Can intra-operative reflexes predict post-operative pain?

“Prediction is very difficult, especially about the future.” – Niels Bohr

Intraoperative monitoring of analgesia using nociceptive reflexes correlates with delayed extubation and immediate postoperative pain

Jakusheit, Weth et al. Eur J Anaesthesiol 2017; 34:297-305

Clinical Question

Whether Pupillary Dilatation Reflex (PDR) and Nociceptive Flexion Reflex (NFR) correlate with immediate post-op pain and time to extubation

Over-analgesia = longer time to extubation

Under-analgesia = higher post op pain score


  • Prospective single-centre observational study
  • 110 patients undergoing primary hip arthroplasty under GA recruited in pre-op assessment.
  • Psychological factors assessed as well as the PDR and NFR for each patient.
  • PDR threshold and NFT threshold calculated
  • Blinding of NFR and PDR from anaesthetic and recovery teams
  • Powered to detect correlation of 0.3 or higher for PDR/NFR using Spearman Rank (101 patients required)
  • Primary endpoints: Post-op pain rating and time to extubation


  • All adult patients undergoing elective primary hip arthroplasty
  • Exclusion:
    • BMI >35, declined to participate, surgery cancelled, lack of staff, technical problems, use of regional anaesthesia


  • Psychological and physiological factors associated with pain assessed in pre-op.
  • Coin toss to decide on order of measuring MFR and PDR
  • Intra-op:
    • Midazolam premedication.
    • Induction with propofol/opiate/non-depolarising muscle relaxant.
    • Maintenance with TIVA (propofol/remifentanyl).
    • Piritramine and metamizole at closure with remifentanyl stopped.
    • At skin closure NFRT/PDRT assessed.
    • ToF assessed prior to discontinuing propofol.
  • Multivariable linear regression analysis to assess for confounding factors.
  • Spearman Rank coefficients calculated for PDRT and NFRT for primary endpoints
  • Area under Curve and Receiver Operating Characteristics for both PDRT and NFRT

Their Results/Analysis

  • PDRT correlated with intensity of post-op pain (ϱ=-0.28, p<0.01) and time to extubation (ϱ=0.33, p<0.01)
  • NFRT correlated to time to extubation only (ϱ=-0.26, p<0.01)
  • Modest but significant prediction probability (ROC)
    • Post-op pain: 0.64 for PDRT; 0.56 for NFRT
    • Time to extubation: 0.76 for PDRT; 0.70 for NFRT
  • “Our results show that the PDRT and the NFRT, both measured at the end of general anaesthesia, correlate with the immediate postoperative pain intensity as well as with the time interval before tracheal extubation. The nociceptive reflexes therefore might be useful tools to indicate an insufficient effect of analgesics”


  • No other studies demonstrating reflex correlation under GA with clinical (rather than physiological) outcomes
  • No validated measure for nociception and analgesia currently exists


  • Weak statistical analyses and over-reliance on p values
    • Most statisticians would feel that ϱ needs to be >0.5 to be moderate (<0.3 is negligible)
    • Predictive probabilities low – (given AUC= 0.50 =flip a coin)
    • No t-testing of variables in multivariate analysis
    • Coefficient of determination (R2) low for all variables
  • Median post-op pain intensity was 5/10 – is there an opportunity to audit their own practice as this seems high
  • No analysis of dose of opiates/propofol given at induction
  • It is cumbersome and expensive to monitor the reflexes in this way
  • Questionable clinical relevance to us as there is more use of regional techniques at the Royal Free Hospital
  • Remifentanil infusion timing may confound testing
  • No monitoring of depth of anaesthesia described, potentially confounding the results


Statistical analysis is not sufficient to draw conclusions on the use of PDR and NFR in assessing over-analgesia (time to extubation) or under-analgesia (post-op pain score).

We need to consider the strength of correlations, not just the p value

Summary by Dr Chris Hellyar (ACCS CT2)

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