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Postoperative Analgesia From Preemptive to Preventive

Ali Eissa, MD Professor of Anesthesiology and Pain Management Al-Azhar University in Cairo


Postoperative Analgesia: From Preemptive to Preventive

INTRODUCTION Factors contribute to the development of acute postoperative pain.

“Head Start” Pain like symphonic music, no two people experience it the same way.

Comfort level and recovery Possibly increasing their self-efficacy in dealing with pain or in mobilization

Different Tissues Incision Specific contribution of different tissues to pain-related behaviors and neuronal hyperexcitability after incision.


Postoperative Analgesia: From Preemptive to Preventive

INTRODUCTION Factors contribute to the development of acute postoperative pain.

A . Pre-operative Factors 1- genetic • Individual experiences that may begin in utero. 2- Nongenetic environmental variables • Expectations (anxiety plays a role in the occurrence of chronic pain after surgery) • Cultural. • Dietary. • Preoperative noxious inputs, and Chronic pain (Already Sensitizes CNS). Theunissen et al. Preoperative Anxiety and Catastrophizing A Systematic Review and Meta-analysis of the Association With Chronic Postsurgical Pain. Clin J Pain 2012;28:819–841 Ririe DG, Barclay D, Prout H, et al. Preoperative sciatic nerve block decreases mechanical allodynia more in young rats: is preemptive analgesia developmentally modulated? Anesth Analg 2004; 99:140–145.


Postoperative Analgesia: From Preemptive to Preventive

INTRODUCTION Factors ontribute to the development of acute postoperative pain.

B . Intraoperative: discharge from cut primary afferents and retraction. 1. Nerve growth factor.

2.

Inflamed tissues.

C . Postoperative: afferent inputs from regenerating wound. 1. Hyperexcitability and ectopic activity in

injured and nearby uninjured primary afferents. 2. Inflammatory response.


Postoperative Analgesia: From Preemptive to Preventive

Surgical Treatment Vs. Surgical Pain Treatment Successful Surgery = Correction or Excision of The Pathology But successful Postoperative Pain Releif = Correct Mainly the Surgical Journey to Reach the Pathology

That Means 1. Different Layers. 2. Different Tissues. 3. Different Mediators.

Different Mode of Actions


Postoperative Analgesia: From Preemptive to Preventive

INTRODUCTION The nature of intra-operative tissue damage and nerve injury. Local chemicals paralleled pain-related behaviors after incision.

(NGF, cannabinoids, IL-6, ischemic mediators, and TRPV1-containing afferents)

Spontaneous activity of afferent fibers in four groups: • 1 day after sham procedure, • 1 day after skin, • 1 day after skin plus deep tissue incision,

• 7 days after skin plus deep tissue incision

Xu J, Brennan TJ. Guarding pain and spontaneous activity of nociceptors after skin versus skin plus deep tissue incision. Anesthesiology 2010; 112:153–164.


Postoperative Analgesia: From Preemptive to Preventive

History Multimodal Regimen Prevent Development of “anoci-association.” Reynolds and Hutchins demonstrated that a procaine block during dental procedures prevented the appearance of referred tooth pain. In 1988, Patrick Wall coined the term “preemptive preoperative analgesia”

Crile GW. The kinetic theory of shock and its prevention through anoci-association (shockless operation). Lancet 1913;185:7–16 Hutchins HC, Reynolds OE. Experimental investigation of the referred pain of aerodontalgia. J Dent Res 1947;26:3–8 Wall PD. The prevention of post-operative pain. Pain 1988;33:289–90


Postoperative Analgesia: From Preemptive to Preventive

Preemptive Preoperative Analgesia The PRE versus CONTROL the commonly used in the initial clinical studies on preemptive analgesia Wall introduced the term “preemptive preoperative analgesia,” with specific reference to 3 clinical studies (Slide Bottom)

None of which used the classic 2-group design* *Classic 2- group design= Pre-operative Versus Intra-operative OR Post-operative Treatment

Bach S, Noreng MF, Tjellden NU. Phantom limb pain in amputees during the first 12 months following limb amputation, after preoperative lumbar epidural blockade. Pain 1988;33:297–301 McQuay HJ, Carroll D, Moore RA. Postoperative orthopaedic pain: the effect of opiate premedication and local anaesthetic blocks. Pain 1988;33:291–5

Smith CM, Guralnick MS, Gelfand MM, Jeans ME. The effects of transcutaneous electrical nerve stimulation on post-cesarean pain. Pain 1986;27:181–93


Postoperative Analgesia: From Preemptive to Preventive

Experimental Preemptive Analgesia Preemptive analgesia reduce postoperative pain.

Contradictory Preemptive analgesia did not reduce pain behaviors beyond the expected duration of the analgesic effect. Woolf CJ, Chong M-S. Preemptive analgesia-treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg 1993; 77:362–379.

Mehta A, Reynolds ML, Woolf CJ. Partial denervation of the medial gastrocnemius muscle results in growth-associated protein-43 immunoreactivity in sprouting axons and Schwann cells. Neurosci 1993; 57:433–442.


Postoperative Analgesia: From Preemptive to Preventive

Timing for drugs administration 1- The preoperative phase • Interventions days before surgery. • Intervension minutes before skin incision. 2- The intraoperative phase • Interventions immediately after incision. • Interventions just before the end of surgery. 3- The postoperative phase • Interventions immediately after the end of surgery

Katz J. Phantom limb pain. Lancet 1997;350:1338


Postoperative Analgesia: From Preemptive to Preventive

Controversy and Confusion About Preemptive Analgesia Classic Two Groups Comparison ? • Intraoperative nociceptive barrage contributes to a greater extent to postoperative pain than does the postoperative nociceptive barrage (Katz et al.) • While in (Fagan et al.) there was No significant difference.

Katz J, Clairoux M, Kavanagh BP, Roger S, Nierenberg H, Redahan C, Sandler AN. Pre-emptive lumbar epidural anaesthesia reduces postoperative pain and patient-controlled morphine consumption after lower abdominal surgery. Pain 1994;59:395–403 Fagan DJ, Martin W, Smith A. A randomized, double-blind trial of pre-emptive local anesthesia in day-case knee arthroscopy. Arthroscopy 2003;19:50–3


Postoperative Analgesia: From Preemptive to Preventive

Controversy and Confusion About Preemptive Analgesia

Control Group Importance

• Despite there was significant difference in Pre-operative group Versus Intra-operative Treatment (pain &analgesic consumption). • There was significant difference In both Treated groups Versus Control in pain disablity at home.

Katz J, Cohen L. Preventive analgesia is associated with reduced pain disability 3 weeks but not 6 months after major gynecologic surgery by laparotomy. Anesthesiology 2004;101:169–74 Katz J, Cohen L, Schmid R, Chan VW, Wowk A. Postoperative morphine use and hyperalgesia are reduced by preoperative but not intraoperative epidural analgesia: implications for preemptive analgesia and the prevention of central sensitization. Anesthesiology 2003;98:1449–60


Postoperative Analgesia: From Preemptive to Preventive

Controversy and Confusion About Preemptive Analgesia Timing Preoperative Night before or Immediately before surgery • Despite there was No significant difference in pain score . • There was significant difference In analgesic consumption 48 hours postoperative.

Klasen J, Haas M, Graf S, Harbach H, Quinzio L, Jurgensen I, Hempelmann G. Impact on postoperative pain of long-lasting pre-emptive epidural analgesia before total hip replacement: a prospective, randomised, double-blind study. Anaesthesia 2005;60:118–23


Postoperative Analgesia: From Preemptive to Preventive

Controversy and Confusion About Preemptive Analgesia Classic Two Groups with Control • There was significant Increase in pain score in Pre-operative group Versus Post-surgery group . • Analgesic consumption did not differ even in Control group.

suggesting that, postoperative factors contribute to a greater extent to the outcomes than intraoperative factors. Gordon SM, Brahim JS, Dubner R, McCullagh LM, Sang C, Dionne RA. Attenuation of pain in a randomized trial by suppression of peripheral nociceptive activity in the immediate postoperative period. Anesth Analg 2002;95:1351–7


Postoperative Analgesia: From Preemptive to Preventive

Controversy and Confusion About Preemptive Analgesia Post-surgical Vs Control

NOT only Decrease in pain score Immediate postoperative BUT also long time after surgery

Blumenthal S, Dullenkopf A, Rentsch K, Borgeat A. Continuous infusion of ropivacaine for pain relief after iliac crest bone grafting for shoulder surgery. Anesthesiology 2005; 102:392–7


Postoperative Analgesia: From Preemptive to Preventive

Fake or Fact or Needs Explanations Different Drugs and Techniques Comparison of the reviews performed by Moiniche et al., Ong et al. and Dahl et al.

Explanations • Peripherally acting or applied drugs give prolonged analgesia with less analgesic consumption (incision-induced sensitization of spinal dorsal horn neurons is maintained at least initially by excitation of primary afferent fibers ). • The early diminishing effect of a pharmacologic treatment, the wound capable of generating pain behaviors equivalent to a post-treatment group.(Prologed Antihyperalgesic effect)

Moiniche S, Kehlet H, Dahl JB. A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief: the role of timing of analgesia. Anesthesiology 2002; 96:725–741. Ong CK, Lirk P, Seymour RA, Jenkins BJ. The efficacy of preemptive analgesia for acute postoperative pain management: a meta-analysis. Anesth Analg 2005; 100:757–773. Dahl JB, Mathiesen O, Moiniche S. ‘Protective premedication’: an option with gabapentin and related drugs? A review of gabapentin and pregabalin in the treatment of postoperative pain. Acta Anaesthesiol Scand 2004; 48:1130–1136.


Postoperative Analgesia: From Preemptive to Preventive

Fake or Fact or Needs Explanations Preemptive of Opioids • Perioperative opioid may evolve 1. Acute opioid tolerance 2. Opioid-induced hyperalgesia. • Opioid administration increase the expression of a particular type of N-

methyl-D-aspartate (NMDA) receptors Coadministration of opioids and low dose NMDA antagonists interfere with the development of acute opioid tolerance and opioid-induced hyperalgesia.

Improve pain relief and Reduce opioid consumption Eisenach JC. Preemptive hyperalgesia, not analgesia? Anesthesiology 2000;92:308–9 Crain SM, Shen KF. Antagonists of excitatory opioid receptor functions enhance morphine’s analgesic potency and attenuate opioid tolerance/dependence liability. Pain 2000;84:121–31 Kissin I, Bright CA, Bradley EL Jr. The effect of ketamine on opioid-induced acute tolerance: can it explain reduction of opioid consumption with ketamine-opioid analgesic combinations? Anesth Analg 2000;91:1483–8 Li X, Angst MS, Clark JD. Opioid-induced hyperalgesia and incisional pain. Anesth Analg 2001;93:204–9 Nesher N, Ekstein MP, Paz Y, Marouani N, Chazan S, Weinbroum AA. Morphine with adjuvant ketamine vs higher dose of morphine alone for immediate postthoracotomy analgesia. Chest 2009;136:245–52 Nesher N, Serovian I, Marouani N, Chazan S, Weinbroum AA. Ketamine spares morphine consumption after transthoracic lung and heart surgery without adverse hemodynamic effects. Pharmacol Res 2008;58:38–44


Postoperative Analgesia: From Preemptive to Preventive

Fake or Fact or Needs Explanations

Central Sensitization Inflammatory cytokines Glial cells are activated

Representing a driving force

(Pain facilitation) Maintain neuronal hyperexcitability in spinal cord


Postoperative Analgesia: From Preemptive to Preventive

Fake or Fact or Needs Explanations

Central Sensitization

LIDOCAINE  Directly act on microglia.  Inhibiting the increase of intracellular calcium.  Attenuated the production of proinflammatory cytokines (including TNF-, IL1, and IL-6).

Diansan Su. et al. Lidocaine Attenuates Proinflammatory Cytokine Production Induced by Extracellular Adenosine Triphosphate in Cultured Rat Microglia. Aneth. Analg. September 2010 • Volume 111 • Number 3


Postoperative Analgesia: From Preemptive to Preventive

Fake or Fact or Needs Explanations Antinociceptive dorsal horn interneurons

Jonathan Short et al. A Single Preoperative Dose of Gabapentin Does Not Improve Postcesarean Delivery Pain Management: A Randomized, DoubleBlind, Placebo-Controlled Dose- Finding Trial. Anesth Analg 2012 (December);115:1336–42


Postoperative Analgesia: From Preemptive to Preventive

In General Anesthesia, with Routine Doses of Opioids; although unconscious, sensitization largely unaffected

Prevent Pain = Stop The Neurochemical Cascade • NMDA-R antagonists. • Neuroprotection of antinociceptive dorsal horn interneurons. • Arresting glial reaction.

SO,

START PREVENTIVE ANALGESIA


Postoperative Analgesia: From Preemptive to Preventive

Preventive Analgesia Pharmacological Blockade Of The Pain Pathway

Perioperatively To Prevent • CNS Pain Imprint • Sensitization • Chronic Postsurgical Pain

Drug Efficacy

Drug Duration of action

Sufficient Treatment Time


Postoperative Analgesia: From Preemptive to Preventive

Take Home Messages • Prolonged hypersensitivity is initiated during the injury period.

(Use drugs with prolonged anti-hyperalgesic effect) • Neuronal hypersensitivity and nociception after incision is mainly maintained by the afferent barrage of sensitized nociceptors.

(Use peripherally acting drugs) • Not the timing of administration (Pre, Intra-operatively or postoperative) but efficacy of an analgesic and antihyperalgesic intervention are most important for treating pain and hyperalgesia after surgery.

(Use potent drugs) • Extending a multimodal analgesic treatment into the postoperative period may be superior to preemptive analgesia.

(Use multimodal analgesic for sufficient time postoperative)



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