Preemptive Analgesia and Surgical Pain

Islam Mohammad Shehata

Mahmoud Alkholany

Elyse M. Cornett

Alan David Kaye

Introduction

Tissue injury from surgical incision is a noxious stimulus that leads to the formation of “inflammatory soup,” resulting in the stimulation of nociceptors. Noxious stimuli provoke two types of alterations in the responsiveness of the nervous system based on its plasticity: peripheral and central sensitization. Peripheral sensitization occurs at the site of the ongoing inflammation, mediated by cytokines and chemokines released from the injured tissues and the immune cells to reduce the threshold of the nociceptor afferent peripheral terminal.¹ These mediators result in modified transduction and enhanced conduction of nociceptive impulses toward the central nervous system. The nociceptive barrage from the nociceptors at the site of injury travels through the small myelinated A and unmyelinated C fibers, increasing the excitability of nociceptive neurons within the central nervous system. This activity-dependent central sensitization (wind-up) amplifies the effects of peripheral inputs. It may cause central hyperexcitability, which accounts for the long-term persistence of pain beyond the offending stimulus.² Therefore, abolition of the initiating event should prevent secondary changes and thereby reduce the subsequent pain experience.

Definition

There is no agreed-upon definition of preemptive analgesia. However, preemptive analgesia can be defined broadly as an antinociceptive modality that has been given before an injury or noxious stimulus, including surgical incision, preventing establishment of the central sensitization and covering both periods of the surgery and the initial postoperative period.³ Thereby, preemptive analgesia reduces acute surgical pain and potentially minimizes the risk of developing chronic postsurgical pain.⁴

This contrasts with preventive analgesia, where an analgesic has a preventive effect if its administration leads to a reduction in pain or analgesic consumption that extends beyond its expected duration of action (usually 5.5 half-lives).⁵ Therefore, preventive analgesia refers to the effect of the intervention on the expected duration of analgesia regardless of the timing of the intervention related to the injury.

Mechanism of Preemptive Analgesia

Pathologic pain (surgery-evoked pain) is different from physiologic pain; it is of higher intensity and faster spread. Moreover, low-intensity stimuli can be activated due to the peripheral
and central sensitization causing postsurgical allodynia and hyperalgesia.⁶ A good understanding of the ascending and descending inhibitory pain pathways and neurotransmitters and receptors is important to understand the proposed mechanism of preemptive analgesia in preventing postoperative pain.⁷ Preemptive analgesia may act by targeting these different levels before the incidence of the noxious stimuli. Consequently, it may preempt the injuryinduced neurophysiological and biochemical modulation of the somatosensory system and reduce hyperexcitability and development of postoperative and chronic pain. This theory is supported by animal studies and in vitro and in vivo laboratory investigations.⁸,⁹

Underlying Physiology

There are four distinct processes in the sensory pathway: transduction, transmission, modulation, and perception. Each of these processes presents a potential target for analgesic therapy used in preemptive analgesia.¹⁰

Transduction

Chemical substances and enzymes called prostanoids (prostaglandins, leukotrienes, and hydroxy acids) are released from the damaged tissues, increasing the transduction of painful stimuli. Blocking the release of those mediators before surgical incision could potentially reduce the risk of perioperative pain and peripheral sensitization.¹⁰

Transmission in the Dorsal Horn

Several mediators are involved in the transmission of painful stimuli from A-delta and C fibers to secondary order neurons at Rexed laminae in the dorsal horn of the spinal cord. These mediators include substance P, the calcitonin gene-related peptide.¹¹,¹² Substance P induces the release of excitatory amino acids, such as aspartate and glutamate, which act on the AMPA (2-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) and NMDA (N-methyl-D-aspartate) receptors contributing to the development of the “wind-up” phenomenon—blocking the release/action of those mediators before surgical incision could decrease the risk of hyperexcitability, the development of central sensitization, and chronic pain.

Perception

The activation of supraspinal structures involved in sensory discrimination and the emotionalaffective component of pain is mediated by EAAs, for example, glutamate.¹³ However, the neurotransmitters involved in central processing of nociceptive information have not yet been elucidated, representing an area for future research and development.

Modulation

Modulation represents the interaction between excitatory and descending inhibitory pathways at the dorsal horn of the spinal cord, for example, periaqueductal gray. Neurotransmitters, including norepinephrine, serotonin, and opiate-like substances (endorphins), are involved in the brainstem inhibitory pathways that modulate pain in the spinal cord, hence the antinociceptive effect of antidepressants, which inhibit the reuptake of noradrenaline and serotonin and the effect of opiates.¹⁴ Gamma-aminobutyric acid and glycine are two important inhibitory neurotransmitters that act at the dorsal horn. Blockade of spinal gamma-aminobutyric acid or glycine can result in allodynia by removing inhibitors that control NMDA receptors.¹⁵

Modalities of Preemptive Analgesia

Multimodal analgesia refers to the management of pain using a combination of analgesic drugs with differing pharmacological modes of action.¹⁶ Combining pharmacological agents that act at one or more sites along the pain pathway (peripheral, spinal, or supraspinal sites) pose an additive effect with better pain relief and fewer side effects.¹⁷,¹⁸ The different modalities of preemptive analgesia include nonopioids, opioids, and regional analgesia (Table 8.1).

TABLE 8.1 MODALITIES OF PREEMPTIVE ANALGESIA

Route	Drug	Mechanism of Action	Dose	Comments
Oral
	Gabapentin	Structural analogues of γ-aminobutyric acid bind to α2δ subunit of voltage-dependent calcium channels and modify the action of a subset of N-methyl-D-aspartate-sensitive glutamate receptors, M-channel, neurexin-1α, and thrombospondin proteins	400 mg	Sedation, nausea, and vomiting especially in the elderly and renal impairment patients
	Pregabalin		150 mg
	Celecoxib	Selective COX-2 inhibitors	200 mg	Increased cardiovascular risk in ischemic patients
Intravenous
Nonopioid
	Paracetamol	A centrally acting drug, which suppresses prostaglandin synthesis and cyclooxygenase (COX)	1 g	Well-tolerated drug
	NSAID	Inhibit both the COX-1 and COX-2 enzymes		Platelet dysfunction Renal dysfunction Peptic ulcer
	Ketamine	N-methyl-D-aspartate receptor antagonist and binds to γ-aminobutyric acid, cholinergic, and voltage-gated sodium channel	0.15-0.5 mg/kg	Psychotomimetic side effects
	Magnesium sulphate	Antagonist of calcium channels and N-methyl-D-aspartate receptors	50 mg/kg	Reduction of requirement of propofol (induction and maintenance), neuromuscular blocking agents, and fentanyl
Opioid	Opioid receptor agonist	Mu, kappa, and delta receptor agonist		Postoperative respiratory depression Urinary retention Ileus Nausea and vomiting Shivering
Regional
Intrathecal and epidural agents	Opioid receptor agents (diamorphine)
Surgical wound infiltration	Bupivacaine, levobupivacaine, liposomal bupivacaine	Amide local anesthetics, which inactivate voltage-dependent sodium channels		No significant risk of surgical wound infection Local anesthetic systemic toxicity: central nervous system and cardiovascular system (cardiac arrest)
Peripheral nerve block	Bupivacaine, levobupivacaine, liposomal bupivacaine

Nonopioids

Paracetamol

Paracetamol, N-acetyl-p-aminophenol, is a centrally acting drug, which suppresses prostaglandin synthesis and cyclooxygenase (COX) similar to the nonsteroidal anti-inflammatory drug (NSAID) agents especially COX-2 selective inhibitors. Paracetamol is a common analgesic (for mild pain) and antipyretic drug with lesser peripheral anti-inflammatory properties and better tolerance than NSAID.¹⁹ Many studies show promising results of preemptive paracetamol (1 g) for different types of surgery. Preemptive paracetamol decreased the pain score, thereby reducing the opioid consumption and the hospital length of stay.²⁰,²¹,²²

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