Overview
This lecture covers the pharmacology of opioids, including their mechanisms of action, major classes, clinical considerations, and key differences among commonly used agents.
Opioid Mechanism of Action
- Opioids act on multiple neural pathways, affecting both ascending (pain signals to brain) and descending (modulatory) pathways.
- They primarily activate the mu-opioid receptor to inhibit pain signal transmission to the cerebral cortex.
- Some opioids require metabolic activation (via enzymes like CYP2D6) to become effective.
Centrally Acting Opioid Analgesics (Example: Tramadol)
- Tramadol is a racemic mixture; both isomers are mu-opioid agonists with additional serotonergic and noradrenergic effects.
- The active M1 metabolite (formed by CYP2D6) is 4–6 times more potent than parent drug; efficacy reduced by CYP2D6 inhibitors (e.g., fluoxetine, paroxetine).
- High doses (>400 mg) raise seizure risk and risk of serotonin syndrome, especially when combined with other serotonergic drugs.
- FDA warning: Avoid in children <17 years, especially after tonsillectomy, due to risk of rapid metabolism and respiratory depression.
Partial Opioid Agonists/Antagonists
- Examples include buprenorphine (Buprenex) and mixed formulations like Suboxone (buprenorphine + naloxone) used for opioid dependence.
- Buprenorphine has a ceiling effect, limiting maximal analgesia and use in chronic pain.
- Do not combine with pure agonists (e.g., morphine), as they may reduce analgesic effectiveness.
Pure Opioid Agonists: Weak & Strong Types
- Weak agonists: Codeine (C-II alone, C-III when combined with acetaminophen); requires CYP2D6 to convert to morphine.
- Strong agonists: Hydrocodone (metabolized to hydromorphone), oxycodone, morphine, hydromorphone, fentanyl, methadone.
- Abuse-deterrent formulations exist (e.g., zohydro, oxycodone ER).
- Hydromorphone and fentanyl do not require activation and are less likely to cause histamine release than morphine.
Special Considerations for Individual Opioids
- Methadone: Used for pain and opioid dependence; long half-life, risks QT prolongation, many drug interactions.
- Meperidine: Rarely used due to toxic metabolite (normeperidine) and seizure risk.
- Morphine: Available in many formulations; metabolites may accumulate in renal failure, causing side effects.
- Oxycodone: Immediate and extended-release options; often combined with acetaminophen or other agents.
- Fentanyl: Highly potent, multiple administration routes (including transdermal patch for chronic pain, mucosal for breakthrough pain); use only in opioid-tolerant patients.
Key Terms & Definitions
- Mu-opioid receptor — primary opioid receptor mediating analgesia and euphoria.
- CYP2D6 — liver enzyme responsible for metabolizing some opioids to active forms.
- Ceiling effect — maximum effect beyond which increasing dose does not increase response.
- Abuse-deterrent formulation — drug designed to prevent misuse via tampering.
- Serotonin syndrome — life-threatening condition from excessive serotonergic activity (confusion, tremor, fever).
Action Items / Next Steps
- Review dose equivalency tables and opioid conversion guides.
- Know which opioids require metabolic activation and the implications of CYP2D6 variability.
- Recognize FDA warnings and contraindications for specific opioids.
- Read up on abuse-deterrent formulations and their clinical significance.