Appendix_C_Medical_Review_Officer_Manual.pdf

Department of Health and Human Services Substance Abuse and Mental Health Services Administration

Center for Substance Abuse Prevention

Medical Review Officer Manual for

Federal Agency Workplace Drug Testing Programs

EFFECTIVE MAY 31, 2014

Note: This manual applies to federal agency drug testing programs that come under Executive Order 12564 dated September 15, 1986, section 503 of Public Law 100-71, 5 U.S.C.

section 7301 note dated July 11, 1987, and the Department of Health and Human Services Mandatory Guidelines for Federal Workplace Drug Testing Programs (73 FR 71858) dated November 25, 2008 (effective October 1, 2010).

This manual does not apply to specimens submitted for testing under U.S. Department of Transportation (DOT) Procedures for Transportation Workplace Drug and Alcohol Testing Programs (49 CFR Part 40).

The current version of this manual and other information including MRO Case Studies are available on the SAMHSA website. The website (currently under construction) is available at:

http://beta.samhsa.gov/workplace.

Previous Versions of this Manual are Obsolete http://beta.samhsa.gov/workplace

HHS MRO Manual May 31, 2014

Table of Contents

Chapter 1. The Medical Review Officer (MRO)

Chapter 2. The Federal Drug Testing Custody and Control Form

A. Use of an Electronic Federal CCF

B. Federal CCF Content Requirements

D. Federal CCF Distribution

Chapter 3. Urine Drug Testing

A. Federal Workplace Drug Testing Overview

B. Test Methods

C. Drug Information

D. Adulterant Information

E. Dilution/Substitution

Chapter 4. The MRO Review and Reporting Process

A. Administrative Review of Documents

B. Donor Interview

C. Refusal to Test

D. Split Specimen Tests

E. Interpretation and Result Verification

F. Reporting

Chapter 5. Documentation and Recordkeeping

Chapter 6. Additional MRO Responsibilities

A. Federal Agency Blind Samples

B. Insufficient Specimen

C. Occupational and Public Safety

D. Donor Rights to Information

Appendix A. Specimen Reporting Criteria

Appendix B. Glossary

Appendix C. IITF Transfer to Laboratory Supplemental Custody and Control Form

Table 1. Immunoassays

Table 2. Some Specimen Validity Test Methods

Table 3. Some Substances that Metabolize to Amphetamines

Table 5. MRO Actions for Primary Specimen Reports (Bottle A)

Table 6. MRO Actions for Split Specimen Reports (Bottle B)

Bibliography

Additional References (examples):

Chapter 1. The Medical Review Officer (MRO)

The final review of results is an essential component of any drug testing program. A positive laboratory test result does not automatically identify an employee or job applicant as an illegal drug user, nor does a laboratory result of invalid, substituted, or adulterated automatically identify specimen tampering. An individual with a detailed knowledge of possible alternative medical explanations must interpret drug test results in the context of information obtained from the donor interview. The Department of Health and Human Services (HHS) requires the Medical Review Officer (MRO) to fulfill this important function.

The HHS Mandatory Guidelines for Federal Workplace Drug Testing Programs (Mandatory Guidelines) define an MRO as a licensed physician holding either a Doctor of Medicine (M.D.) or Doctor of Osteopathy (D.O.) degree who has:

• Knowledge regarding the pharmacology and toxicology of illicit drugs;

• Training in the collection procedures used to collect federal agency specimens; the interpretation of test results reported by laboratories; chain of custody, reporting, and recordkeeping requirements for federal agency specimens; the HHS Mandatory Guidelines for Federal Workplace Drug Testing Programs; and procedures for interpretation, review, and reporting of results as specified by the federal agency or agencies for which the individual may serve as MRO; and

• Satisfactorily passed an examination administered by an HHS-approved organization

(i.e., a nationally recognized entity that certifies MROs or a subspecialty board for physicians performing a review of federal employee drug test results). HHS publishes an annual list of approved organizations in the Federal Register.

The MRO serves as the common point of contact between all participants in a drug test (i.e., the donor, the collector, the test facility, and the federal agency’s designated representative). The MRO may be an employee or a contractor for a federal agency; however, the following restrictions apply:

• The MRO must not be an employee or agent of or have any financial interest in an instrumented initial test facility (IITF) or laboratory for which the MRO is reviewing drug test results, and

• The MRO must not derive any financial benefit by having an agency use a specific test facility or have any agreement with an IITF or laboratory that may be construed as a potential conflict of interest.

The purpose of these prohibitions is to prevent any arrangement between an IITF or laboratory and an MRO that could possibly influence the MRO and prevent him or her from reporting a problem identified with the test results or testing procedures.

The MRO has the following responsibilities:

• Review all specimens reported as positive, adulterated, substituted, invalid, or rejected for testing, and report the verified result to the federal agency;

• Ensure that specimens reported as negative or as negative and dilute are properly reviewed (i.e., at least 5% personally and the remainder by staff under the MRO’s direct, personal supervision) and reported to the federal agency;

• Review the results of all federal agency blind samples and perform the initial investigation into discrepant results;

• Discuss potential invalid results with the laboratory to determine whether further testing at another HHS-certified laboratory is warranted;

• Conduct or facilitate a medical evaluation of the donor when a collector reports that the donor was unable to provide a urine specimen;

• Perform an initial investigation of problems identified in the drug testing process and notify the appropriate regulatory authority of findings;

• Monitor the frequency of errors and notify responsible parties to take corrective action to prevent recurrence; and

• Maintain records and confidentiality of drug test information.

HHS recommends that each MRO use the information contained in this manual to ensure consistency and to improve the overall quality of the MRO review process.

Chapter 2. The Federal Drug Testing Custody and Control Form

Federal agencies are required to use the Office of Management and Budget (OMB)-approved Federal Custody and Control Form (CCF) for their agency workplace drug testing programs.

Federal CCFs are available from a number of different sources (e.g., IITFs, laboratories, collectors, third party administrators, MROs).

2014 Federal CCF OMB extended the use of the Federal CCF as of May 31, 2014 The 2014 Federal CCF may be used as a paper (hardcopy) or electronic (digital) form, or in a combination paper and electronic format.

A proof of the 2014 Federal CCF and guidance for its use are on the SAMHSA website. The website (currently under construction) is available at: http://beta.samhsa.gov/workplace.

2010 Federal CCF The form content of the 2010 Federal CCF (published in the Federal Register on July 16, 2010) is the same as the 2014 Federal CCF; only minor changes were made to the required statements and instructions to allow its use as an electronic document.

Therefore, SAMHSA is allowing service providers to continue to use preprinted paper 2010 Federal CCFs until supplies are depleted.

Employers are prohibited from using the Federal CCF for:

• Private-sector employee drug testing programs, other than testing conducted under the Department of Transportation (DOT) regulations

• State workplace drug testing programs http://beta.samhsa.gov/workplace

• Department of Justice drug testing programs

The use of an incorrect form for a federal agency specimen does not, in and of itself, constitute a reason for the test facility to reject the specimen for testing or for the MRO to cancel the test. For example, in rare cases, a collector may use a non-federal form or incorrect Federal CCF for a federal agency collection by mistake or as the only means to conduct a collection under unusual circumstances (e.g., post-accident test with insufficient time to obtain a Federal CCF).

In such cases, the test facility processes and tests the specimen, but holds the report pending receipt of a memorandum for the record (MFR) from the collector stating the reason why the correct Federal CCF was not used for the federal agency collection. The form used and the collector MFR should provide all information required on the Federal CCF.

• If the collector realizes an incorrect form was used, he or she must send an MFR with the specimen.

• If an IITF or laboratory discovers the use of a non-federal or incorrect federal form, the collector is notified to provide an MFR with the reason for using the incorrect form. If the collector does not provide an MFR after five business days, the IITF or laboratory will report a rejected for testing result to the MRO who will cancel the test.

• If an MRO discovers the use of a non-federal or incorrect federal form, the collector is notified to provide an MFR with the reason for using the incorrect form. If the collector does not provide an MFR after five business days, the MRO will cancel the test.

A. Use of an Electronic Federal CCF

A federal agency may use the Federal CCF as an electronic document in its federal workplace drug testing program. An electronic Federal CCF must be the functional equivalent of a paper Federal CCF with respect to integrity, accuracy, and accessibility.

“Personally identifiable information” (PII) is information that can be used to distinguish or trace an individual’s identity alone or when combined with other personal identifying information which is linked or linkable to a specific individual. PII that may be on the Federal CCF includes the donor’s Social Security Number (SSN), name, date of birth, telephone numbers, and employment status. All federally regulated employers and drug testing service providers (e.g., collectors, test facilities, MROs, third party electronic CCF providers) must implement procedures and administrative, technical, and physical controls to ensure donor privacy by restricting access to PII and to drug test results on hardcopy and electronic Federal CCFs, and entered into a computer system or database. Access to donor PII and drug test results must be limited to those individuals requiring access to fulfill job duties. Such individuals must receive training to make them aware of their responsibilities for protecting the information. The confidentiality must be maintained from the time the donor PII is obtained through transmission/transport of the Federal CCF, specimen testing, and records handling (i.e., storage, retrieval, and final destruction).

Federally regulated employers and drug testing service providers (e.g., collectors, test facilities, MROs) who use electronic or combination electronic and paper Federal CCFs must implement procedures and administrative, technical, and physical controls to ensure the authenticity, integrity, and confidentiality of electronic records, and to ensure that electronic signatures are the legally binding equivalent of traditional handwritten signatures. These procedures and controls include, but are not limited to:

• System validation

• The ability to generate accurate and complete copies of records in both human readable and electronic form suitable for inspection, review, and copying upon request of authorized parties (e.g., the MRO, federal agency, or SAMHSA)

• Protection of records to enable accurate and ready retrieval throughout the records retention period

• Limiting system access to authorized individuals. Procedures must be in place for managing the user authentication system (e.g., assignment, review, revocation).

• Secure, computer-generated, time-stamped audit trails to independently record the date and time of operator entries and actions that create, modify, or delete records from the time of initiation of the Federal CCF (changes should be evident when reviewing the original record, and any electronic or paper copy of the original record)

• Use of authority checks to ensure that only authorized individuals can use the system, electronically sign a record, access the operation or computer system input or output device, alter a record, or perform the operation at hand.

Before implementing an electronic Federal CCF, HHS-certified IITFs and laboratories must provide a detailed plan and proposed standard operating procedures (SOPs) which include the above items for SAMHSA review and approval (i.e., through SAMHSA’s National Laboratory Certification Program, NLCP), and must undergo an onsite inspection. The review of validation records, specimen records, SOPs, staff training records, and practices associated with the electronic Federal CCF will be part of the NLCP inspection process.

B. Federal CCF Content Requirements

Test Facility Identification

At the top of the Federal CCF, the test facility must be identified by one of the following:

• A specific IITF or laboratory name and address

• A list of addresses with check boxes to allow the collector to check the box for the IITF or laboratory to which the specimen will be shipped

• A corporate name and telephone number (the collector will annotate the address of the

IITF or laboratory to which the specimen will be shipped, or the test facility that receives the specimen for testing will annotate its address)

Bottle Labels/Seals

The tamper-evident specimen bottle labels/seals may be at the bottom of Copy 1 or may be separate from the form:

• There must be two labels/seals: one marked with the letter “A” to designate the primary specimen and the other marked with the letter “B” to designate the split specimen.

• Each label/seal must have:

o The same specimen identification number that is at the top of the Federal CCF, o A place for the collector to annotate the date of the collection, and o A place for the donor to initial the label/seal after it is placed on the specimen bottle.

Required Statements

Wording of required statements must be identical to that on the OMB-approved Federal CCF.

The statements must be provided as follows:

• Instructions for Completing the Federal Drug Testing Custody and Control Form for Urine Specimen Collection o Paper Federal CCF: printed on the back of the donor copy (Copy 5) o Electronic Federal CCF: provided to the donor as a separate page (e.g., hardcopy, onscreen, posted at the collection site).

• Public Burden Statement o Paper Federal CCF: printed on the back of each copy (i.e., Copies 1 through 5) o Electronic Federal CCF: provided to CCF recipients as a separate page (i.e., with the electronically transmitted Federal CCF copies). The Public Burden Statement may be displayed onscreen or posted at the collection site for the donor and collector, and/or provided to the donor as a hardcopy.

• Privacy Act Statement (For Federal Employees Only) o Paper Federal CCF: printed on the back of the donor copy (Copy 5) o Electronic Federal CCF: provided to the donor as a separate page (e.g., hardcopy, onscreen, posted at the collection site).

C. Federal CCF Distribution

Employers, collectors, test facilities, and MROs who use electronic or combination paper and electronic CCFs are responsible for ensuring the security of data transmissions and limiting access to any data transmission, storage, and retrieval systems.

Collector Distribution of the CCF

At the end of the collection, the collector distributes the CCF as described below.

Paper Federal CCF

• Copy 1 (Test Facility Copy) signed by the collector is shipped with the specimen package to the IITF or laboratory.

• Copy 2 (MRO Copy) signed by the donor is sent to the MRO o Original Copy 2 is sent by courier or mail, or o A copy of Copy 2 is sent via fax or provided electronically. The collector maintains the original Copy 2 in the collection site records.

• Copy 3 (Collector Copy) is maintained in the collection site records.

• Copy 4 (Employer Copy) is sent via fax, courier, or mail, or is provided electronically.

• Copy 5 (Donor Copy) is given to the donor.

Note: Copies 2 through 5 are identical. The Instructions for Completing the Federal Drug Testing Custody and Control Form for Urine Specimen Collection are printed on the back of Copy 5.

Electronic Federal CCF

• Copy 1 (Test Facility Copy) signed by the collector is electronically provided to the IITF or laboratory.

To facilitate linkage of the specimen package to the electronic Federal CCF sent to the test facility, the collector must either:

o Include a printed copy of the Test Facility copy (i.e., Copy 1) of the Federal CCF with the specimen; or o Apply a label to the outside of the specimen package, with the specimen identification number, test facility name and contact information, and collection site name and contact information.

• Copy 2 signed by the donor is maintained as an electronic file by the collector/collection site and:

o A copy is provided electronically to the MRO o A copy is provided electronically to the Employer o A copy is provided to the donor. This may be a printed copy or a copy that is electronically provided.

Note: The Instructions for Completing the Federal Drug Testing Custody and Control Form for Urine Specimen Collection are provided to the donor as a separate page (e.g., hardcopy, onscreen, posted at the collection site).

Test Facility Report to MRO

When testing has been completed, the IITF or laboratory records the results for a primary specimen (Bottle A) on the CCF by marking the appropriate result boxes and includes any additional comments concerning the specimen’s testing or processing on the “Remarks” line.

The original Federal CCF Copy 1 is retained in the specimen records at the test facility that reported the result. The IITF or laboratory reports results to the MRO as described below.

The test facility must fax, courier, mail, or electronically provide the completed Federal CCF (copy of Copy 1) to the MRO, with one exception. The test facility may report specimens that were received with a paper Federal CCF as negative or negative-dilute using only a computer-generated electronic report, provided that the report contains sufficient information to ensure that the test result is properly associated with the MRO copy (Copy 2) of the Federal CCF.

Specimens forwarded by an IITF to a laboratory: The laboratory must also send a copy of the completed IITF Supplemental CCF to the MRO for all results. The laboratory may fax, courier, mail, or electronically provide this form. . An example form is provided in Appendix C of this Manual.

For specimens other than negative, laboratories are required to report all results for a specimen as supported by their data. Therefore, the MRO may receive a Federal CCF marked with more than one of the following results:

• Positive for one or more drugs (with the analyte concentration recorded on the Remarks line),

• Adulterated (with the adulterant or pH value recorded on the Remarks line),

• Substituted (with the creatinine and specific gravity values recorded on the Remarks line), or

• “Invalid result” (with the reason for the invalid result and value, as appropriate, recorded on the Remarks line).

These are separate results. For example, “invalid result” does not refer to the drug(s)/drug metabolite(s) marked positive. The MRO should contact the laboratory if there is any confusion about the reported results.

Chapter 3. Urine Drug Testing

A. Federal Workplace Drug Testing Overview

Drugs

Federal agencies must test each specimen for marijuana and cocaine, and may test each specimen for opiates, amphetamines, and phencyclidine. Appendix A lists the analytes (i.e., drugs and drug metabolites) and test cutoffs specified by the Mandatory Guidelines.

Testing for an additional drug is allowed for the following reasons:

1. A federal agency may test a specimen for another drug, on a case-by-case basis, when the agency is conducting a specimen collection for reasonable suspicion, post-accident, or unsafe practice testing. The specimen may be tested for any drugs listed in Schedule I or II of the Controlled Substances Act (other than drugs listed in Appendix A or when used pursuant to a valid prescription or when used as otherwise authorized by law). Information on drug schedules is available on the Drug Enforcement Administration website, http://www.justice.gov/dea/.

2. A federal agency may routinely test its federal employees for a drug or drug class other than those listed in Appendix A when the agency has been granted a waiver by the Secretary of HHS to do so.

When testing for an additional drug is justified or authorized as described above, the federal agency must request the HHS-certified laboratory to test for the additional drug, include a justification to test a specific specimen for the drug, and ensure that the HHS-certified laboratory has the capability to test for the drug and has established properly validated initial and confirmatory analytical methods. If an initial test procedure is not available upon request for an additional Schedule I or II drug, the federal agency may request the laboratory to test for the drug by directing two separate aliquots of a specimen using the confirmatory analytical method.

Specimen Validity

Specimen validity testing must be performed for each federal agency specimen. At a minimum, creatinine and pH must be determined for each specimen, specific gravity must be determined for each specimen with creatinine less than 20 mg/dL, and one or more tests for oxidizing adulterants must be performed. federal agencies may order specimen validity tests in addition to those outlined above routinely (i.e., on every primary specimen) or on an individual specimen basis. Laboratories may also perform additional specimen validity tests when a specimen exhibits abnormal physical characteristics or abnormal drug test results (e.g., abnormal immunoassay absorbance reading, reduced internal standard recovery upon confirmatory drug testing). Specimen validity tests must be performed for split specimens (Bottle B) when a laboratory fails to reconfirm a drug analyte reported positive in the primary specimen (Bottle A).

Specimen Collection

The MRO must be very familiar with the specimen collection procedures required by the Mandatory Guidelines. At this time, urine is the only specimen allowed for federal agency workplace drug testing. Each federal agency specimen is collected as a split specimen. The collector prepares a split specimen by pouring the urine from the collection container into two bottles, which are then labeled as Bottle A (the primary specimen) and Bottle B (the split specimen). The HHS Urine Specimen Collection Handbook (available at http://www.workplace.samhsa.gov) contains guidance for collectors to supplement the collection procedures required by the Mandatory Guidelines.

Security and Chain of Custody

The Mandatory Guidelines specify requirements for collection sites, IITFs, and laboratories to ensure the security and integrity of specimens and to maintain confidentiality of donor and drug test information. Collection sites, IITFs, and laboratories must be secured, with access limited to authorized personnel, to prevent unauthorized access to specimens, aliquots, and records.

http://www.justice.gov/dea/ http://www.workplace.samhsa.gov/

Permanent sites used solely for specimen collections must be secured at all times. At facilities that are not dedicated specimen collection sites, access to the area used for specimen collections must be restricted to only authorized personnel during the collection. Individual areas within an IITF or laboratory (e.g., receiving/accessioning area, testing areas, sample preparation area, specimen and records storage areas) are usually separately secured, to limit access to staff with job duties in the area. All visitors to secured areas within a test facility must be escorted and their access must be documented.

All federal agency specimens are handled using strict chain of custody procedures, to provide a clear record of each specimen’s handling from the time it was collected until final disposition.

The collector initiates the chain of custody documentation for the specimen using the Federal CCF, and must maintain line-of-sight custody or provide for the secure storage of specimens from the time the specimen is collected until the bottles are sealed in a shipping container prior to transfer. Since specimens are sealed in packages that would indicate any tampering during transit to the test facility, there is no requirement for delivery service personnel (e.g., couriers, express carriers, postal service personnel) to document chain of custody.

IITFs and laboratories annotate the appropriate chain of custody section of the Federal CCF (i.e., upon receipt of the specimen, and continue chain of custody documentation using internal forms. At the test facility, all specimens and all aliquots taken from each specimen are kept in secured storage or in the line of sight of an authorized individual, with appropriate chain of custody entries (i.e., signature, date, and action/purpose of each custody transfer) made at the time of actions. When an IITF forwards a specimen to a laboratory for testing, the IITF initiates a separate chain of custody form (i.e., IITF Supplemental Custody and Control Form) to document the transfer to the laboratory. This form is sent with the Federal CCF to the laboratory and is used by the laboratory to continue the chain of custody documentation. An example form is provided in Appendix C of this Manual.

Specimen and Records Storage

Laboratories are required to maintain the following specimens in a secure frozen storage area for at least one year after reporting:

• Drug positive specimens

• Substituted specimens

• Adulterated specimens

• Invalid specimens

• Split specimens (B Bottles) of the primary specimens (A Bottles) listed above

• Any split specimens or specimen aliquots received from another laboratory for testing

A federal agency may request the laboratory to retain a specimen for a longer period (e.g., specimens under legal challenge). The agency’s request must be in writing and must specify the period of time for specimen retention.

IITFs and laboratories may discard negative, negative-dilute, and rejected specimens after reporting them to the MRO.

Collection site records (e.g., collector copies of the Federal CCF) must be maintained for at least two years by the collector or collector employer. IITFs and laboratories must maintain records generated to support test results for a minimum of two years. A federal agency may request the test facility to maintain a copy of the documentation package for a specimen that is under legal challenge (see Chapter 6, Section D, Donor Rights to Information). The agency’s request must be in writing and must specify the period of time for record retention.

Testing

Test facilities must be certified by HHS in order to test federal agency workplace specimens.

HHS publishes a monthly list of certified test facilities in the Federal Register. The two types of test facilities allowed under the Mandatory Guidelines are Initial Instrumented Test Facilities (IITFs) and laboratories.

IITFs perform only the first tests for a specimen, and are allowed to report specimens as negative, negative and dilute (with creatinine greater than 5 mg/dL), and rejected for testing. All other federally regulated specimens must be forwarded to an HHS-certified laboratory for testing.

Laboratories perform all tests for a specimen (initial and confirmatory) and are the only facilities that may report specimens as positive, adulterated, substituted, invalid, and dilute (with creatinine less than or equal to 5 mg/dL).

For forensic as well as scientific acceptability, laboratories are required to perform initial and confirmatory tests using separate aliquots of a specimen to support a positive, adulterated, or substituted result. The confirmatory test uses a different test method that is usually more specific than the initial test. Laboratories must also test two separate aliquots of a specimen prior to reporting the specimen as invalid. Specimen reporting criteria are in Appendix A.

The MRO is not allowed to request retesting of a primary specimen (Bottle A). Primary specimens may be reanalyzed only:

• When a federal agency has requested reanalysis as part of a legal or administrative proceeding to defend an original positive, adulterated, or substituted result.

• When the MRO (on behalf of the donor) has requested analysis of the primary specimen (Bottle A) for adulteration and/or substitution because a second HHS-certified laboratory failed to reconfirm the drug(s) reported in the primary specimen, and reported that the split specimen (Bottle B) was adulterated or substituted.

• When HHS has directed the laboratory to reanalyze the specimen.

When the primary specimen (Bottle A) is positive, adulterated, or substituted, the donor is given an opportunity to request testing of the split specimen (Bottle B) at a second HHS-certified laboratory. Split specimens are tested using only the confirmatory test(s) needed to reconfirm the primary specimen result(s), and split specimen test results are not subject to the HHS test cutoffs. Chapter 4, Section E, Interpretation and Result Verification, has additional information concerning testing of split specimens for amphetamines. If the laboratory fails to reconfirm one or more drug analytes reported as positive in the primary specimen (Bottle A), the laboratory performs specimen validity tests for the split specimen (Bottle B).

If the split testing laboratory believes that the analyte (i.e., drug, drug metabolite, adulterant) is present in the split specimen (Bottle B), but cannot reconfirm its presence, the laboratory must consult with the MRO to decide whether to send the specimen to a third HHS-certified laboratory for additional confirmatory testing. The third laboratory should be selected such that it uses a confirmatory test method more similar to that used by the first laboratory (i.e., the laboratory that reported the primary specimen result).

If a donor chooses not to have the split specimen (Bottle B) tested, a federal agency may have the split specimen tested as part of a legal or administrative proceeding as part of a legal or administrative proceeding to defend an original positive, adulterated, or substituted result.

B. Test Methods

An MRO is not required to be as technically knowledgeable of analytical procedures and data as a certifying scientist. However, the MRO must know what tests were used to generate the specimen results that he/she reviews and should understand the general scientific principles of the technologies.

Initial drug tests

IITFs and laboratories are required to use immunoassay for initial drug tests. Immunoassays are immunochemical testing methods that use antigen (drug) and antibody binding to identify drug analytes. The antibodies are produced to be drug-specific. A known amount of antibody is added to a specimen, along with a drug that has been labeled to distinguish it from the drug in a donor’s urine specimen. The labeled drug and the unlabeled drug (if any) compete for the antibody, to form an antigen-antibody complex. The ratio of the labeled and unlabeled drug bound to the antibody allows the measurement of the amount of drug in the donor’s urine specimen. Immunoassays are used as initial drug tests to identify specimens that require further testing. The method is not specific enough to use as a confirmatory test. For example, many structurally similar drugs may cross-react with an immunoassay reagent, giving a positive result.

Specimens that are positive by immunoassay must be further tested using a different analytical method as a confirmatory test.

Table 1 provides brief descriptions of common immunoassays used for drugs of abuse.

Confirmatory Drug Tests

Laboratories are required to use a confirmatory drug test method different from the initial test method (i.e., immunoassay), to specifically identify and quantify the drug or drug metabolite. The analytical method used for the confirmatory drug test must combine chromatographic separation and mass spectrometric identification. For confirmatory drug testing, the Mandatory Guidelines require laboratories to use a combined analytical method coupling a chromatographic instrument with a mass spectrometer. Chromatographic techniques such as gas chromatography (GC) and liquid chromatography (LC) are used to separate and analyze mixtures of chemical substances. After the chromatographic instrument has separated the analytes in a specimen, the specimen enters the mass spectrometer (MS), which identifies and quantitates the separated analytes. The MS creates charged particles (ions) and separates them according to their mass-to-charge (m/z) ratios. The ions form unique mass spectra, which are used to identify analytes. Urine specimens must undergo a specimen preparation process

(i.e., extraction) prior to GC/MS analysis and may require preparation prior to LC/MS analysis.

Specimen Validity Tests

The Mandatory Guidelines specify test method requirements for some specimen validity tests (e.g., refractometry for specific gravity testing, pH meter tests for the initial and confirmatory pH tests). However, it is not possible to provide guidance on test methods for all substances that may be used to adulterate a urine specimen. As new adulterants are identified, IITFs and laboratories are permitted to implement appropriate tests for their analysis. There may be more than one acceptable test method for a particular measurand. All specimen validity tests must be scientifically and forensically supportable.

Table 2 provides brief descriptions of some methods that may be used for specimen validity tests.

C. Drug Information

The federal government classifies controlled substances under five schedules established under the Controlled Substances Act (CSA). Information on drug schedules is available on the DEA website (http://justice.gov/dea/).

Schedule I:

• The drug or other substance has a high potential for abuse.

• The drug or other substance has no currently accepted medical use in treatment in the

United States.

• There is a lack of accepted safety for use of the drug or other substance under medical supervision.

Schedule II:

• The drug or other substance has a high potential for abuse.

• The drug or other substance has a currently accepted medical use in treatment in the

United States or a currently accepted medical use with severe restrictions.

• Abuse of the drug or other substances may lead to severe psychological or physical dependence.

Schedule III:

• The drug or other substance has a potential for abuse less than the drugs or other substances in schedules I and II.

United States.

• Abuse of the drug or other substance may lead to moderate or low physical dependence or high psychological dependence.

Schedule IV:

• The drug or other substance has a low potential for abuse relative to the drugs or other substances in schedule III.

• Abuse of the drug or other substance may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in schedule III.

Schedule V:

• The drug or other substance has a low potential for abuse relative to the drugs or other substances in schedule IV.

• Abuse of the drug or other substance may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in schedule IV.

The President’s Executive Order 12564 defines “illegal drugs” as those under Schedule I or Schedule II. The DEA enforces the provisions of the CSA.

Cannabinoids (Marijuana)

1. Background

Cannabinoid-containing compounds come from the hemp plant, Cannabis sativa. The principal psychoactive agent in cannabinoids is delta-9-tetrahydrocannabinol (THC). Certified laboratories are required to use confirmatory testing that specifically identifies the major marijuana metabolite, delta-9-tetrahydrocannabinol-9-carboxylic acid (commonly referred to as THCA or THC-COOH).

Cannabinoid-containing compounds are found in two forms, marijuana and hashish. Marijuana is a mixture of crushed leaves, flowers, and sometimes the stems of the cannabis plant.

Hashish contains the dried resinous secretions of the cannabis plant and, in general, has a higher concentration of THC than marijuana.

Marijuana is a Schedule I drug. Medical marijuana is a controversial issue, and there has been some scientific evidence that smoked marijuana is beneficial for patients with debilitating symptoms such as unmanageable pain and vomiting. However, use of marijuana is not an acceptable alternative medical explanation for a positive THCA result in federally regulated drug testing programs.

Dronabinol is chemically synthesized delta-9-tetrahydrocannabinol (THC). It is the sole pharmaceutical source of THC and is available as Marinol® (Roxane Laboratories). The drug has psychoactive effects that may present safety issues.

Nabilone (Cesamet®) is a synthetic cannabinoid. This drug does not metabolize to delta-9-THC.

Therefore, the use of Nabilone is not an acceptable medical explanation for a positive confirmed drug test.

Cannabinoids produce a pleasant euphoria or "high” and a sense of relaxation and well-being that is commonly followed by drowsiness. The initial psychoactive effects of smoking THC occur within minutes, reach a peak within 10 to 30 minutes, and may persist for 2 to 4 hours.

Intoxication temporarily impairs concentration, learning, and perceptual-motor skills. Reduced functional ability lasts for at least 4 to 8 hours after a dose of marijuana, beyond the user’s perception of the high.

In addition to tolerance, a mild abstinence syndrome may follow abrupt termination of very high-dose, chronic marijuana use. Withdrawal signs include irritability, sleep disturbance, diminished appetite, gastrointestinal distress, salivation, sweating, and tremors. Marijuana abstinence syndromes are uncommon when marijuana is used at the usual doses.

Routes of administration:

• Marijuana – smoking (preferred) and oral (i.e., eating).

• Hashish – smoking (preferred) and oral (i.e., eating).

2. Metabolism and Excretion

Cannabinoids are usually smoked. Trans-pulmonary absorption occurs quickly, putting THC into the bloodstream and causing a direct psychoactive response in the brain. Cannabinoids are sometimes eaten because the drug also is absorbed through the gastrointestinal tract; however, gastro-intestinal absorption occurs much more slowly. THC is distributed into different parts of the body where it is metabolized, excreted, or stored. The THC that is stored in fatty tissue gradually reenters the bloodstream at very low levels, permitting metabolism and eventual excretion. THC is metabolized extensively in the liver and the major metabolite is delta- 9-tetrahydrocannabinol-9-carboxylic acid (THCA or THC-COOH).

The immunoassay procedures detect multiple metabolites of marijuana, while the confirmatory test specifically identifies and quantitates delta-9 THCA. To be reported positive, a specimen must test positive at or above the 50 ng/mL cutoff for the initial test and have a concentration of the delta-9 THCA that is equal to or greater than the 15 ng/mL confirmatory cutoff level.

Infrequent marijuana use may cause positive initial test results for 1 to 5 days. With repeated smoking, THC accumulates in fatty tissue. Chronic smokers slowly release THC over a longer time and may continue to produce detectable levels of drug for longer periods of time.

Cocaine

1. Background

Cocaine is an alkaloid from the coca plant that is usually sold as cocaine hydrochloride, a fine, white crystalline powder. "Freebasing" is a method used to chemically alter cocaine hydrochloride to remove the hydrochloride salt. “Crack” is one form of free base cocaine that has become popular in recent years. It is sold as small lumps or shavings and is the product of a manufacturing process that uses sodium bicarbonate or ammonia rather than a flammable solvent. Crack is smoked because, unlike cocaine hydrochloride, free base cocaine survives high temperatures and is absorbed into the bloodstream as rapidly as if it were injected.

Cocaine is rapidly metabolized to its major metabolite, benzoylecgonine. The federal drug testing program requires analysis for the cocaine metabolite benzoylecgonine.

Cocaine has only a limited legal use in the United States as a topical anesthetic in ear, nose, and throat surgery. It is a widely used drug of abuse and is classified as a Schedule II drug.

Cocaine produces psychomotor and autonomic stimulation with a euphoric subjective "high."

Larger doses may induce mental confusion or paranoid delusions. Serious overdoses cause seizures, respiratory depression, cardiac arrhythmias, and death.

Short-term tolerance (tachyphylaxis) develops when several doses of cocaine are administered over a brief period. Among chronic users, the stimulant effect may seem progressively weaker, and exhaustion, lethargy, and mental depression appear. Cocaine abusers often report vocational impairment due to exhaustion even though they do not use the drug at work.

Patients withdrawing from cocaine experience moderate lethargy and drowsiness, severe headaches, hyperphagia, vivid dreams, and some mental depression. These symptoms usually subside within a few days to a few weeks.

• Intranasal (i.e., snorting) is the most common

• Smoking the "freebase" or "crack" form of the drug

• Intravenous injection

Cocaine is rapidly and extensively metabolized by liver and plasma enzymes to its major metabolite, benzoylecgonine. Benzoylecgonine can usually be detected in urine for two to three days after a single dose using a test cutoff of 300 ng/mL. The detection window may be longer using the 150 ng/mL initial test cutoff and 100 ng/mL confirmatory test cutoff specified by the Mandatory Guidelines. Cocaine and benzoylecgonine are not significantly stored in the body.

Therefore, even after heavy, chronic use, urine specimens may be negative when collected several days after last use.

Opiates

1. Background

The term “opiate” specifically refers to natural alkaloids extracted from the opium poppy. The term “opioid” refers to synthetic opiates and opiate-like drugs in addition to the naturally occurring opiates. Opioids are classified as narcotics, drugs that in moderate doses dull the senses, relieve pain, and induce deep sleep. Excessive doses of such drugs cause stupor, coma, or convulsions. The federal agency drug testing program’s focus is on illicit use of morphine, codeine, and heroin:

• Morphine – is the most abundant naturally occurring opiate and is considered the prototype of the opioid class of drugs. Morphine is available as a prescription drug (Schedule II) and is used primarily for its potent analgesic properties.

• Codeine – can be naturally occurring; however, it can also be synthesized chemically by

3-O-methylation of morphine. Depending on concentration and preparation, codeine medications are available as a prescription drug (Schedule II and Schedule III) and over-the-counter (Schedule V). Codeine is commonly used in analgesic, antitussive, and anti-diarrheal agents.

• Heroin (diacetylmorphine) – is a semisynthetic opiate obtained by reacting natural morphine with acetic anhydride. Heroin has no legitimate medical use in the United States and is only available illegally (Schedule I). Heroin is not easily detected in urine and, therefore, usage is determined by detection of its intermediate metabolite 6-acetylmorphine (6-AM).

Cognitive and psychomotor performance can be impaired by opiates, although the duration and extent of impairment depend on the type of opiate, the dose, and the experience and drug history of the user. Ingestion of low to moderate amounts produces a short-lived feeling of euphoria followed by a state of physical and mental relaxation that persists for several hours.

Opioid intoxication may cause miosis, a dull facies, confusion or mental dullness, slurring of speech, drowsiness, or partial ptosis (i.e., nodding, the head drooping toward the chest and then bobbing up).

It is common for opioid abusers to develop tolerance and, therefore, continually increase the dose taken in an attempt to maintain the euphoric effect. All opiates are physically and psychologically addictive and produce withdrawal symptoms that differ in type and severity.

Flu-like symptoms are common during opiate withdrawal (e.g., watery eyes, nausea and vomiting, muscle cramps, and loss of appetite).

• Morphine – injection, intranasal (i.e., snorting), oral (i.e., tablets), and smoking

• Codeine – injection and oral (i.e., tablets, elixir)

• Heroin– intravenous injection, intranasal (i.e., snorting), and smoking.

Morphine is rapidly absorbed and excreted as:

• unchanged morphine

• glucuronide conjugates o morphine-3-glucuronide (primary metabolite) o morphine-6-glucuronide

• minor metabolites (e.g., normorphine, morphine-3-ethereal sulfate, morphine-3,6-diglucuronide)

Morphine and its metabolites can be detected in urine up to about 4 days after morphine use.

Morphine is not metabolized to codeine.

Codeine (methylmorphine) is also rapidly absorbed and is excreted as:

• unchanged codeine,

• morphine

• glucuronide conjugates o codeine-6-glucuronide o morphine-3-glucuronide o morphine-6-glucuronide o minor metabolites (e.g., norcodeine, normorphine, morphine-3-ethereal sulfate, morphine-3,6-diglucuronide)

The presence of both codeine and morphine in urine indicates the recent use of codeine;

however, morphine alone may be detected as a remnant of codeine that has been completely metabolized.

Heroin (diacetylmorphine) is deacetylated to its primary metabolite, 6-acetylmorphine (6-AM), within minutes of administration, and 6-AM is further metabolized to morphine. Therefore, heroin itself is rarely detected in urine. 6-AM is most likely to be detected within the first 24 hours post-administration because of heroin’s rapid metabolism to morphine. Codeine may be found in the urine of heroin users as a result of codeine present as a contaminant in the morphine used to synthesize the heroin.

Additional issues regarding opioids:

• Poppy seeds are a significant dietary source of morphine and/or codeine. In December 1998, HHS revised the Mandatory Guidelines for Federal Workplace Drug Testing Programs to:

o Increase the initial testing and confirmatory cutoffs for opiates (i.e., from 300 ng/mL to

2000 ng/mL).

o Require laboratories to test all morphine-positive specimens for heroin metabolite (6-

AM).

These measures were taken to eliminate most specimens that test positive due to poppy seed ingestion or due to the use of legitimate morphine or codeine medication.

• In October 2010, HHS revised the Mandatory Guidelines to require laboratories to test all federal agency specimens for heroin metabolite (6-AM) regardless of morphine concentration, by performing a 6-AM initial test and confirmatory test. The requirement was implemented because data from laboratories indicated that 6-AM could be present in specimens with morphine less than 2000 ng/mL.

• Synthetic or semi-synthetic narcotics do not metabolize to codeine, morphine, or 6-acetylmorphine. These include, but are not limited to:

o alphaprodine o hydromorphone o oxymorphone o hydrocodone o dihydrocodeine o oxycodone o propoxyphene o methadone o meperidine o fentanyl o pentazocine o buprenorphine o tramadol

• Products containing codeine or morphine are available by prescription or over-the-counter (OTC). MROs should have access to references with up-to-date information on such products. (Some example references are listed at the end of this manual.)

Note: Further information regarding the interpretation and reporting of opiates is found in Chapter 4, Section E, Interpretation and Result Verification.

Amphetamines

Amphetamine and Methamphetamine

1. Background

Amphetamine and methamphetamine are substances regulated under the CSA as Schedule II stimulants. Both drugs have been used for treating attention deficit disorder in children, obesity, and narcolepsy.

Amphetamine and methamphetamine are central nervous system stimulants that initially produce euphoria, a feeling of well-being, increased self-esteem and appetite suppression followed by restlessness and irritability. A single therapeutic dose often enhances attention and performance, but exhaustion eventually occurs and performance deteriorates as the effects wear off. Frequently, repeated high dose use produces lethargy, exhaustion, mental confusion, and paranoid thoughts.

Tolerance can develop to the effects of amphetamine and methamphetamine. A typical therapeutic dose is five milligrams. Individuals who abuse these drugs are reported to inject up to one gram in a single intravenous dose. Physical dependence is modest. Lethargy, drowsiness, hyperphagia, vivid dreams, and some mental depression may persist for a few days to several weeks after abrupt termination of repeated high doses.

Amphetamine and methamphetamine exist in two isomeric structural forms known as enantiomers. Enantiomers are non-superimposable mirror images. The two isomers of each substance are designated as d- (dextro) and l- (levo), indicating the direction in which they rotate a beam of polarized light. As do many pharmacological enantiomers, the d- and l- isomers have distinct pharmacological properties. In this case, the d- isomer of each substance has a strong central nervous system stimulant effect while the l-isomer of each substance has primarily a peripheral action. Illegally manufactured amphetamine and methamphetamine are principally found as the d-isomer. However, significant amounts of the l- isomer of each substance may be present depending on the starting materials used by the clandestine laboratories.

• Amphetamine – oral (i.e., tablets or…