Opioids

Diagnosis

Indications for Testing

Laboratory Testing

  • For drug testing strategies and methods, see ARUP Pain Management site or http://www.aruplab.com
  • Specimen types
    • Urine testing
      • Quantitate opioids
      • Commonly used for compliance testing and for identifying inappropriate drug use or exposure; the time during which a drug can be detected is drug-specific
      • For more information, refer to Drug Analytes Detected in Plasma and Urine
    • Serum/plasma testing 
      • Best specimen to correlate physiological signs and symptoms (eg, impairment, toxicity, therapeutic response) with drug use or drug concentration; also used when urine is unavailable
      • For most drugs, the time during which a drug can be detected is shorter than for urine
      • For more information, refer to Drug Analytes Detected in Plasma and Urine
    • Meconium/umbilical cord tissue
  • Note: Many opioid metabolites are available as independent drugs and may be identified by testing; ratios of parent to metabolite may help determine whether a patient used only the parent drug or more than one drug
    • Metabolic Pathways for Opioids

Monitoring

  • The interpretation of opioid drug testing is complicated because some prescription opioids are metabolized into other prescription opioids; additional opioid presence may be due to metabolism and not direct use
  • Some opioid drug preparations contain small amounts of other opioids – impurities in the manufacturing process
    • A very small amount of a known opioid contaminant in the presence of a large amount of parent drug is consistent with pharmaceutical impurity rather than direct use of the second drug
  • The following information assists in the correct interpretation of opioid drug abuse testing results
    • Possible explanations for drug(s) prescribed but not detected include the following
      • Noncompliance
      • Dilute urine, leading to drug concentrations that fall below analytical detection limits
      • Time lapse between last dose and specimen collection
      • Accelerated metabolism due to drug-to-drug interactions, altered expression of drug metabolizing enzymes, or genetic variation
      • Poor drug absorption
    • Possible explanations for drug(s) detected but not prescribed include the following
      • Drug metabolism (see discussion below)
      • Lack of disclosure of other prescriptions from health care providers
      • Process impurity of the pharmaceutical product
      • Voluntary use of nonprescription drug(s)
      • Incorrect prescription drug used
    • Possible explanations for unexpected drug concentrations include the following
      • Dosing less or more frequently than prescribed
      • Time lapse between last dose and specimen collection
      • Other variables as described above
  • Differentiation between production from metabolism or from direct use of an additional drug can sometimes be discerned by metabolic pathways
    • Two general categories of metabolism are major pathways and minor pathways; percentage ratios provided below are derived from an ARUP database review in 2006 that included 2,114 positive urine opioid test results
    • Major pathways
      • Morphine as a metabolite of codeine
        • When free morphine as a percent of free codeine in a urine specimen is <55%, morphine may have come from metabolism of codeine and not from separate use of morphine
        • The conversion of codeine to morphine is mediated by the cytochrome P450 isozyme 2D6 (CYP2D6), which is known to exhibit genetic variability and is vulnerable to drug-drug interactions
          • Genetic testing for CYP2D6 variants is available separately
      • Morphine and 6-monoacetylmorphine as a metabolite of heroin
        • Detection of 6-AM, along with morphine, is definitive evidence for the use of heroin; however, failure to detect 6-AM (which has a short half-life) with morphine present does not rule out the use of heroin 
        • Morphine can be derived from other sources such as poppy seeds, codeine metabolism, and morphine-containing medications
      • Hydromorphone or norhydrocodone as a metabolite of hydrocodone
        • When free hydromorphone as a percent of hydrocodone in a urine specimen is <30%, the hydromorphone may have come from metabolism of hydrocodone and not from separate use of hydromorphone
        • The amount of norhydrocodone that appears in the urine after metabolism of hydrocodone often exceeds the hydrocodone concentration
          • Norhydrocodone may persist in urine longer than the parent hydrocodone
      • Oxymorphone, noroxymorphone, and noroxycodone are metabolites of oxycodone
        • The amount of oxymorphone that appears in the urine after metabolism of oxycodone is small, generally representing <20% of the oxycodone concentration
        • The amount of noroxycodone that appears in the urine after metabolism of oxycodone often exceeds the oxycodone concentration
          • Noroxycodone may persist in urine longer than parent oxycodone
        • The amount of noroxymorphone that appears in the urine after metabolism of oxymorphone or noroxycodone often exceeds the oxymorphone concentration
          • Noroxymorphone may persist in urine longer than the parent oxymorphone
    • Other (minor) pathways
      • Hydrocodone as a metabolite of codeine
        • When hydrocodone as a percent of free codeine in a urine specimen is <40%, hydrocodone may have come from metabolism of codeine and not from the separate use of hydrocodone
      • Hydromorphone as a metabolite of morphine
        • When free hydromorphone as a percent of free morphine is <25%, hydromorphone may have come from metabolism of morphine and not from separate use of hydromorphone

Pharmacogenetics and Therapeutic Drug Monitoring

  • Opioid receptor, Mu (OPRM1) genotype
    • Predict response to opioid agents
    • Pre-therapeutic identification of individuals who may
      • Require higher or lower doses of opioid drugs to achieve adequate pain control
      • Have a better response to naltrexone for the treatment of alcohol and/or opioid dependency
    • OPRM1 gene is associated with the pharmacodynamics of opioids
    • Variants in OPRM1 can result in different binding affinities to and clinical effects of opioids
    • Association of OPRM1 and drug sensitivity
      • Not definitive
      • May be different for individual opioids

Clinical Background

Opiates and related pain medications (opioids), while effective analgesics, can produce dependency and severe withdrawal effects. In overdose, opioids may contribute to life-threatening respiratory and neurological depression. Compliance with use of prescribed opioids is monitored in pain management programs and in treatment/rehabilitation to detect possible diversion and assure abstinence from nonprescribed drugs.

Other clinical applications of opioids testing include the following

Epidemiology 

  • Prevalence
    • More than 100 million prescriptions filled annually in the U.S.
    • Approximately one million Americans are opioid-dependant
  • Sex – M>F

Risk Factors

  • Groups at particular risk – chronic pain management patients, health care providers, and those with a history of substance abuse or addiction
    • Screener and Opioid Assessment for Patients with Pain (SOAPP) is a widely used risk-assessment tool
  • Substance abuse often involves more than just opioids

Pathophysiology

  • All opioids are capable of producing tolerance and withdrawal
    • Tolerance is defined as a state of progressively decreased responsiveness to a drug
    • Withdrawal is defined as a constellation of symptoms that occur after a patient stops taking a drug
  • Opioids include many natural (opiate), synthetic and semi-synthetic forms that exert activity through an opioid receptor; the following drugs are discussed in this topic
    • Heroin (metabolites 6-monoacetylmorphine [6-AM] and morphine)
    • Morphine
    • Codeine
    • Hydrocodone
    • Hydromorphone
    • Oxycodone
    • Oxymorphone
  • Additional tests are available that detect opioid drugs not discussed in this topic
    • Buprenorphine
    • Methadone
    • Propoxyphene
    • Fentanyl 
    • Meperidine
    • Tramadol
    • Tapentadol

Clinical Presentation

  • Effects on organs
    • Central nervous system
      • Opiate euphoria
      • Withdrawal
    • Respiratory
      • Depression of respiratory drive
    • Gastrointestinal
      • Nausea
      • Emesis
      • Constipation

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Pain Management Drug Panel by High-Resolution Time-of-Flight Mass Spectrometry and Enzyme Immunoassay, Urine 2007479
Method: Qualitative Liquid Chromatography/Time of Flight Mass Spectrometry/Enzyme Immunoassay/Quantitative Spectrophotometry

Multidrug panel, including opioids

Preferred test for medication monitoring in urine

In most cases, high-resolution testing eliminates need for secondary (confirmation) testing

Qualitative testing only

Detects free (unconjugated) drug only

Targeted quantitative tests are available if needed

Opiates - Confirmation/Quantitation - Urine 0090364
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Confirm and quantitate opioids in urine

Drugs covered – codeine, morphine, 6-acetylmorphine, hydrocodone, norhydrocodone, hydromorphone, oxycodone, noroxycodone , oxymorphone, and noroxymorphone

Fewer false negatives with normetabolite tests

Detects free (unconjugated) drug only

Targeted quantitative testing for other opioids is available separately

Cytochrome P450 Pain Management Panel (CYP2D6, CYP2C9, CYP2C19), Common Variants 2008920
Method: Polymerase Chain Reaction/Primer Extension

Preferred test for analysis of common CYP450 variants

CYP2D6 variants tested

  • Functional
    • *2 (2850C>T)
    • *2A (-1584C>G; 2850C>T)
    • Decreased function
    • *9 (2613-5delAGA)
    • *10 (100C>T)
    • *17 (1023C>T)
    • *29 (1659G>A)
    • *41 (2988G>A)
  • Nonfunctional
    • *3 (2549delA)
    • *4 (1846G>A)
    • *5 (gene deletion)
    • *6 (1707delT)
    • *7 (2935A>C)
    • *8 (1758G>T)
    • *12 (124G>A)
    • *14 (1758G>A)
  • Increased function
    • Duplicated functional alleles

CYP2C9 variants tested

  • Decreased function
    • *2 (c.430C>T)
  • Nonfunctional
    • *3 (c.1075A>C)

CYP2C19 variants tested

  • Decreased function
    • *9 (c.431G>A)
    • *10 (c.680C>T)
  • Nonfunctional
    • *2 (c.681G>A)
    • *3 (c.636G>A)
    • *4 (c.1A>G)
    • *6 (c.395G>A)
    • *7 (c.819+2T>A)
    • *8 (c.358T>C)
  • Increased function
    • *17 (c.806C>T; increased gene transcription)

Only the targeted CYP2D6, CYP2C9, and CYP2C19 variants are detected

Diagnostic errors can occur due to rare sequence variations

Variant detection is not a substitute for therapeutic drug monitoring or other clinical monitoring

 
Drug Detection Panel by High-Resolution Time-of-Flight Mass Spectrometry, Serum or Plasma 2003254
Method: Qualitative Liquid Chromatography-Time of Flight Mass Spectrometry

Multidrug panel, including opioids

Preferred test for medication monitoring in serum/plasma

In most cases, high-resolution testing eliminates need for secondary (confirmation) testing

Qualitative testing only

Detects free (unconjugated) drug only

Targeted quantitative tests are available if needed

Drug Screen 9 Panel, Serum or Plasma - Immunoassay Screen with Reflex to Mass Spectrometry Confirmation/Quantitation 0092420
Method: Qualitative Enzyme-Linked Immunosorbent Assay/ Quantitative Gas Chromatography-Mass Spectrometry/Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Multidrug panel, including opioids

Traditional qualitative immunoassay-based detection, and quantitative confirmation testing, reflexed for samples that test positive by immunoassay

False negatives possible, based on cross-reactivity of the immunoassay to the drug(s) of interest

 
Opiates - Confirmation/Quantitation - Serum or Plasma 0092354
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Confirm and quantitate opioids in serum or plasma

Drugs covered – codeine,  morphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, and 6-monoacetylmorphine (heroin metabolite)

 

Targeted quantitative testing for other opioids is available separately

Drugs of Abuse Panel, Meconium - Screen with Reflex to Confirmation/Quantitation 0092516
Method: Qualitative Enzyme-Linked Immunosorbent Assay/Quantitative Gas Chromatography-Mass Spectrometry/Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Multidrug panel, including opioids, designed to detect drug-exposed infants

Traditional qualitative immunoassay-based detection, and quantitative confirmation testing, reflexed for samples that test positive by immunoassay

May detect drugs administered during labor and delivery, or drugs administered to the newborn prior to meconium collection

 
Drugs of Abuse Confirmation/Quantitation - Opiates - Meconium 0092314
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Confirm and quantitate opioids in meconium

Drugs covered – codeine, morphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, and 6-acetylmorphine (heroin metabolite)

May detect drugs administered during labor and delivery, or drugs administered to the newborn prior to meconium collection

 
Drug Detection Panel by High-Resolution Time-of-Flight Mass Spectrometry, Umbilical Cord Tissue 2006621
Method: Qualitative Liquid Chromatography-Time of Flight Mass Spectrometry/Qualitative Enzyme-Linked Immunosorbent Assay

Qualitative detection of drugs and drug metabolites to assess prenatal drug exposure

Panel includes:

  • Opioids (buprenorphine, codeine, fentanyl, heroin [6-acetylmorphine], dihydrocodeine, hydrocodone, hydromorphone, meperidine, methadone, morphine, naloxone, naltrexone, oxycodone, oxymorphone, propoxyphene, tapentadol, tramadol)
  • Stimulants (amphetamine, cocaine, methamphetamine, MDMA, MDEA, MDA, phentermine)
  • Sedative-hypnotics (alprazolam, butalbital, clonazepam, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, nordiazepam, oxazepam, phenobarbital, secobarbital, temazepam, triazolam, zolpidem)
  • Phencyclidine (PCP)
  • Cannabinoids (11-nor-9-carboxy-THC)

Details regarding the specific formulation, amount/dose, or time and length of exposure cannot be established by this testing

Minimum reporting limits (ng/g, pg/g) are established for each compound, but quantitation of detected drugs is not performed

Deposition of drugs in umbilical cord is not identical to meconium; concentrations of drugs and metabolites in cord tissue are generally lower than those found in meconium

This test is qualitative and does not provide quantitative results

While testing may be performed with chain of custody, ARUP is not a forensic laboratory; this test is intended for clinical use

Confirmation testing usually not required due to specificity of technology employed (high resolution, accurate mass spectometry)

Opioid Receptor, Mu (OPRM1) Genotype, 1 Variant 2008767
Method: Polymerase Chain Reaction/High Resolution Melt Analysis

Identify individuals who may

  • Require higher or lower doses of opioid drugs to achieve adequate pain control
  • Have a better response to naltrexone for the treatment of alcohol and/or opioid dependency

OPRM1 variants other than c.118A>G are not evaluated by this assay

Diagnostic errors can occur due to rare sequence variations

Genetic testing is not a substitute for therapeutic drug-monitoring or clinical evaluations

Genetic test results should be interpreted with clinical information

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Methadone and Metabolite - Confirmation/Quantitation - Urine 0090362
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

If uncertain about interpretation, call the technical supervisor or medical director of the lab performing the test

Methadone and Metabolite - Confirmation/Quantitation - Serum or Plasma 0090699
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

If uncertain about interpretation, call the technical supervisor or medical director of the lab performing the test

Drugs of Abuse Confirmation/Quantitation - Methadone and Metabolite - Meconium 0092313
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

If uncertain about interpretation, call the technical supervisor or medical director of the lab performing the test

Propoxyphene and Metabolite - Confirmation/Quantitation - Urine 2010468
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

If uncertain about interpretation, call the technical supervisor or medical director of the lab performing the test

Propoxyphene and Metabolite - Confirmation/Quantitation - Serum or Plasma 2010464
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

If uncertain about interpretation, call the technical supervisor or medical director of the lab performing the test

Drugs of Abuse Confirmation/Quantitation - Propoxyphene and Metabolite - Meconium 0092524
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

If uncertain about interpretation, call the technical supervisor or medical director of the lab performing the test

Fentanyl and Metabolite - Confirmation/Quantitation - Serum or Plasma 0092569
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

If uncertain about interpretation, call the technical supervisor or medical director of the lab performing the test

Fentanyl and Metabolite - Confirmation/Quantitation - Urine 0092570
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

If uncertain about interpretation, call the technical supervisor or medical director of the lab performing the test

Buprenorphine and Metabolites - Confirmation/Quantitation, Urine 2010092
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

If uncertain about interpretation, call the technical supervisor or medical director of the lab performing the test

Buprenorphine and Metabolites - Confirmation/Quantitation - Serum/Plasma 2002742
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

If uncertain about interpretation, call the technical supervisor or medical director of the lab performing the test

Meperidine and Metabolite - Confirmation/Quantitation - Serum or Plasma 2002756
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

If uncertain about interpretation, call the technical supervisor or medical director of the lab performing the test

Meperidine and Metabolite - Confirmation/Quantitation - Urine 2002760
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

If uncertain about interpretation, call the technical supervisor or medical director of the lab performing the test

Tramadol and Metabolites - Confirmation/Quantitation - Serum or Plasma 2002764
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

If uncertain about interpretation, call the technical supervisor or medical director of the lab performing the test

Tramadol and Metabolites - Confirmation/Quantitation - Urine 2002736
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

If uncertain about interpretation, call the technical supervisor or medical director of the lab performing the test

Tapentadol and Metabolite - Confirmation/Quantitation - Serum or Plasma 2003133
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Confirm and quantitate tapentadol and metabolite in serum or plasma

If uncertain about interpretation, call the technical supervisor or medical director of the lab performing the test

Tapentadol and Metabolite - Confirmation/Quantitation - Urine 2003128
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Confirm and quantitate tapentadol and metabolite in urine

If uncertain about interpretation, call the technical supervisor or medical director of the lab performing the test

Drug Panel 7, Urine - Screen with Reflex to Confirmation/Quantitation 0092184
Method: Qualitative Enzyme Multiplied Immunoassay Technique/ Quantitative Gas Chromatography-Mass Spectrometry/Quantitative Liquid Chromatography-Tandem Mass Spectrometry

If uncertain about interpretation, call the technical supervisor or medical director of the lab performing the test

If specimen screens positive, Confirmation/Quantitation by GC/MS and/or LC-MS/MS will be added to confirm result

Oxycodone results reported with the opiates results; MDMA results reported with the amphetamines results

Drug Panel 7A, Urine - Screen with Reflex to Confirmation/Quantitation 0092185
Method: Enzyme Immunoassay/Gas Chromatography-Flame Ionization Detection/Gas Chromatography-Mass Spectrometry/Liquid Chromatography-Tandem Mass Spectrometry

If uncertain about interpretation, call the technical supervisor or medical director of the lab performing the test

If specimen screens positive, Confirmation/Quantitation by GC/MS, GC/FID, and/or LC-MS/MS will be added to confirm result

Oxycodone results reported with the opiates results; MDMA results reported with the amphetamines results

Drug Panel 9, Urine - Screen with Reflex to Confirmation/Quantitation 0092186
Method: Qualitative Enzyme Multiplied Immunoassay Technique/ Quantitative Gas Chromatography-Mass Spectrometry/Quantitative Liquid Chromatography-Tandem Mass Spectrometry

If uncertain about interpretation, call the technical supervisor or medical director of the lab performing the test

If specimen screens positive, Confirmation/Quantitation by GC/MS and/or LC-MS/MS will be added to confirm result

Oxycodone results reported with the opiates results; MDMA results reported with the amphetamines results

The following opioids are not detected in this test – fentanyl, buprenorphine, meperidine, tramadol, and tapentadol

Drug Panel 9A, Urine - Screen with Reflex to Confirmation/Quantitation 0092187
Method: Enzyme Immunoassay/Gas Chromatography-Flame Ionization Detection/Gas Chromatography-Mass Spectrometry/Liquid Chromatography-Tandem Mass Spectrometry

If uncertain about interpretation, call the technical supervisor or medical director of the lab performing the test

If specimen screens positive, Confirmation/Quantitation by GC/MS, GC/FID, and/or LC-MS/MS will be added to confirm result

Oxycodone results reported with the opiates results; MDMA results reported with the amphetamines results

The following opioids are not detected in this test – fentanyl, buprenorphine, meperidine, tramadol, and tapentadol