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EPIC CODE: LAB6370 Methadone Confirmation, Random, Urine

Additional Codes

Sunquest:   MTDNUM
Mayo:           MTDNU

Reporting Name

Methadone Confirmation, U

Useful For

Monitoring for compliance of methadone treatment for analgesia or drug rehabilitation


Assessing compliance with rehabilitation programs by urine measurement of 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine

Performing Laboratory

Mayo Clinic Laboratories in Rochester

Specimen Type


Ordering Guidance

1. For situations where chain of custody is required, a Chain-of-Custody Kit (T282) is available. For chain-of-custody testing, order MTDNX / Methadone Confirmation, Chain of Custody, Random, Urine.

2. Additional drug panels and specific requests are available. Call 800-533-1710 or 507-266-5700.

3. If urine creatinine is required or adulteration of the sample is suspected, order ADULT / Adulterants Survey, Random, Urine.

Specimen Required

Supplies: Urine Tubes, 10 mL (T068)

Container/Tube: Plastic, 10-mL urine tube

Specimen Volume: 10 mL

Collection Instructions:

1. Collect a random urine specimen.

2. No preservative.

Specimen Minimum Volume

2.5 mL

Specimen Stability Information

Specimen Type Temperature Time Special Container
Urine Refrigerated (preferred) 28 days
  Frozen  28 days
  Ambient  14 days

Reference Values



Cutoff concentrations:


<100 ng/mL


<100 ng/mL

Day(s) Performed

Monday, Wednesday, Friday

Test Classification

This test was developed, and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the US Food and Drug Administration.

CPT Code Information


G0480 (if appropriate)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
MTDNU Methadone Confirmation, U In Process


Result ID Test Result Name Result LOINC Value
56028 EDDP-by GC-MS 58428-4
83129 Methadone-by GC-MS 16246-1
21107 Methadone Interpretation 69050-3
21110 Chain of Custody 77202-0

Clinical Information

Methadone (Dolophine) is a synthetic opioid, a compound that is structurally unrelated to natural opiates but is capable of binding to opioid receptors. These receptor interactions create many of the same effects seen with natural opiates including analgesia and sedation. However, methadone does not produce feelings of euphoria and has substantially fewer withdrawal symptoms than opiates such as heroin.(1) Methadone is used clinically to relieve pain, treat opioid abstinence syndrome, and treat heroin addiction in an attempt to wean patients from illicit drug use.


Metabolism of methadone to inactive forms is the main form of elimination. Oral delivery of methadone makes it subject to first-pass metabolism by the liver and creates interindividual variability in its bioavailability, which ranges from 80% to 95%. The most important enzymes in methadone metabolism are cytochrome P450 (CYP) 3A4 and CYP2B6.(1-4) CYP2D6 appears to have a minor role, and CYP1A2 may possibly be involved.(1-5) Methadone is metabolized to a variety of metabolites with the primary metabolite being 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP).(1-4) The efficiency of this process is prone to wide inter- and intraindividual variability, due to inherent differences in enzymatic activity as well as enzyme induction or inhibition by numerous drugs. Excretion of methadone and its metabolites (including EDDP) occurs primarily through the kidneys.(1,4)


Patients who are taking methadone for therapeutic purposes excrete both parent methadone and EDDP in their urine. Clinically, it is important to measure levels of both methadone and EDDP. Methadone levels in urine vary widely depending on factors such as dose, metabolism, and urine pH.(5) EDDP levels, in contrast, are relatively unaffected by the influence of pH and are, therefore, preferable for assessing compliance with therapy.(5)


Some patients undergoing treatment with methadone have attempted to pass compliance testing by adding a portion of the supplied methadone to the urine.(6) This is commonly referred to as "spiking.'' In these situations the specimen will contain large amounts of methadone and no or very small amounts of EDDP.(6) The absence of EDDP in the presence of methadone in urine strongly suggests adulteration of the urine specimen by direct addition of methadone to the specimen.


The absolute concentration of methadone and its metabolites found in patient urine specimen can be highly variable and do not correlate with dose. However, the medical literature and our experience show that patients who are known to be compliant with their methadone therapy have ratios of 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP):methadone of greater than 0.60.(7)


An EDDP:methadone ratio less than 0.090 strongly suggests manipulation of the urine specimen by direct addition of methadone to the specimen.(6)


Urine pH has a considerable effect on the ability to detect methadone, thus 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine is preferable for urine measurements.


Urine concentrations of methadone show very poor correlation to serum levels or the amount of drug administered.

Clinical Reference

1. Gutstein HB, Akil H: Opioid analgesics. In: Hardman JG, Limbird LE, eds. Goodman and Gilman's: The Pharmacological Basis of Therapeutics. 10th ed. McGraw-Hill; 2001:569-619

2. Eap CB, Buclin T, Baumann P: Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41(14):1153-1193

3. Ferrari A, Coccia CP, Bertolini A, Sternieri E: Methadone-metabolism, pharmacokinetics and interactions. Pharmacol Res. 2004 Dec;50(6):551-559

4. Baselt RC: Disposition of Toxic Drugs and Chemicals in Man. 10th ed. Biomedical Publications; 2014

5. Levine B: Principles of Forensic Toxicology. 2nd ed. AACC Press; 2003: 385

6. Galloway FR, Bellet NF: Methadone conversion to EDDP during GC-MS analysis of urine samples. J Anal Toxicol. Nov-Dec 1999;23(7):615-619

7. George S, Braithwaite RA: A pilot study to determine the usefulness of the urinary excretion of methadone and its primary metabolite (EDDP) as potential markers of compliance in methadone detoxification programs. J Anal Toxicol. Mar-Apr 1999;23(2):81-85

8. Langman LJ, Bechtel LK, Meier BM, Holstege C: Clinical toxicology. In: Rifai N, Horwath AR, Wittwer CT. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018

Method Description

Confirmation is performed by gas chromatography-mass spectrometry, solid phase extraction.(Unpublished Mayo method)

Report Available

3 to 5 days

Reject Due To

Gross hemolysis OK
Gross icterus OK

NY State Approved


Method Name

Gas Chromatography-Mass Spectrometry (GC-MS) Confirmation with Quantitation

Specimen Retention Time

14 days

Secondary ID



If not ordering electronically, complete, print, and send a Therapeutics Test Request (T831) with the specimen.