Remifentanil-Induced Hyperalgesia

Remifentanil induced hyperalgesia is increased pain sensitivity and greater postoperative analgesic need after high dose intraoperative remifentanil, shown by a lower pain threshold, allodynia and spread of pain beyond the wound.

Epidemiology. It is linked to infusions over about 0.2 microgram/kg/min or high total doses. Studies show higher pain scores and morphine use for 24 hours, but the clinical size of the effect, and the difference from acute tolerance and abrupt loss of analgesia, remain contested.

Risk factors. High infusion rate, long infusion, abrupt cessation without transition analgesia, volatile only anaesthesia without adjuncts, and previous opioid exposure.

Pathophysiology.

Mu receptor activation triggers N-methyl-D-aspartate receptor activation, central sensitisation, descending facilitation and receptor desensitisation.

Remifentanil has a context sensitive half time of about 3 to 4 minutes, so analgesia vanishes within minutes and the sensitised state is unmasked.

Severe pain within 1 to 2 hours of stopping remifentanil, rising analgesic needs, allodynia or pain beyond the incision, and poor response to usual opioid doses.

A diagnosis of exclusion. Assess pain site and character, wound, drains and haemodynamics, and exclude surgical causes, withdrawal in opioid dependent patients, urinary retention and inadequate transition analgesia.

Differential diagnosis.

• Rapid loss of remifentanil analgesia.
• Acute opioid tolerance.
• Surgical complication such as bleeding, ischaemia or compartment syndrome.
• Neuropathic pain.
• Opioid withdrawal.
• Bladder distension.

Prevention. Keep remifentanil under 0.2 microgram/kg/min where possible, never stop it abruptly without transition analgesia, and use a multimodal regimen (regional or local anaesthetic, paracetamol, anti-inflammatory drug where suitable).

• Morphine (transition analgesia): 0.05 to 0.1 mg/kg IV given 30 to 60 minutes before the end of surgery, then titrated in 1 to 2 mg doses every 5 to 10 minutes; maximum 10 mg in the first hour in opioid naive adults; monitor sedation and respiratory rate; halve the dose in older adults and avoid with creatinine clearance under 30 mL/min.
• Paracetamol: 1 g IV or orally every 6 hours (over 50 kg) for 3 to 5 days; maximum 4 g in 24 hours; 2 to 3 g daily if under 50 kg, malnourished, chronic alcohol use or hepatic impairment.
• Ketamine (low dose): 0.25 to 0.5 mg/kg IV at induction, then 0.1 to 0.25 mg/kg/h until closure or up to 24 hours; maximum 0.25 mg/kg/h in this use; monitor sedation, hallucinations, blood pressure and heart rate; avoid in uncontrolled hypertension, psychosis and raised intracranial pressure; reduce in hepatic impairment.

Treatment. The cause is undertreated pain, so use regional block, scheduled non-opioid analgesia, and titrated opioid with ketamine if pain persists.

Monitoring. Pain score, sedation and respiratory rate every 15 minutes for the first hour, then hourly.

Referral and escalation. Acute pain service for refractory pain or high opioid use. Surgical review if pain suggests a complication.