Urine Drug Testing Processes

Testing for drugs of abuse in urine generally is restricted to alcohol and several drugs that have high prevalence of abuse, not all of which are illicit drugs. The test menu varies with the intents of the testing programs and includes various combinations of the following drugs or metabolites:

• Amphetamines* (amphetamine* and methamphetamine*, sympathomimetic amines).

• Barbiturates (amobarbital, butalbital, and secobarbital).

• Benzodiazepines (alprazolam, clonazepam, diazepam, nitrazepam, nordiazepam, oxazepam, and temazepam).

• Buprenorphine.

• Cocaine metabolites* (cocaine, benzoylecgonine*).

• Methylenedioxyamphetamine (MDA).

• Methylenedioxymethamphetamine (MDMA).

• Opiates* (morphine*, codeine*, 6-acetylmorphine*, hydrocodone, and hydromor-phone).

• Propoxyphene.

For example, the Federal Drug Testing Programs mandate the testing of those drugs which have an asterisk (the "NIDA five"), and a pain management clinic may be interested in monitoring its patients for the opioids (buprenorphine, opiates, oxycodone, methadone and propoxyphene). Typical testing protocol is based on an initial test (screening test) using immunoassays in a qualitative mode. Results are designated as positive or negative according to the cutoffs chosen, and, depending on the testing requirements, positive results are then subjected to confirmation testing (see Section 4).

The immunoassays are calibrated at the cutoff concentrations, and a specimen that yields a response equal to or greater than that of the cutoff calibrator is positive, and negative if the response is less. The cutoffs mandated by the Federal Drug Testing Programs for Federal Employees (SAMHSA) and those by the DOT are listed in Table 1. These cutoffs are not at the limits of detection of the assays. Each cutoff is chosen as a compromise: higher than the assay detection limit to distinguish reliably a positive response from analytical noise and yet low enough not to miss the detection of drug use. Therefore, a negative result should not be interpreted as being devoid of drug.

It should be pointed out that workplace drug testing programs that do not fall under the regulations of the Federal and DOT Guidelines can choose not to use the cutoffs mandated for the federal programs. Although these are forensic drug testing cutoffs, many clinical laboratories have adopted them as well. Workplace drug testing cutoffs, however, may be too high for clinical testing; using lower cutoffs will greatly increase the clinical sensitivity of the test (18,19).

3.1. Initial Test Immunoassays

Initial immunoassays are either performed on an automated instrument in the laboratory, or by single-use point-of-care or POC devices (see Section 5). The most commonly used immunoassays are RIA, enzyme-multiplied immunoassay technique (EMIT; Dade Behring Diagnostics), fluorescence polarization immunoassay (FPIA, Abbott Diagnostics), cloned enzyme donor immunoassay (CEDIA, Microgenics Corp.), kinetic interaction of microparticles in solution (KIMS, Roche Diagnostics), and ELISA. These assays differ from each other in their immunospecificity, assay dynamic range, linearity and slope of the response curve around the cutoff, and susceptibility to the actions of adulterants.

The immunospecificity of an immunoassay determines its accuracy. An immunoassay with poor specificity can yield erroneous results, which can be either false positive [e.g., dextromethorphan triggering the phencyclidine (PCP) assay] or false negative (the opiate assay failing to detect oxycodone). In the following sections for individual drug groups, the issue of immunospecificity will be discussed in terms of (a) lack of specificity—detecting a compound other than the target analyte, yielding a false-positive result; (b) too restricted or inadequate specificity—inability to detect some important members of a drug group.

3.2. Amphetamines

Immunoassays for amphetamine and methamphetamine can be divided into two general types: those designed to favor the detection of amphetamine and methamphetamine only and those that also have variable cross-reactivities with "designer amphetamines" such as MDA, MDMA, MDEA methylenedioxyethylam-phetamine and with sympathomimetic amines such as ephedrine, pseudoephedrine, phenylpropanolamine, and phentermine. In workplace drug-of-abuse screening, those amphetamine immunoassays that have high specificity for amphetamine and metham-phetamine are considered operationally advantageous because they reduce the number of initial positives caused by sympathomimetic amines; consequently, fewer samples have to go to costly confirmation testing. For clinical toxicology, however, amphetamines "class" assays directed toward a broad spectrum of sympathomimetic amines should be used so that patients exposed to sympathomimetic amines will not be missed (20). Immunoassays designed specifically to detect the designer amphetamines are available (21,22).

Pharmaceutical methamphetamine is d-methamphetamine; amphetamine, however, is available as d-amphetamine as well as a racemic mixture (e.g., Adderall8). Illicit methamphetamine products are either the d-isomer or racemic mixture, and l-methamphetamine, compared to the d-isomer, has much lower potency as a central nervous system stimulant and is of little interest to drug abusers and is available as a nonprescription nasal inhalant. For detection of illicit amphetamine and metham-phetamine use, immunoassays are designed to detect the d-isomers of metham-phetamine and amphetamine, and assays are calibrated with d-isomer of either amphetamine or methamphetamine (23). Definitive identification of the enantiomer is needed to distinguish between illicit use of d-methamphetamine and over-the-counter use of l-methamphetamine. Standard gas chromatography-mass spectrometry (GC-MS) confirmation methods cannot distinguish between these isomers. The isomers must be converted by optically active derivatizing reagent into diasteriomers, which then can be chromatographically separated prior to mass spectrometric analysis (24).

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