What’s the relevance?
Remifentanil’s ultrashort-acting kinetics have driven its growth as a reliable technique for maintaining intraoperative analgesia. It is now one of the most widely used synthetic opioids in anesthesia.
However these unique pharmacological characteristics are associated with both Opioid Induced Hyperalgesia and Acute Opioid Tolerance, and possibly increase the risk of chronic pain after surgery.
Niedermayer and team performed a large, multicenter, propensity-matched observational study of remifentanil use during intra-abdominal surgery, and its association with postoperative pain in the PACU. Importantly the patients receiving epidural analgesia in addition to TIVA GA were also included. Volatile GA was excluded.
Among 16,420 patients meeting inclusion criteria, 3,652 GA/TIVA patients received remifentanil and were matched to 3,318 controls, and 829 GA/epi received remifentanil, being matched to 631 controls. Mean remifentanil infusions rates were 0.11 and 0.13 mcg/kg/min for non-EA and EA groups respectively.
Among GA-only patients, remifentanil was associated with higher PACU pain scores (both on arrival and discharge), greater analgesic requirements and more PONV – however there was no decrease of either time-to-extubation or PACU discharge.
Interestingly, the epidural analgesia cohort also showed higher PACU pain scores when receiving remifentanil.
The rapid nociceptive changes due to remifentil are well known, however real clincial consequences remain unclear. This large observational study highlights the detrimental analgesic effects of remifentanil in the most immediate post-op period, reminding anesthetists and anesthesiologists that gold-standard intraoperative analgesia may come at a cost.
Explore collected articles answering: Is remifentanil associated with Opioid Induced Hyperalgesia and Acute Opioid Tolerance?
Intra-operative remifentanil infusion for intra-abdominal surgery is associated with worse post-operative pain scores and higher analgesic requirements in the PACU.
There is no evidence supporting routinely ceasing buprenorphine perioperatively, even up to SL doses of 16mg/d.
Buprenorphine does not need to be ceased in patients requiring opioid analgesia post-operatively.
Why is this important?
Buprenorphine (Subutex, Tamgesic, Suboxone, Norspan) is a partial opioid agonist with high mu-receptor affinity, though limited by a ceiling effect. Because of its favourable safety profile it is used for opioid dependence, chronic and, increasingly, acute pain.1
Patients historically often have regular buprenorphine (BUP) ceased post-operatively when needing opioid analgesia. It was assumed that because of it’s high mu-receptor affinity, BUP blocks the efficacy of additional opioid analgesics. In reality, ceasing buprenorphine creates more complexity and may precipitate acute withdrawal.
Haber, DeFries & Martin point out that despite the high receptor affinity of BUP, there are still additional receptors remaining for full-agonist opioids to bind and activate. This is supported by the literature (Kornfeld 2010 & Harrison 2018). Even in the post-operative period buprenorphine can be easily continued, although with patients sometimes needing higher doses of acute opioid analgesics (Goel 2019 & Hansen 2016).
“Temporarily discontinuing buprenorphine introduces unnecessary complexity to a hospitalization, places the patient at risk of exacerbation of pain, opioid withdrawal...“
If buprenorphine is regularly being taken then it should not be ceased for hospital admission. Additional short-acting opioids can be added if needed. Doses required may be higher, but this is primarily due to opioid tolerance rather than receptor competition with BUP. Alternatively, a maintenance BUP dose can be split into 3-4 divided doses and/or increased to cover acute analgesic needs.
Buprenorphine is also a kappa and delta receptor antagonist, a weak partial NOP/Nociceptin receptor agonist, and has potent local anaesthetic effects. It behaves as a full agonist for analgesia in the opioid-naive, but a partial agonist for respiratory depression. ↩
What’s all the fuss?
Significant observational evidence suggested an association between mortality and deep anaesthesia, in particular a 2017 meta-analysis. However it has been suspected that anaesthetic depth may merely be a surrogate marker for intraoperative hypotension, a well-established risk factor for post-operative mortality and morbidity.
With this large RCT, the Balanced Anaesthesia Study Group has shown that deep general anaesthesia is not associated with an increase 1-year mortality.
What did they do?
The researchers conducted an ambitious, large (6,644 patients), multi-center, randomised controlled trial. Patients aged ≥60 years undergoing major surgery (expected ≥2h surgery and ≥2d hospital stay) were randomised to receive volatile general anaesthesia targeting BIS 50 or BIS 35.
To minimise intra-operative blood pressure as a confounder, anaesthetists were required to specify a target MAP before BIS-group allocation.
Not only was there no mortality difference between the BIS 50 and BIS 35 groups, there were also no major or moderate morbidity differences, or difference in recovery or length of stay. BIS targets were adequately achieved, though not perfect, and MAP was clinically similar for both groups.
Context is everything
This is about as high-quality as a large, modern study looking at longer-term outcomes can get. It is widely applicable to most populations and common general anaesthetic scenarios, except for a few important caveats:
- Very few ASA 4 (5%) patients were enrolled.
- Only volatile-maintenance anaesthesia was studied not propofol/TIVA.
- We can draw no conclusion regarding the consequences of extreme-depth (ie. BIS << 35).
- The actual depth difference between the BIS-35 and BIS-50 groups was not as much as perhaps ideal: mean BIS 39 vs 47 respectively...
...there was (only) one case of awareness in the light-depth BIS 50 group, despite 39% of patients receiving volatile < 0.7 MAC.
Among older patients undergoing major surgery, there is no difference in 1-year mortality between light and deep general anaesthesia.
Pholcodine, rocuronium and suxamethonium, showing common tertiary/quaternary ammonium epitopes.
Australia and New Zealand both experience an unusually high incidence of perioperative anaphylaxis, particularly to neuromuscular blocking drugs. The opioid-based anti-tussive pholcodine has been implicated in increasing population hypersensitivity to muscle relaxants.
Although historically difficult to identify accurate denominator numbers for incidence calculations, more recent data shows that the anaphylaxis risk for rocuronium is particularly high in Australia & New Zealand and may in fact be roughly comparable to the local risk of suxamethonium anaphylaxis, at 1 in 2,000-3,000 exposures.
Rocuronium also has a higher risk of anaphylaxis than it’s aminosteroid-sibling vecuronium, and up to a ten-times greater risk than the benzylisoquinolinium atracurium (~1 in 22,500, depending on population). Cisatracurium demonstrates the lowest incidence of anaphylaxis (~1 in 50,000).
This retrospective, observational cohort study over 6 years from Auckland, New Zealand identified a 10 fold higher incidence of anaphylaxis for rocuronium than for atracurium.
Also of note, the rate of anaphylaxis to rocuronium was similar to that for suxamethonium.
Anaphylaxis incidence for the three muscle relaxants were approximately:
- Atracurium – 1 in 22,500
- Rocuronium – 1 in 2,500
- Suxamethonium – 1 in 2,000