Remifentanil: Effect as an ultra-short acting opioid

Remifentanil (brand name Ultiva and generics) is a synthetic opioid with a unique pharmacokinetic characteristic: it is not metabolised hepatically or renally, but is inactivated by non-specific esterases in plasma and tissue within a few minutes. This results in a context-sensitive half-life of approximately 3 minutes independent of infusion duration. This property makes remifentanil one of the most important opioids in modern anaesthesia and intensive care medicine, especially for procedures with rapid changes in pain intensity.

Remifentanil is administered exclusively intravenously as a continuous infusion. The application allows very fine control of analgesia independent of liver or kidney function. Even with very prolonged infusion, awakening time remains short, which is clinically valuable in critically ill patients with impaired metabolism. At the same time, the short duration of action requires careful planning of postoperative analgesia, as pain can develop very rapidly after the infusion is stopped.

Mechanism of action

Remifentanil is a selective μ opioid receptor agonist with high affinity and very high potency. The analgesic potency is approximately equivalent to that of fentanyl, but the effect is extremely short-lived due to rapid ester hydrolysis. An ester bond in the chemical structure makes remifentanil a substrate for non-specific esterases, which are widely distributed in plasma and all tissue types.

Unlike sufentanil, fentanyl or alfentanil, remifentanil shows no relevant accumulation and no context-sensitive half-life prolongation. This means that the awakening time after short and after several hours of infusion is virtually identical. In contrast, the context-sensitive half-life of fentanyl can increase to over 60 minutes after 4 hours of infusion.

Pharmacokinetically, remifentanil achieves peak effect within 1 minute of bolus, with a duration of action of only 3 to 5 minutes after stopping the infusion. The terminal elimination half-life is 10 to 20 minutes; the context-sensitive half-life of 3 to 4 minutes is clinically more relevant. The metabolite remifentanil acid is 4000 times less active and clinically irrelevant.

Indications

• Analgesia and anaesthesia in surgery, especially for procedures with rapidly changing pain intensity (for example, abdominal surgery, vascular surgery, neurosurgery)
• Analgesedation in intensive care medicine, often in combination with propofol or midazolam, with advantage in patients with impaired liver or kidney function
• Liver resection and liver transplantation, because remifentanil is metabolised independently of impaired liver function
• Obstetrics as an alternative analgesia when contraindications to epidural anaesthesia exist, with patient-controlled application (remifentanil PCA)
• Bronchoscopy and other brief procedures requiring rapid awakening

Remifentanil is not suitable for postoperative pain management because its short duration of action would require continuous infusion. For chronic pain or outpatient use, other opioids are more appropriate.

Dosage and administration

Anaesthesia adults: Bolus 0.5 to 1 µg per kg body weight, followed by continuous infusion 0.1 to 0.5 µg per kg per minute, individualised according to pain intensity and ventilation situation.

Intensive care unit: 0.03 to 0.15 µg per kg per minute as analgesedation in combination with propofol or midazolam.

Obstetrics (remifentanil PCA): Bolus 20 to 40 µg on demand, lockout interval 2 to 3 minutes, with continuous monitoring of mother and CTG.

Paediatric: established in paediatric anaesthesia, weight-adapted according to product information.

Administration: exclusively intravenous via secure access, ideally dedicated infusion line. Continuous airway monitoring, pulse oximetry and ability for immediate ventilation are prerequisites.

Renal insufficiency and hepatic insufficiency: usually no dose adjustment required because remifentanil is metabolised by plasma esterases independent of liver and kidney.

Postoperative analgesia: due to very short duration of action, a longer-acting opioid (for example, morphine, hydromorphone, sufentanil) or regional anaesthesia must be established before stopping the remifentanil infusion, otherwise a painful awakening phase will result.

Side effects

Very common: Respiratory depression up to apnoea, bradycardia, hypotension, nausea, vomiting.

Common: Muscle rigidity (especially with too rapid bolus administration), flushing, dizziness.

Occasional to rare: Bronchospasm, AV block, postoperative hyperalgesia after prolonged use, histamine release with hypotension and flushing.

Postoperative hyperalgesia is a characteristic phenomenon after remifentanil. Patients experience increased pain sensitivity during the awakening phase, which can be mitigated by preoperatively established longer-acting opioid or low-dose esketamine infusion.

Acute tolerance can develop within a few hours of infusion, requiring higher doses for equivalent pain control. Conscious selection of intraoperative dosing and limiting infusion time to what is necessary reduces this phenomenon.

With pH changes or mixing in the same infusion line: Incompatibility with alkaline solutions, therefore use only dedicated lines.

Drug interactions

• Other centrally depressing substances (propofol, midazolam, inhalational anaesthetics, alcohol): additive central depression and respiratory depression. Careful dose adjustment and airway securing.
• Other opioids (morphine, sufentanil, fentanyl): additive respiratory depression and sedation, planned transitions to postoperative analgesia.
• Antihypertensives and diuretics: additive hypotension, caution in hypovolaemia.
• Beta blockers and calcium antagonists: additive bradycardia.
• MAO inhibitors: theoretical risk of severe reactions, avoid combination.
• Naloxone: antagonist for respiratory depression, used in rare cases during anaesthesia.
• Respiratory stimulating agents (doxapram): not standard therapy after remifentanil because the short half-life already allows rapid awakening.

Special notes

Pregnancy: Use in obstetrics as PCA is possible, with continuous monitoring of mother and child. Breast-feeding: Because of very short half-life, breast-feeding is unproblematic after the effect has worn off.

Children: established in paediatric anaesthesia, especially for procedures with rapid pain changes.

Postoperative planning: Because of very short duration of action, the establishment of longer-acting analgesia before the end of remifentanil infusion is essential. Standard is the administration of morphine, hydromorphone or sufentanil approximately 30 minutes before end of surgery, alternatively regional anaesthesia such as epidural catheter or nerve block.

Acute tolerance and hyperalgesia: In longer procedures, low-dose esketamine infusion or use of lower remifentanil doses can reduce hyperalgesia.

Avoid bolus administration: Too rapid bolus can trigger muscle rigidity up to thoracic syndrome. Always inject bolus slowly or use diluted.

Storage: Remifentanil is a controlled substance and is subject to strict control regulations. Storage in the clinic in locked cabinets with documented access.

Driving and operating machinery: After anaesthesia with remifentanil, do not drive a car or operate machinery independently for at least 24 hours.

You might also be interested in

• Sufentanil, highly potent opioid in anaesthesia
• Morphine, gold standard of strong opioids
• Oxycodone, semi-synthetic strong opioid
• Buprenorphine, partial μ agonist
• Esketamine, anaesthetic with anti-hyperalgesia effect

Frequently asked questions

Sources

• Gelbe Liste, Remifentanil active substance profile
• BfArM, Federal Institute for Drugs and Medical Devices
• AWMF, Guidelines for anaesthesia and obstetrics
• German Society for Anaesthesiology and Intensive Care Medicine