Background

Pain in the perioperative setting is unique in some ways. The most relevant is that the pain is the result of intentional trauma. This uniqueness allows us to study and understand in a ‘before and after’ comparison. We can then apply this understanding to predict and anticipate pain and then be prepared to treat it. To accomplish this goal of pain control in the perioperative setting we rely on our understanding not just of anatomy and physiology, but also on surgical principles such as the gentle handling of tissues [1]. The therapeutic targets are chosen along criteria of safety, efficacy and ease of access.

Neurophysiology of Pain

Sensing pain begins with converting the biophysical activity into a transmittible message in the process known as transduction. Transduction happens via the activation of specific neuron types with specific features. One of these features is a projection of their dendrites into fibers which penetrate connective tissues such as the skin [2]. Though slightly thickened at the terminal end, these fibers lack a complex sensory structure, do not formally engage another cell and thus are known as free nerve endings (FNE). Some FNE will be activated by moderate heat or cold (thermoception), some by light touch (mechanoreception) and others by painful (nociception) amounts of temperature, touch and chemicals [2, 3].

The cell membranes of neurons regulate the electric charge between the cell’s interior and exterior through ion channels. A class of ion channels particularly relevant to nociceptor neurons is Transient Receptor Potential (TRP) channels [3]. They allow the passage of positively charged ions like calcium and sodium in a proportion of 8:1 when open. Upon activation, the channel opens and the ions rush in depolarizing the cell. This initiates an action potential which is then transmitted across the cell. There are several classes of TRP channel and it is the specific TRP channels in the cell membrane which determine whether the nociceptor is activated by chemicals, by temperature or by mechanical stress. This model of FNE and TRP channels alone does not account for episodes of increased pain (hyperalgesia) or increased sensitivity to noxious stimulation (allodynia) that are seen after injury. In their baseline state some nociceptors are effectively silent. The routine stimulus is not enough to activate the TRP channel and transduce a message of pain. However, after tissue injury the release of chemical mediators such as serotonin, bradykinin and histamine as well as the decreased pH of the environment change the behavior of the nociceptive neuron [4]. The altered responses to noxious stimuli following tissue injury are collectively described peripheral sensitization. These may directly activate the channel or raise the resting membrane potential making the neuron more easily activated [4, 5, 6]. In addition, the local effects of swelling and increased blood flow of these chemical mediators lead to increased activation of thermal and mechanical nociceptors.

Knowledge of these ion channels allows us to identify some therapeutic targets. Topical capsaicin works by opening the TRPV1 channel long enough to defunctionalize the neuron, preventing it from transducing painful stimuli. However, capsaicin can induce an unpleasant sense of warmth when first applied which makes it unsuitable for perioperative pain management. Similarly, topical camphor exerts its effect through TRPM8. Less specific to nociception, voltage sensitive sodium channels in the neuron are susceptible to local anesthetics (LAs). The local anesthetic prevents the channel from permitting sodium to flow into the cell, thus preventing the action potential. Applying surgical principles of gentle tissue handling and preservation of blood supply reduce tissue damage. This decreases the release of inflammatory chemical mediators thus diminishing peripheral sensitization. Nonsteroidal anti‐inflammatory drugs (NSAIDs) and intravenous local anesthetic also exert an effect against peripheral sensitization by interrupting the inflammatory chemical mediator signaling.

The first order nociceptive neuron’s cell body resides near the spinal cord in a dorsal root ganglion. It is these neuron’s dendritic fibers that extend to the FNE throughout the body. Two subtypes of primary neurons exist, Aδ (A delta) and C. These primary neurons pass their action potential messages via synapse to spinal cord neurons. This process is known as transmission.

Both Aδ (A delta) and C fibers are small and slow in comparison to other nerve fiber types. C fibers are smaller, slower than Aδ and have no myelin while Aδ are thinly myelinated. C fibers also branch closer to the cell body and will innervate a larger distribution of tissue than Aδ fibers. Consequently, sensations from Aδ fibers are more discrete and localized than the diffuse sensations carried on C fibers. Both Aδ and C fibers synapse with second order neurons in Rexed laminae II and V of the dorsal horn of the spinal cord.

When an action potential travelling on a neuron reaches the end of the cell involved in synapse it triggers the release of neurotransmitters into the synaptic cleft. The neuron produces these neurotransmitters and packages them into closed synaptic vesicles. The release of synaptic vesical contents into the cleft is mediated through the activation of voltage gates calcium channels (VGCCs). The excitatory neurotransmitters released by pain neurons include substance P, calcitonin related gene peptide (CGRP), brain derived neurotrophic factor (BDNF) and glutamate [7, 8]. In opposition, when presynaptic opioid receptors are activated, this hyperpolarizes the resting membrane potential of the neuron decreasing the release of these excitatory neurotransmitters [9]. A particular type of glutamate receptor, N‐methyl‐d‐aspartate (NMDA), in the post‐synaptic neuron in the spinal cord induces hyperexcitability when activated. NMDA receptor (NMDAR) activation in glial cells around the primary neuron contribute to central sensitization.

The anatomy and physiology of transmission present several potential therapeutic targets. Identification of the nerve through which the C and/or Aδ fibers are traveling and then bathing it in local anesthetic will stop pain transmission; and there are many well described peripheral nerve blocks. Gabapentin and pregabalin bind to the α2δ subunit of VGCCs modulating signal transmission at the synapse. Both have been shown to reduce pain and opioid requirements in the perioperative setting. Local anesthetic and opioid can be delivered via an epidural catheter. The local anesthetic will cover a broader area of the body than a peripheral nerve block. The opioid will decrease pain transmission by reducing release of excitatory neurotransmitters at the synapse. Ketamine antagonizes the NMDAR, reducing peripheral sensitization and interrupting pain transmission, and can be given as a continuous infusion.

Transmission continues from the dorsal horn of the spinal cord through the spinothalamic and spinoreticulothalamic tracts. These tracts communicate with the ventral posterolateral (VPL), ventral posterior inferior (VPI) and other nuclei in the thalamus, the mesencephalic reticular formation, the periaqueductal gray (PAG) and tectum of the brain stem. Perception of pain occurs as these structures communicate via the third order neurons with the cerebral cortical structures such as the primary somatosensory cortex.

Pain signals are modulated significantly in the brainstem and midbrain. There are projections into the limbic structures and hypothalamus which mediate the emotional and visceral responses to pain. Opioid receptors in the PAG, rostral ventral medulla (RVM), caudate nucleus, nucleus raphe magnus and others perform a similar function as in the spinal cord by hyperpolarizing their target neurons. This decreases the pain signal transmission when activated by endogenous ligands and pharmaceuticals.

The PAG, nucleus raphe magnus, locus coerulus and others comprise a circuit that when activated suppresses painful signals. This is the descending inhibitory pathway. The opioid receptor plays a different role here. Neurons in the RVM which can suppress ascending painful signals are at baseline kept inactive by neurons in the PAG. When opioid receptors in these PAG neurons are activated, this “off switch” is disengaged activating the RVM neurons to suppress these ascending signals [10]. Thus, opioids play two distinct roles in pain attenuation depending on the where the opioid receptors are located.

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