LCD L36393: Controlled Substance Monitoring and Drugs of Abuse Testing

History/Background and/or General Information

Urine drug testing (UDT) provides objective information to assist clinicians in identifying the presences or absence of drugs or drug classes in the body and assist in making treatment decisions.

This LCD details:

• The appropriate indications and expected frequency of testing for safe medication management of prescribed substances in risk stratified pain management patients and/or in identifying and treating substance use disorders.

• Designates documentation, by the clinician in the patient’s medical record, of medical necessity for, and testing ordered on an individual patient basis;

• Provides an overview of presumptive urine drug testing (UDT) and definitive UDT testing by various methodologies.

Definitions

By way of definition and as used in this LCD, the following terminology relates to the basic forms of controlled substance and drug of abuse testing:

• Presumptive/Qualitative Drug Testing (hereafter called "presumptive" UDT) - Used when medically necessary to determine the presence or absence of drugs or drug classes in a urine sample; Results expressed as negative or positive or as a numerical result; Includes competitive immunoassays (IA) and thin layer chromatography.

• Definitive/Quantitative/Confirmation (hereafter called “definitive” UDT) - Used when medically necessary to identify specific medications, illicit substances and metabolites; Reports the results of drugs absent or present in concentrations of ng/ml; Limited to GC-MS and LC-MS/MS testing methods.

• Specimen Validity Testing - Urine specimen testing to ensure that it is consistent with normal human urine and has not been adulterated or substituted; May include pH, specific gravity, oxidants and creatinine.

• Point of Care Testing (POCT) - Used when medically necessary by clinicians for immediate test results for the immediate management of the patient; Available when the patient and physician are in the same location; IA test method that primarily identifies drug classes and a few specific drugs; Platform consists of cups, dipsticks, cassettes, or strips; Read by the human eye.

• Immunoassay (IA) - Ordered by clinicians primarily to identify the presence or absence of drug classes and some specific drugs; Biochemical tests that measure the presence above a cutoff level of a substance (drug) with the use of an antibody; Read by photometric technology.

• Standing Orders - Test request for a specific patient representing repetitive testing to monitor a condition or disease for a limited number of sequential visits; Individualized orders for certain patients for pre-determined tests based on historical use, risk and community trend patient profiles; Clinician can alter the standing order. Note: A “profile” differs from a “panel” in that a profile responds to the clinical risks of a particular patient, whereas a panel encourages unnecessary or excessive testing when no clinical cause exists.

• Blanket Orders - Test request that is not for a specific patient; rather, it is an identical order for all patient’s in a clinician’s practice without individualized decision making at every visit.

• Reflex Testing - Laboratory testing that is performed reflexively after initial test results to identify further diagnostic information essential to patient care. Testing performed as a step necessary to complete a physician’s order is not considered reflex testing.

Drug Test Methods

The Clinical Laboratory Improvement Amendments (CLIA) regulates laboratory testing and requires clinical labs to be certified by their State as well as the CMS before they can accept human samples for diagnostic testing. Multiple types of CLIA certificates may be obtained based on the complexity of testing a lab conducts. CLIA levels of complexity (CLIA-waived, moderate complexity and high complexity) are addressed only as they relate to the HCPCS code description and the coding/billing guidance.

A. Presumptive Testing Methods:

1. CLIA-waived Presumptive UDT:

CLIA-waived presumptive UDT consists of various platforms including cards, dipsticks, cassettes and cups based on qualitative competitive immunoassay methodology with one or more analytes in the test. A CLIA- waived presumptive IA test detects the presence of the amount of drug/substance present in urine above a predetermined “cut-off” value.

A positive test result is reported when the concentration of drug is above the cut-off value; a negative test result is reported when the concentration of drug is below the cut-off value. Positive test results are presumptive or not definitive due to sensitivity and cross-reactivity limitations. Negative test results do not necessarily indicate the absence of a drug or substance in the urine specimen. The accuracy of the results of a CLIA-waived presumptive UDT will depend on the testing environment, type of test, and training of the individual conducting the test.

This type of test should only be used when results are needed immediately.

2. Presumptive UDT by FDA Approved/Cleared IA Analysis:

Chemistry analyzers with IA UDT technology are used in an office or clinical laboratory setting. When FDA approved/cleared platforms and reagents are used, testing is classified as moderately complex. This test may be used when less immediate test results are required. At no time is IA technology by chemistry analyzer considered confirmatory testing.

A presumptive positive IA test detects the amount of drug/substance present in urine above a predetermined cut-off value. If the concentration of the drug is below the cut-off value, the result will be negative. Presumptive positive tests are not definitive due to sensitivity, specificity, and cross-reactivity limitations. Negative test results do not necessarily indicate the absences of a drug or substance in the urine specimen.

3. Presumptive UDT by Laboratory Developed Test (LDT) IA Analysis:

Subject to appropriate internal quality control and test validation, an immunoassay performed on a bench top chemistry analyzer becomes a high complexity test in the following two situations:

a. Test Assay Not Classified: Per CFR 493.17(c)(4), if a laboratory test system, assay and examination does not appear on the list of tests in the Federal Register notices, it is considered a test of high complexity until Public Health Service (PHS) reviews the matter and notifies the applicant of its decision. Examples of current tests that fall into this category are listed below:

• Extended opioids such as fentanyl, meperidine, tramadol and tapentadol,

• Muscle relaxants such as carisoprodol and meprobamate

• Stimulants such as methylpenidate,

• Sleep aids such as zolpidem

b. Lowering Cutoff for Detection: Modified FDA approved/cleared test platforms and/or reagents are considered laboratory developed tests (LDTs). Drug testing platforms and/or reagents that are not FDA approved/cleared are also considered LDTs. LDTs have presumably been modified to test at a lower cutoff in order to detect substances that would have been missed at a higher threshold. For example, a FDA labeled cutoff may be 300 ng/mL and the LDT cutoff for the same drug may be a 100 ng/mL.

Presumptive UDT can be carried out at any validated cut-off concentration. Lowering of the cut-off concentration provides more stringent cut-off values for illicit drugs. LDTs may include non-FDA cleared tests not available in CLIA-waived or moderate complexity tests (e.g. tramadol, tapentadol, carisoprodol, fentanyl, zolpidem, etc.) Lowering the cut-off values increases the possibility of detecting a drug when the test has been modified from the recipe of the manufacturer.

4. Limitations of Presumptive UDT

Presumptive UDT testing is limited due to

• Primarily screens for drug classes rather than specific drugs, and therefore, the practitioner may not be able to determine if a different drug within the same class is causing the positive;

• Produces erroneous results due to cross-reactivity with other compounds or does not detect all drugs within a drug class;

• Not all prescription medications or synthetic/analog drugs are detectable; it is unclear as to whether other drugs are present

• Cut-off value may be too high to detect presence of drug

This information could cause a practitioner to make a wrong assumption.

An IA involves an antibody that reacts best with the stimulating drug, and reacts to a lesser extent (cross- reactive) or not at all with other drugs in the drug class. While presumptive tests vary in their ability to detect illicit drugs such as tetrahydrocannabinol (THC), cocaine, 3, 4-methylenedioxy-N-methylamphetamine (MDMA; “ecstasy”), and phencyclidine (PCP), they may not be optimal tests for many prescription drugs, namely opiates, barbiturates, benzodiazepines and opioids.

For example, opiate reagents are formulated for morphine. Consequently, the cross-reactivity for other opioids and opiates varies based on the manufacturer and lot number. The semisynthetic opioids, hydromorphone and hydrocodone, may contribute to a positive presumptive result, while the semisynthetic opioids, oxycodone and oxymorphone, will not typically be detected even at 300 ng/mL cut-off value. Synthetic opioids, such as fentanyl, meperidine and methadone, will not be detected by current opiate IA testing. Consequently, a positive opiate result by IA necessitates more specific identification of the substance(s) that account for the positive result, and a negative result does not rule out the presence of opiates or opioids.

Presumptive UDT reagents for benzodiazepine are formulated for oxazepam, a metabolite of diazepam (Valium®) and chlordiazepoxide (Librium®), the main benzodiazepines prescribed twenty years ago. However, many of the more than 10 benzodiazepines that are currently available do not cross-react with IA benzodiazepine reagents. In particular, clonazepam and lorazepam give false negative results with presumptive IA tests and may necessitate more specific identification to account for the negative result. Similarly, a positive screening test result may require definitive UDT to identify the specific drug(s).

Synthetic/analog or “designer” drugs manufactured to elude law enforcement require definitive testing for detection. Most commercially available IA reagents fail to detect designer drugs, such as psychedelic phenethylamines even at very high concentrations.

In summary, presumptive IA UDT is unable to identify specific drugs within many drug classes, particularly within the amphetamine, barbiturate, benzodiazepine, tricyclic antidepressants, and opitate/opioid drug classes. Drugs such as fentanyl, carisoprodol, tramadol, tapentadol and synthetic designer drugs cannot be detected by presumptive IA. Therefore, it may be medically necessary for clinicians to utilize definitive UDT with lower cut-off levels when the presumptive tests for these drugs are negative.

B. Definitive UDT:

Gas Chromatography coupled with Mass Spectrometry (GC-MS) and High Performance Liquid Chromatography coupled with Tandem Mass Spectrometry (LC-MS/MS) are complex technologies that use the separation capabilities of gaseous or liquid chromatography with the analytical capabilities of mass spectrometry. Both methodologies require the competency of on-site highly trained experts in this technology and interpretation of results. While these tests require different sample preparation and analytical runs, they identify all specific drugs, metabolites, and most illicit substances and report the results as absent or present in concentrations of ng/mL.

Quantification should not be used to determine adherence with a specific dosage or time of dose of a pain medication or illicit drug for clinical purposes. Rather, the use of quantitative drug data may be important for many reasons such as in a differential patient assessment. For example, when several opioids are present in the urine of a patient prescribed a single opioid, quantification may help the clinician decide whether the presence of the other opioids is consistent with metabolism of the prescribed opioid, opioid contamination during manufacturing, or if more than one drug within a class is being used.

Quantification may also provide information in the setting of illicit drug use. Serial creatinine-corrected quantitative values may assist in the differential assessment of ongoing drug use or cessation of drug use with continued drug excretion.

1. GC-MS

GC-MS can only be performed on molecules that are volatile. If the test drug is not volatile in its own right, it must be modified or derivatized to a volatile form. To derivatize, the test drug must be extracted from the urine, eluted from the extraction device, concentrated, and then reacted with a chemical reagent to make a volatile product. Each drug class may require a different derivatizing agent. For patients on multiple classes of medications, laboratories using GC procedures must make different volatile derivatives in order to perform comprehensive testing. Since a GC column may not be able to separate more than one class of compounds, multiple chromatographic runs on different column types may be required to monitor multiple drug classes. Newer GC-MS instruments use tandem systems. GC-MS methodology allows for the testing of multiple substances but differs in ease of run.

2. LC-MS/MS

LC-MS/MS is roughly 100 times more sensitive and selective, involves less human steps, provides quicker turn- around time, uses less specimen volume and can test for a larger number of substances simultaneously when compared to GC-MS. After sample preparation, it is injected into the LC-MS/MS. The sample has to undergo hydrolysis to break the glucuronide bond that frees the drug and drug metabolites. Hydrolysis is followed by multiple additional steps including protein precipitation, centrifugation and purification. Deuterium-labeled isotopic internal standards are added prior to sample preparation to quantify the drugs and drug metabolites.

The sample is injected when the mobile phase is flowing through the chromatographic column. Each drug and drug metabolite interacts with the mobile phase and stationary phase differently and moves at different speeds depending on their chemical properties. In other words, each analyte elutes at different times. Specific drugs are identified by their retention time and mass spectrum of each peak, and quantified against isotropic internal standards for each drug and metabolite. Each drug peak has a minimum of two mass transitions, which the technician has to compare to drug standards (calibrators) in order to ensure identification.

CLIA-Certified Laboratories

CLIA specifies quality standards for proficiency testing, facility administration, general laboratory systems, pre- analytic, analytic and post-analytic systems, onsite supervision requirements, personnel qualifications and responsibilities, quality control, and quality assessment.

High complexity laboratories must ensure that testing is carried out by onsite qualified, trained personnel using validated reliable methods compliant with regulatory procedures (42 CFR Part 493). Both GC-MS and LC-MS/MS require a quality program to monitor the quality and audit the competency of the staff. LC-MS/MS instrument maintenance must be performed daily as well as instrument performance prior to patient specimens. Final review and approval of GC-MS and LC-MS/MS results must be performed by qualified clinical laboratory scientist as defined in 42 CFR Part 493.1489 (Testing Personnel Qualifications). A GC-MS or LC-MS/MS laboratory must have a qualified laboratory director as provided in 42 CFR 493.1443 (Laboratory Director Qualifications).

Assay validation must be consistent with FDA guidelines. Laboratories that use “application notes” from vendors to establish drug validation do not comply with federal standards, and put providers at risk for reporting inaccurate test results. Only FDA 510(k) cleared test methods can be distributed by vendors.

Purpose of UDT:

Presumptive UDT may be ordered when it is necessary to rapidly obtain and integrate results into clinical assessment and treatment decisions.

Definitive UDT is reasonable and necessary for the following circumstances:

• Identify a specific substance or metabolite that is inadequately detected by a presumptive UDT screen;

• Definitively identify specific drugs in a large family of drugs;

• Identify a specific substance or metabolite that is not detected by presumptive UDT such as fentanyl, Meperidine, synthetic cannabinoids and other synthetic/analog drugs;

• Identify drugs when a definitive concentration of a drug is needed to guide management (e.g., discontinuation of THC use according to a treatment plan);

• Identify a negative, or confirm a positive, presumptive UDT result that is inconsistent with a patient’s self- report, presentation, medical history, or current prescribed pain medication plan;

• Rule out an error as the cause of an unexpected presumptive UDT result;

• Identify non-prescribed medication or illicit use for ongoing safe prescribing of controlled substances; and

• Use in a differential assessment of medication efficacy, side effects, or drug-drug interactions.

Definitive UDT may be reasonable and necessary based on patient specific indications, including historical use, medication response, and clinical assessment, when accurate results are necessary to make clinical decisions. The clinician’s rationale for the definitive UDT and the tests ordered must be documented in the patient’s medical record.

Drug Test Panels

1. Presumptive UDT Panels

Presumptive UDT testing may be ordered as a panel because the Medicare billing codes are defined on a “per patient encounter” basis regardless of the number of analytes tested. Presumptive UDT orders should be individualized based on clinical history and risk assessment, and must be documented in the medical record.

2. Definitive UDT Panels

At the current time, physician-directed definitive profile testing is reasonable and necessary when ordered for a particular patient based upon historical use and community trends. However, the same physician-defined profile is not reasonable and necessary for every patient in a physician’s practice. Definitive UDT orders should be individualized based on clinical history and risk assessment, and must be documented in the medical record.

Specimen Type

Urine or oral fluid is the preferred biologic specimen for testing because of the ease of collection, storage, and cost- effectiveness. UDT cannot detect the dosage of drug ingested/used, the time of use, or the means of delivery (intravenous vs. oral vs. inhaled). Detection time of a substance in urine is typically 1-3 days depending on the drug, rate of metabolism, and rate of excretion. Lipid-soluble drugs, such as marijuana, may remain in body fat and be detected upwards of a week or more.

Covered Indications for UDT

Group A – Symptomatic patients, multiple drug ingestion and/or patients with unreliable history

A patient who presents in a variety of medical settings with signs or symptoms of substance use toxicity will be treated presumptively to stabilize the patient while awaiting rapid test results, then definitive testing to determine the cause(s) of the presentation. The need for definitive UDT is based upon rapid test findings, responses to medical interventions, and treatment plan.

A presumptive UDT screen should be performed as part of the evaluation and management of a patient who presents in an urgent care setting with any of the following:

• Coma

• Altered mental status in the absence of a clinically defined toxic syndrome or toxidrome

• Severe or unexplained cardiovascular instability (cardiotoxicity)

• Unexplained metabolic or respiratory acidosis in the absence of a clinically defined toxic syndrome or toxidrome

• Seizures with an undetermined history

• To provide antagonist to specific drug

The presumptive findings, definitive drug tests ordered and reasons for the testing must be documented in the patient’s medical record.

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