Injection Remifentanil

Introduction

Physicochemical Properties

Important: Formulated with glycine, which acts as an inhibitory neurotransmitter and causes reversible motor weakness when injected intrathecally. Hence, remifentanil is NOT approved for spinal or epidural use.

Pharmacokinetics

Metabolism - The Key Feature

• The ester structure renders it susceptible to hydrolysis by nonspecific blood and tissue esterases (similar to esmolol) - NOT by pseudocholinesterase.
• Metabolism is therefore unaffected by pseudocholinesterase deficiency, hepatic failure, or renal failure.
• Primary metabolic pathway: de-esterification → inactive carboxylic acid metabolite GI90291 (GR90291), which is only 0.001-0.003 times as potent as remifentanil. GI90291 is excreted renally.
• NOT significantly metabolized in the lungs.

Pharmacokinetic Model

• Best described by a three-compartment model.
• Clearance is several times greater than hepatic blood flow - confirming extensive extrahepatic metabolism.

Key Parameters

Context-Sensitivity - The Most Clinically Important Feature

Special Population Dosing

• Elderly: Dose requirements reduced by at least 50% due to decreased central volume of distribution, reduced clearance, and increased CNS sensitivity.
• Children (2-11 years): Requirements nearly twofold higher than adults to block somatic and autonomic responses to skin incision.
• Obese patients: Dose based on lean body mass (LBM), not total body weight. TBW-based dosing leads to significantly higher effect-site concentrations. However, the context-sensitive half-time remains similar between obese and lean subjects.
• Renal/Hepatic failure: No dose adjustment needed. The inactive metabolite GI90291 accumulates in renal failure but has negligible clinical effect.

Pharmacodynamics / Clinical Effects

CNS

• Produces dose-dependent analgesia, sedation, and respiratory depression.
• At sedative doses, may cause minor increases in cerebral blood flow (CBF) by a disinhibition mechanism. At anesthetic doses with adjuvants, CBF is unaltered or modestly reduced.
• ICP: At doses of 1 μg/kg, no change in ICP was observed in patients undergoing craniotomy.

Cardiovascular

• Similar to other synthetic opioids; may produce hypotension and bradycardia especially with rapid large bolus doses. Bradycardia can be severe.

Respiratory

• Produces dose-dependent respiratory depression. Onset and offset are very rapid - respiratory depression appears almost simultaneously with plasma concentration changes (minimal hysteresis).
• Infusion rates of 0.1 ± 0.05 mcg/kg/min permit return of spontaneous ventilation while maintaining analgesia.

Chest Wall Rigidity

• Can cause chest wall rigidity, especially with bolus administration. Risk is reduced by slow bolus administration (over 30-90 seconds) or by using a continuous infusion technique.

Dosing

Rapid large boluses may produce severe hypotension and bradycardia - avoid or administer very slowly.

Synergism with Other Agents

• Propofol: Synergistic. Increasing remifentanil from 0 to 2 ng/mL reduces propofol CP50 for laryngoscopy by >60%.
• Volatile agents: Synergistic reduction of MAC. Remifentanil 3 ng/mL reduced sevoflurane MAC from ~4% to 0.36% in adult females.
• Midazolam: Reduces remifentanil dose requirements by up to 50%.
• Ketamine: Reduces intraoperative remifentanil requirement and postoperative opioid consumption; also mitigates hyperalgesia.

Indications

1. Balanced general anesthesia as the analgesic component (TIVA with propofol or with volatile agents)
2. Monitored Anesthesia Care (MAC) - for brief, painful procedures (endoscopy, diagnostic procedures)
3. Cardiac surgery (minimally invasive CABG - allows rapid awakening and extubation)
4. Neurosurgery - favorable cerebral hemodynamic profile
5. ICU sedation and analgesia
6. Obstetric labor analgesia (PCA technique)
7. Patients with hepatic or renal disease (no dose adjustment required)

Adverse Effects

Opioid-Induced Hyperalgesia (OIH) - A Key Exam Point

• Preoperative/intraoperative ketamine (0.15 mg/kg bolus + 2 mcg/kg/min infusion) reduces intraoperative remifentanil requirement and postoperative opioid consumption.
• Postoperative analgesics (morphine, NSAIDs, paracetamol) must be prescribed before or at cessation of remifentanil infusion since there is no residual analgesic effect.
• Standard doses of morphine (0.15-0.25 mg/kg IV) or fentanyl (150 mcg) may not provide entirely adequate immediate postoperative pain control after major abdominal surgery under remifentanil-isoflurane anesthesia.

Contraindications / Limitations

• NOT for intrathecal or epidural use (glycine formulation)
• NOT for bolus IV administration in epidural/spinal catheter
• Requires infusion pump; cannot be given as intermittent bolus alone for maintenance

Why Remifentanil is Unique - Summary Points for Exam

1. Only opioid metabolized by tissue esterases - not liver-dependent
2. Context-sensitive half-time is constant (~3-5 min) - unaffected by infusion duration
3. No dose adjustment in renal or hepatic failure
4. No accumulation - most predictable emergence
5. Cannot be given intrathecally (glycine formulation)
6. Risk of postoperative hyperalgesia - plan ahead for multimodal analgesia
7. Dose based on LBM in obese patients
8. Reduce dose by ≥50% in elderly
9. Effect-site equilibration time (t½ ke0) of 1-1.5 min - very rapid titration