Opioids

  • Diagnosis
  • Monitoring
  • Pharmacogenetics
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

Indications for Testing

Laboratory Testing

  • For drug testing strategies and methods, see ARUP Pain Management site or ARUP test offerings
  • 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
      • Not recommended for drug screening; urine is preferred; may be 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
  • 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
  • Opioid receptor, Mu 1, OPRM1 genotype, 1 variant
    • 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

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
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.

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

Limitations 

Qualitative testing only

Detects free (unconjugated) drug only

Carisoprodol immunoassay has cross-reactivity to carisoprodol and meprobamate

Follow-up 

Targeted quantitative tests are available if needed

Opiates, Urine, Quantitative 0090364
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Limitations 

Detects free (unconjugated) drug only

Follow-up 

Targeted quantitative testing for other opioids is available separately

Cytochrome P450 Genotype Panel 2013098
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations 

Only the targeted CYP2D6, CYP2C9, CYP2C19, and CYP3A5  variants will be detected

Diagnostic errors can occur due to rare sequence variations

Risk of therapeutic failure or adverse reactions with CYP2D6, CYP2C9, CYP2C19, or CYP3A5 substrates may be affected by genetic and nongenetic factors that are not detected by this test

Variant detection does not replace therapeutic drug and 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

Limitations 

Qualitative testing only

Detects free (unconjugated) drug only

Follow-up 

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

Limitations 

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

Opiates, Serum or Plasma, Quantitative 0092354
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Follow-up 

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

Limitations 

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

Limitations 

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

Drug Detection Panel, Umbilical Cord Tissue, Qualitative 2006621
Method: Qualitative Liquid Chromatography/Tandem Mass Spectrometry/Enzyme-Linked Immunosorbent Assay

Limitations 

Cannot determine date of maternal drug use, what specific drug was taken, or amount taken

Marijuana metabolites (eg, THC) are detected by immunoassay and are not confirmed

This test is qualitative and does not provide quantitative results

Follow-up 

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/Fluorescence Monitoring

Limitations 

Only the targeted OPRM1 mutation, c.118A>G, will be detected

Diagnostic errors can occur due to rare sequence variations

Risk of therapeutic failure or adverse reactions with opioids may be affected by genetic and nongenetic factors that are not detected by this test

Genetic testing does not replace the need for therapeutic or clinical monitoring

General References

Aquina CT, Marques-Baptista A, Bridgeman P, Merlin MA. OxyContin abuse and overdose. Postgrad Med. 2009; 121(2): 163-7. PubMed

Clay SW, Allen J, Parran T. A review of addiction. Postgrad Med. 2008; 120(2): E01-7. PubMed

Cone EJ, Huestis MA. Interpretation of oral fluid tests for drugs of abuse. Ann N Y Acad Sci. 2007; 1098: 51-103. PubMed

Cone EJ, Zichterman A, Heltsley R, Black DL, Cawthon B, Robert T, Moser F, Caplan YH. Urine testing for norcodeine, norhydrocodone, and noroxycodone facilitates interpretation and reduces false negatives. Forensic Sci Int. 2010; 198(1-3): 58-61. PubMed

Gutstein H, Akil H. Opioid Analgesics, Ch 18. In Hardman JG et al. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12th ed. New York: McGraw-Hill, 2010.

Haroz R, Greenberg MI. New drugs of abuse in North America. Clin Lab Med. 2006; 26(1): 147-64, ix. PubMed

Kreek MJ, Zhou Y, Butelman ER, Levran O. Opiate and cocaine addiction: from bench to clinic and back to the bench. Curr Opin Pharmacol. 2009; 9(1): 74-80. PubMed

O’Brien C. Drug Addiction and Drug Abuse, Ch 24. In Hardman JG et al. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12th ed. New York: McGraw-Hill, 2010.

Passik SD. Issues in long-term opioid therapy: unmet needs, risks, and solutions. Mayo Clin Proc. 2009; 84(7): 593-601. PubMed

Pragst F, Balikova MA. State of the art in hair analysis for detection of drug and alcohol abuse. Clin Chim Acta. 2006; 370(1-2): 17-49. PubMed

Smith HS. Opioid metabolism. Mayo Clin Proc. 2009; 84(7): 613-24. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology

Johnson-Davis KL, Slawson MH. Ethyl Glucuronide Positivity Rate in a Pain Management Population J Anal Toxicol. 2015; 39(9): 686-90. PubMed

Johnson-Davis KL, Thompson CD, Clark CJ, McMillin GA, Lehman CM. Method comparison of the Ortho Vitros Fusion 5,1 chemistry analyzer and the Roche COBAS Integra 400 for urine drug screen testing in the emergency department. J Anal Toxicol. 2012; 36(5): 345-8. PubMed

Marin SJ, Hughes JM, Lawlor BG, Clark CJ, McMillin GA. Rapid screening for 67 drugs and metabolites in serum or plasma by accurate-mass LC-TOF-MS. J Anal Toxicol. 2012; 36(7): 477-86. PubMed

McMillin GA, Marin SJ, Johnson-Davis KL, Lawlor BG, Strathmann FG. A hybrid approach to urine drug testing using high-resolution mass spectrometry and select immunoassays Am J Clin Pathol. 2015; 143(2): 234-40. PubMed

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Last Update: October 2016