Perioperative prevention of chronic pain

From WikiAnesthesia


Chronic surgical pain is a commonly overlooked surgical complication that can lead to significant functional limitations and psychological distress

Acute Pain

Noxious stimulus ->local inflammatory mediators -> peripheral sensitization and hyperexcitability

  • Typically short lived and resolves with injury healing ​
  • Pain appears to be a mix of mostly nociceptive with some neuropathic pain​
  • Acute neuropathic pain generally responds poorly to conventional analgesics  [1]

Acute to Chronic Pain Transition

  • Pain lasting longer than the normal healing process after surgery is an unwanted adverse event in any operation.
  • Diagnosis of Chronic Post Surgical Pain (CPSP)
    • The pain developed after a surgical procedure
    • The pain is of at least two months duration
    • Other causes of pain have been excluded, such as malignancy or chronic infection
  • Impairs function, limits quality of life, and frequently difficult to treat [2]

Risk Factors

  • Chronic pain rate
    • Thoracotomy (30-60%)
    • Limb amputation (30-50%)
    • Coronary artery bypass surgery (30-50%)
    • Breast cancer surgery (20-30%)
    • Total knee arthroplasty (20%)
    • Inguinal hernia repair (16%)
    • Caesarean section (10%)[3]
  • Surgery near major nerves and intraoperative nerve injuries
    • Nerve transection does not always equal chronic pain
    • But lack of known nerve injury can still result in chronic pain
  • Others
    • Other ongoing nerve injury/inflammation, preoperative pain, female sex, psychological factors [4]

Preventive vs. Pre-emptive

  • Pre-emptive Analgesia
    • Analgesia administered before incision targeting immediate perioperative period
  • Preventive Analgesia
    • Reduce sensitization from the barrage of nociceptive afferent input to achieve neuroprotection from pathological changes in central pain pathways.
    • The effects must outlast the expected pharmacokinetic effect of the drug itself
      • Usually described as 5.5 times the half-life (t1/2 × 5.5)[3]

Preventative Techniques

  • Modification of surgical technique
    1. Minimize risk of nerve damage, Less surgical trauma = less chronic pain –Cochrane review of 41 trials, Laparoscopic vs open inguinal hernia repair •Less persisting pain (pain of any severity at 12 months) in laparoscopic group – OR 0.54, 95% CI 0.46 to 0.64; p<0.0001), and •Less persisting numbness (numbness of any severity at 12 months) –(OR 0.38, 95% CI 0.4286 to 0.49; p<0.0001)[5]
  • Control preoperative pain/risk factors
    1. Poorly controlled preop pain may be a trigger for central sensitization
      1. Karanikolas et al., Optimized perioperative analgesia reduces chronic phantom limb pain intensity, prevalence, and frequency –Prospective, randomized, trial of 65 patients undergoing lower limb amputation –Treated preop pain with epidural and/or PCA 48 hours prior to surgery and continued 48 hours postoperatively vs traditional GA/opioid therapy –Incidence of phantom limb pain after 6 months decreased significantly following the use of an optimized perioperative analgesia[6]
  • Modification of anesthetic technique
    1. General (TIVA vs volatile) vs regional
      1. Regional anesthesia is well established for acute pain –Do these benefits extend to chronic pain? •Cochrane meta-analysis: Regional anesthesia to prevent chronic pain (23 RCTs) at 6 months –Thoracotomy (250 patients): Epidural vs GA •Favored epidural for prevention of chronic pain OR .33, (95% CI .2-.56) •NNT = 4 –Breast cancer surgery (89 patients): paravertebral block vs GA •Favored block OR .37 (95% CI .14-.94) •NNT = 5[7]
    2. TIVA vs Gas
      1. Yu et al., Single center double blind RCT of cardiac patients with midline sternotomy volatile vs TIVA (propofol) –Primary outcome of pain at 3,6, or 12 months •Saw no significant difference in incidence of pain –Secondary outcome of acute pain and perioperative opioid use also saw no significant difference [8]
    3. Short-term Gain, Long-term Pain? Remifentanil
      1. Remifentanil: ultra-short-acting opioid –Metabolism by non-specific blood esterases results in minimal context-sensitive half life –Acute receptor desensitization: downregulation of opioid receptor –Also may be agonist at NMDA
      2. Hoogd et al., RCT of intraoperative fentanyl vs remifentanil on incidence of chronic pain after cardiac surgery (n=126) –Post op remi group used more opioids –At 3 months significantly more patients reports pain in remi group vs fentanyl •51% vs 33% (P=.047) –No difference at 1 year[9]
  • Pharmacological therapy
    1. Gabapentinoids
      1. Most CPSP is neuropathic in nature; can gabapentin prevent this? –Bind alpha-2-delta subunit VGCC, decreased synaptic transmission and decrease glutamate and substance P release –Decreased excitability of DRG neurons –May help limit central sensitization [10]
      2. Meta-analysis by Clarke et al. –8 double blinded RCTs on gabapentin found reduction in occurrence of CPSP •Pooled OR .52, (95% CI .27-.98) –4 double blinded RCTs on pregabalin found large reduction •Pooled OR .09, (95% CI .02-.79)[3]
      3. Systematic review by Chaparro et al. on the use of gabapentin, 5 RCTs –3-month postoperative pain, •None of the included five studies demonstrated a significant difference over placebo (n=280) •71/133 patients receiving gabapentin and 79/147 patients receiving placebo went on to develop CPSP •A similar non-significant result when comparing gabapentin and placebo was found for 6-month postoperative pain (however only 2 included studies) [11]
      4. Dosing
        1. High degree of heterogeneity in trials regarding doses –Gabapentin: some used only single dose (600mg or 1200mg) vs 1200mg total daily continued for 10 days post op •Buvanendran et al., Incidence of CPSP –Excluded patients with chronic pain at baseline –Randomized to receive a 300-mg preop dose of pregabalin followed by a 14-day BID regimen of pregabalin (50 mg to 150 mg) or placebo after total knee arthroplasty. (240 patients) –8.7% and 5.2% of placebo patients, at 3 and 6 months respectively, were diagnosed with CPSP vs 0 patients in treatment arm [3]
    2. Antidepressants
    3. NMDA antagonists
      1. Ketamine: nonbarbiturate dissociative anesthetic
        1. N-methyl-D-aspartate (NMDA) receptor required in wind-up phenomenon
          1. Ketamine can inhibit NMDAR-Glutamate nociceptive signals
          2. Chronic increased signaling leads to upregulation of NMDA-R, Does antagonism reduce CPSP? Meta-analysis by McNicol et al. on ketamine to prevent CPSP
            • 17 double blind RCTs utilized ketamine by any route did not show reduction in prevalence of CPSP (RR .84, P=.06) or mean intensity
              • Subgroup of IV ketamine only RCTs however did show significant reduction of CPSP •at 3 months RR of 0.75 (P = 0.01), NNT 12, and 6 months RR .7 (P = .04)
              • Recommend bolus of .2mg/kg followed by infusion .2-.3mg/kg/hr[12]
        2. Suzuki and colleagues, administering ketamine by infusion for 3 days, but at only 0.05 mg/kg/h. (n=49)Despite the small dose – they saw a reduction in CPSP at 3 months, but not at 6 months following thoracotomy
          1. Dualé and colleagues refuted these results with a negative trial following the use of twice the dose of ketamine infusion per hour –However this infusion was continued for only 24 hours
        3. Cogan et al., (n=230) using similar dosing in cardiac surgery patients did not show a significant difference in the incidence of CPSP at 9 months –Average infusion duration of 26 hours [13]
        4. Chaparro et al. systematic review, 14 RCTs –Ketamine showed a non-significant effect for the reduction of CPSP 3 months after surgery, (odds ratio (OR) 0.74, 95% confidence interval (CI) 0.45 to 1.23). –Subgroup analysis of trials with patients receiving longer than 24 h of ketamine treatment demonstrated ketamine’s superiority over placebo (OR 0.37, 95% CI 0.14 to 0.98) –A more definitive result was found for ketamine 6 months following surgery, with an overall significant decrease in the incidence of CPSP.[11]
    4. Alpha-2 agonists
    5. local anesthetics
      1. IV lidocaine has been increasingly used for adjunctive perioperative pain control
        1. –Could this be a method of limiting CPSP? •Grigoras et al. utilized a lidocaine infusion 1.5mg/kg/hr vs. control group (n=36, randomized double blind) in breast cancer surgery –At 3 months 11.8% in lidocaine group vs 47.7% in control group reported CPSP (P=.03) •Cerfolio et al., local Lidocaine infiltration had no impact on acute or chronic pain in thoracotomy patients [14]
    6. steroids
    7. opioids
  • Key overall study limitations across various Pharmacological therapy include differences in:
    • Intervention dose
    • Intervention duration
    • Controlling for preop pain levels
    • Generalizability to other surgeries

Overview Summary Systematic Review

  • A systematic review of therapeutic interventions to reduce acute and chronic post-surgical pain after amputation, thoracotomy or mastectomy[15]
    • 32 RCTs: Overall high heterogeneity in studies. •Gabapentinoids: reduced chronic pain after mastectomy, but single preop doses not effective •Ketamine: found no impact on chronic pain •RA: reduced chronic pain after amputation and thoracotomy


Chronic surgical pain is commonly overlooked as a surgical complication that can lead to significant functional limitation and psychological distress

  1. Evaluate for risk factors and aggressive control of preoperative and postoperative pain
  2. Minimize surgical trauma where possible
  3. Incorporate regional anesthesia when possible
  4. Consider adjuncts like gabapentin and ketamine, however more research is required


  1. Reddi, D. (2016-01). "Preventing chronic postoperative pain". Anaesthesia. 71: 64–71. doi:10.1111/anae.13306. Check date values in: |date= (help)
  2. Thapa, Parineeta; Euasobhon, Pramote (2018-07-31). "Chronic postsurgical pain: current evidence for prevention and management". The Korean Journal of Pain. 31 (3): 155–173. doi:10.3344/kjp.2018.31.3.155. ISSN 2005-9159. PMC 6037807. PMID 30013730.CS1 maint: PMC format (link)
  3. 3.0 3.1 3.2 3.3 Clarke, Hance; Poon, Michael; Weinrib, Aliza; Katznelson, Rita; Wentlandt, Kirsten; Katz, Joel (2015-03). "Preventive Analgesia and Novel Strategies for the Prevention of Chronic Post-Surgical Pain". Drugs. 75 (4): 339–351. doi:10.1007/s40265-015-0365-2. ISSN 0012-6667. Check date values in: |date= (help)
  4. Pak, D.J., Yong, R.J., Kaye, A.D. et al. Chronification of Pain: Mechanisms, Current Understanding, and Clinical Implications. Curr Pain Headache Rep 22, 9 (2018). Reddi, D. (2016), Preventing chronic postoperative pain. Anaesthesia, 71: 64-71.
  5. McCormack K, Scott NW, Go PM, Ross S, Grant AM; EU Hernia Trialists Collaboration. Laparoscopic techniques versus open techniques for inguinal hernia repair. Cochrane Database Syst Rev. 2003;(1):CD001785. doi: 10.1002/14651858.CD001785. PMID: 12535413. Thapa P, Euasobhon P. Chronic postsurgical pain: current evidence for prevention and management. Korean J Pain. 2018;31(3):155-173. doi:10.3344/kjp.2018.31.3.155
  6. Karanikolas M, Aretha D, Tsolakis I, Monantera G, Kiekkas P, Papadoulas S, Swarm RA, Filos KS. Optimized perioperative analgesia reduces chronic phantom limb pain intensity, prevalence, and frequency: a prospective, randomized, clinical trial. Anesthesiology. 2011 May;114(5):1144-54. doi: 10.1097/ALN.0b013e31820fc7d2. PMID: 21368651.
  7. Andreae MH, Andreae DA. Regional anaesthesia to prevent chronic pain after surgery: a Cochrane systematic review and meta-analysis. Br J Anaesth. 2013;111:711–720.
  8. Yu H, Xu Z, Dai SH, Jiang JL, He LL, Zheng JQ, Yu H. The Effect of Propofol Versus Volatile Anesthetics on Persistent Pain After Cardiac Surgery: A Randomized Controlled Trial. J Cardiothorac Vasc Anesth. 2020 Oct 19:S1053-0770(20)31139-3. doi: 10.1053/j.jvca.2020.10.025. Epub ahead of print. PMID: 33183935.
  9. Hoogd S, Ahlers SJGM, van Dongen EPA, van de Garde EMW, Daeter EJ, Dahan A, Tibboel D, Knibbe CAJ. Randomized Controlled Trial on the Influence of Intraoperative Remifentanil versus Fentanyl on Acute and Chronic Pain after Cardiac Surgery. Pain Pract. 2018 Apr;18(4):443-451. doi: 10.1111/papr.12615. Epub 2017 Sep 28. PMID: 28741894.
  10. Kukkar, A., Bali, A., Singh, N. et al. Implications and mechanism of action of gabapentin in neuropathic pain. Arch. Pharm. Res. 36, 237–251 (2013).
  11. 11.0 11.1 Chaparro LE, Smith SA, Moore RA, Wiffen PJ, Gilron I. Pharmacotherapy for the prevention of chronic pain after surgery in adults. Cochrane Database Syst Rev. 2013 Jul 24;2013(7):CD008307. doi: 10.1002/14651858.CD008307.pub2. PMID: 23881791; PMCID: PMC6481826.
  12. MCNICOL, E.D., SCHUMANN, R. and HAROUTOUNIAN, S. (2014), Ketamine for prevention of PPSP. Acta Anaesthesiol Scand, 58: 1199-1213.
  13. Suzuki M, Haraguti S, Sugimoto K, et al. Low-dose intravenous ketamine potentiates epidural analgesia after thoracotomy. Anesthesiol 2006; 105(1): 111–119.
  14. Grigoras A, Lee P, Sattar F, Shorten G. Perioperative intravenous lidocaine decreases the incidence of persistent pain after breast surgery. Clin J Pain. 2012;28:567–572.
  15. Humble SR, Dalton AJ, Li L. A sythoracotomystematic review of therapeutic interventions to reduce acute and chronic post-surgical pain after amputation, or mastectomy. Eur J Pain. 2015;19(4):451-465. doi:10.1002/ejp.567