hydrocodone

**Class/Mechanism:** Semisynthetic opioid, full agonist at mu (µ) opioid receptors (Gi/Go-coupled GPCRs). Receptor activation causes: ↑ K+ efflux (hyperpolarization), ↓ Ca2+ influx (presynaptic), and ↓ cAMP, which reduces release of neurotransmitters (substance P, glutamate, ACh) and blunts pain transmission. Derived from codeine (it is a hydrogenated, oxidized form of codeine; 6-keto, 7,8-dihydro derivative).

**Pharmacokinetics:** - Oral absorption is good; peak effect ~1 hr; duration ~4-6 hr (immediate release). - Metabolized by hepatic CYP3A4 (to norhydrocodone, mostly inactive) and CYP2D6 (to hydromorphone, a more potent active metabolite). CYP3A4 inhibitors (macrolides, azole antifungals, grapefruit juice, ritonavir) ↑ levels and toxicity risk. CYP3A4 inducers (rifampin, carbamazepine, phenytoin) ↓ levels and can precipitate withdrawal. CYP2D6 inhibitors (fluoxetine, paroxetine, quinidine) may reduce analgesic effect. - Renally excreted metabolites.

**Indications:** Moderate to severe acute pain (typically combined with acetaminophen or ibuprofen); extended-release single-entity formulations for chronic severe pain requiring around-the-clock therapy; antitussive (combined with homatropine) for cough.

**Adverse effects:** Sedation, respiratory depression (most serious, most common cause of death in overdose), miosis (pinpoint pupils; tolerance does NOT develop to miosis), constipation (no tolerance develops; due to ↓ GI motility, ↑ sphincter tone), nausea/vomiting (CTZ stimulation), pruritus (histamine release), urinary retention, biliary spasm (sphincter of Oddi constriction; may ↑ amylase/lipase), orthostatic hypotension, cough suppression, and dependence. Can raise intracranial pressure via CO2 retention and cerebral vasodilation (avoid in head trauma).

**Overdose/Toxicity:** Triad of CNS depression, respiratory depression, and miosis. Treat with airway support and naloxone (short-acting mu antagonist, half-life ~1 hr, shorter than most opioids, so repeat dosing or an infusion may be needed to prevent renarcotization). Combination products: acetaminophen toxicity (NAPQI depletes glutathione, causing centrilobular (zone 3) hepatic necrosis); treat with N-acetylcysteine (NAC) and use the Rumack-Matthew nomogram (4 hr post-ingestion level). Chronic opioid use can cause hearing loss with hydrocodone/acetaminophen (reported sensorineural hearing loss with high doses).

**Withdrawal:** Not typically life-threatening: mydriasis, lacrimation, rhinorrhea, yawning, piloerection ("cold turkey"), diarrhea, myalgias, nausea, anxiety, insomnia. Treat with clonidine for autonomic symptoms, and long-term with methadone or buprenorphine (partial agonist), or naltrexone (antagonist) for relapse prevention after detox.

**Regulatory/Public health:** Reclassified from Schedule III to Schedule II by the DEA in October 2014 (applies to hydrocodone combination products). Frequently implicated in the US opioid epidemic. Boxed warnings: addiction/abuse/misuse, respiratory depression, accidental ingestion (esp. children), neonatal opioid withdrawal syndrome, CYP3A4 interactions, and concomitant use with benzodiazepines/CNS depressants (risk of profound sedation, respiratory depression, and death). Also, hepatotoxicity warning for acetaminophen combinations.

**Pregnancy/Special populations:** Can cause neonatal abstinence syndrome (irritability, high-pitched cry, tremor, diarrhea, poor feeding, sneezing, seizures) with prolonged use in pregnancy. Use caution in elderly, hepatic/renal impairment, COPD, and sleep apnea.

**High-yield exam pearls:** - Opioid + acetaminophen = think of both toxicities. - Pinpoint pupils + respiratory depression → opioid overdose → naloxone. - Tolerance develops to analgesia, euphoria, respiratory depression, sedation, and nausea, but NOT to miosis, constipation, or convulsions (seizures). - Hydrocodone is more potent than codeine (roughly 1:1 oral equivalence to morphine in some tables; commonly ~1 mg hydrocodone ≈ 1 mg oral morphine), but less potent than oxycodone (oxycodone ≈ 1.5x morphine). - Opioid-induced constipation: treat with laxatives and peripheral mu antagonists (methylnaltrexone, naloxegol, alvimopan for postoperative ileus). - Opioids contraindicated or used cautiously with MAOIs (serotonin syndrome risk applies mainly to meperidine, tramadol, methadone, and fentanyl, less so hydrocodone).