Clinical Drug Testing

Article Author:
Alain Verstraete
Article Editor:
Taif Mukhdomi
Updated:
5/13/2020 3:16:24 PM
PubMed Link:
Clinical Drug Testing

Introduction

Clinical drug testing is the process of analyzing plasma (serum) or urine to detect the presence or absence of a drug or its metabolites. As the metabolization rate of drugs differs, the window of detection for certain drugs or metabolites varies. Clinical drug testing plays an important role in the management of poisonings because the self-report of the drugs that have been taken is often unreliable. The same is true in the treatment of addiction disorders because clinical examination, patient self-reporting, and hetero-anamnesis will underreport the actual incidence of substance use. 

Drug testing can be indicated in cases of suspected overdose or when monitoring abstinence in patients treated for addiction or in pain management clinics. No universal standard exists today in clinical drug testing for addiction identification, diagnosis, treatment, medication monitoring, or recovery. Guidelines exist for laboratory analyses for poisoned patients.[1][2]

In poisoning cases, the indications for laboratory assays are to confirm the suspicion of poisoning when this is in doubt and to influence patient management. Some examples of indications are to establish or eliminate the need for further investigations or administration of antidotes, hemodialysis, or other invasive extracorporeal epuration methods. Clinical drug testing may also be needed to determine if the cessation of treatment is indicated or to plan the re-institution of chronic therapy. In the intensive care unit, clinical drug testing is used to aid in the diagnosis of brain death and to determine the suitability of potential organ donors. The use of laboratory investigations out-of-hours should be restricted to those instances when an urgent result is needed to guide immediate patient management. It may also be appropriate to obtain samples and store them for later analysis.[1]

Etiology and Epidemiology

It is been estimated that 271 million people used drugs in 2017, and 35 million people suffered from drug use disorders. Opiate medications abuse cause the most harm, accounting for 66% of the deaths attributed to drug use disorders. According to the 2019 world drug report, 188 million people reported past-year use of cannabis, 53 million used opiate medications, 29 million used amphetamines and prescription stimulants, 21 million used 3,4-methylenedioxymethamphetamine (MDMA) and 18 million used cocaine. Globally, in 2017, there were 585,000 deaths and 42 million years of “healthy” life lost as a result of drug abuse.[3]

In the White Paper, The American Society of Addiction Medicine (ASAM) advocates for the use of ‘‘smarter’’ drug testing. Smarter drug testing means an increased frequency of random testing. It also means testing not only urine but also other matrices such as blood (serum or plasma), oral fluid (saliva), hair, etc. when those matrices match the intended assessment process, e.g., hair testing has a much longer detection window. Smarter testing means testing for a broad and rotating panel of drugs based upon the clinical indication rather than only testing for the traditional five-drug panel that was designed for government-mandated workplace testing. Smarter testing means careful sample collection and detection technologies to decrease sample adulteration and substitution rates, as well as careful consideration of the financial costs of testing in relation to the value and medical necessity of the test results.[4]

The main indications for urine drug testing in addiction medicine are to determine adherence, to monitor abstinence, and to detect early relapse.[4]

The drugs involved in poisoning differ according to the geographical region. In Western Europe, benzodiazepines and antidepressants are the most common.[5][6][7]

The most recent data from the EuroDEN study[8] that monitored almost 24,000 drug-related emergency presentations at 32 sentinel hospitals across Europe over the first 4 years show that most commonly involved drugs in acute drug toxicity presentations included heroin, cocaine, and cannabis. More than one-quarter of all presentations involved the misuse of at least one prescription medicine, most commonly opiate medication and benzodiazepines such as methadone, diazepam, and clonazepam. 

In Chile, benzodiazepines, selective serotonin reuptake inhibitors, and tricyclic antidepressants (TCA) were commonly abused, comprising 87.2% of all cases. Acetaminophen was involved in 6.8% of the cases.[9]

Pathophysiology

When a drug is taken, it is absorbed from the gastrointestinal tract, distributed to the rest of the body, metabolized in the liver and in other organs, and eliminated, mainly in the urine. These processes occur at different speeds for different drugs. Therefore the target analytes (parent drug or metabolite), times of the first detection, and detection times will differ for the different drugs. For some drugs like amphetamines, the parent drug will be detected in urine, for most other drugs, metabolites will be detectable for a longer time than the parent drug. The main target metabolites are 11-Nor-9-carboxy-Δ-tetrahydrocannabinol (THCCOOH) for cannabis, benzoylecgonine for cocaine, and morphine for heroin. In general, drugs first appear in the urine 1 to 2 hours after intake. After a small drug dose, a drug can be detected for 1 to 3 days in the urine, but after heavy, chronic use, amphetamines can be detectable for 10 days, cannabinoids for 3 months, cocaine metabolites for 3 weeks and heroin metabolites for 11 days.[10] In plasma, the detection times are shorter, often 1 to 2 days.

Specimen Requirements and Procedure

Drug abuse testing is most often performed on a urine sample, but increasingly laboratory-based screening immunoassays for abused drugs in plasma are becoming available.[11] Tests for drugs in the oral fluid also exist, but they are not commonly used in hospitals. A few milliliters of urine or blood is usually sufficient. Serum or plasma can be used interchangeably. Tubes containing gel separators may affect some assays. Analysis of gastric lavage fluid is now very rare.[1]

Diagnostic Tests

Drug testing can be divided into 2 categories: screening and confirmation. Screening tests (point-of-care (POCT) or laboratory-based immunoassays) generally have lower sensitivity and/or specificity compared to definitive tests as they mainly serve to detect the presence of a drug in the system. The primary benefit is a quick result that allows for immediate intervention. Therefore, presumptive tests should be used when it is a priority to have more immediate results. If there are disputes of the results of a speculative test, the test should be confirmed using a definitive method. Confirmation tests are performed when the screening test is positive, or when one needs to test for drugs for which no immunoassays are available. For screening, different techniques can be used, lateral-flow immunoassays for POCT testing and immunoassays are performed in the laboratory.[12] When used by trained laboratory personnel, there is evidence that the current POCT devices for urine drug screening produce results that are comparable to laboratory-based screening methods.[13] When used by trained, nonlaboratory personnel, results are poorly reliable.[14] Advice from laboratory specialists should be sought before implementing POCT testing.

Depending on the setting, the laboratory might add a confirmation test as a reflex test when the screening is positive, or the confirmation test should be ordered separately. For confirmation, chromatographic techniques like gas or liquid chromatography are used, coupled to (tandem) mass spectrometry, including high-resolution mass spectrometry.[15][16][17] With a confirmation test, the drugs and or metabolites present in the sample will be identified, and in some cases, particularly in plasma, quantified.

Testing Procedures

Knowledge of laboratory methods involved with urine drug testing help to facilitate test result interpretation. Drug testing is often a two-step process: screening and confirmation. Screening tests via biological samples are usually first administered for speculative testing. In some settings, if the patient confirms test findings, a confirmative test is not necessary. If the patient's response is in contradiction to speculative test results, a definitive/confirmatory test is required. Clear guidelines should be developed regarding the need to confirm positive test results using a more sensitive and specific laboratory method, particularly for situations where definitive punitive action will be taken based on the result. In clinical settings where treatment may be based upon unconfirmed results, staff using the data should be educated with respect to the limitations of the testing. In emergency clinical toxicology, for overdose cases, decisions will often be based on preliminary testing (that has a turnaround time of one hour or less), and sometimes, e.g., in suspected opiate overdoses, naloxone will be given for a diagnostic purpose, without waiting for the result of testing.

Interfering Factors

Some substances interfere with drug testing (e.g., poppy seeds interfere with opiate testing). In these cases, a confirmatory test or metabolite test may be required through mass spectrometry or immunoassays to verify the correct substance in the patient's system.[18] Some common interferences are:[19][20][21]

  • Amphetamine immunoassays: amantadine, bupropion, ephedrine, labetalol, phentermine, pseudoephedrine, ranitidine, selegiline, and trazodone metabolites
  • Benzodiazepine immunoassays: oxaprozin, sertraline, efavirenz
  • Cannabis immunoassays: ibuprofen, naproxen, efavirenz, pantoprazole, baby washes
  • Cocaine immunoassays: few interferences are known, but the medical use of cocaine as a local anesthetic or drinking tea from coca leaves is a possible cause of interference.
  • Opiate immunoassays: quinolones, verapamil
  • Tricyclic antidepressant immunoassays: carbamazepine, cyclobenzaprine, diphenhydramine, phenothiazines 

The interference depends on the immunoassay that is used. The package insert of the immunoassay reagent kit contains a list of cross-reacting drugs. This list should not be considered exhaustive as not all drugs have been tested, and many other substances could cross-react.

On the other hand, immunoassays can fail to detect related substances. Some examples are:

  • Amphetamine immunoassays: 3,4-Methylenedioxymethamphetamine (MDMA or ecstasy), synthetic amphetamines (cathinones, bath salts, etc.)
  • Benzodiazepine immunoassays: Depending on the cut-off, some higher potency benzodiazepines might be missed
  • Cannabis immunoassays: synthetic cannabinoids will be missed
  • Opiate immunoassays: Buprenorphine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, oxycodone, propoxyphene, tilidine
  • Tricyclic antidepressant immunoassays: All newer antidepressants like selective serotonin reuptake inhibitors (fluoxetine, sertraline, paroxetine) or serotonin-norepinephrine reuptake inhibitors (venlafaxine) will not be detected

Even with confirmatory testing, interferences are possible, e.g., confusion between tramadol and venlafaxine in liquid chromatography with tandem mass spectrometry testing.[22]

Results, Reporting, Critical Findings

Screening results will be reported qualitatively: negative or positive, or with some variations. In some cases, with results close to the cut-off, an 'indeterminate' result might be given. In serum, chromatographic techniques can give quantitative determinations of the specific drugs and metabolites. Several lists exist with therapeutic and toxic concentrations of drugs.[23][24] These limits should always be used with caution, e.g., when drug combinations have been used, or when the distribution of the drug is not complete, the serum drug concentration is not representative of the concentration at the site of action.

Users of POCT devices should understand any limitations of the devices, particularly the sensitivity and specificity. The nomenclature of the devices can be misleading, e.g., a POCT test labeled 'morphine' that detects all opiate medications, including codeine. In addition, in addiction medicine settings, the user must be aware of the possibility of sample adulteration/manipulation.

Clear guidelines should be developed regarding the need to confirm positive test results using a more sensitive and specific laboratory method, particularly for situations where definitive punitive action will be taken based on the result. In clinical settings where treatment may be based upon unconfirmed results, staff using the data should be educated with respect to the limitations of the testing.[13]

The results of drug testing should be interpreted together with history/physical and psychosocial assessment for documentation of the use of illicit substances and assessing therapeutic levels of medications, or in other words, 'treat the patient, not the drug.' 

Clinical Significance

Presumptive testing should be a routine assessment. Definitive testing should be used when there is a dispute about the findings of a presumptive test or when the results will inform a decision with major implications for the patient (e.g., treatment transition or changes in medication therapy).

Multiple studies in the adult and pediatric populations confirm that the results of a urine drug screen very rarely change clinical management. In a study of 160 pediatric cases in Australia to determine whether a rapid comprehensive urine drug screen that detects over 300 substances altered management, only three cases were found in which overall clinical management was altered based on the results.[25] A study in the Netherlands to quantify the influence of POCT tests for drugs-of-abuse and therapeutic drugs in urine on diagnosis and patient care in an emergency department, 37% were reported having a substantial influence on diagnosis and 25% on patient care. These tests were most useful in patients with decreased consciousness, and who presented with psychiatric or neurological symptoms. They were not helpful in patients who were already known to be intoxicated.[26] 

A negative urine drug screen does not “rule-out” that a patient’s presenting signs and symptoms are due to a drug, because the immunoassays have a narrow scope, and many drugs are not detected. A positive drug screen does not mean that the patient is addicted to the drug or that he is under the influence of the drug. For example, a urine drug screen positive for cocaine does not mean that the patient’s presenting signs or symptoms can be explained by the clinical result.[19]

Quality control and Lab Safety

All analyses, whether POCT or laboratory-based, must be subject to quality control (QC) and quality assurance measures. This should encompass a quality system that includes effective training, record-keeping, and review. All users of POCT devices must use QC material and participate in external quality assurance (EQA) schemes.[13]

If powders or liquids (e.g., obtained from patients) are analyzed, special precautions are needed, in order to avoid contamination of laboratory equipment with high quantities of drugs and to protect laboratory personnel from highly potent drugs (e.g., carfentanil) or toxic substances (e.g., cholinesterase inhibitors).

Enhancing Healthcare Team Outcomes

Interpretation of drug tests is notoriously difficult because of the limited sensitivity and specificity of the assays and the variability among assays. Results of urine drug tests should be discussed with each patient, and decision making surrounding urine drug test values should include a multidisciplinary team as well as the patient. Because of the complex nature of result interpretation and test ordering, it is critical that a close working relationship is established with the laboratory. Clinicians should be encouraged to discuss these issues with a toxicologist or clinical chemist for a correct interpretation and in order to select further tests.

A recent study found that 25 of 160 provider interpretations were discordant with the laboratory toxicologist's interpretation.[27] With national policies directing the limitation of opiate medication use, surgeons strategize pain control and surgery protocols to limit opiate medication abuse.[28] Pain physicians also utilize clinical drug testing in chronic pain patients to ensure conforming to opiate use contracts and avoiding the utilization of controlled substances.[29]


References

[1] Thompson JP,Watson ID,Thanacoody HK,Morley S,Thomas SH,Eddleston M,Vale JA,Bateman DN,Krishna CV, Guidelines for laboratory analyses for poisoned patients in the United Kingdom. Annals of clinical biochemistry. 2014 May;     [PubMed PMID: 24477115]
[2] Wu AH,McKay C,Broussard LA,Hoffman RS,Kwong TC,Moyer TP,Otten EM,Welch SL,Wax P, National academy of clinical biochemistry laboratory medicine practice guidelines: recommendations for the use of laboratory tests to support poisoned patients who present to the emergency department. Clinical chemistry. 2003 Mar     [PubMed PMID: 12600948]
[3] Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet (London, England). 2018 Nov 10     [PubMed PMID: 30496104]
[4] Kirsh KL,Baxter LE,Rzetelny A,Mazuk M,Passik SD, A Survey of ASAM Members' Knowledge, Attitudes, and Practices in Urine Drug Testing. Journal of addiction medicine. 2015 Sep-Oct;     [PubMed PMID: 26335003]
[5] Hendrix L,Verelst S,Desruelles D,Gillet JB, Deliberate self-poisoning: characteristics of patients and impact on the emergency department of a large university hospital. Emergency medicine journal : EMJ. 2013 Jan;     [PubMed PMID: 22328636]
[6] Ambrosius RG,Vroegop MP,Jansman FG,Hoedemaekers CW,Aarnoutse RE,van der Wilt GJ,Kramers C, Acute intoxication patients presenting to an emergency department in The Netherlands: admit or not? Prospective testing of two algorithms. Emergency medicine journal : EMJ. 2012 Jun;     [PubMed PMID: 21546510]
[7] Beaune S,Juvin P,Beauchet A,Casalino E,Megarbane B, Deliberate drug poisonings admitted to an emergency department in Paris area - a descriptive study and assessment of risk factors for intensive care admission. European review for medical and pharmacological sciences. 2016;     [PubMed PMID: 27049274]
[8] Wood DM,Heyerdahl F,Yates CB,Dines AM,Giraudon I,Hovda KE,Dargan PI, The European Drug Emergencies Network (Euro-DEN). Clinical toxicology (Philadelphia, Pa.). 2014 Apr;     [PubMed PMID: 24654801]
[9] Aguilera P,Garrido M,Lessard E,Swanson J,Mallon WK,Saldias F,Basaure C,Lara B,Swadron SP, Medication Overdoses at a Public Emergency Department in Santiago, Chile. The western journal of emergency medicine. 2016 Jan;     [PubMed PMID: 26823936]
[10] Verstraete AG, Detection times of drugs of abuse in blood, urine, and oral fluid. Therapeutic drug monitoring. 2004 Apr     [PubMed PMID: 15228165]
[11]     [PubMed PMID: 21775079]
[12]     [PubMed PMID: 22939301]
[13]     [PubMed PMID: 17270169]
[14]     [PubMed PMID: 8746925]
[15]     [PubMed PMID: 29750739]
[16]     [PubMed PMID: 26924594]
[17]     [PubMed PMID: 27369376]
[18] Maas A,Madea B,Hess C, Confirmation of recent heroin abuse: Accepting the challenge. Drug testing and analysis. 2018 Jan;     [PubMed PMID: 28681463]
[19]     [PubMed PMID: 26168592]
[20]     [PubMed PMID: 28325505]
[21]     [PubMed PMID: 24986836]
[22]     [PubMed PMID: 16615670]
[23]     [PubMed PMID: 28910830]
[24]     [PubMed PMID: 22835221]
[25]     [PubMed PMID: 28594290]
[26]     [PubMed PMID: 29270362]
[27] Chua I,Petrides AK,Schiff GD,Ransohoff JR,Kantartjis M,Streid J,Demetriou CA,Melanson SEF, Provider Misinterpretation, Documentation, and Follow-Up of Definitive Urine Drug Testing Results. Journal of general internal medicine. 2020 Jan;     [PubMed PMID: 31713040]
[28]     [PubMed PMID: 31563339]
[29]     [PubMed PMID: 32186725]