Case Overview

A 22-year-old, 55 kg male presents for tibial interlocking surgery 10 days after sustaining a head injury with pneumocephalus and an open tibial fracture. He was ventilated for 3 days, extubated 6 days ago, and has a history of seizure disorder, untreated for 10 years. He is currently maintained on levetiracetam (Levipil) for seizure control. Despite receiving both a buprenorphine patch (Zuprinor 10 mcg/hr for 4 days) and a fentanyl patch (Sanjesic 20 mcg/hr for 2 days), he continues to report significant pain. Regional anesthesia is contraindicated due to surgical concerns regarding tendon involvement.

This article addresses the opioid-related challenges, the safety of ketamine in this seizure-prone patient, and an anesthetic strategy tailored to his clinical profile.

I. Opioid Patch Pharmacology1. Buprenorphine (Zuprinor)

• Mechanism: Partial μ-opioid receptor (MOR) agonist, κ-opioid receptor antagonist, and δ-opioid receptor antagonist.
• Pharmacodynamics: Exhibits high affinity for the MOR (Ki ≈ 0.2 nM) with slow dissociation, resulting in prolonged receptor occupancy and functional blockade of full agonists such as fentanyl and morphine.
• Pharmacokinetics: Delivered transdermally, producing steady-state levels over 72 hours. Offset is slow (12–24 hours after patch removal), which reduces intraoperative flexibility.
• Clinical Implication: Limits efficacy of intraoperative opioids due to receptor blockade, thereby contributing to inadequate analgesia.

2. Fentanyl (Sanjesic)

• Mechanism: Full MOR agonist with high lipophilicity and rapid CNS penetration.
• Pharmacokinetics: Transdermal delivery begins acting in 12–24 hours, with steady-state levels achieved over 24–72 hours. Accumulates in adipose tissue, potentially prolonging CNS effects.
• Clinical Implication: Provides background analgesia but is insufficient for acute surgical pain and predisposes to tolerance.

Pathophysiology of Persistent Pain

Persistent pain in this patient arises from several mechanisms:

• Buprenorphine receptor blockade: High MOR affinity prevents effective binding of full agonists during high-intensity nociceptive stimuli such as surgery.
• Opioid tolerance: Chronic exposure desensitizes MORs through G-protein uncoupling and β-arrestin-mediated receptor internalization, diminishing cAMP inhibition and analgesic efficacy.
• Opioid-induced hyperalgesia (OIH): Prolonged fentanyl exposure activates spinal NMDA receptors and dynorphin release, increasing pain sensitivity.
• Inflammatory mediators: Post-traumatic cytokines (IL-1β, TNF-α, prostaglandins) downregulate MOR expression and impair G-protein coupling, further reducing opioid effectiveness.

II. Ketamine in Seizure-Prone PatientsMechanism and Seizure Threshold

Ketamine is an NMDA receptor antagonist that reduces glutamate-mediated excitotoxicity, a key driver of seizures. At subanesthetic doses (0.25–0.5 mg/kg), it has demonstrated anticonvulsant effects, especially in refractory status epilepticus in intensive care settings.

Levetiracetam, which targets synaptic vesicle protein SV2A and inhibits voltage-gated calcium channels, complements ketamine’s mechanism, together stabilizing neuronal excitability.

Evidence on Seizure Risk

Earlier concerns about ketamine lowering seizure threshold were based on isolated reports in patients with uncontrolled epilepsy or following high-dose administration (>2 mg/kg). Contemporary studies indicate that low doses do not increase seizure risk in patients stabilized on antiepileptic drugs, including levetiracetam.

Clinical Application in This Patient

• The patient is currently seizure-free on levetiracetam.
• Low-dose ketamine (0.25–0.5 mg/kg bolus with or without infusion) is unlikely to precipitate seizures.
• Ketamine offers the additional advantage of mitigating OIH and improving analgesia.

III. Anesthetic StrategyPatch Management

• Buprenorphine: Should be removed preoperatively, preferably before induction, to allow restoration of MOR availability (within 6–12 hours). This improves intraoperative opioid responsiveness.
• Fentanyl: Should be retained to maintain baseline analgesia and prevent withdrawal, recognizing that it will not be sufficient for surgical pain.

Intraoperative Analgesia

• Ketamine: Administer a 0.25–0.5 mg/kg bolus with a possible infusion (0.1–0.2 mg/kg/hr). This provides analgesia, counteracts OIH, and minimizes reliance on opioids.
• Dexmedetomidine: Infusion at 0.2–0.7 mcg/kg/hr provides sedation and opioid-sparing analgesia.
• Paracetamol: Intravenous paracetamol (1 g every 6 hours) enhances multimodal analgesia.
• Tramadol: Should be avoided due to its ability to lower seizure threshold, particularly concerning in post-traumatic brain injury patients.
• Lidocaine infusion: Should be avoided or used with great caution due to seizure risk; EEG monitoring is recommended if considered.

Opioid Use

If buprenorphine’s receptor blockade persists, higher doses of potent opioids such as fentanyl, remifentanil, or sufentanil may be required. Careful titration is essential to avoid respiratory depression from receptor saturation.

Postoperative Plan

• Continue fentanyl patch for baseline analgesia.
• Supplement with low-dose ketamine and paracetamol for breakthrough pain.
• Maintain levetiracetam therapy to reduce seizure risk.
• Consider dexmedetomidine in the ICU setting if opioid-resistant pain persists.
• Monitor closely for seizures and respiratory depression in the PACU or ICU.

Conclusion

This patient’s history of traumatic brain injury, seizure disorder, and concurrent use of buprenorphine and fentanyl patches presents a complex analgesic challenge. Buprenorphine’s high MOR affinity necessitates its removal preoperatively to restore opioid responsiveness, while the fentanyl patch should be continued to maintain baseline analgesia. Low-dose ketamine represents a safe and effective adjuvant in this seizure-prone patient stabilized on levetiracetam, offering opioid-sparing effects and counteracting opioid-induced hyperalgesia. A multimodal approach incorporating ketamine, dexmedetomidine, and paracetamol while avoiding tramadol and lidocaine infusion optimizes perioperative pain control while minimizing seizure risk.