Medical Pharmacology Chapter 13:  Pain Management:  Opioids

Pharmacokinetics

• Absorption:

  • Opioid analgesics are generally well absorbed by cutaneous/intramuscular/mucosal surfaces

  • Transdermal fentanyl represents an important route of administration

  • Gastrointestinal absorption:

    • Some opioids are subject to first-pass metabolism.

    • Codeine and oxycodone exhibit both high oral and parenteral potency (protected from conjugation by substitution on C₃ aromatic hydroxyl)

• Distribution:

  • Various extent of plasma protein binding

  • Highest concentrations in tissues will be a  function of perfusion

  • Skeletal muscle represents the largest reservoir

  • For highly lipophilic opioids (e.g. fentanyl), there is significant concentration in adipose tissue

  • Blood Brain Barrier:

    • Amphoteric agents (possessing both an acidic and basic group, e.g. morphine {phenolic hydroxyl at C₃}: greatest difficulty for brain entry

    • Other substitutions that C₃ improve blood-brain barrier penetration: e.g., heroin, codeine

    •  Neonatal considerations: neonates lack the blood-brain barrier:

      1.   Placental opioid transfer (uses in obstetric analgesia) can result in depressed respiration in the newborn.

• Metabolism:

  • Opioid and Opiate Metabolism

    Andor Labs:  Opioid and Opiate Metabolism Pathways http://www.justmeans.org

  • Conversion to polar metabolites; renal excretion

  • Opioids with hydroxyl groups are likely conjugated with glucuronic acid

    • Examples:

      • Morphine

      • Levorphanol (Levo-dromoran) 

    • Morphine-6-glucuronide: analgesic potency (perhaps > parent compound morphine)

    • In patients with compromised renal function, accumulation of metabolites occurs which prolongs  analgesia

  • Esters-type opioids are: hydrolyzed by tissue esterases:

    • Examples:

      • Heroin

      • Remifentanil (short duration of action)

  • N-demethylation: minor pathway

    • Accumulation of demethylated meperidine (Demerol)  metabolite, normeperidine:

      • Patients with decreased renal function or on high dosages: CNS excitatory effects:

        •   Seizures (more likely in children)

  • Oxidative metabolism (hepatic) primary route of phenylpiperidine opioid metabolism:

    • Fentanyl (Sublimaze)

    • Alfentanil (Alfenta)

    • Sufentanil (Sufenta)

• Excretion:

  • Polar metabolites are often excreted by the kidney (renal excretion) with small amounts excreted unchanged.

  • Glucuronide conjugates enter the bile  and may be subject to enterohepatic circulation to a minor extent.