Generic Name

Oxycodone

Mechanism

• Oxycodone is a potent, selective agonist at the mu‑opioid receptor (MOR), producing analgesia, sedation, and euphoria through inhibition of cyclic‑AMP production in nerve terminals.
• Partial agonism at the kappa‑opioid receptor contributes to its analgesic profile but also accounts for some dysphoric and psychotomimetic effects.
• Activation of MOR in the rostral ventral medulla (RVM) enhances descending inhibition of nociceptive pathways, while peripheral MOR stimulation dampens inflammatory signaling via reduced release of substance P and glutamate.

Pharmacokinetics

• Absorption: Oral bioavailability ≈ 60‑70 % (first‑pass metabolism). Rapid peak plasma concentration (~ 30 min IV; 60‑75 min oral).
• Distribution: Highly lipophilic; wide tissue distribution and high plasma protein binding (~ 50 %). Extensive penetration into CNS and placenta → caution in pregnancy.
• Metabolism: 70‑80 % metabolized by CYP3A4 to nor‑oxycodone (inactive) and CYP2D6 to oxymorphone (potent, active metabolite).
• Elimination: Renally excreted (~ 15 % unchanged). Half‑life 4‑6 h IR, 10‑12 h ER.
• Drug interactions:
• Potentiation by CYP3A4 inhibitors (ketoconazole, clarithromycin, erythromycin).
• Reduced analgesia with CYP2D6 poor metabolizers.
• Co‑administration with other CNS depressants increases risk of respiratory depression.

Indications

• Acute moderate‑to‑severe pain (post‑operative, injury).
• Chronic cancer‑related pain.
• Non‑cancer refractory chronic pain when other analgesics fail.

Contraindications

• Absolute:
• Severe respiratory insufficiency, mechanical obstruction of upper airway, severe chronic obstructive pulmonary disease (COPD).
• Acute overdose or severe opioid intoxication.
• Relative:
• Use with caution in elderly, hepatic or renal impairment.
• History of substance‑abuse or opioid dependence.
• Concurrent medications: CNS depressants (benzodiazepines, barbiturates, alcohol) → ↑ risk of respiratory depression.

Dosing

Titration: Start low, go slow. Increase by 5‑10 % per 48–72 h until adequate analgesia.

Adverse Effects

• Common (≥ 10 %):
• Constipation, nausea, vomiting, pruritus, sedation, dizziness, muscle cramps, dry mouth, urinary retention.
• Serious (≤ 1 % but high‑impact):
• Respiratory depression, central sleep apnea, severe hypotension, paradoxical agitation, serotonin syndrome (with MAOIs/SSRIs), opioid‑induced hyperalgesia, seizures (high‑dose), fatal overdose.

Monitoring

• Respiratory status: rate, minute ventilation, oxygen saturation (especially first 24 h or after dose escalation).
• Analgesic efficacy: pain score (NRS/MPQ) every 4‑6 h initially.
• Adverse effects: constipation score, sedation scale, GI symptoms.
• Laboratory: CBC, CMP in chronic users; LFTs in hepatic impairment.
• Drug‑level: Plasma oxycodone may be measured if overdose or therapeutic drug monitoring is warranted.

Clinical Pearls

1. Avoid “break‑through” IR dosing in opioid‑naïve patients – start with 5 mg IR only after 8–12 h of opioid therapy.

2. Use of a scheduled laxative (senna or polyethylene glycol) at initiation prevents opioid‑induced constipation; consider a pro‑kinetic if severe.

3. CYP2D6 poor metabolizers receive less oxymorphone; consider using non‑opioid adjuncts or a non‑CYP2D6 metabolite opioid (e.g., fentanyl).

4. Co‑treat with naloxone‑injected formulations (Oxy‑NE) in high‑risk populations to counteract potential aspiration or overdose.

5. Monitor renal function: dose reduction > 50 % if CrCl  2 months, assess for tolerance vs. appropriate opioid‑tolerant indication.

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