Surgical Pain

Pathophysiology, Assessment, and Treatment Strategies

The nervous system detects and interprets a wide range of thermal and mechanical stimuli, as well as environmental and endogenous chemical irritants. When intense, these stimuli generate acute pain. The ability to detect noxious stimuli is essential to an organism’s survival. In the setting of intense noxious stimuli (e.g., bone fracture, surgery) and persistent injury (e.g., osteoarthritis), both peripheral and central nervous system components of the pain transmission pathway exhibit tremendous plasticity, enhancing pain signals and producing hypersensitivity. When plasticity facilitates protective reflexes, it can be beneficial, but when changes persist, a persistent or chronic pain condition may result. These changes are on a continuum, that is, there are no such things as the distinct neurobiological entities of “acute” and “chronic” pain.

Unlike other senses, such as vision, receptors for tissue damage do not return to their prestimulus state after activation but remain “switched on” for a period of time. It is now known that not only is the sensitivity of damage-detecting sensory nerve endings altered after injury, but their synaptic connections inside the central nervous system may be significantly modified and reorganized. The ability of the pain-sensing system to change in response to input is referred to as plasticity. The end result of these plastic changes is heightened activity and responsiveness of the system, making it easier for a signal to get through and be perceived as painful (hyperalgesia); stimuli that would not normally have been felt as painful (both from the site of surgery and from other areas) may be felt as painful when the animal regains consciousness (allodynia). Changes that occur in the peripheral and central nervous systems are known as peripheral and central sensitization. This sensitization can occur very quickly after surgery.^46,47 The clinical implications of this sensitization include the following: (1) once “pain” is established, analgesic drugs, for a given dose, are much less effective (i.e., pain is more difficult to control), and (2) for a constant input over time, the “pain” felt by the animal increases.

This sensitization may disappear when a wound is completely healed. However, under certain circumstances, permanent changes to central connections may occur, leading to permanent perception of pain due to ongoing spontaneous production of nociceptive signals (e.g., chronic postoperative pain or phantom limb pain).

Superimposed on these plastic changes are genetic influences, the hypothalamic-adrenal axis and other endocrine systems, and cognitive brain functions. Thus, although a discussion of nociceptive pathways, acute pain processing, and an overview of plasticity is limited in its ability to explain the complexities of the full pain experience, an understanding of these processes is fundamental to the ability to appropriately prevent or treat clinical pain.

Sensory nerve fibers recognize and transform (transduction) environmental stimuli into electrical signals (action potentials) that are conveyed (transmission) to the dorsal horn of the spinal cord, where they are processed (modulation) and then relayed (projection) to the brainstem and brain, where the signal is integrated, recognized, and identified (perception) as pain (Figure 22-1). Nociception is the creation and transfer of signals after activation of nerve endings by a noxious stimulus. The term pain implies that noxious stimuli have been perceived at the thalamic or cortical level and interrupted as “pain.” Most of us believe (correctly) that the veterinary species we work with “feel” pain; however, some scientists still believe that these animals do not feel pain—that their reactions are simply a complex series of different reflex systems.

Figure 22-1 Sensory nerve fibers recognize and transform (transduction) environmental stimuli into electrical signals (action potentials) that are conveyed (transmission) to the dorsal horn of the spinal cord, where they are processed (modulation) and then relayed (projection) to the brainstem and the brain (regions of the cerebral cortex), where the signal is integrated, recognized, and identified (perception) as pain. Passage of the signal can be relatively simple, or it can involve multiple projections and levels of processing (see later). (© B. Duncan X. Lascelles, North Carolina State University.)

Transduction (Peripheral Nociceptors)

Nociception is the process by which potentially damaging thermal, mechanical, or chemical stimuli are detected by a subpopulation of peripheral nerve fibers called nociceptors. There appears to be movement away from defining nociceptors as distinct nerve endings, and rather toward defining neurons as nociceptors. These peripheral nerve fibers (nociceptors, part of the primary sensory afferent population) have their cell body in the dorsal root ganglion or trigeminal ganglion, and they have a peripheral and central axonal branch that innervates their target organ and the spinal cord, respectively.

Two major classes of nociceptors have been identified: Aδ afferents and C-fiber afferents. These nociceptors are excited only when stimulus intensities reach the noxious range, suggesting that they possess bioelectrophysical and molecular properties that enable them to respond selectively to potentially injurious stimuli. Medium-diameter myelinated (Aδ) afferents mediate acute, well-localized first or fast pain. These myelinated afferents differ considerably from the larger-diameter and rapidly conducting Aβ fibers that respond to innocuous mechanical stimulation (i.e., light touch). The second class of nociceptors includes small-diameter unmyelinated C-fibers that convey poorly localized second or slow pain. Other specialized nerve endings responding to innocuous mechanical stimulation are found in skin, muscles, and joints. These receptors are concerned with touch, vibration, movement, and proprioception. Innocuous sensory information from these nerve endings is conveyed by Aβ fibers. As described later, changes in the peripheral and central nervous systems may result in Aβ fibers encoding information that is eventually interpreted as noxious.

Most nociceptors are relatively nonselective ion channels gated not by voltage but by the stimulus (temperature, chemicals, mechanical forces). Once activated, the channels open and the inward flux of Na⁺ and Ca²⁺ ions produces an inward current that depolarizes the membrane. The presence, specificity, and threshold of these transducers define the different classes of primary afferent fibers. Most fibers are considered polymodal, responding to multiple types of noxious stimuli, whereas some are unimodal and respond to only one form of stimulus. Almost all C-fibers are high-threshold and polymodal. Considerable progress has been made over the past decade in identifying the molecular structure and function of various nociceptor ion channels.⁵

Electrophysiologic studies have subdivided Aδ nociceptors into two main classes. Type I (high-threshold mechanical [HTM] nociceptors) respond to both mechanical and chemical stimuli but have relatively high heat thresholds (>50 °C). These afferents, like all components of the system, can be sensitized by ongoing stimuli. Type II Aδ nociceptors have a much lower heat threshold, but a very high mechanical threshold.

Most C-fibers are polymodal, being both heat and mechanically sensitive (C-fiber nociceptors).⁶³ Certain C-fiber nociceptors, called silent nociceptors, are heat responsive but mechanically insensitive, and are not normally active. These develop mechanical sensitivity only in the setting of injury and become more responsive when the so-called “inflammatory soup” alters their properties. Subsets of these C-fiber nociceptors afferents are also responsive to a variety of itch-producing substances. Approximately 10% of all C-fiber nerve endings respond to low-intensity stimuli, such as stroking, and may mediate pleasant touch.

Neuroanatomic and molecular characterization of nociceptors has further defined their characteristics. The peptidergic C-fibers release neuropeptides, substance P, and calcitonin gene-related peptide; they also express the TrkA neurotrophin receptor, which responds to nerve growth factor. The nonpeptidergic population of C-fibers expresses the c-Ret neurotrophin receptor that is targeted by glial-derived neurotrophic factor, as well as neurturin and artemin.

Nociceptors can also be distinguished according to their differential expression of channels that confer sensitivity to heat (transient receptor potential vanilloid-1 [TRPV1]), cold (transient receptor potential menthol-8 [TRPM8]), acid environment (acid-sensing ion channels), and a host of chemical irritants [TRPA1])^5,41 (Figure 22-2).

Figure 22-2 Three major C-fiber nociceptor subtypes are shown here, as are some known expressed receptors. The different subtypes are undoubtedly more complex in the expression patterns of different receptors, and this can likely change as a result of plasticity. However, the unique repertoires of transduction complexes allow each nociceptor to detect one or more stimulus modalities and submodalities. For example, heat-sensitive afferents express TRPV1 receptors, and cold-sensitive afferents express TPRM8 receptors. However, as yet unidentified heat and cold receptors also alter the specific characteristics of the afferent. Polymodal nociceptors express chemoreceptors such as TRPA1, but also heat and mechanotransduction receptors. Sodium channels (e.g., NaV1.8, NaV 1.9) and potassium channels (e.g., TRAAK, TREK-1) are expressed on all these nociceptor afferents and function to modulate the excitability of the nociceptors. (© B. Duncan X. Lascelles, North Carolina State University.)

Heat Transduction

The human pain threshold to heat, which typically rests around 43° C, parallels the heat sensitivity of C and type II Aδ nociceptors described earlier. Capsaicin and related vanilloid compounds produce burning pain by depolarizing specific subsets of C and Aδ nociceptors through activation of the capsaicin (or vanilloid) receptor, transient receptor potential vanilloid-1—one of approximately 30 members of the greater transient receptor potential (TRP) ion channel family.¹³ Recent studies indicate that TRPV1 is not solely responsible for heat transduction but plays an important role. Current data indicate that both TRPV1-dependent and TRPV1-independent components of noxious heat sensitivity are mediated via TRPV1-expressing nociceptors. This is an important concept, because targeting TRPV1-expressing neurons (e.g., molecular neurosurgery) may have greater utility than selective targeting of TRPV1 receptors. Recent unpublished data from human patients support this.

Transmission and Projection

Type I and type II Aδ fibers range in size from 1 to 5 µm in diameter, are myelinated, and conduct impulses rapidly at a rate of 5 to 30 m/sec. The conduction rate is correlated with the initial sensation of pain—sharp, localized, and transient. These afferents have small receptive fields and specific high-threshold ion channels that are activated by noxious thermal or mechanical input. C-fibers are small, ranging in size from 0.25 to 1.5 µm in diameter, are unmyelinated with conduction velocities of only 0.5 to 2 m/sec, and have larger receptive fields compared with Aδ fibers. These characteristics contribute to the poorly localized, burning, gnawing sensation of second pain, which persists after termination of the noxious stimulus.

If the depolarizing current initiated during transduction is of sufficient magnitude, voltage-gated ion channels are activated, further depolarizing the membrane and causing a burst of action potentials. Voltage-gated Na⁺ and K⁺ channels are critical to the generation of action potentials. Several isoforms of Na⁺ channels have been recognized for their specific role in nociception. The tetrodotoxin (TTX)-sensitive Na⁺ channel, Na_v1.7, and the TTX-resistant Na⁺ channels, Na_v1.8 and Na_v1.9,^5,14 have attracted the most attention. The Na_v1.7 has received attention because of the finding that altered activity in this channel leads to a variety of human pain disorders,^24,33,67 and the finding that Na_v1.7 is upregulated in a variety of rodent inflammatory pain models.⁶⁰ The Na_v1.8 is also highly expressed by most C-fiber nociceptors and is not inactivated at low temperatures, making it the predominant action potential generator under cold conditions. Much of the analgesic effect of cold is considered to be due to inactivation of sodium channels.

These voltage-gated sodium channels are the targets of local anesthetics and are the focus of intense development of specific channel blockers (such as Na_v1.7 blockers). Additionally, many drugs have some sodium channel blocking activity. For example, the analgesic effects of serotonin and norepinephrine reuptake inhibitors may result in part from their ability to block sodium channels.²⁵

Dorsal Horn Neurons and Ascending Spinal Tracts

Sensory nerve fibers enter the spinal cord primarily through the dorsal nerve root, but some fibers enter through the ventral nerve root as well. Nociceptive fibers enter the dorsal horn of the gray matter, where they are somatotopically oriented into laminae or layers and synapse with dorsal horn neurons (Figure 22-3). Many of the fibers bifurcate, sending branches that ascend and descend several spinal cord segments before entering and synapsing in the dorsal horn. Sensory nerve fibers can synapse directly with projection neurons, which relay information to the brain, or with local excitatory and inhibitory interneurons, which regulate and modify sensory information before it is relayed to projection neurons. Sensory input from the head region enters the central nervous system via the trigeminal nerve. Noxious information is relayed to the nucleus caudalis, which is part of the trigeminal sensory complex, and, in turn, these neurons project to the ventroposterior thalamus and reticular formation.

Figure 22-3 Different subsets of primary afferent fibers synapse with spinal neurons arranged in discrete laminae in the dorsal horn of the spinal cord. Peptidergic C (yellow) and myelinated Aδ (red) fibers synapse with projection neurons (red) in lamina I and with interneurons (blue) in outer lamina II. Nonpeptidergic (green) fibers synapse with interneurons (green) in inner lamina II. Innocuous Aβ input (purple) synapses with protein kinase C (PKC)γ-expressing interneurons (blue) in the ventral half of lamina II, lamina III, and lamina IV. Other projection neurons (purple) in lamina V receive input from both Aδ and Aβ fibers. (© B. Duncan X. Lascelles, North Carolina State University.)

Primary afferent nerve fibers project to the dorsal horn of the spinal cord, which is organized into anatomically and functionally distinct laminae (see Figure 22-3). C-fibers terminate in laminae I and II; Aδ terminate in lamina I and the deeper dorsal horn, lamina V; Aβ afferents (which under normal conditions respond to light touch) terminate in laminae III, IV, and V. Even within this organization, further suborganization is evident. Most peptidergic C-fibers terminate within lamina I and the most dorsal part of lamina II. In contrast, the nonpeptidergic C-fiber afferents, including the Mrg-expressing subset, terminate in the midregion of lamina II. Lamina II is also referred to as the substantia gelatinosa. These afferent terminals synapse with dorsal horn neurons. Most transmission between primary afferents and dorsal horn neurons occurs through postsynaptically located ionotropic α-amino-3-hydroxyl-5-methyl-4-isoxazole propionic acid (AMPA) receptors with a small N-methyl-D-aspartate (NMDA) component. Consistent with this organization, electrophysiologic studies have evaluated the responses of spinal cord neurons within these laminae: spinal cord neurons within lamina I are generally responsive to noxious stimulation (via Aδ and C-fibers) and are termed noxious-specific neurons; neurons in laminae III and IV are primarily responsive to innocuous stimulation (via Aβ); and neurons in lamina V receive convergent nonnoxious and noxious input via direct (monosynaptic) Aδ and Aβ inputs and indirect (polysynaptic) C-fiber inputs, and are termed wide dynamic range neurons, in that they respond to a broad range of stimulus intensities. Wide dynamic range neurons respond in a graded manner over large receptive fields, often receive convergent deep and visceral input, and likely contribute to the phenomenon of referred pain, whereby noxious signals from a visceral tissue are referred to a somatic structure. Noxious-specific neurons have smaller receptive fields compared with wide dynamic range neurons and function in stimulus localization and discrimination.

Wide dynamic range and noxious-specific neurons project to the reticular formation and thalamus of the brainstem by way of multiple parallel pathways called tracts, including the spinothalamic and spinoreticulothalamic tracts, the spinocervicothalamic tract, and the spinomesencephalic tract. Considerable species variation in the relative importance of these tracts with regard to nociception is likely. Data from human beings suggest that projections to the thalamus are concerned with the sensory-discriminative aspects of the pain experience (i.e., where it is, how intense it is), whereas projections to the brainstem may be more important with regard to poorly localized pain. Spinal cord projections to the parabrachial region of the dorsolateral pons, which provide a very rapid connection with the amygdala, are likely associated with processing of aversive properties of the pain experience. Noxious information reaches cortical structures via the brainstem and thalamic areas (Figure 22-4).

Figure 22-4 Basic projection pathways to the brain. Projection neurons from the dorsal horn transmit information to the somatosensory cortex via connections in the thalamus. This information encodes information about the location and intensity of pain. Other projection neurons, via connections in the brainstem (parabrachial nucleus) and amygdala, transmit information to the cingulated and insular cortices and encode information about the affective component of pain. Ascending projection neurons also connect with neurons in the periaqueductal gray and rostral ventral medulla—neurons that project descending information that regulates output from the spinal cord. (© B. Duncan X. Lascelles, North Carolina State University.)

Thalamocortical System

The sensory-discriminative aspects of pain are produced in the lateral thalamocortical system, which consists of relay nuclei in the lateral thalamus and the primary and secondary somatosensory cortices. Motivational and affective aspects of the pain experience arise in the medial thalamocortical system, which includes relay nuclei in the medial thalamus that send projections to limbic structures, such as the anterior cingulate gyrus and prefrontal cortex, but that also includes spinal projections to the hypothalamus and amygdala (see Figure 22-4). Human imaging studies also demonstrate activation of prefrontal cortical areas and the basal ganglia and cerebellum during noxious stimulation.

Supraspinal Modulation of Sensory Input

It is important to recognize that powerful descending pathways are able to modulate the pain response. Descending modulation is controlled from three main sources: the periaqueductal gray matter of the midbrain; the rostroventral medulla and pons of the brainstem; and the thalamocortical structures (see Figure 22-4).⁵²

Descending neurons from the neocortex and hypothalamus activate enkephalinergic interneurons in the periaqueductal gray matter. The caudate nucleus and the amygdala, two other forebrain structures, have also been implicated in antinociception. Projections from the periaqueductal gray matter terminate in various brainstem structures in the rostroventral medulla, including the nucleus raphe magnus, the reticularis magnocellularis, and the nucleus paragigantocellularis. Descending serotonergic fibers originate in the nucleus raphe magnus; serotonergic, noradrenergic, enkephalinergic and joint enkephalinergic, and serotonergic fibers originate in the nucleus paragigantocellularis; and noradrenergic axons originate from cell groups lateral to the nucleus paragigantocellularis. These fibers descend in the dorsal lateral funiculus and synapse onto thalamic projection neurons in lamina I, and local opioid-containing inhibitory interneurons in lamina II (the substantia gelatinosa). These descending pathways are often activated by stressful events (pain, fear, hypoxia), and opioid-like analgesic effects are produced. Within the rostroventral medulla are populations of cells referred to as on and off cells.⁵³ Off cells hyperpolarize in response to spinothalamic tract input and reduce the transmission of nociceptive signals through the brainstem. On cells are excited by nociceptive input from the spinothalamic tract and facilitate nociceptive transmission to areas involved in arousal and aversive reactions to pain. Activity of these neurons can also affect local spinal cord modulation of nociceptive processing. Control of these rostroventral medulla neurons is being investigated.

Local Modulation of Sensory Input at the Spinal Cord

Sensory homeostasis is maintained by a balance of activity between peripheral nerve inputs and descending excitatory and inhibitory influences from the brain. At the level of the spinal cord, selective stimulation of peripheral afferent nerve input, release of local endogenous modulators of synaptic transmission, and activation of descending inhibitory pathways modify sensory input and the response to a painful stimulus. This normal modulation has three main features:

1. Gate control theory ⁵⁵: inhibitory interneurons normally inhibit output of projection neurons. Input from large myelinated Aβ fibers encoding non-noxious information can increase inhibitory interneuron activity, and limit the amount of noxious sensory information going to the brain.