Preemptive Analgesia to Prevent Chronic Postsurgical Pain

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Nerve injury often underlies chronic postsurgical pain, as indicated by a subset of patients who develop neuropathic pain.
Nerve injury often underlies chronic postsurgical pain, as indicated by a subset of patients who develop neuropathic pain.
The following article features coverage from PAINWeek 2017 in Las Vegas, Nevada. Click here to read more of Clinical Pain Advisor's conference coverage.

LAS VEGAS — A presentation given by Gary W. Jay, MD, professor in the Department of Neurology, University of North Carolina, Chapel Hill, and Robert Barkin, PharmD, professor in the Department of Pharmacology and Family Medicine at Rush Medical College, Chicago, Illinois, at PAINWeek 2017, held September 5-9 in Las Vegas, Nevada, and titled "Treatment of preemptive and perioperative pain after spine surgery: Can we improve the patient experience?" highlighted risk factors and preemptive analgesic treatments with demonstrated efficacy for the prevention of chronic postsurgical pain (CPSP).1

CPSP is defined as pain lasting ≥2 months after a surgical procedure that cannot be explained by other causes or a preexisting condition, is associated with an increased use of analgesics and the healthcare system, and is known to affect daily activities and quality of life. The incidence of CPSP varies with surgery types, with 30% to 85% of patients affected after amputation, 5% to 67% after thoracotomy, 11% to 57% after mastectomy, and 19% to 43% after knee arthroplasty.2


Nerve injury often underlies CPSP, as indicated by a subset of patients who develop neuropathic pain.3 On axonal damage during surgery, immune and inflammatory reaction-associated neurotransmitter release results in hypersensitivity and contributes to central sensitization.4 In addition, peripheral nerve injury leads to the upregulation of sodium channel expression in sensitized primary afferent nerve fibers, which become spontaneously activated through sustained glutamate release. Excess glutamate binds to postsynaptic receptors, leading to altered electrical properties in postsynaptic neurons, a mechanism that contributes to central sensitization.4 Inhibitory neuron apoptosis and microglial activation in the dorsal horn in response to repetitive nociceptive activity have also been implicated in the maintenance of CPSP by causing neuropathic pain, allodynia, and hyperalgesia.4

CPSP risk factors include:

  • Perioperative pain intensity and duration (eg, >1 month for mastectomy and amputation)
  • Genetic susceptibility (eg, single-nucleotide polymorphisms in the catechol-O-methyl-transferase gene known to predispose to temporomandibular disorders)5
  • Psychosocial factors
  • Preoperative psychological traits (eg, fear of surgery)
  • Surgery duration and complexity
  • Surgery adjuvant interventions (eg, radiotherapy)

Preemptive analgesia seeks to prevent central sensitization and ensuing chronic pain. This recently developed concept has shown promising results in preliminary studies. For example, gabapentin combined with local anesthetics was shown to reduce the incidence of breast cancer surgery-related CPSP,6 and ketamine administered perioperatively was found to be effective in alleviating mastectomy-, thoracotomy-, and rectal cancer surgery-related pain.7 Other effective preemptive analgesic treatments include a combination of clonidine and local anesthetics, shown to decrease CPSP incidence,8 and multimodal analgesia (eg, local anesthetics plus gabapentin).

According to studies presented at the Benzon Symposium in Copenhagen in 2010,9 elective surgery-related CPSP could be prevented with preemptive analgesia starting 3 weeks before surgery and followed by a 4-week-long analgesic treatment after surgery. This long regimen duration for preemptive analgesia is in stark contrast with that from published studies, in which gabapentin administered 2 to 3 hours before surgery was shown to effectively prevent pain chronification.

Similar discrepancies prompted a study conducted in 1997 to 1998 in Denver, Colorado, in which 60 patients scheduled to undergo elective surgery (66% thoracotomy) were given a preemptive analgesic regimen of gabapentin (1200 mg/day) plus celecoxib (200 mg/day), starting 3 weeks before surgery and lasting 4 weeks after surgery: 60% to 67% of patients undergoing thoracotomy surgery are known to develop neuropathic-type CPSP. As indicated by pain levels that were assessed in this cohort at 3, 6, and 12 months postsurgery, 62% of patients did not develop CPSP. The study, however, did not include a control group of patients. In a 2016 review of 15 trials investigating the efficacy of preemptive analgesia with gabapentin (300, 600, or 1200 mg) or pregabalin (150 or 300 mg) administered immediately before surgery and after surgery (1-14 days), little to no reduction in neuropathic pain levels was detected.10 However, the authors of a 2010 review note that "prolonged multimodal therapy, with anti-hyperalgesic drugs with effects on central sensitization, along with regional anesthesia and nerve sparing surgical techniques may together be more appropriate to meet the goal of decreasing the incidence of CPSP."11

Read more of Clinical Pain Advisor's coverage of PAINWeek 2017 by visiting the conference page.

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References

  1. Jay GW, Barkin R. Treatment of pre-emptive and perioperative pain after spine surgery: can we improve the patient experience? Presented at: PAINWeek 2017. Las Vegas, NV; September 5-9, 2017.
  2. Visser EJ. Chronic post-surgical pain: epidemiology and clinical implications for acute pain managementAcute Pain 2006;8(2):73-81.
  3. Schaefer C, Sadosky A, Mann R, et al. Pain severity and the economic burden of neuropathic pain in the United States: BEAT Neuropathic Pain Observational Study. Clinicoecon Outcomes Res. 2014;6:483-496.
  4. Finnerup NB, Jensen TS. Mechanisms of disease: mechanism-based classification of neuropathic pain-a critical analysis. Nat Clin Pract Neurol. 2006;2(2):107-115.
  5. Michelotti A, Liguori R, Toriello M, et al. . Clin J Pain. 2014;30(2):129-133.
  6. Dirks J, Fredensborg BB, Christensen D, Fomsgaard JS, Flyger H, Dahl JB. A randomized study of the effects of single dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomyAnesthesiology. 2002;97:560-564.
  7. Gorlin AW, Rosenfeld DM, Ramakrishna H. Intravenous sub-anesthetic ketamine for perioperative analgesia. J Anaesthesiol Clin Pharmacol. 2016;32(2):160-167.
  8. Andreae MH, Andreae DA. Local anaesthetics and regional anaesthesia for preventing chronic pain after surgery. Cochrane Database Syst Rev. 2012;10:CD007105.
  9. Jay, GW, Donevan S, Cheung R. Potential role for the alpha-2-delta sub-unit in pain chronification. Accepted by the Benzon Symposium, Copenhagen 2010.
  10. Reddi D. Preventing chronic postoperative pain. Anaesthesia. 2016;71(Suppl 1):64-71.
  11. Dahl JB, Mathiesen O, Kehlet H. An expert opinion on postoperative pain management, with special reference to new developments. Expert Opin Pharmacother. 2010;11(15):2459-2470.
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