Buprenorphine

Introduction

Buprenorphine is a unique and potent semi-synthetic opioid that has become an increasingly important tool in the anesthesiologist's arsenal, particularly for pain management and in the perioperative care of patients with opioid use disorder (OUD). Its distinct pharmacological profile sets it apart from the full mu-opioid agonists (e.g., fentanyl, morphine, hydromorphone) that we use daily.

Chemical Structure

Buprenorphine is a derivative of thebaine, an opioid alkaloid. It is a highly lipophilic molecule, which contributes to its widespread distribution and long duration of action. Its structure allows it to bind with very high affinity to opioid receptors.

Buprenorphine_Structure

Pharmacokinetics

  • Absorption: Buprenorphine has poor oral bioavailability (~10%) due to extensive first-pass metabolism. It is therefore administered via other routes:
    • Sublingual (SL): Bypasses first-pass metabolism, allowing for good bioavailability. Common for OUD treatment.
    • Transdermal (TD): Provides steady, prolonged plasma levels over 7 days.
    • Parenteral (IV/IM): Provides rapid onset (IV) or slightly prolonged onset (IM). Used for acute post-operative pain.
  • Distribution: Its high lipophilicity leads to rapid distribution into the CNS and other tissues. It is ~96% protein-bound, primarily to albumin and globulins.
  • Metabolism: It undergoes extensive hepatic metabolism primarily via the CYP3A4 isoenzyme into an active metabolite, norbuprenorphine. This metabolite is also a potent mu-agonist but is less able to cross the blood-brain barrier due to its lower lipophilicity.
  • Excretion: Excreted primarily via the biliary system into the feces, with some renal elimination of metabolites. Its terminal elimination half-life is long, ranging from 20 to 70 hours, and even longer with the transdermal patch.

Pharmacodynamics

This is the most critical section for understanding buprenorphine's unique clinical effects.

  • Mechanism of Action: Buprenorphine is a partial agonist at the mu-opioid receptor (MOR), a weak antagonist at the kappa-opioid receptor (KOR), and an antagonist at the delta-opioid receptor.
    • Partial Mu Agonism: This is its defining feature. It binds to and activates the MOR, but produces a sub-maximal effect even when all receptors are occupied. This results in a "ceiling effect" for both analgesia and, more importantly, for respiratory depression and sedation.
    • High Affinity, Low Intrinsic Activity: Buprenorphine has a very high affinity for the MOR, even higher than full agonists like morphine or fentanyl. This means it can displace other opioids from the receptor. However, its ability to activate the receptor (intrinsic activity) is lower. This combination is key to its clinical profile.
    • Kappa Antagonism: Kappa receptor activation is associated with dysphoria, hallucinations, and stress-induced analgesia. By acting as a kappa antagonist, buprenorphine may reduce dysphoria and potentially possess anti-hyperalgesic properties, making it a valuable component of multimodal analgesia.

Clinical Uses (Anesthesia Perspective)

  1. Buprenorphine VialPerioperative Analgesia:

    • IV/IM Buprenorphine: Can be used for post-operative pain management, particularly in patients at high risk for respiratory depression or when a long-acting opioid is desired. A single dose can provide analgesia for 6-8 hours or more.
    • Transdermal Buprenorphine: Can be initiated pre-operatively for patients undergoing major surgery with anticipated severe post-operative pain, as part of a multimodal plan to reduce reliance on short-acting full agonists.

  2. Management of the Patient with Opioid Use Disorder (OUD): This is a common and challenging scenario.

    • The Dilemma: These patients have a high opioid tolerance and complex pain needs. Abruptly stopping their buprenorphine can cause acute withdrawal and uncontrolled pain.
    • Current Standard of Care (Continue Buprenorphine): The prevailing evidence supports continuing the patient's home dose of buprenorphine perioperatively. This prevents withdrawal, provides a baseline level of analgesia, and has been shown not to worsen post-operative pain. For breakthrough pain, high-dose, short-acting full agonists (e.g., fentanyl, hydromorphone) are required to overcome the high-affinity receptor blockade.
    • Alternative (Rotating to Methadone): In some complex cases, the buprenorphine may be stopped and the patient rotated to an equivalent dose of methadone pre-operatively. This is a complex decision requiring specialist input and is now less common.

Side Effects and Toxicity

  • Common Opioid Side Effects: Nausea, vomiting, constipation, dizziness, and headache are common. Nausea can be particularly prominent.
  • Respiratory Depression: Occurs, but due to the ceiling effect, the risk is significantly lower than with full agonists, especially when used as a single agent. However, the risk is potentiated when combined with other CNS depressants (benzodiazepines, propofol, volatile anesthetics, alcohol).
  • Cardiovascular Effects: Buprenorphine can cause QTc prolongation. Use with caution in patients with a history of arrhythmias or those taking other QT-prolonging drugs. Obtain a baseline ECG in high-risk patients.
  • Precipitated Withdrawal: If administered to a patient who is physically dependent on full agonists and has them in their system, buprenorphine's high affinity can displace the full agonist, leading to a rapid onset of withdrawal. This is why it is used to induce OUD treatment only after a patient is in mild withdrawal.

Contraindications

  • Known hypersensitivity to buprenorphine.
  • Significant respiratory depression (e.g., severe COPD, status asthmaticus).
  • Paralytic ileus or acute abdomen.
  • Use within 14 days of an MAO inhibitor (theoretical risk of hypertensive crisis).

Special Considerations for the Anesthesia Provider

  • Reversal is Difficult: The high affinity of buprenorphine means standard doses of naloxone are often ineffective. Very high, continuous infusions of naloxone may be required to reverse respiratory depression, but this can also precipitate severe pain and withdrawal symptoms. The primary treatment is supportive care (ventilation).
  • Pre-operative Planning is Key: For patients on buprenorphine, a clear plan must be made pre-operatively in coordination with the surgical team, the patient, and potentially the pain or addiction medicine service. The decision to continue or hold buprenorphine will dictate the entire intraoperative and postoperative analgesic strategy.
  • Drug-Drug Interactions: Be mindful of CYP3A4 inhibitors (e.g., ketoconazole, macrolide antibiotics) which can increase buprenorphine levels, and inducers (e.g., carbamazepine, phenytoin) which can decrease them.
  • Hepatic Impairment: Dose reduction is necessary in patients with moderate to severe hepatic dysfunction, as clearance is significantly reduced. Avoid use in severe hepatic failure.

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