3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.5. Opioids
 3.1.3.5.4. Opioid agonist-antagonists 

Opioid agonist-antagonists

[SH4:p117-120; "Opioid receptors" CEACCP 2005 Vol 5(I) p22-25]

Opioid agonist-antagonists include

  • Pentazocine
  • Butorphanol
  • Nalbuphine
  • Buprenorphine
  • Nalorphine
  • Bremazocine
  • Dezocine

Mechanisms of action

  • The opioid agonist-antagonists bind to mu receptors and produce limited responses or no effect
    * Also exert partial agonist actions at DOP and/or KOP receptors

Effects

  • Similar to opioid agonists
  • Also produce dysphoria

Clinicial

Opioid agonist-antagonists should be reserved for patients who cannot tolerate a pure agonist

Advantage of opioid agonist-antagonists

Ability to produce analgesia with
* Limited depression of ventilation
* Low potential to produce physical dependence

Disadvantage of opioid agonist-antagonists

Ceiling effects
--> Increasing doses do not produce additional responses

Some examples of the opioid agonist-antagonists

Butorphanol

  • Resembles pentazocine
  • It is speculated that butorphanol has
    * Low affinity for MOP receptors (antagonism)
    * Moderate affinity for KOP receptors (analgesia and antishivering)
    * Minimal affinity for sigma receptors (low incidence of dysphoria)

Butorphanol vs pentazocine

  • Butorphanol has
    * 20 times greater agonist effect
    * 10-30 times greater antagonist effect

Side effects of butorphanol

  • Sedation
  • Nausea
  • Diaphoresis
  • Respiratory depression
  • Catecholamine release
    * Like pentazocine
  • Withdrawal symptoms after acute discontinuation of butorphanol
    * But mild symptoms only
  • Dysphoria is uncommon
    * Unlike other opioid agonist-antagonists

Pharmacokinetics of butorphanol

  • Rapid and almost complete absorption after IM
  • Also administered intranasally
  • Elimination half-time of butorphanol = 2.5 - 3.5 hours
  • Metabolism: Mainly to hydroxybutorphanol (which is excreted mostly in bile and some in urine)

Nalbuphine

  • Chemically related to oxymorphone and naloxone
  • Equal in analgesic potency as morphine
    * Reversed by naloxone
  • 1/4 in antagonist potency as nalorphine
  • Sedation is the most common side effect
  • Does not cause catecholamine release
  • Less incidence of dysphoria
    * Increases with higher doses

Nalorphine

  • Equally potent as morphine
  • NOT clinically useful due to high incidence of dysphoria
    * May be due to action at sigma receptor

Bremazocine

  • Benzomorphan derivative
  • Twice as potent as morphine as an analgesic
  • Does not produce respiratory depression or physical dependence
  • May interact selectively with KOP receptors
  • Sedation is NOT reversed by naloxone

Dezocine

  • Analgesic potency and onset and duration of action are comparable to morphine
  • High affinity for MOP receptors
  • Moderate affinity for DOP receptors
    --> Facilitate the agonist effect at MOP receptors
  • Minimal dysphoria

Meptazinol

  • Partial opioid agonist
  • Relative selectivity at mu1 receptor
  • Depression of ventilation does NOT occur with analgesic doses of meptazinol
  • Meptazinol 100mg IM is equivalent to morphine 8mg IM
  • Rapid onset, short duration of action (<2 hours)
  • No physical dependence or constipation
  • Slight miosis effect
  • N&V is common side effect