Perioperative prevention of chronic pain

Intro

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  

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

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%)
• 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

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)

Preventative Techniques

Modification of surgical technique

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)
• Less persisting numbness (numbness of any severity at 12 months) – (OR 0.38, 95% CI 0.4286 to 0.49; p<0.0001)

Control preoperative pain/risk factors

Poorly controlled preop pain may be a trigger for central sensitization

• 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

Modification of anesthetic technique

General vs regional

• Regional/neuraxial anesthesia is well established for acute pain. Do these benefits extend to chronic pain?
• A 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.
  • This evidence was graded as low-moderate quality
• A recent prospective RCT compared general anesthesia plus preoperative paravertebral block with ropivacaine vs saline placebo for partial or complete mastectomy.
  • Less acute postoperative pain was reported in the block group vs control group by VAS score (2.9 vs 4.3, P<.001) and by 73% less morphine use in the block group (OR .272, 95% CI .17-.43)
  • At 3 months chronic pain was reported in 52.2% in the paravertebral group vs 47.7% in the control group (OR 1.2, 95%CI .79-1.82)
  • At 6 months chronic pain was reported in 58.4% in the paravertebral group vs 45.4% in the control group.
  • Is is important to note that the paravertebral block may be insufficient for major breast surgery, as it misses key deep anatomic structures such as the pectoralis major and its fascia. This remains an important limitation to this study.

TIVA vs Gas

• 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

Pharmacological therapy

Short-term Gain, Long-term Pain? 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.

• 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

Gabapentin

Most CPSP is neuropathic in nature; can gabapentin prevent this? Gabapentin binds alpha-2-delta subunit VGCC causing decreased synaptic transmission, decreased glutamate and substance P release, and decreased excitability of DRG neurons. Collectively may help limit central sensitization

• 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)
• Systematic review by Chaparro et al. on the use of gabapentin, 5 RCTs, on 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)
• Gabapentin Dosing
  • 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

Ketamine

Ketamine, a nonbarbiturate dissociative anesthetic acting though NMDA antagonism. The N-methyl-D-aspartate (NMDA) receptor is required in wind-up phenomenon. Also Ketamine can inhibit NMDAR-Glutamate nociceptive signals

• 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 administration route and 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

• 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
  • 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

• 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
• 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.

Local anesthetics

• IV lidocaine has been increasingly used for adjunctive perioperative pain control. 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

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
  • 32 RCTs with overall high heterogeneity in studies. •
    • Gabapentinoids: reduced chronic pain after mastectomy, but single preop doses not effective
    • Ketamine: found no impact on chronic pain
    • Regional anesthesia: reduced chronic pain after amputation and thoracotomy

Summary

Chronic surgical pain is commonly overlooked as a surgical complication that can lead to significant functional limitation and psychological distress. Despite highly heterogenous data, some perioperative interventions can help mitigate the transition from acute to chronic surgical pain.

1. Evaluate for chronic pain risk factors and aggressively control 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, high quality, research is required