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