Buprenorphine: partial agonist at the mu receptor
Buprenorphine is a partial agonist: it switches the mu receptor (the main target of opioid drugs) on only part of the way, which puts a ceiling on slowed breathing.
Remember
Buprenorphine is a partial agonist at the mu receptor, so respiratory depression (slow, shallow breathing) reaches a ceiling as the dose rises; that makes it safer than full agonists, but not risk-free.
Memory aid
a strong grip with a partial push
Affinity is the grip on the receptor and intrinsic activity is the push, so buprenorphine has a strong grip but only a partial push.
Buprenorphine is an opioid (a morphine-like drug) used in the community to treat opioid use disorder (opioid dependence). It acts at the mu (MOP) opioid receptor, the receptor that produces most opioid effects, including pain relief and slowed breathing.
Two properties describe how a drug acts at a receptor. Affinity is how tightly it binds, and efficacy (also called intrinsic activity) is how strongly it switches the receptor on once bound. A full agonist, such as morphine, has high efficacy. Buprenorphine has very high affinity but only partial intrinsic activity, so it is a partial agonist: it switches the receptor on only part of the way.
A full agonist keeps giving a bigger effect as the dose goes up, including more respiratory depression (slow, shallow breathing), the main cause of death in opioid overdose. A partial agonist's dose-response curve (the graph of effect against dose) flattens out, so the effect on breathing levels off as the dose rises. This is the ceiling effect.
The ceiling lowers the risk but does not remove it. Significant respiratory depression can still occur, particularly with other sedatives or in frail patients who are new to opioids.
Because buprenorphine grips the receptor so tightly, it is hard to displace with naloxone (the opioid antagonist used to reverse overdose), so higher doses or a continuous infusion of naloxone may be needed to reverse it. The same tight binding lets it displace heroin from the receptors, so heroin gives little euphoria (the 'high').
Key facts
- Receptor action
- buprenorphine binds the mu receptor with very high affinity but activates it only partly.
- Ceiling effect
- respiratory depression levels off at higher doses, unlike with full agonists such as morphine.
- Not risk-free
- the risk is lower than with full agonists but not zero.
- Pain relief
- the ceiling effect is demonstrated for respiratory depression in humans, but not for pain relief.
- Naloxone
- buprenorphine is hard to displace with naloxone because it binds tightly and dissociates (comes off the receptor) slowly.
- Methadone
- methadone is a full agonist that is also used in opioid substitution therapy (a prescribed opioid taken in place of an illicit one to reduce cravings and relapse), so it does not share the ceiling effect.
Exam traps
- Buprenorphine is not a competitive antagonist at the mu receptor: a drug with no intrinsic activity only blocks the receptor, as naloxone does, but buprenorphine does have intrinsic activity, though less than a full agonist.
- Buprenorphine is a partial agonist with very high affinity for the mu receptor, not low affinity: the high affinity is why it sticks tightly and is hard to displace with naloxone.
- Methadone is also used in opioid substitution therapy, but it is a full agonist, so it does not share buprenorphine's ceiling effect on respiratory depression.
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