Opioid-receptor Agonists

There are three types of opioid receptors: mu (μ), delta (δ), and kappa (K). Opioid-receptor agonists produce analgesia primarily by acting at μ-receptors found in primary afferent sensory neurons, the spinal cord, the brainstem, and the brain.21-23 Presynaptic μ-receptor activation inhibits calcium influx into sensory neurons, which decreases neurotransmitter release. Postsynaptic μ-receptor activation increases K+ conductance, which decreases postsynaptic neurotransmission.

Morphine is a naturally occurring strong, full μ-receptor agonist. However, after oral administration, morphine is rapidly metabolized by hepatic glucuronidation and its bioavailability is low. Oxycodone is a semi-synthetic strong, full μ-receptor agonist. After oral administration its bioavailability is high. Oxycodone is metabolized by glucuronidation to noroxycodone and by the CYP450 isoenzyme 2D6 to oxymorphone; however, oxycodone and not oxymorphone is primarily responsible for analgesia.

Codeine is a naturally occurring weak, full μ-receptor agonist. Its analgesic action is largely dependent on its hepatic demethylation to morphine. Demethylation by the CYP450 isoenzyme 2D6 is subject to genetic polymorphism. Up to 10% of the general population are poor metabolizers of codeine and do not experience analgesia in response to treatment; while another 10% rapidly convert codeine to morphine, which can lead to severe toxicity (including death) even with therapeutic doses.

Hydrocodone is a synthetic weak, full μ-receptor agonist. It is similar in structure to codeine, but hydrocodone is a more effective analgesic. Hydrocodone is demethylated by the CYP450 isoenzyme 2D6 to hydromorphone, which has a much stronger affinity for the μ-receptor than hydrocodone and is primarily responsible for hydrocodone’s analgesic effect. Patients who are CYP450 isoenzyme 2D6 deficient and those on CYP450 isoenzyme 2D6 inhibitors may not achieve adequate analgesia.