group of substances. This determination is also called a toxicology screen or tox screen. Urine is the specimen of choice, and it is widely used for most situations requiring a drug screen. The collection of urine is generally noninvasive and can be collected in unresponsive patients after urinary catheterization. Adequate urine samples of 20 to 100 mL are easily collected. Most drugs and their metabolites are excreted and concentrated in urine. They are also stable in frozen urine, allowing long-term storage for batched analyses or reanalysis. Urine is a relatively clean matrix for analysis due to the usual absence of protein and cellular components, thereby eliminating preparatory steps for analysis.1014

A urine drug screen result does not provide an exact determination of how much of the substance is present in the urine. The concentration of the substance is actually measured by urine drug screen assays in the process of determining whether the drug is present in a significant amount to render the test result as positive. For each substance, the test has performance standards established by the intrinsic specificity and sensitivity of the analytical process that are linked to regulatory or clinical thresholds, commonly called cutoff values. These thresholds are a balance of the actual analytical performance, likelihood for interfering substances, and the potential for false positives, which together suggest that the substance is actually present in the urine. Cutoff values may be set by an individual laboratory to meet regulatory or clinical needs or by purchasing immunoassay kits with the desired cutoff values.

Regulatory cutoff values are typically used to monitor people in the workplace or patients undergoing therapy for substance use disorder. The Substance Abuse and Mental Health Services Administration (SAMHSA) in the Department of Health and Human Services specifies cutoff values for the drug categories that should be routinely included in urine screens for federal requirements (Table 22-5).15 (See the SAMHSA website for updated rules at www.samhsa.gov/workplace/drug-testing.) In hospital and forensic settings, cutoff values are sometimes lowered relative to workplace values to detect more positive results, which can serve as an aid in verifying or detecting an overdose or poisoning.13,15 Reports of urine drug screen results typically list the cutoff value for a substance and whether the substance was detected at the specified value.

TABLE 22-5.

Federal Cutoff Concentrations for Urine Drug Testsa

DRUG

INITIAL TEST (ng/mL)

CONFIRMATORY TEST (ng/mL)

Amphetamine/methamphetamine

500

250

MDMA/MDA

500

250

Cocaine metaboliteb

150

100

Marijuana metabolitec

50

15

Codeine/morphine

2,000

2,000

Hydrocodone/hydromorphone

300

100

Oxycodone/oxymorphone

100

100

6-acetylmorphined

10

10

PCP

25

25

MDA = 3,4-methylenedioxyamphetamine.

aStandards issued by Substance Abuse Mental Health Services Administration for urine specimens collected by federal agencies and by employers regulated by the Department of Transportation effective October 2017; see website for changes (https://www.samhsa.gov/workplace/drug-testing).

bMetabolite as benzoylecgonine.

cMetabolite as δ-9-tetrahydrocannabinol-9-carboxylic acid.

dA metabolite specific to heroin.

Source: Adapted from Department of Health and Human Services, Substance Abuse and Mental Health Services Administration. Mandatory guidelines for federal workplace drug testing programs. Fed Regist. 2017; 82:7920–7970. https://www.samhsa.gov/workplace/drug-testing.

General Analytical Techniques

There is no standardized urine drug screen that uses the same panel of tested drugs, analytical techniques, or turnaround times. Although there is some commonality among laboratories, tests differ by individual laboratory. Generally, urine drug screens are categorized by level of sensitivity and specificity of the analytical technique (preliminary versus confirmatory) and by the variety of drugs tested.11,16 Preliminary tests, also known as initial, provisional, or stat urine drug screens, typically use one of six currently available immunoassays (EMIT, KIMS, CEDIA, RIA, FPIA, or ELISA). (See Chapter 2 for more in-depth discussion.)

Immunoassays can be performed on auto-analyzers that are available in most hospitals. These assays are available for many substances of abuse, and results can be reported within 1 to 2 hours.13,16 Many point-of-care tests (POCTs) also use an immunoassay technique, and results can be available within 5 to 15 minutes. Unfortunately, the result of an immunoassay is preliminary due to compromises in specificity that lead to cross-reactivity, particularly with amphetamines and opioids. A preliminary urine drug screen result cannot stand alone for medicolegal purposes and must be confirmed with another type of analysis that is more specific.10,14 For clinical purposes, some laboratories routinely confirm the results of preliminary drug screens, but others do so only on request of the physician. The need for confirming preliminary test results is based on several factors: whether the result would affect the patient’s care, whether the patient is expected to be discharged by the time the results are known, whether any legal actions are anticipated, and whether the cost justifies the possible outcome.

Confirmatory techniques are more specific than preliminary tests and use another analytical technique.11,16 These tests include high-performance liquid chromatography, gas chromatography, or mass spectrometry, depending on the substances being confirmed. The “gold standards” of confirmatory tests are gas chromatography with mass spectrometry, often referred to as GC mass spec or GC-MS and liquid chromatography with tandem mass spectrometry. Compared with preliminary tests, these techniques are more time-consuming and more costly, require greater technical expertise, and require greater time for analysis—often several hours to days. Most hospital clinical laboratories do not have the capability to perform confirmatory tests and must send the specimen to a local reference laboratory or a regional laboratory. Transportation of the specimen adds to the delay in obtaining results. Confirmatory tests are routinely performed for workplace settings and forensic and medicolegal purposes, and the delay is often less critical than in clinical settings (Minicase 1).10

Common Applications

The purpose of a urine drug screen depends on the circumstances for its use, the condition of the patient, and the setting of the test. In an emergency department (ED) where a patient is being evaluated for a poisoning or overdose, the primary purposes are to verify substances claimed to be taken by the patient and to identify other toxins that could be likely causes of the poisoning or symptoms.13 This is particularly important when the patient has an altered mental status and cannot give a clear history or is experiencing nondrug causes of coma, such as traumatic head injury or stroke. The value of routinely performing urine drug screens in the ED for patients who overdose has been questioned.17 The benefits include having objective evidence of the toxin’s presence to confirm the exposure, suggesting alternative toxins in the diagnosis, ruling out a toxin as a cause of symptoms of unknown etiology, and providing medicolegal documentation. The disadvantages include being misled by false-positive results, impractical delays in receiving the results that do not influence therapy, and limited practical value because many poisonings can be recognized by a collection of signs and symptoms.18,19

The American College of Emergency Physicians states in a clinical policy on the immediate treatment of poisonings that “qualitative toxicologic screening tests rarely assist the emergency physician in patient management.”20 Urine drug testing can be important, with substances exhibiting delayed onset of toxic symptoms, such as sustained-release products, when patients ingest multiple agents, or when patients are found with multiple agents at the scene. Some trauma centers routinely perform urine drug screens on newly admitted patients, although the value of this practice has been questioned.21 People who are experiencing suicidal thoughts or with substance use disorder can be poor or misleading historians, whereby the amounts, number of substances, and routes of exposure may be exaggerated or downplayed. A urine drug screen may assist in identifying potential substances involved in these cases and lead to specific monitoring or treatment (Minicase 2).

Reliability of Amphetamine Results

Kisha T., a 21-year-old college student, is brought to the ED by her family because of bizarre behavior. She is having visual hallucinations and is paranoid and jittery. She is clinically dehydrated, tachycardic, and delirious. A stat preliminary urine drug screen is positive for amphetamines.

QUESTION: Is this patient abusing amphetamine?

DISCUSSION: Amphetamine abuse is possible, but alternative causes should be considered. Her parents report that she has just completed a week of final exams, is taking a full course load, and is working two part-time jobs. She is described as studious and a compulsive achiever. After 6 hours of supportive therapy, rest, and intravenous (IV) fluids, she is lucid and confesses to drinking more than a dozen energy drinks to stay awake in the past 2 days and taking two loratadine with pseudoephedrine 12-hour tablets 6 hours ago for allergy symptoms. A targeted confirmatory assay for amphetamines was negative for amphetamines and methamphetamine. Urine drug screens by immunoassay for amphetamines are subject to cross-reactivity with several sympathomimetic amine-type drugs (eg, ephedrine and pseudoephedrine and their variants are often found in dietary supplements marketed for energy and weight loss and as decongestants), which would cause a false-positive result for amphetamines by immunoassay. Caffeine found in many energy drinks and dietary supplements for weight loss and energy are likely the principal causes of her symptoms. Caffeine was not detected in the urine screen because it was not on the testing panel of screened drugs.

The inclusion of a substance on a drug screen is also subject to individual laboratory discretion. Workplace and substance abuse monitoring programs are required to test for five categories of substances (marijuana metabolites, cocaine metabolites, opiate metabolites, PCP, and amphetamines) as specified by the “Fed 5″ (Table 22-5). Most immunoassay manufacturers design the range of assays to meet this need and offer additional categories that a laboratory may choose to include.13,24 The expense of developing an immunoassay is balanced with the promise of economic recovery with widespread use. This economic reality precludes the development of a test for emerging substances of abuse, such as synthetic cathinones, synthetic cannabinoids, designer fentanyl analogs, and life-threatening overdoses, such as calcium channel antagonists and β-adrenergic blockers. Techniques used for confirmatory tests would be required to detect many of the substances not included in the panel of the preliminary drug screen.

In the workplace, the purpose of a urine drug screen may include pre-employment tests, monitoring during work, postaccident evaluation, and substance abuse treatment monitoring.10 Employers who conduct pre-employment urine drug tests generally make hiring contingent on a negative test result. Many positions in the healthcare industry require pre-employment drug tests, and some employers perform random tests for employees in positions requiring safety or security as a means to deter drug use and abuse that could affect performance. In addition to random tests, some employers test individuals based on a reasonable suspicion of substance abuse, such as evidence of use or possession, unusual or erratic behavior, or arrests for drug-related crimes. For employees involved in a serious accident, employers may test for substances when there is suspicion of use—to determine whether substance abuse was a factor—or as a necessity for legal or insurance purposes. Employees who return to work after treatment for substance abuse are often randomly tested as one of their conditions for continued employment or licensure. In the workplace setting, specific procedures must be followed to ensure that the rights of employees and employers are observed.

The Division of Workplace Programs of SAMHSA specifies guidelines for procedures, due process, and the appeals process and lists certified laboratories.10 Two critical elements of workplace drug testing include establishing a chain-of-custody and control for the specimen and involving a medical review officer (MRO) to interpret positive test results. The chain-of-custody starts with close observation of urine collection. Patients are required to empty their pockets, and they are placed in a collection room without running water and where blue dye has been added to the toilet water. These measures minimize the risk of adulteration or dilution of the urine sample. After urine is placed in the container, the temperature is taken, the container is sealed, and the chain-of-custody documentation is completed. After the chain-of-custody form is completed by everyone in possession of the specimen, it reaches the laboratory, where the seal is broken and further procedures are observed. Positive specimens are often frozen for 1 year or longer if requested by the client or if the results are contested by a court. Chain-of-custody procedures are time-consuming and are not typically considered in the clinical management of poisonings and overdoses, but they are important to sustain the validity of the sample and its result in a court of law.10

An MRO is typically a physician trained in this specialty who has responsibility to determine whether the result of the drug test is related to substance abuse.10,22 Duties involve interviewing the donor; reviewing his or her therapeutic drug regimen; reviewing possible extraneous causes of a positive result, such as a false-positive result from a prescribed medication or substance interfering with the analytical test; rendering an opinion on the validity of the test result; considering a retest of the donor or the same specimen; reporting the result to the employer; and maintaining confidential records. This individualized interpretation is critical not only because people’s careers, reputations, livelihood, and legal status can be affected but also because it is a regulatory requirement.

Drug Screens and Emergent Care

Bob C., a 26-year-old man, is dropped off at an ED in the late evening after he becomes progressively more unresponsive in a hotel room. His acquaintances do not know his medical history but eventually admit that he had swallowed some drugs. They promptly leave the area. Bob C. is unconscious with some response to painful stimuli, and he exhibits pinpoint pupils and depressed respirations at 12 breaths/min. His other vital signs are satisfactory. Oxygen administration and IV fluids are started. A bedside stat glucose determination yields a result of 60 mg/dL. A 50-mL IV bolus of dextrose 50% is administered with no change in his level of consciousness. Naloxone 0.8 mg is given IV push, and within minutes Bob C. awakens, begins talking, and exhibits an improved respiratory rate. He admits to drinking some whiskey and taking a handful of several combination tablets of hydrocodone and acetaminophen shortly before he was dropped off at the ED.

In addition to routine laboratory assessment, a serum acetaminophen concentration is determined. During the next 24 hours, he receives supportive care in the critical care unit and requires two additional doses of naloxone. He is scheduled for a psychiatric evaluation to assess treatment options for his substance abuse, but he walks out of the hospital against medical advice on the second day. A urine drug screen by immunoassay that was obtained in the ED is reported as positive for opiates and marijuana on the morning of his second day of hospitalization. The serum acetaminophen concentration reported 2 hours after ED arrival was 60 mcg/mL, which was obtained approximately 6 hours after drug ingestion. Ethanol was not included in the drug screen panel.

QUESTION: Was a urine drug screen necessary for the immediate care of this patient? How is a urine drug screen helpful in this type of situation?

DISCUSSION: In emergent situations like this one, which involves an apparent acute opiate overdose, the results of a urine drug screen are not necessary for immediate evaluation and effective treatment. The symptoms and history clearly indicate that an opiate overdose is likely.18,19 The response to naloxone confirms that an opiate is responsible for the CNS depressant effects. Because immediate treatment was necessary, waiting for the results of the preliminary drug screen—even if it was reported within hours—would not change the use of supportive care, glucose, and naloxone. The urine drug screen may be helpful to confirm the diagnosis for the record and assist in guiding substance abuse treatment. Obtaining a serum acetaminophen concentration is important in cases of intentional drug use (ie, suicide attempt and substance abuse). This practice is particularly important in situations of multiple drug exposure, unknown drug exposure, or when acetaminophen may be contained in multiple-ingredient, oral drug products (eg, analgesics, cough and cold medicines, sleep aids, and nonprescription allergy medicines). A serum specimen is needed because acetaminophen is not part of routine urine drug screens, and serum assays on acetaminophen generally have a quick turnaround time so they can be used clinically to assess the potential severity of the exposure. In this patient’s case, the serum acetaminophen concentration did not indicate a risk for hepatotoxicity (Figure 22-1). Another benefit of obtaining a serum acetaminophen concentration in this case is that it indirectly confirms that an opioid combination product was involved and is consistent with his response to naloxone.

Drug screening is also used in the criminal justice system for several purposes, such as informing judges for setting bail and sentencing, monitoring whether specified drug abstinence is being observed, and identifying individuals in need of treatment. For example, a positive drug test result at the time of arrest may identify substance abusers who need medical treatment prior to incarceration, which may result in a pretrial release condition that incorporates periodic drug testing. If a defendant is being monitored while on parole or work release, a drug screen can verify that he or she is remaining drug free. Drug tests in prisons can also assist in monitoring substance use in jail.

The impact of a drug screen result can be profound if it affects decisions of medical care, employment, legal importance, and a person’s reputation. In addition, several factors can affect the reliability and interpretation of drug screen results. These issues should be considered when evaluating a drug screen and are described in the following section.

Unique Considerations

When a urine drug screen is reported as negative, it does not mean that the drug was not present or not taken—it means that it was not detected. The drug in question may not be part of a testing panel of the particular drug screen (Table 22-6). For example, methadone, meperidine, and fentanyl are not detected on opiate immunoassays.13,23 Illicitly synthesized and manufactured analogs or homologs of drugs or substances, also called designer drugs, are not detected by routine drug screens because the chemical structure is often unknown, a reference standard and assay have yet to be developed, and variations of a chemical structure are frequently introduced into the illicit drug marketplace. At this time, there are no commercial immunoassays for the increasing number of illicit fentanyl analogs. Another factor may involve urine that is too dilute for detection of the substance. This may be due to renal disease, intentional dilution to avoid detection, or administration of large volumes of IV fluids as part of a critically ill patient’s care. The urine may have been collected before the drug was excreted, but this is unlikely in most symptomatic acute overdoses or poisonings. The time that an individual tests positive (ie, the drug detection time) depends on pharmacologic factors, including dose, route of administration, rates of metabolism and elimination, and analytical factors (eg, sensitivity, specificity, and accuracy). In some cases, the urine sample may have been intentionally adulterated to mask or avoid detection.

TABLE 22-6.

Categories of Drugs and Chemicals Often Not Detected by Routine Drug Screensa

Androgenic anabolic steroids

Anesthetics (eg, ketamine, lidocaine)

Angiotensin-converting enzyme inhibitors

Animal venoms

Antidysrhythmic drugs

Anticoagulant drugs

β-adrenergic agonists

β-adrenergic antagonists

Calcium channel antagonists

Chemical terrorism agents

Dietary supplementsb

Designer cannabinoids

Designer cathinones (eg, bath salts, flakka)

Designer phenethylamines (eg, 2Cs, N-BOMe drugs)

Heavy metals (eg, lead, arsenic, and mercury)c

Hydrocarbon solvents and inhalants

Nonbenzodiazepine hypnotics (eg, zolpidem, eszopiclone, zaleplon)

Pesticides

Plant toxins

Selective serotonin reuptake inhibitors

Synthetic opioids (eg, fentanyl, meperidine, methadone)

aSee Quickviews for more examples.

bThose without chemically similar drug counterparts are not detected on a drug screen.

cHeavy metals require a special collection container, collection duration, and assay.

Adulteration of a urine sample either intentionally or unintentionally can lead to negative or false-positive results through several means.10,23,24 A freshly voided urine sample may be replaced with a drug-free sample when urine collection is not directly observed. The ingestion of large volumes of water with or without a diuretic may dilute a drug in the urine, thereby reducing the concentration of the urine below the assay detection limit. Urine specimens for workplace testing and substance abuse monitoring are tested for temperature within 4 to 5 minutes after collection and later tested for creatinine concentration, pH, specific gravity, and the presence of oxidizing adulterants (eg, chromates, nitrites) as part of routine specimen validity testing.

Adding a chemical to a urine sample may invalidate some test results. Adulteration products that are available through the Internet contain chemicals such as soaps, glutaraldehyde, nitrites, other oxidants, and hydrochloric acid. Depending on the assay method and test, these substances may interfere with absorbance rates or enzyme activity, produce false-positive or false-negative results, or oxidize metabolites that are measured in the immunoassay. For example, some chromate-based and peroxidase-based oxidizers degrade 9-carboxy-tetrahydrocannabinol, a principal metabolite of tetrahydrocannabinol, and lead to a negative result for marijuana.23,24 Taking large amounts of sustained-release niacin (2.5 to 5.5 g over 36 to 48 hours) has been promoted on the Internet as a means to rid the body of cocaine and marijuana and interfere with urine drug screens. Niacin may also darken diluted urine to seem “normal” in appearance. This practice is unlikely to produce the desired outcome, but it has produced niacin poisonings ranging from skin flushing to life-threatening symptoms that required hospitalization.25 The effects of adulterants vary with the immunoassay technique and the specific test used by the laboratory; they are not reliable ways to mask drug use. Most adulterants do not affect the GC-MS or liquid chromatography with tandem mass spectrometry analysis for drugs in urine, but such a confirmatory step would be ordered only if there was a high suspicion of adulteration. A positive immunoassay result is typically used to justify the use of a confirmatory GC-MS or liquid chromatography with tandem mass spectrometry analysis.

A positive drug test can show the presence of specific drugs in urine at the detectable level of the test. It does not indicate the dosage, when the drug was administered, how it was administered, or the degree of impairment. Many drugs can be detected in urine for up to 3 days after being taken and some up to 2 weeks or more (Table 22-7).11,13,23,24 It is possible for a legitimate substance in the urine to interact with the immunoassay and produce a false-positive result.13,24,26,27

TABLE 22-7.

Detection Times and Interfering Substances for Immunoassay Urine Drug Screensa,b

DRUG

DETECTION TIME

POTENTIAL FALSE-POSITIVE AGENTS AND COMMENTS

Amphetamines

2–4 days; up to 7–10 days with prolonged or heavy use

Ephedrine, pseudoephedrine, ephedra (ma huang), phenylephrine, selegiline, chlorpromazine, promethazine, trazodone, bupropion, desipramine, trimipramine, ritodrine, amantadine, ranitidine, phenylpropanolamine, brompheniramine, 3,4-methylenedioxy-N-methamphetamine (MDMA, Ecstacy), isometheptene, labetalol, phentermine, methylphenidate, isoxsuprine, trimethobenzamide

Barbiturates

Short-acting, 1–7 days; intermediate-acting, 1–3 wk; chronic use, up to 4 wks

Ibuprofen, naproxen

Benzodiazepines

Up to 1 wk; up to 4 wk with chronic use of some agents

Oxaprozin, sertraline; benzodiazepines vary in cross-reactivity, persistence, and detectability; flunitrazepam may not be detected

Cocaine metabolite (benzoylecgonine)

12–72 hr; up to 1–2 wk with prolonged or heavy use

Cross-reactivity with cocaethylene varies with the assay because assay is directed to benzoylecgonine; false positives from caine anesthetics and other drugs are unlikely

LSD

1–2 days typically; up to 5 days possible

Marijuana metabolite (δ 9-tetrahydrocannabinol-9-carboxylic acid)

1–5 days; 1 mo or more with prolonged or heavy use

Efavirenz, pantoprazole; ibuprofen, naproxen, tolmetin are possible but uncommon; patients taking dronabinol also have positive test results; designer cannabinoids are not detected

Methadone

3–14 days

Diphenhydramine, doxylamine, clomipramine, chlorpromazine, thioridazine, quetiapine, verapamil

Opioids

2–3 days typically; up to 6 days with sustained-release formulations; up to 1 wk with prolonged or heavy use

Rifampin, some fluoroquinolones, poppy seeds, quinine in tonic water; the assay is directed toward morphine with varying cross-reactivity for codeine, oxycodone, hydrocodone, and other semisynthetic opioids; synthetic opioids (eg, fentanyl, meperidine, methadone, pentazocine, propoxyphene, tramadol, buprenorphine, loperamide) have minimal cross-reactivity and may not be detected

Phencyclidine (PCP)

2–10 days; 1 mo or more with prolonged or heavy use

Ketamine, dextromethorphan, diphenhydramine, imipramine, mesoridazine, thioridazine, venlafaxine, ibuprofen, meperidine, tramadol

aTime after which a drug screen remains positive after last use.

bBecause performance characteristics may vary with the type of immunoassay, manufacturer, and lot; consult the laboratory technician and package insert for the particular test.

Source: Data from references 11, 23, 24, 26, 27.

Exposure to interfering substances can affect the results of an immunoassay urine drug screen (Table 22-7). A positive immunoassay result for opiates may result from the ingestion of pastries containing poppy seeds because they contain codeine and morphine in small, but sufficient, amounts to render the test positive. The result is a true positive but not a positive indicator of drug abuse. The immunoassay for amphetamines is prone to false-positive results from drugs with similar structures such as ephedrine, pseudoephedrine, and bupropion.13,24,26 Also, drugs seemingly dissimilar from the target of an immunoassay can cause false-positive results. For example, naproxen can produce false-positive results for marijuana and barbiturates and was found to do so in 1 of 14 volunteers tested.28 Most fluoroquinolone antibiotics can produce false-positive opiate results, but this interference varies with the fluoroquinolone and immunoassay.29 The immunoassay manufacturer’s package insert should be consulted for information on known interfering substances. In workplace settings, the MRO is obligated to assess whether a person’s legitimate drug therapy could interfere with the result (Minicase 3).

The persistence of the substance in the urine is an important factor in the interpretation of the results (Table 22-7).26 For laboratory results reported as negative, it may indicate that the specimen was obtained too early or too late after exposure to a chemical, thereby producing a urine specimen with insufficient concentration of the drug to lead to a positive result. Drugs with short half-lives, such as amphetamines, may not be detectable several hours after use. A common concern for individuals undergoing workplace testing is the length of time after use that the drug is still detectable. This varies with the sensitivity of the assay, whether the assay is directed to the parent drug or the metabolite, whether the drug or its metabolites exhibits extensive distribution to tissues that will affect its half-life, the dose of the drug taken, and whether the drug was used chronically or only once. For example, cocaine is rarely detected in a urine specimen because of its rapid metabolism. Immunoassays are directed to cocaine metabolites, such as benzoylecgonine, which are detected for up to 2 to 3 days after use and up to 1 to 2 weeks with heavy use. The major active component of marijuana, δ-9-tetrahydrocannabinol, is converted to several metabolites of which δ-9-tetrahydrocannabinol-9-carboxylic acid is the agent to which antibodies are directed in many immunoassays. This metabolite is distributed to tissues and can be detected for days to weeks after use.13,26 Chronic or heavy use can lead to detection up to a month or more after stopping use (Minicase 4). Immunoassays may lead to false-negative reports in part due to incomplete cross-reactivity across a drug class. For example, the benzodiazepine immunoassay is designed to detect oxazepam, nordiazepam, and temazepam, which are metabolites of diazepam, but the assay does not react with alprazolam, clonazepam, or lorazepam.30

Workplace Drug Screen Interpretations

Beau G., a 45-year-old pharmacist, applies for a position at a hospital pharmacy. As part of his pre-employment evaluation, he is asked to provide a urine specimen in a specially designed room for drug testing. His urine sample is positive for opiates and marijuana by immunoassay. His case is referred to the hospital’s MRO for a review of the findings. The physician orders a confirmatory test on the same urine specimen. The human resources department of the hospital learns from his current employer that he is an above average worker with no history of substance abuse. A criminal background check is negative for any criminal record. The MRO contacts Beau G. and learns that he was taking acetaminophen and codeine prescribed for pain from suturing of a laceration of his hand for 2 days prior to drug testing. He also routinely takes pantoprazole (Protonix) for gastroesophageal reflux. He had forgotten to list the recent use of these drugs on his employment application because his injured hand began to ache while writing.

QUESTION: Has this patient used any drugs or substances that should prevent him from being considered for employment?

DISCUSSION: Consideration of several factors is important in interpreting the urine drug screen result in this case. The patient has no obvious symptoms of intoxication and has a good employment record. It is likely that the codeine prescribed for pain control produced the positive opiate result. This drug is being used for a legitimate purpose with a valid prescription. The positive test for marijuana is likely from his use of pantoprazole causing a false-positive result. The confirmatory test by GC-MS was negative for marijuana, but it was positive for codeine and morphine. Codeine is metabolized in part to morphine. The MRO reviewing this case would likely conclude that the test results are not indicative of opioid abuse and the marijuana immunoassay result was a false positive. If there are concerns about his suitability for employment, he may be subjected to an unannounced drug test during his probationary employment period. Acetaminophen and pantoprazole were not reported as a result because they were not on the routine assay panel.

Evidence of Heroin

Danny W., a 23-year-old assembly line worker at a computer manufacturing facility, is examined by the company’s physician within an hour of being involved in a workplace accident. She observes a laceration on his left arm, pupil size of 1 to 2 mm (normal, 2 to 5 mm), bilateral ptosis, and recent punctate lesions on the left antecubital fossa. The rest of the physical exam is unremarkable. Danny W. denies eating poppy seeds, taking any medication or dietary supplement, or having a neurologic condition. He has no history of substance abuse in his files. The physician suspects heroin use and orders a focused urine drug test for opiates. Several days later, the laboratory report indicates positive results for morphine, codeine, and 6-acetylmorphine.

QUESTION: Has this patient used a drug or substance that would impair his ability to work? What, if any, substance is likely?

DISCUSSION: This patient has likely used heroin several hours before the accident and several symptoms are consistent with opiate intoxication. Heroin may not be present in sufficient amounts to be detected, in part, because it is metabolized to several compounds such as morphine and 6-acetylmorphine, which can be detected in the urine of heroin users. Because 6-acetylmorphine is only found in urine following heroin use, its presence confirms heroin but other opioids could also contribute to his symptoms. The presence of small amounts of codeine in heroin abusers is likely from contamination of the heroin with codeine and is not because codeine is a metabolic byproduct of heroin or because he had consumed codeine.

Interpreting Cocaine Results

Shelly N., a 56-year-old supervisor for a large utility company, had recently conducted an inspection at a nuclear power plant. She then left for a 2-week vacation with a friend. After returning to work, she was asked to submit a urine sample for drug testing because the company performs random drug tests for compliance with regulatory, insurance, and contractual requirements. A week later, the results of the immunoassay are reported as positive for the cocaine metabolite, benzoylecgonine. A confirmatory test by GC-MS confirms the immunoassay result. Shelly N. is asked to report to the company’s medical office. During the interview with the physician, she denies illicit drug use but states that she had dental work performed immediately before returning to work from her vacation and that she had received procaine hydrochloride (Novocaine) for local anesthesia.

QUESTION: What caused the positive test result for cocaine?

DISCUSSION: This patient apparently believed that any substance with a name ending in -caine must share chemical similarity with cocaine and could be a probable cause of a false-positive result. Although interference with immunoassays is possible, a false positive for cocaine with local anesthetics is unlikely unless the anesthetic preparation contains cocaine. The positive result was confirmed by a confirmatory test that is not subject to this type of interference. In this patient’s case, use of cocaine is the most likely explanation for the positive result.

For clinical applications, the time it takes for the test result to be reported to the clinician after specimen collection, also known as turnaround time, can affect the use of the drug screen. Many hospital laboratories can perform preliminary immunoassay urine drug screens using mechanized analytical technology, which is used for common clinical tests or using dedicated desktop analyzers. Results from in-hospital laboratories can often be returned within 2 hours of collection. For many urgent situations, such as an acute overdose or poisoning, this delay is unlikely to influence the immediate therapy of the victim. The results may lead to later consideration of alternative or additional diagnoses. Most clinics, small hospitals, or specimen collection sites do not possess such capability and must rely on making the specimen a “send out” that is performed at a nearby or regional reference laboratory. The turnaround time from a reference laboratory varies with the laboratory and the need for urgency. Most results for clinical applications are reported within 24 to 48 hours. However, some results may take up to 3 to 7 days. In some situations, such as pre-employment workplace testing, this delay is acceptable. The turnaround time for confirmatory testing depends on the laboratory, transportation time from the collection site to the laboratory, the tests being performed or requested, and the need for urgency. The delay could be as short as 24 hours or as long as a month or more, particularly for postmortem samples (Minicase 5).

SERUM CONCENTRATIONS

Objectives of Analysis

Quantitative assays determine the concentration of a substance in a biological specimen; typically this involves serum. The availability of serum concentrations for toxins is based on considerations of whether the concentration correlates with an effect, the outcome or need for therapy, the existing use of the assay for another application such as therapeutic drug monitoring, and technical ease of performing the assay. Serum is typically not used for drug screening purposes in clinical or workplace settings.

Many poisonings and overdoses can be adequately managed without quantitative analysis.9,19 A history of the exposure, signs and symptoms, and routinely available clinical tests—such as full blood count, electrolytes, glucose, International Normalized Ratio, liver function tests, blood urea nitrogen, serum creatinine, anion gap, serum osmolality and osmolal gap, arterial blood gases, and creatinine kinase—can guide patient management decisions. Intravenous lipid emulsion (ILE) therapy (eg, infusing bolus doses of Intralipid) is an increasingly used rescue therapy for toxicity and poisoning from local anesthetics and highly lipophilic drugs. There is mounting evidence that the resulting lipemia from ILE may affect common clinical laboratory tests and drug concentration assays, leading to spurious results when the blood sample is drawn during or close to the administration of ILE.31

Serum concentrations of potential toxins can be complementary to clinical tests or become essential in several situations (Table 22-8).16 A serum concentration can confirm the diagnosis of a poisoning when in doubt or when a quantitative assessment in the serum is important to interpret a qualitative urine drug screen. When there is a relationship between serum concentration and toxicity, a serum concentration can assist in patient evaluation or for medicolegal purposes. When sustained-release drug formulations have been ingested, serial serum concentrations can indicate when peak serum concentrations have occurred and whether efforts to decontaminate the gastrointestinal tract with activated charcoal or whole bowel irrigation have been achieved. A serum concentration can also be useful in determining when to reinitiate drug therapy after the drug has caused toxicity. For some agents, serum concentrations can guide the decision to use therapies that are often risky, invasive, or expensive such as antidotes (eg, acetylcysteine, digoxin immune antibody, and fomepizole) or special treatments (eg, hemodialysis and hyperbaric oxygen).

TABLE 22-8.

Examples of the Use of Therapies to Treat Toxicity Guided by Serum Concentrations

THERAPY

DRUG OR TOXIN

Antidote

Acetaminophen, ethylene glycol, methanol

Chelation

Iron, lead

Hemodialysis

Ethylene glycol, lithium, methanol, salicylate, theophylline, valproic acid

Multiple-dose activated charcoal

Carbamazepine, phenobarbital, theophylline, valproic acid

Toxin-specific antibody

Digoxin

Urine alkalinization

Phenobarbital, salicylate

General Analytical Techniques

There is no standardized panel of quantitative serum assays for toxicologic use, and the availability of tests differs by individual laboratory. Generally, serum concentrations use existing technologies (eg, immunoassay, spectrophotometry, gas chromatography, high-performance liquid chromatography, and atomic absorption spectrometry) that are commonly used for therapeutic drug monitoring (see Chapter 2). Assays for carboxyhemoglobin, methemoglobinemia, and serum cholinesterase activity are available in many hospitals.16 In most toxicological applications, the specimen is usually 5 to 10 mL of blood in adults (1 to 5 mL in children depending on the assay) that has been allowed to clot for several minutes. It is then centrifuged, and the clear serum, which is devoid of red blood cells and coagulants, is aspirated and subjected to analysis or frozen for later analysis. The type of test tube, test tube additive, and quantity of blood necessary should be verified with the laboratory prior to blood collection.

Common Applications

Serum concentrations of several drugs and chemicals can be helpful in the assessment of patients who may be poisoned or overdosed and arrive at a hospital for evaluation and treatment. Although general treatment approaches—such as supportive care, resuscitation, symptomatic care, and decontamination—are performed without the need of serum concentrations, the severity of several toxicities are related to serum concentrations (Table 22-8). The examples of ethanol, salicylates, acetaminophen, and digoxin demonstrate important principles in the application of serum concentrations to toxicity and therapy.

One of the most widely studied and used toxicologic tests involves blood, serum, or breath ethanol concentrations. Because of the absence of protein binding and small volume of ethanol distribution, the serum concentration generally correlates with many of the acute toxic effects of ethanol, as shown in Table 22-9.32 Regular ethanol use can lead to tolerance, and ethanol concentrations in excess of 0.4% (400 mg/dL) can easily be tolerated by some patients (eg, they can converse and exhibit stable vital signs).33,34 Conversely, uninitiated drinkers, such as small children who ingest household products containing ethanol (eg, cologne and mouthwash) and those who concurrently ingest other central nervous system (CNS) depressants, may have an exaggerated effect. Most acute poisonings can be managed with supportive and symptomatic care; an unstable patient with exceedingly high ethanol concentrations may be the rare candidate for hemodialysis.

TABLE 22-9.

Relationship of Blood Ethanol Concentration and Toxic Effects

BLOOD ETHANOL CONCENTRATION (mg/dL)

TOXIC EFFECT OR CONSEQUENCE

0.08% (80)

Legal definition for driving impairment

0.15% (150)

Euphoria, loss of critical judgment, slurred speech, incoordination, drowsiness

0.2% (200)

Increased incoordination, staggering gait, slurred speech, lethargy, disorientation, visual disturbances (diplopia, reduced acuity, and perception)

0.3% (300)

Loss of motor functions, marked decreased response to stimuli, impaired consciousness, marked incoordination and inability to stand or walk, vomiting and incontinence, possible amnesia of the event

0.4% (≥400)

Comatose, unresponsive to physical stimuli, absent reflexes, unstable vital signs, shallow and decreased respirations, hypotension, hypothermia, potentially lethal

Source: Adapted from National Highway Traffic Safety Administration. The ABCs of BAC: a guide to understanding blood alcohol concentration and alcohol impairment. https://www.nhtsa.gov/sites/nhtsa.dot.gov/files/809844-theabcsofbac.pdf.

Ethanol concentrations also have medicolegal applications involving driving or work performance and ethanol intake. In 2005, the minimum legal threshold for driving under the influence of ethanol intoxication was set by all states of the United States at blood ethanol concentrations of 0.08% (equivalent to 0.08 g/dL or 80 mg/dL).32 This value can be determined at the scene or at bedside by a breath alcohol test.35 The breath alcohol test is based on the assumption that equilibrium exists between ethanol in the blood supply of the lung and the alveolar air at a relatively uniform partition ratio. A number of variables can affect this relationship, such as temperature, hematocrit, and sampling technique. The National Highway Traffic and Safety Administration publishes a list of breath alcohol testing devices that conform to their standards (www.nhtsa.gov).

Because ethanol concentrations are reported in several different units for either serum or blood, verification of the unit of measure is important.16,36 Further, many hospital-based laboratories perform ethanol determinations on serum and use the units of milligrams/deciliter versus forensic situations that typically use blood and report the value as %, g%, or grams/deciliter (all of which are equivalent expressions except milligrams/deciliter). Serum concentrations of ethanol are greater than blood concentrations by a median factor of 1.2, which varies with the hematocrit value because of the greater water content of serum compared with whole blood.16,36 Although legal standards are written in terms of whole blood concentrations, this difference is without clinical significance.

Ethanol is also used as a drug to treat poisonings by methanol (blindness, acidosis, and death) and ethylene glycol (acidosis, renal failure, and death). To achieve a consistent concentration near 100 mg/dL, serial serum ethanol concentrations are obtained to ensure that sufficient quantities have been administered to prevent severe toxicities of methanol and ethylene glycol (during therapy, hemodialysis removes ethanol while also removing methanol and ethylene glycol). Fomepizole, which blocks the metabolism of methanol and ethylene glycol to prevent the formation of toxic metabolites, was U.S. Food and Drug Administration (FDA)-approved for use in 1997, and the use of ethanol for these poisonings has decreased.

An early attempt to correlate serum drug concentrations with acute toxicity over time involved the Done nomogram for salicylate poisoning.37 Categories of toxicity (mild, moderate, and severe) were demarcated on a semilogarithmic plot of serum salicylate versus time after ingestion as an aid to interpreting serum concentrations. Given the limited knowledge available at the time, the nomogram was based on several assumptions (zero-order kinetics and back extrapolation of single concentrations to time zero) that were later proven to be false. The nomogram did not guide therapy to any great extent and was not confirmed to be clinically useful in subsequent studies.38

Clinical findings such as vital signs, electrolytes, anion gap, and arterial blood gases, which have quick turnaround times in most hospitals, are more direct indicators of salicylate toxicity and are now preferred to the Done nomogram. A patient, with exceedingly high serum salicylate concentrations (> 90 mg/dL) who is unresponsive to supportive and symptomatic therapy, may benefit from hemodialysis to remove salicylate from the body.39 Elderly and very young patients with unexplained changes in consciousness, acid–base balance, and respiratory rate who present to an ED could be suffering from unrecognized acute or chronic salicylate poisoning.39,40 A routine serum salicylate concentration in such patients could determine the contribution of excessive salicylate to their symptoms.

Serum acetaminophen concentrations after acute overdoses are essential in assessing the potential severity of poisoning and determining the need for antidotal therapy with acetylcysteine.41,42 Acetaminophen toxicity differs from many other poisonings in that there is delay of significant symptoms by 1 to 3 days after ingestion, whereas most other poisonings have definite symptoms within 6 hours of exposure. This delay in onset makes it difficult to use signs, symptoms, and clinical diagnostic tests (such as serum transaminase, bilirubin, or International Normalized Ratio) as an early means to assess the risk of acetaminophen toxicity.9 A serum concentration of acetaminophen obtained at least 4 hours after an acute ingestion (Figure 22-1) can be used to assess whether a patient is at risk for developing acetaminophen hepatotoxicity.41,42 The acetaminophen nomogram is intended to be used only for an acute, single-episode ingestion of immediate-release acetaminophen and not in situations when acetaminophen is ingested in supratherapeutic doses over several hours or days.

FIGURE 22-1.
FIGURE 22-1.

Risk of hepatotoxicity after an acute ingestion of acetaminophen. Acetaminophen serum concentrations in the shaded area are not associated with hepatotoxicity, whereas those above the line are at risk for developing hepatotoxicity and acetylcysteine therapy should be considered.

The semilogarithmic plot of serum acetaminophen concentration versus time, also called the Rumack-Matthew nomogram or acetaminophen nomogram, is also used to determine whether there is a need to administer acetylcysteine to reduce the risk of toxicity.41,42 If the results are not expected to be available within 10 hours of ingestion, acetylcysteine is typically administered provisionally and then continued or discontinued based on the serum acetaminophen concentration. In situations when the specimen is sent to a reference laboratory, the results may take several days to be reported, and, consequently, the patient may receive the entire course of therapy that may last for 72 hours with the oral regimen or 21 hours with the IV regimen. Because of the widespread availability of acetaminophen, it is commonly ingested in suicide attempts. Several professional groups have advocated that all patients who are suspected of intentionally taking drugs should have a serum acetaminophen concentration determined as part of their evaluation in the ED.19 In the case of acetaminophen poisoning, the serum concentration becomes a valuable determinant of recognition, therapy, and disposition (Minicase 6).

Value of Acetaminophen Concentrations

A mother calls a poison control center about her 16-year-old daughter, Kelly A., who has acutely ingested approximately 30 acetaminophen 500-mg tablets 1 hour ago. She thinks that her daughter was “trying to hurt herself.” The pharmacist at the poison center refers Kelly A. to the nearest hospital for evaluation due to the amount of acetaminophen and the intent of the ingestion. The mother is asked to bring any medicine to which Kelly A. may have had access. At the ED, Kelly A. vomits several times but has no other physical complaints or symptoms. A physical exam is unremarkable except for the vomiting. Baseline electrolytes, complete blood count, liver function tests, urine drug screen, and a pregnancy test are ordered. An IV line is placed and maintenance IV fluids are started. At 4 hours after the acetaminophen ingestion, a blood specimen is drawn to determine the serum acetaminophen concentration. Ninety minutes later, the result is reported as 234 mcg/mL.

QUESTION: Is this patient at risk for acetaminophen hepatotoxicity? Should she be treated with acetylcysteine?

DISCUSSION: When the serum acetaminophen concentration of 234 mcg/mL is plotted on the acetaminophen nomogram at 4 hours (Figure 22-1), it is clearly above the treatment line. This indicates that this patient is at risk for developing hepatotoxicity and that treatment with acetylcysteine should be initiated immediately.41 The dose of acetaminophen that she ingested is also associated with a risk of developing hepatotoxicity, but patients with intentional overdoses (substance abuse or attempted suicide) do not always provide accurate histories. If the results of the acetaminophen assay would not have been available within 2 hours of sampling or within 8 to 10 hours of ingestion, acetylcysteine therapy would have been started provisionally. After learning the acetaminophen concentration, the physician would have decided to continue or stop acetylcysteine. Because most patients do not exhibit signs and symptoms of acute hepatic injury until 1 to 3 days after acute acetaminophen overdose, serum transaminase and bilirubin values would not be expected to be abnormal at the time of this patient’s assessment in the ED.

A serum concentration can also guide the use or dosage determination of antidotes that are in short supply or are expensive, such as digoxin immune fragment antibody (DigiFab). Life-threatening acute or chronic digoxin toxicity may require the administration of digoxin immune fragment antibody to quickly reverse the toxic effects of digoxin. The dose of digoxin immune fragment antibody can be determined empirically, based on the amount ingested, or by a steady-state serum concentration (consult current prescribing information).43,44
Number of vials of digoxin immune fragment antibody=serum concentration of digoxin(ng/mL)×patient weight(kg)/100

Once the digoxin immune fragment antibody is administered, the serum concentration of digoxin precipitously rises and has no correlation to the degree of toxicity (Figure 22-2).43,44 This sharp increase of digoxin reflects total digoxin (protein-bound and unbound) in the serum that has been redistributed from tissue sites. The digoxin bound to digoxin immune fragment antibody is not pharmacologically active, and it is eventually excreted in the urine.

FIGURE 22-2.
FIGURE 22-2.

Simulated serum digoxin concentrations before and after administration of digoxin fragment antibodies (Fab). Total digoxin concentrations (solid line) rapidly rise to often dramatically high concentrations after administration of digoxin-Fab. Total digoxin concentrations fall with the excretion of digoxin bound to Fab. Free digoxin concentrations (dashed line) are associated with pharmacologic activity and rapidly drop to low or unmeasurable concentrations within one hour of digoxin-Fab administration. The shaded area represents the range of therapeutic serum digoxin concentrations.

Unique Considerations

The timing of sample collection for poisoned or overdosed patients is variable due to the varying times of arrival at an ED after the exposure and the delay in the recognition of poisoning (unless it is obvious from the history or symptoms).45 Most specimens are collected at the time of admission to the ED except when specified times are important, such as acetaminophen or when adequate absorption has yet to occur. This variability of serum concentrations among patients makes it difficult to clearly establish a relationship with the concentration and toxicity.

The pharmacokinetics of drugs and chemicals on overdose, sometimes termed toxicokinetics, can affect interpretation of a serum concentration.9 Few studies have compared the pharmacokinetics of drugs in therapeutic and toxic doses because toxic doses cannot be administered to human volunteers and overdosed patients are too heterogeneous to make clear assessments. Nevertheless, there are several examples in which the absorption, distribution, metabolism, and elimination of drugs are significantly different on overdose.46,47 It is generally inappropriate to apply pharmacokinetic parameters derived from therapeutic doses to situations when massive overdoses are involved. Many patients who are poisoned or have overdosed are critically ill, and multiple samples of blood have been obtained for a variety of tests to monitor their condition. When the toxic agent is recognized late in the course of therapy or when serial determinations could be helpful in understanding some aspect of therapy or toxicity, scavenging aliquots of existing serum samples may be helpful for retrospective toxicological analysis. Laboratories often retain serum samples for several days in case a retest is needed so immediate consultation with the clinical laboratory technician is essential to save the specimen for testing. Another sample collection technique involves collecting a blood or urine specimen at presentation to the ED but not performing the assay. This approach, sometimes called toxicology hold, allows collection of a specimen at a time when concentrations may be highest even if the need for the assay may not be clear.13 The blood specimen can be refrigerated or the serum or urine can be frozen and assayed on request.

SPECIAL SITUATIONS

Other Biological Specimens

There is great interest in using other biological specimen—such as hair, saliva, perspiration, and expired breath—and the application of POCTs for quantitative or qualitative analysis.46 These are typically less invasive than venipuncture, and some provide unique markers of long-term exposure or use (Table 22-10). Once a technology has been fully validated and sampling techniques refined to minimize interference, POCTs can be useful for drug screens at the bedside and worksite or longitudinal evaluation of chronic use (eg, cocaine and marijuana in hair samples). The FDA has approved several types of POCTs for clinical use. Although POCT results are typically available within 5 to 10 minutes, the test may be less accurate than laboratory-based analysis when the operator is not sufficiently trained and experienced with the particular POCT device.14 A common and accepted application of POCTs is breath alcohol determination to assess driving impairment from ethanol use at the scene of an accident or arrest.35

TABLE 22-10.

Characteristics of Selected Specimens for Toxicological Analysis

SPECIMEN

STRENGTHS

WEAKNESSES

DETECTION TIMES

Urine

Available in sufficient quantities

Higher concentrations of drugs or metabolites in urine than in blood

Well-researched testing techniques

Relatively inexpensive

Availability of POCTs

Specimen can be adulterated, substituted, or diluted

May require observed collection

Some individuals experience “shy bladder” syndrome and cannot produce a specimen

Biological hazard for specimen handling and shipping to laboratory

Limited window of detection after drug use

Typically 1–5 days, some substances are detected for 1–4 wk

Hair

Observed and noninvasive specimen collection

Good specimen stability (does not deteriorate)

Convenient shipping and storage (no need to refrigerate)

Difficult to adulterate or substitute

Few labs perform testing

Costly and time-consuming to prepare specimen for testing

Difficult to interpret results

Cannot detect alcohol use

Does not detect recent drug use (ie, 7–10 days prior to test)

Difficult to detect low-level use (eg, single-episode)

Costly

Longest window of detection; best suited for chronic drug use

Depends on hair length in the sample

1.5-in specimen reflects a 3-mo history; hair grows about 0.5 in per month

Saliva

Observed and noninvasive specimen collection

Minimal risk of tampering

Samples can be collected easily in virtually any setting

Availability of POCTs

Drugs and metabolites do not remain in oral fluids as long as they do in urine

Limited specimen volume

Requires supervision for 10–30 min before sampling

Oral fluids contaminated by marijuana do not reflect presence in saliva and blood

Reflects recent drug use

(ie, approximately 10–24 hr prior to test)

Sweat

Observed and noninvasive specimen collection

Simple application and removal of skin patch

Variable application time of 1–2 wk

Difficult to adulterate

Few labs perform testing

Risk of accidental or deliberate removal of patch

External contamination of the patch may affect results

Requires two visits (application and removal of patch)

Patch retains evidence of drug use for at least 7 days

Detects low levels of some drugs 2–5 hr after last use

Source: Adapted with permission from references 14,24,48.

Forensic and Legal Issues

In addition to clinical and regulatory applications for urine drug screens and serum drug concentrations, toxicological analysis has an important role in providing evidence for suspected cases of homicide, suicide, child abuse, drug-facilitated sexual assault (“drugged date rape”), environmental contamination, malpractice, workers’ compensation, insurance claims, and product liability litigation. Chemical exposure monitoring of workers or the work environment requires specialized approaches such as long-term, onsite monitoring by an industrial hygiene specialist. Toxicological tests are also important in establishing brain death in patients being considered for organ donation or to remove life support. It is essential to establish that the apparent vegetative or unresponsive state is not due to drugs. Whenever legal action is anticipated, it is necessary to maintain a specimen chain-of-custody that can be documented as part of the evidence presentation.10,13

Postmortem analysis of biological specimens, such as gastric contents, organs, vitreous humor, bile, blood, and urine, can assist in determining the cause of death. These specimens are often collected at the time of autopsy, which may be days to weeks after death. The study of the changes that occur in drug distribution and metabolism after death has been called postmortem toxicology or necrokinetics. In addition to diffusion of some drugs to or from tissues and blood after death, the effects of putrefaction, fluid shifts on drug concentrations, and chemical stability need to be considered. This is an evolving field of study, which has already demonstrated that postmortem drug concentrations from various biological specimens may not always be appropriately referenced to drug concentration results derived from living humans.49,50

When unknown powders, tablets, liquids, plant material, or animal material are found at the scene of a suspected life-threatening poisoning or overdose, specialized analysis is required, such as GC-MS and liquid chromatography with tandem mass spectrometry. At times the specimen is sent to a specialized laboratory for analysis, such as the Federal Bureau of Investigation Laboratory. This situation typically involves the local medical examiner, who would oversee the analysis and report the findings to law enforcement officials and prosecuting attorneys.

Pediatrics

The toxicological testing of newborn babies, preschool-age poisoning victims, and adolescents involves several unique ethical, technical, and societal concerns. Intrauterine drug exposure can lead to medical complications of newborns; such abuse may be confirmed by drug screens. When mothers do not admit to prepartal drug use, the routine screening of a newborn’s urine or meconium poses economic and practical challenges, such as the cost of a generalized screening policy, difficulty in obtaining an adequate urine sample from a neonate, and the preanalytical processing of meconium to make it suitable for analysis. Toxicological analysis of the mother’s urine and the neonate’s urine and meconium is helpful for identifying substances that would lead to neonatal abstinence syndrome and informing clinicians of its anticipated onset and duration.51,52

The use of urine drug screens in the pediatric ED provides minimally useful information because the offending agent is typically known and attempts at concealment are infrequent.53 However, a broad or focused drug screen may be helpful for cases of suspected child abuse by poisoning or when the history of the poisoning is unclear.51

Prerequisite drug testing of adolescents for participation in school activities and routine screening by school officials, concerned parents, and pediatricians present several ethical dilemmas. Parents and school officials want assurance that substance abuse is not occurring, but the confidentiality and consent of the adolescent should be recognized. The American Academy of Pediatrics states that it “has strong reservations about testing adolescents at school or at home and believes that more research is needed on both safety and efficacy before school-based testing programs are implemented.”54 This policy statement is at odds with the desire of some parent groups to perform such tests without the adolescent’s consent and with court rulings upholding a school’s ability to perform mass or random drug tests of its students.55 Drug use in school-age children has been associated with a variety of risk-taking behaviors, such as carrying a gun, engaging in unprotected sexual intercourse with multiple partners, and suffering injury from a physical fight.56 These behaviors may indicate the need for monitoring drug abuse with appropriate behavioral and health counseling. Many drug testing products are promoted for home use on the Internet, but their reliability and benefits are questionable.57

Sports and Drugs

Drugs are used by some amateur and professional athletes in hopes of enhancing athletic performance and by nonathletes to improve physical appearance. In 2017, an estimated 2.9% (range by 21 states = 2.1% to 9.2%) of high school seniors (3.3% boys and 2.4% girls) have used androgenic anabolic steroids; of these students, nearly one-third do not participate in sports but use steroids to change their appearance.56,58 The types and variety of substances are typically different from those encountered in poisonings or substance abuse. Most workplace or clinical drug screens do not detect athletic performance-enhancing drugs such as anabolic androgenic steroids, growth hormone, and erythroid-stimulating agents (Table 22-11).59 The international term for drug use in sports is doping, and efforts to combat this practice are referred to as doping control or antidoping.

TABLE 22-11.

Some Purported Athletic Performance-Enhancing Substances

Amino acids (eg, arginine, ornithine, lysine, aspartate, glutamine, leucine, tryptophan, carnitine)

Amphetaminesa

Androgenic anabolic steroids

Androstenedione

Antiestrogenic agents (eg, anastrozole, tamoxifen, clomiphene, fulvestrant)

Antioxidants (eg, megadoses of ascorbic acid [vitamin C], tocopherol [vitamin E], β-carotene)

β-adrenergic blockers

β-2 agonists

Caffeine

Clenbuterol

Cocainea

Corticotropin (ACTH)

Creatine

Designer anabolic steroids

Dehydroepiandrostenedione (DHEA)

Diuretics

Erythropoietin

Ethanol

γ-hydroxybutyrate (GHB)

Human chorionic gonadotropin

Human growth hormone

Selective androgen receptor modulators

Theophylline

aCan be detected on most routine immunoassay urine drug screens. The other substances are typically not detected in routine clinical drug screens.

Governing athletic organizations, such as the International Olympic Committee, the United States Olympic Committee, and the National Collegiate Athletic Association, have established policies and analytical procedures for testing athletes as well as lists of banned substances. Most organized sports observe the World Antidoping Agency’s guidelines for analytical tests, banned substances, and screening procedures.60 The technical and scientific challenges in detecting many of these substances are unique to this field. Using banned drugs can result in an unfair, artificial advantage for competitive athletes and physical injury or permanent disability from the drug’s effects, such as those from anabolic steroids.58,59

Substance Use Disorders

During the past two decades, the abuse of prescription and illicit drugs has risen dramatically and has increased in adolescent and adult age groups.7 This trend has been recognized as a national epidemic.24,61 A consequence of drug and substance abuse is the escalation of a chronic condition—substance abuse disorder. “Substance use disorders are characterized by impairment caused by the recurrent use of alcohol or other drugs (or both), including health problems, disability, and failure to meet major responsibilities at work, school, or home.”5 Virtually any one or more illicit drugs or alcohol can lead to substance use disorder. In 2018, 20.3 million people aged 12 years or older developed substance abuse disorder during the past year. There were 12.2 million people only with alcohol use disorder, 5.4 million people with only illicit drug use disorder, and 2.7 million with alcohol use disorder and illicit drug use disorder.5

Guidelines for the management of chronic pain have been developed or adopted by professional societies, governmental agencies, and medical practices that typically provide guidance for monitoring pain medication with urine drug screening. The frequency and type of drug testing varies with the patient’s history, behavior, adherence, and response. An example of a three-tier approach (Table 22-12) takes these factors in consideration.14

TABLE 22-12.

Example of Three-Tier Approach to Drug Testing for Chronic Pain Medicine

WHEN TO ORDER

DRUG CLASS TO TEST

Tier 1

Routine Monitoring

Amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates/opioids

Tier 2

High-risk patients with a known history of abuse for a medication, prevalence of drug abuse locally, risky polypharmacy, multiple providers, or lack of efficacy or toxicity for a prescribed drug

Alcohol, anticonvulsants, antidepressants, synthetic cathinones, hallucinogens, muscle relaxants, dextromethorphan, ketamine, propoxyphene

Tier 3

As clinically indicated

Nonprescription analgesics, antihistamines, antipsychotics, synthetic cannabinoids

Source: Adapted with permission from Langman LJ, Jannetto PJ. Laboratory medicine practice guideline: using clinical data to monitor drug therapy in pain management patients. American Association of Clinical Chemistry Academy, 2018. https://www.aacc.org/-/media/Files/Science-and-Practice/Practice-Guidelines/Pain-Management/LMPGPain-Management20171220.pdf?la=en&hash=19670524407619F78999AB60731A24CB4901939D.

In evaluating patients who may be abusing prescription drugs, a careful history, physical examination, review of a prescription drug monitoring program, and use of behavioral screening tools are important elements that can be supported by drug screens.41,48,62,63 A urine drug screen can assist in the detection of inappropriate use when there is sufficient suspicion. If a patient is on a methadone treatment program or is regularly receiving opioids for the relief of chronic pain, the urine drug screen should produce positive results. A negative finding could suggest poor adherence and possible diversion (Minicase 7). Characteristics of the drug (eg, short duration of action) and the assay (eg, ability to detect some synthetic opioids) should be considered before discussing the issue with the patient. Knowledge and training at primary care settings on urine drug screening would enhance the ability to detect and help patients who are abusing prescription drugs and help stem the rise in substance use disorder, diversion, and deaths.48 Differences in federal workplace testing and the clinical setting, such as specimen type, collection procedures, drug testing panel, cutoff concentrations, and MRO involvement, should be recognized.10,14,24,48

SUMMARY

Testing for substance abuse, poisonings, and overdose affects society at several levels. Knowledge of assay limitations, sampling procedures, interfering substances, patient factors, and regulatory requirements aids in the interpretation of the value of the test and its clinical relevance. In this chapter, several approaches and applications are discussed, but other situations that involve potential toxins—such as environmental contamination, chemical terrorism, and product safety testing—call for different approaches and pose unique challenges.

Sources of Information

Because test characteristics vary with the type of test, manufacturer, assay kit, setting, and application, information about a specific test is critical for proper use and interpretation. Good communication with laboratory technicians is an important first step in ensuring proper testing. Laboratory technicians can provide guidance on sample collection, cutoff values, interfering substances, and other technical aspects. The package insert for immunoassays or other commercial assay kits is an important and specific guide to assay performance and known interfering substances with the specific assay. There are several textbooks that can be helpful in understanding techniques, values, and interfering substances.6468 Clinical toxicologists in poison control centers (list at www.aapcc.org or contact the local program at 1-800-222-1222 nationwide) can also provide useful information on laboratory tests particularly as they relate to poisonings. Several relevant publications are available at Internet websites of governmental agencies, such as the SAMHSA (www.samhsa.gov) and the U.S. Drug Enforcement Administration (www.dea.gov). These websites can also increase awareness of persistent or emerging drugs of abuse (Minicase 8). Quickviews of eight common urine drug screens by immunoassay include information on the signs and symptoms of these agents after abuse and overdose.9,11,14,23,67,68

Monitoring Chronic Therapy with Opioid Analgesics

Alex P., a 32-year-old construction worker, developed chronic pain after a lower back injury. He currently has a prescription for a long-acting morphine preparation. Alex P. has had a history of anxiety and substance abuse of a variety of illicit and prescription drugs. He is otherwise healthy. During the past 24 months on this medication, he has lost his prescription twice and asked for a replacement. His physician has also written additional prescriptions at times when he complained that the dosage was inadequate to provide pain relief. His current daily total dose of morphine is 120 mg. He was recently arrested for forging a prescription to obtain additional opioid medication. Alex P. has had several random urine drug screens during the past 18 months that have been positive for morphine. On one occasion, the test result was positive for oxycodone for which he had a prescription from another physician.

QUESTION: How can urine drug screens be helpful in assessing adherence to an opioid analgesic regimen and identifying potential abuse of opioids?

DISCUSSION: The opioid drug treatment of non cancer-related chronic pain can be complicated by many factors, such as the need for escalating doses for adequate pain relief, potential for diversion of the drugs by selling or giving the drugs to others, abuse of the drugs to get high or satisfy a drug craving, and the risks of overdose and death. One of the approaches to monitor chronic therapy with opioids is to perform random drug screens. A positive drug screen can support that the person is taking the drug, whereas a negative result should raise the question of whether the person is diverting it to others or has stopped taking it for some reason. A drug screen that shows illicit, nonprescribed drugs or prescriptions from multiple or other prescribers, such as oxycodone in this case, strongly suggests that abuse of other medications is taking place or his current pain medicine is inadequate, which raise the risks for addiction, overdose, and death. The physician is faced with several significant signals in this case that need attention to provide safe and effective care. If the physician is not a pain specialist, referral to one for this patient’s chronic pain care should be considered.

Where’s the LSD?

In a backyard with two friends, Jacob C., an 18-year-old man, began exhibiting bizarre, agitated, hyperactive behavior 30 minutes after putting two paper blotters on his tongue, which were believed to contain lysergic acid diethylamide (LSD). When he soon exhibited seizure activity lasting 15 to 20 minutes, an ambulance was called to the scene. Tonic-clonic seizures continued during transport and hospitalization for another hour, despite aggressive therapy to stop the seizures. During the next 36 hours, Jacob C. exhibited tachycardia, hyperthermia, acidosis, hypertension, renal failure, and minimal responsiveness. A computed tomography scan of his head indicated cerebral edema. A urine drug screen on admission was positive for marijuana and benzodiazepines, the latter from drugs used to manage his seizures. After a complicated hospital course, his pupils became pinpoint and minimally responsive. Magnetic resonance imaging indicated anoxic brain injury. He expired on the fifth day of hospitalization. At autopsy, anoxic brain injury was confirmed, and a sophisticated analysis of his blood, urine, and tissues revealed the presence of a designer hallucinogenic amphetamine, 2C-1NBOMe.

QUESTION: Why was the designer amphetamine not detected in the initial urine drug screen?

DISCUSSION: Only drugs or substances that are part of the drug screen analysis can be detected when considering all potential limitations of a false-negative or false-positive result. In this case, an immunoassay was used for a stat urine drug screen that only included the substances required by SAMHSA (Table 22-5). Marijuana and benzodiazepines are included in this panel, but LSD is not. In this case, knowing the identity of the substance would not have changed the symptomatic and resuscitative treatment he appropriately received. When the medical examiner pursued a more extensive analysis at autopsy, the designer drug was identified. No LSD was detected. This patient’s friends had purchased the 2C-1NBOMe as a “research chemical” on the Internet thinking it was a form of LSD.

LEARNING POINTS

1. How long does it take for a drug to clear the body and result in a negative urine drug screen?

ANSWER: It depends on several factors. Length of time for detection varies with the sensitivity of the assay, whether the assay is directed to the parent drug or the metabolite, whether the drug or its metabolites exhibit extensive distribution to tissues, whether the drug is a sustained release dosage form or is known to form pharmacobezoars (concretions), the drug’s elimination rate (with therapeutic doses and overdoses) from the body, the dose of the drug taken, and whether the drug was used chronically or only once.

2. What does a negative test result from a drug screen mean?

ANSWER: A negative test result does not mean that the drug was not present or not taken; it means that it was not detected. Some reasons include that the drug may not have been part of the testing panel, the concentration of the drug is below the assay’s detection level, the urine may have been too dilute for detection, the urine may have been collected before the drug was excreted in the urine, the urine sample may have been adulterated after collection to mask or avoid detection, or the specimen was obtained too late after the exposure.

3. How can serum concentrations be useful in the treatment of poisoned patients?

ANSWER: When a poisoning or overdose is suspected, a serum concentration is obtained to confirm the diagnosis of a poisoning when in doubt, aid the interpretation of a qualitative urine drug screen, determine whether antidotal therapy is indicated, or determine the effectiveness of a therapy. For assays not primarily intended for overdoses or poisonings (eg, digoxin, iron, phenytoin), drug concentrations occasionally are measured when the assay is used for another application such as therapeutic drug monitoring. In clinical settings, serum is typically not used for drug screening.

4. What should you do if the results do not make sense?

ANSWER: Consider actions that include checking the report and units of measure, talking with the laboratory technician, checking the package insert of the assay, searching the literature, seeking alternative causes of symptoms, and repeating the assay at the same or different laboratory.

5. Why are there so few drugs and substances on drug screens?

ANSWER: Whether a drug or substance is on a drug screen depends on several factors, as follows. The entity paying or requiring the drug screen can include as many drugs on the panel as financially and technically feasible. The SAMHSA panel (Table 22-5) reflects several common drugs of abuse and has been updated periodically through the federal regulatory process. Employers can and do add other drugs of concern for pre-employment, random monitoring, and accident investigation situations. Clinicians can often request or choose from a menu of drug panels to meet the needs of the patient situation or purpose, such as monitoring specific opioid analgesic use, misuse, and adherence. Assays beyond the routine menu are typically performed at a reference laboratory and require a longer turnaround time. In forensic settings, more extensive and sophisticated analytical techniques are often used to identify substances that are compared with an analytical library of known substances. A novel substance, such as a designer drug, poses significant analytical challenges when developing a procedure specific for the substance to identify its chemical composition. The decision to pursue analysis of a specific drug or substance is based on the consideration of the need for analysis, assay availability, timeliness, and cost. A key question to ask is “How will the results be useful for the particular circumstance?”

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QUICKVIEW | Urine Drug Screen, Amphetamines, and Methamphetamine

PARAMETER

DESCRIPTION

COMMENTS

Critical value

Positive

Check for possible interferents; confirm result with confirmatory test

Major causes of…

Positive results

Following ingestion, intranasal application, injection, smoking (methamphetamine)

Associated signs and symptoms

None may be evident at time of specimen collection; may involve exposure to illicit substances; may be used for legitimate purposes; abuse may involve exposure to illicit forms

Typical symptoms include CNS stimulation, euphoria, irritability, insomnia, tremors, seizures, paranoia, and aggressiveness; overdoses cause hypertension, tachycardia, stroke, arrhythmias, cardiovascular collapse, rhabdomyolysis, and hyperthermia

After use, time to…

Negative result from light, sporadic use

2–5 days; clearance is faster in acidic urine

Methylphenidate typically will not be detected

Negative result from chronic use

Up to 2 wk

Possible spurious positive results with immunoassays

Ephedrine, pseudoephedrine, ephedra (ma huang), phenylephrine, selegiline, chlorpromazine, promethazine, trazodone, bupropion, desipramine, trimipramine, ritodrine, amantadine, ranitidine, phenylpropanolamine, brompheniramine, isometheptene, labetalol, phentermine, methylphenidate, isoxsuprine, trimethobenzamide, 3,4-methylenedioxy-N-methamphetamine (MDMA, Ecstasy)

A false-positive result may be caused by patient’s use of drugs and dietary supplements; verify possible false-positive with laboratory and assay package insert

QUICKVIEW | Urine Drug Screen, Barbiturates

PARAMETER

DESCRIPTION

COMMENTS

Critical value

Positive

Check for possible interferents; confirm result with confirmatory test

Major causes of…

Positive results

Following ingestion; rarely injected or used as a suppository

Associated signs and symptoms

None may be evident at time of specimen collection; may involve exposure to medicines used for legitimate purposes or abuse

Typical symptoms include sedation; overdoses cause coma, ataxia, nystagmus, depressed reflexes, hypotension, and respiratory depression; increased sedation with ethanol or other sedatives; primidone is metabolized to phenobarbital

After use, time to…

Negative result from light, sporadic use

1–7 days

Depends on drug and extent and duration of use

Negative result from chronic use

1–3 wk

Phenobarbital may be detected up to 4 wk after stopping use

Possible spurious positive results with immunoassays

Ibuprofen, naproxen

Verify possible false positive with laboratory and assay package insert

QUICKVIEW | Urine Drug Screen, Benzodiazepines

PARAMETER

DESCRIPTION

COMMENTS

Critical value

Positive

Check for possible interferents; confirm result with confirmatory test

Major causes of…

Positive results

Following ingestion or injection

Benzodiazepines vary in cross-reactivity and detectability

Associated signs and symptoms

None may be evident at time of specimen collection; may involve exposure to medicines used for legitimate purposes or abuse; may involve exposure to illicit forms

Typical symptoms include drowsiness, ataxia, slurred speech, sedation; oral overdoses can cause tachycardia and coma with rare severe respiratory or cardiovascular depression; rapid IV use can cause severe respiratory depression; increased sedation with ethanol or other sedatives

After use, time to…

Negative result

Typically up to 2 wk; up to 6 wk with chronic use of some agents

Some benzodiazepines may persist for a longer period of time and some have an active metabolite that may or may not be detected; flunitrazepam may not be detected; not all benzodiazepines will be detected by all immunoassays

Possible spurious positive results with immunoassays

Oxaprozin, sertraline

Verify possible false positive with laboratory and assay package insert

QUICKVIEW | Urine Drug Screen, Benzoylecgonine (Cocaine Metabolite)

PARAMETER

DESCRIPTION

COMMENTS

Critical value

Positive

Check for possible interferents; confirm result with confirmatory test

Major causes of…

Positive results

Following snorting, smoking, injection, topical application (vagina, penis) or rectal insertion; ingestion

Associated signs and symptoms

None may be evident at time of specimen collection with heavy or chronic use; may involve exposure to illicit forms

Typical symptoms include CNS stimulation that produces euphoric effects and hyperstimulation such as dilated pupils, increased temperature, tachycardia and hypertension; overdoses cause stroke, myocardial infarction, seizures, coma, respiratory depression, arrhythmias

After use, time to…

Negative result from light, sporadic use

12–72 hr

Cross-reactivity with cocaethylene (metabolic product of concurrent cocaine and ethanol abuse) varies with the assay

Negative result from

chronic use

Up to 1–2 wk

Possible spurious positive results with immunoassays

Topical anesthetics containing cocaine; coca leaf tea

False positives from caine anesthetics (eg, lidocaine, procaine, benzocaine) are unlikely; verify possible false positive with laboratory and assay package insert

QUICKVIEW | Urine Drug Screen, ∆-9-tetrahydrocannabinol-9-carboxylic Acid

PARAMETER

DESCRIPTION

COMMENTS

Critical value

Positive

Check for possible interferents; confirm result with confirmatory test

Major causes of…

Positive results

Following smoking, ingestion, possible passive inhalation

Patients taking dronabinol will have positive test results

Associated signs and symptoms

None may be evident at time of specimen collection with heavy or chronic use; may involve exposure to illicit substances; may involve exposure to medicine used for legitimate purposes or abuse

Typical symptoms include delirium, conjunctivitis, food craving; other effects include problems with memory, thinking, problem solving, distorted perception, loss of coordination, sedation, tachycardia, hyperemesis syndrome

After use, time to…

Negative result from light, sporadic use

5–7 days

Negative result from chronic use

6–8 wk typically, up to 3 mo possible

May persist for a longer period of time with heavy, long-term use

Possible spurious positive results with immunoassays

Efavirenz, pantoprazole; ibuprofen, naproxen, tolmetin are possible but uncommon

False-positive result

False positive for abuse; verify possible false positive with laboratory and assay package insert

QUICKVIEW | Urine Drug Screen, LSD

PARAMETER

DESCRIPTION

COMMENTS

Critical value

Positive

Check for possible interferents; confirm result with confirmatory test

Major causes of…

Positive results

Following ingestion, placement in buccal cavity or ocular instillation

Not well-absorbed topically

Associated signs and symptoms

May involve exposure to illicit substances

Typical symptoms include unpredictable hallucinogenic effects; physical effects include mydriasis, elevated temperature, tachycardia, hypertension, sweating, loss of appetite, sleeplessness, dry mouth, and tremors; flash-backs months later are possible

After use, time to…

Negative result

24–48 hr typically, up to 5 days possible with heavy use

Possible spurious positive results with immunoassays

LSD is a schedule I drug with no legitimate routine medical use; verify possible false positive with laboratory and assay package insert

QUICKVIEW | Urine Drug Screen, Opioids

PARAMETER

DESCRIPTION

COMMENTS

Critical value

Positive

Check for possible interferents; confirm result with confirmatory test

Major causes of…

Positive results

Following ingestion, injection, dermal application of drug-containing patches, rectal insertion

Synthetic opioids (eg, fentanyl, fentanyl analogs, meperidine, methadone, tramadol, buprenorphine, loperamide) have minimal cross-reactivity and may not be detected

Associated signs and symptoms

None may be evident at time of specimen collection; may involve exposure to illicit substances; may involve exposure to medicines used for legitimate purposes or abuse; ingestion of large amounts of food products made with poppy seeds

Typical symptoms include CNS depression, drowsiness, miosis, constipation; overdoses cause coma, hypotension, respiratory depression, pulmonary edema, seizures; increased sedation with ethanol or other sedatives

Heroin use is confirmed by the presence of 6-acetylmorphine (6-AM)

After use, time to…

Negative result

2–3 days typically, up to 6 days with sustained-release formulations, up to 1 wk with prolonged or heavy use

Possible spurious positive results with immunoassays

Poppy seeds

False positive for drug abuse

Rifampin, some fluoroquinolones, quinine

False-positive result; consider patient’s legitimate use of opioid analgesics, including long-term pain management and opioid withdrawal treatment with methadone, or buprenorphine; verify possible false positive with laboratory and assay package insert

QUICKVIEW | Urine Drug Screen, PCP

PARAMETER

DESCRIPTION

COMMENTS

Critical value

Positive

Check for possible interferents; confirm result with confirmatory test such as GC-MS

Major causes of…

Positive results

Following ingestion, smoking, snorting, or injection

Associated signs and symptoms

None may be evident at time of specimen collection; may involve exposure to illicit substances; may involve exposure to medicines containing dextromethorphan or diphenhydramine used for legitimate purposes or abuse

Typical symptoms include hallucinations, schizophrenia-like behavior, hypertension, elevated temperature, diaphoresis, tachycardia; high doses cause nystagmus, ataxia, hypotension, bradycardia, depressed respirations, seizures, and coma

After use, time to…

Negative result from light, sporadic use

2–5 days

May persist for a longer period of time with heavy, long-term use or massive overdose preceded by chronic use

Negative result from chronic use

Weeks or months

Possible spurious positive results with immunoassays

Ketamine, dextromethorphan, diphenhydramine, imipramine, mesoridazine, thioridazine, venlafaxine, ibuprofen, meperidine, tramadol

False-positive result; verify possible false positive with laboratory and assay package insert