oxycodone

**Class/Mechanism:** Semisynthetic opioid made from thebaine (an opium alkaloid). It is a full agonist at the mu (μ) opioid receptor, a Gi/Go-coupled GPCR. Receptor activation causes: - Decreased adenylyl cyclase activity and lower cAMP. - Increased K+ efflux (hyperpolarization). - Decreased Ca2+ influx. - Reduced presynaptic release of pain neurotransmitters (substance P, glutamate). The net effect is analgesia, with decreased nociceptive transmission in the dorsal horn and altered pain perception in the brain.

**Pharmacokinetics:** - Good oral bioavailability (~60-87%), better than morphine's. - Immediate-release (IR) lasts ~4-6 h. Extended-release (ER, OxyContin) is dosed every 12 h. - Hepatic metabolism: CYP3A4 (major) to noroxycodone, and CYP2D6 (minor) to oxymorphone (active). CYP3A4 inhibitors (ketoconazole, macrolides, ritonavir, grapefruit juice) raise levels and the risk of toxicity. CYP3A4 inducers (rifampin, carbamazepine, phenytoin) lower levels and efficacy. - Renally excreted. Use caution in renal and hepatic impairment. - Common combination products: oxycodone/acetaminophen (Percocet) and oxycodone/aspirin. Chronic high-dose use of the combination carries a risk of acetaminophen hepatotoxicity (N-acetylcysteine is the antidote).

**Clinical uses:** Moderate-to-severe acute pain (postoperative, trauma) and chronic severe pain (cancer pain) when other options are inadequate.

**Adverse effects:** - Respiratory depression (the leading cause of death in overdose), sedation, and miosis (pinpoint pupils). - Constipation: tolerance does not develop to this or to miosis. It is treated with laxatives or peripherally acting mu antagonists (methylnaltrexone, naloxegol). - Nausea/vomiting (CTZ stimulation), urinary retention, and biliary spasm (sphincter of Oddi contraction, which can raise amylase/lipase and cause biliary colic). - Pruritus and histamine release (less than with morphine). Hypotension and bradycardia are possible. - Serotonin syndrome is rare, mainly with other serotonergic drugs. - Hyperalgesia with chronic use.

**Tolerance/dependence/addiction:** It is a Schedule II controlled substance with high abuse potential. Tolerance develops to analgesia, euphoria, sedation, and respiratory depression. Physical dependence leads to withdrawal if the drug is stopped abruptly. Withdrawal is rarely life-threatening but very uncomfortable: rhinorrhea, lacrimation, yawning, mydriasis, piloerection ("cold turkey"), myalgias, diarrhea, nausea/vomiting, and anxiety. Treat with methadone or buprenorphine, with clonidine for autonomic symptoms. The ER formulation has been crushed, snorted, or injected (a major driver of the opioid epidemic), which led to abuse-deterrent formulations.

**Overdose triad:** Coma/CNS depression, respiratory depression, and pinpoint pupils. - Treat with airway support and naloxone, a competitive mu antagonist (IV, IM, or intranasal). - Naloxone's half-life is shorter than that of many opioids (especially ER oxycodone), so renarcotization can occur. Repeat dosing or an infusion and monitoring are needed. - Naloxone can precipitate acute withdrawal in dependent patients. - Naltrexone (long-acting oral/depot) is used for relapse prevention in opioid and alcohol use disorder.

**Other points:** - Contraindications: significant respiratory depression, acute or severe asthma, paralytic ileus, and concurrent use with MAOIs (relative). - Avoid concurrent benzodiazepines or alcohol (additive CNS and respiratory depression, with a boxed warning). - Pregnancy: use can cause neonatal abstinence syndrome. - Comparison of potency: morphine 1 (reference), oxycodone ~1.5x oral morphine, hydrocodone ~1x, hydromorphone ~4-5x (oral), fentanyl ~50-100x. - Related opioids: codeine, hydrocodone, and oxymorphone are semisynthetic. Methadone and fentanyl are synthetic. Tramadol is a weak mu agonist with SNRI activity (lowers the seizure threshold). - Board pearl: A patient with pinpoint pupils, bradypnea, and decreased consciousness should be given naloxone. Opioid intoxication with mydriasis suggests co-ingestion (e.g., meperidine) or severe hypoxia.