BUPRENORPHINE

1. Drug Name

• Generic Name: Buprenorphine

• Brand Names: Suboxone (with naloxone), Subutex, Belbuca, Butrans, Buprenex, Probuphine, Sublocade

2. Drug Classification

• Class: Opioid partial agonist

• Subclass: Mixed agonist-antagonist opioid

3. Mechanism of Action

• Primary Action: Buprenorphine is a partial agonist at the μ-opioid receptor and an antagonist at the κ-opioid receptor. This partial agonism at μ-receptors provides analgesia and euphoria, though with a ceiling effect, which reduces the risk of respiratory depression and overdose compared to full agonists.

• Antagonistic Action: Buprenorphine’s antagonism at κ-receptors can decrease the dysphoric effects associated with other opioids and may play a role in mood stabilization.

• High Affinity: Buprenorphine has a high binding affinity for μ-receptors, which allows it to displace full agonists and limits effects from other opioids.

4. Pharmacokinetics

• Absorption: Bioavailability varies by administration route (sublingual: ~30%, transdermal: ~15%, IV: 100%). Absorbed more effectively via sublingual and buccal routes.

• Distribution: Volume of distribution (Vd) is approximately 3-5 L/kg, with high protein binding (~96%).

• Metabolism: Primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8, mainly in the liver, producing the active metabolite norbuprenorphine.

• Excretion: Half-life (t½) is approximately 24-60 hours, varying by formulation and route; elimination is primarily biliary.

• Special Considerations: Liver impairment may prolong half-life, necessitating dosage adjustments.

5. Indications

• Primary Indications:

  • Management of moderate-to-severe pain unresponsive to other analgesics.

  • Opioid dependence and opioid use disorder (OUD) maintenance therapy.

• Off-label Uses:

  • Management of treatment-resistant depression (in select cases, with monitoring).

• Beneficial Populations: Individuals requiring chronic pain management, those in opioid dependence treatment programs, and patients at high risk for opioid overdose.

6. Dosage and Administration

• Adult Dosing:

  • Pain Management: 0.3 mg IV/IM every 6 hours (acute pain), or 5-20 mcg/hour transdermal patch applied every 7 days (chronic pain).

  • Opioid Dependence: Sublingual or buccal 2-24 mg/day; typical maintenance dose around 16 mg/day.

• Pediatric Dosing: Generally not recommended in children under 16, except in specific pain management scenarios with careful dosing.

• Routes: Sublingual, buccal, transdermal, IV, IM, subcutaneous injection (Sublocade).

• Renal/Hepatic Adjustments: Use caution in hepatic impairment due to prolonged effects; dosing adjustments recommended.

7. Contraindications

• Hypersensitivity to buprenorphine or any formulation components.

• Severe respiratory impairment or severe asthma in unmonitored settings.

• Gastrointestinal obstruction, including paralytic ileus.

8. Warnings and Precautions

• Black Box Warnings: Risk of addiction, abuse, and misuse; potential for life-threatening respiratory depression; accidental exposure risks; neonatal opioid withdrawal syndrome with prolonged use in pregnancy.

• Pregnancy and Lactation: Can cause neonatal withdrawal syndrome if used long-term during pregnancy; buprenorphine passes into breast milk, so caution is advised.

• Monitoring Parameters: Respiratory function, liver function tests (LFTs), signs of misuse or addiction, and mental status, especially during initial therapy.

• Special Considerations: Patients with chronic respiratory conditions or hepatic impairment require close monitoring due to increased risk of adverse effects.

9. Adverse Effects

• Common Adverse Effects (≥10%): Nausea, headache, constipation, sweating, dizziness, and sedation.

• Less Common but Clinically Significant: Hypotension, pruritus, vomiting, oral hypoesthesia (for buccal and sublingual routes).

• Serious Adverse Reactions: Severe respiratory depression, serotonin syndrome (when combined with serotonergic drugs), anaphylactic reactions, opioid withdrawal symptoms if used with full opioid agonists.

10. Drug Interactions

• Major Drug Interactions:

  • CNS Depressants (e.g., benzodiazepines, alcohol): Increased risk of sedation, respiratory depression, coma, and death.

  • CYP3A4 Inhibitors (e.g., ketoconazole, clarithromycin): Can elevate buprenorphine plasma levels, leading to enhanced effects or toxicity.

  • CYP3A4 Inducers (e.g., rifampin): May reduce buprenorphine levels, compromising efficacy.

• Food-Drug Interactions: High-fat meals can affect absorption rates of certain buccal and sublingual formulations.

• Lab Test Interference: Buprenorphine may cause false positives for opiates in some drug screens.

11. Clinical Pharmacology

• Pharmacodynamic Profile: Buprenorphine’s partial agonism at μ-receptors and antagonism at κ-receptors provide effective analgesia with a relatively reduced risk of euphoria and abuse compared to full agonist opioids. The ceiling effect in respiratory depression is clinically significant, offering a safety advantage.

• Additional Effects: May have mood-stabilizing properties due to κ-receptor antagonism.

12. Special Populations

• Pregnancy: Category C; use only if clearly needed, as prolonged use may result in neonatal opioid withdrawal.

• Lactation: Excreted in breast milk; caution is advised.

• Geriatric Use: Dose adjustments and close monitoring may be necessary due to higher sensitivity to effects.

• Renal/Hepatic Impairment: Adjustments recommended in hepatic impairment; generally safe in renal impairment but monitor for accumulation in severe dysfunction.

13. Therapeutic Uses

• First-Line Use: As a maintenance therapy for opioid dependence; effective for pain management in chronic pain requiring opioid analgesia.

• Combinational Therapy: Used with naloxone in formulations (e.g., Suboxone) to reduce misuse potential; may be combined with non-opioid analgesics for multimodal pain management.

• Clinical Trials and Efficacy: Numerous trials support buprenorphine’s safety and efficacy in both chronic pain and opioid dependence, demonstrating reduced misuse potential and a favorable safety profile for long-term use.

14. Monitoring and Follow-Up

• Recommended Lab Tests: Baseline liver function tests, respiratory function, and monitoring for sedation during initial therapy.

• Patient Symptom Checklists: Regular checks for symptoms of misuse or withdrawal, respiratory function, and adherence.

• Therapeutic and Toxic Levels: Clinical assessment of efficacy and toxicity signs; dose adjustments for maximum therapeutic effect with minimized adverse outcomes.

15. Overdose Management

• Symptoms of Overdose: Respiratory depression, miosis, somnolence, bradycardia, hypotension.

• Treatment Protocols:

  • Naloxone can partially reverse buprenorphine’s effects; however, higher doses or repeated administration may be necessary due to buprenorphine's high receptor affinity.

  • Supportive Measures: Ensure airway patency, mechanical ventilation as needed.

• Monitoring in Overdose: Continuous observation of respiratory and cardiovascular function is critical.

16. Patient Counseling Information

• Key Counseling Points:

  • Advise against combining with alcohol or other sedatives.

  • Instruct on proper sublingual/buccal administration to avoid swallowing, which reduces efficacy.

  • Highlight signs of overdose and importance of seeking immediate help if symptoms like trouble breathing or severe drowsiness occur.

  • Emphasize adherence and caution with transdermal patches to avoid accidental exposure, particularly with children.

• Signs Requiring Immediate Attention: Difficulty breathing, extreme drowsiness, confusion, severe allergic reactions (e.g., facial swelling, rash).