Oxycodone - Drug Monograph

Introduction

Oxycodone is a semi-synthetic opioid analgesic derived from thebaine, an alkaloid of the opium poppy. It is classified as a Schedule II controlled substance in the United States due to its high potential for abuse and dependence. First synthesized in Germany in 1916, oxycodone has become one of the most widely prescribed opioid medications for managing moderate to severe pain.

Mechanism of Action

Oxycodone exerts its analgesic effects primarily through agonist activity at mu-opioid receptors in the central nervous system. Binding to these G-protein coupled receptors results in:

• Inhibition of adenylate cyclase activity
• Modulation of voltage-gated calcium channels
• Activation of potassium channels
• Inhibition of neurotransmitter release (particularly substance P)

These mechanisms collectively result in decreased pain signal transmission, altered pain perception, and increased pain tolerance. Oxycodone also produces euphoria and sedation through its effects on the limbic system.

Indications

FDA-approved indications:

• Management of moderate to severe pain requiring around-the-clock opioid analgesia
• Extended-release formulations for chronic pain management

Off-label uses (with caution):

• Cancer-related pain
• Post-operative pain management
• Pain associated with traumatic injuries

Dosage and Administration

• Adults: 5-15 mg every 4-6 hours as needed for pain
• Opioid-naïve patients: Start with 5 mg every 4-6 hours

• For opioid-tolerant patients only
• Administer every 12 hours
• Individualize dosage based on pain severity and patient response

• Hepatic impairment: Reduce initial dose by 50-75%
• Renal impairment (CrCl <60 mL/min): Reduce initial dose
• Geriatric patients: Start with lower doses (2.5-5 mg)
• Pediatrics: Safety not established for children <11 years

Pharmacokinetics

• Oral bioavailability: 60-87%
• Tmax: 1-1.5 hours (immediate-release); 4-5 hours (extended-release)
• Food may increase AUC by approximately 25%

• Volume of distribution: 2.6 L/kg
• Protein binding: 38-45%
• Crosses placenta and blood-brain barrier

• Primarily hepatic via CYP3A4 (to noroxycodone) and CYP2D6 (to oxymorphone)
• Noroxycodone (weak activity) and oxymorphone (potent mu-agonist) are active metabolites

• Half-life: 3-5 hours (immediate-release); 4-9 hours (extended-release)
• Excretion: Primarily renal (unchanged drug and metabolites)

Contraindications

• Significant respiratory depression
• Acute or severe bronchial asthma
• Known or suspected gastrointestinal obstruction
• Hypersensitivity to oxycodone
• Concurrent use with monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuation

Warnings and Precautions

• High potential for abuse, addiction, and dependence
• Risk of life-threatening respiratory depression
• Accidental ingestion can be fatal, especially in children
• Neonatal opioid withdrawal syndrome with prolonged use during pregnancy
• CYP3A4 interactions may affect metabolism

• Increased risk in elderly, debilitated patients, and those with respiratory conditions
• Risk of adrenal insufficiency with chronic use
• May cause severe hypotension
• Risk of seizures in patients with seizure disorders
• Potential for increased intracranial pressure

Drug Interactions

• CNS depressants (benzodiazepines, alcohol, sedatives): Additive CNS depression
• CYP3A4 inhibitors (ketoconazole, clarithromycin): Increased oxycodone levels
• CYP3A4 inducers (rifampin, carbamazepine): Decreased oxycodone efficacy
• Serotonergic drugs: Risk of serotonin syndrome
• Anticholinergics: Increased risk of constipation and urinary retention

• Mixed agonist/antagonist opioids (pentazocine, butorphanol): May reduce analgesia
• Diuretics: Reduced efficacy due to release of antidiuretic hormone

Adverse Effects

• Nausea (30-50%)
• Constipation (30-40%)
• Somnolence (20-30%)
• Pruritus (15-25%)
• Dizziness (15-20%)

• Respiratory depression
• Hypotension
• Adrenal insufficiency
• Androgen deficiency
• Anaphylaxis
• Seizures
• Serotonin syndrome
• Severe constipation leading to bowel obstruction

Monitoring Parameters

• Pain assessment using validated scales (e.g., Numeric Rating Scale)
• Respiratory rate and oxygen saturation
• Blood pressure, especially during initiation and titration
• Bowel function and need for laxatives
• Signs of misuse, abuse, or addiction
• Mental status changes
• Renal and hepatic function with long-term use
• Signs of hypogonadism with chronic therapy

Patient Education

• Take exactly as prescribed; do not crush, chew, or break extended-release tablets
• Avoid alcohol and other CNS depressants
• Report any difficulty breathing or unusual drowsiness
• Maintain adequate hydration and fiber intake to prevent constipation
• Do not abruptly stop medication; taper under medical supervision
• Store securely away from children and others
• Dispose of unused medication properly
• Inform all healthcare providers of oxycodone use
• Understand risks of dependence and addiction
• Avoid driving or operating machinery until effects are known

References

1. FDA Prescribing Information: OxyContin® (oxycodone HCl extended-release tablets) 2. Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain Physician. 2008;11(2 Suppl):S133-S153. 3. Pasternak GW. Molecular biology of opioid analgesia. J Pain Symptom Manage. 2005;29(5 Suppl):S2-S9. 4. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician. 2008;11(2 Suppl):S105-S120. 5. Webster LR. Update on the pharmacology of oxycodone. Pain Med. 2009;10 Suppl 1:S3-S10. 6. Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain. J Pain. 2009;10(2):113-130. 7. American Pain Society. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. 6th ed. 2008.