Codeine

Codeine is an opioid. The main effect of codeine comes from its metabolite morphine. In the liver, codeine undergoes O-demethylation by the CYP2D6 enzyme and is converted into morphine. Morphine is primarily a potent μ-opioid receptor agonist. After μ-receptor activation, adenylate cyclase is inhibited, cAMP production decreases, and presynaptic calcium channels close, thereby suppressing the release of pain-related neurotransmitters such as substance P and glutamate. At the same time, postsynaptic potassium efflux increases, causing neuronal hyperpolarization. However, some studies suggest that another metabolite of codeine, codeine-6-glucuronide, may also contribute to analgesia and can likewise bind to the μ-opioid receptor. Codeine can even be further metabolized into morphine-6-glucuronide, which has stronger analgesic potency than morphine itself.