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 non-prescribed drugs. Other clinical applications of opioids testing include the following:

• Evaluating abstinence for rehabilitation clinics 
• Explaining clinical signs and symptoms of intoxication 
• Documenting abuse 
• Identifying neonates exposed to opioids in utero who may experience withdrawal symptoms or be at risk for either acute or chronic complications

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 and/or addiction
  • The Screener and Opioid Assessment for Patients with Pain ( SOAPP^®) is a widely used risk-assessment tool
  • Substance abuse often involves more than just opioids
• Addiction is related to environmental factors; however, genetics may also contribute

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 the 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 that detect other opioid drugs are not discussed specifically 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 Testing

• Patient with prescribed opioid therapy – evaluate compliance
• Patients with suspected opioid abuse and overdose situations, as well as newborns with suspected abuse exposure

Laboratory Testing

• Specimen types
  • Urine testing
    • Confirm and quantitate opioids
    • Commonly used for compliance testing and to identify inappropriate drug use or exposure; the specific time over which a drug can be detected is drug-specific
    • For more information, refer to the Drug Analytes Detected in Plasma and Urine table
  • Serum/plasma testing 
    • Best specimen to correlate physiological signs and symptoms (eg, impairment, toxicity, therapeutic response) with drug use and/or drug concentration; also used when urine is unavailable
    • For most drugs, the specific time over which a drug can be detected is shorter than for urine
    • For more information, refer to the Drug Analytes Detected in Plasma and Urine table
  • Meconium/umbilical cord tissue
    • Used to detect drug use during approximately the last trimester of pregnancy
    • For more information, refer to the Drug Analytes Detected in Meconium and Umbilical Cord table
• See ARUP's Pain Management resource for further information
• 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

    

• 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 from direct use
• 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
    • Non-compliance
    • 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, genetic variation, or 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 non-prescribed 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 were 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), an enzyme that 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 and/or dihydrocodeine 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 percentage of dihydrocodeine derived from metabolism of hydrocodone is not well characterized
    • Oxymorphone as a metabolite of oxycodone
      • The percentage of oxymorphone derived from metabolism of oxycodone is not well characterized
  • Minor pathways (percentages reported are from an ARUP database study, 2006)
    • 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

Tests generally appear in the order most useful for common clinical situations

General

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Drug Testing
Newborn Drug Screening
Pharmacogenetics
Sepsis