Jessica A. Boyette-Davis
Patrick M. Dougherty
• Acute pain can be produced from trauma sustained during surgery. This injury results in activation of the nociceptive system, including activation of primary afferent nerve fibers in the periphery, excitation of dorsal horn neurons in the spinal cord, and recruitment of key brain areas. It will further lead to the release of multiple inflammatory mediators, which then potentiate pain.
• Persistent activation of the nociceptive system can lead to chronic pain. If nerves are damaged during surgery, this chronic pain can present in the form of neuropathy. In both instances, the chronic pain seems to be predominately centrally, as opposed to peripherally, mediated.
• Analgesic interventions are generally effective for acute postoperative pain. However, for patients who develop chronic post-thoracotomy pain, pain relief is less easily achieved and may be best accomplished best by preemptive analgesia.
Pain is a sensation that is normally associated with the application of noxious or injurious stimuli. In the context of thoracic surgery, pain can develop in multiple ways. Acute pain occurs as a direct result of physical trauma sustained during thoracic surgery. This trauma can include tissue damage from surgical incisions or manipulation, fractures to ribs, and hematomas.1 As will be discussed in this chapter, this acute pain may then develop into a chronic pain state in approximately half of all patients. Damage to nerves, most often the intercostal nerves, during surgery also contributes significantly to pain, as this damage manifests as a distinct form of chronic pain termed neuropathy. Thus, pain in thoracic surgery patients involves multiple components and mechanisms including those mediating acute somatic pain, hyperalgesia, and neuropathic pain. In the instance where these multiple components are all observed in a patient, the condition is referred to as chronic post-thoracotomy pain. To explain this condition in part or in its entirety, this chapter will review the basic physiology of pain, including pain pathways and neurochemistry, the neural mechanisms and neurochemical mediators of primary and secondary hyperalgesia, and the unique mechanisms of neuropathic pain.
OVERVIEW OF PAIN PATHWAYS AND NEUROCHEMISTRY
Peripheral Neural Mechanisms
In general, pain begins in a distinct class of primary afferent fibers that respond selectively to noxious stimuli. These nociceptors are located in the periphery, with the cell bodies located in dorsal root ganglia (DRG) outside the spinal cord, and terminate in the dorsal horn. Nociceptors respond to a number of different stimulus modalities including thermal, chemical, and mechanical stimuli.2,3 However, there are different classifications of nociceptors, generally based on the conduction velocity of the axons of these nociceptive neurons. The C fibers are generally unmyelinated fibers that conduct at velocities of less than 2 m/s and constitute over 75% of afferent fibers present in peripheral nerves. Several lines of evidence indicate that C-fiber nociceptors are essential for the normal perception of pain. For instance, intraneural electrical stimulation of identified C-fiber nociceptors in humans elicits the sensation of pain, and blockade of C-fiber transmission prevents thermal pain perception at the normal heat pain threshold.4 Absence of C fibers, either via capsaicin ablation5 or as is seen in patients with congenital insensitivity to pain,6 results in diminished or altogether absent pain sensation. Recordings from C fibers in humans suggest that C-fiber activity is associated with a prolonged burning sensation. In contrast, activation of faster conducting (5 to 20 m/s) myelinated Aδ fibers evokes a sharp, intense, tingling sensation. Combined, Aδ- and C-fiber nociceptors encode and transmit information to the central nervous system concerning the intensity, location, and duration of noxious stimuli.
Following transduction by peripheral afferents, nociceptive information is transmitted via nerves to the central nervous system. Within the thoracic cavity, it is the intercostal nerves of the peripheral nervous system that transmit pain signals to the spinal cord. These nerves, which are located with the intercostal space, are often damaged during thoracic surgery, leading to symptoms of neuropathic pain. The mechanisms of this pain are discussed below.
Central Neural Mechanisms
The axons of primary afferents terminate at the ipsilateral side of the dorsal horn of the spinal cord in a highly organized manner.7,8 As can be seen in Figure 6–1, the cells of the dorsal horn are arranged in layers, or laminae,9 with C fibers terminating primarily in the most superficial lamina (I and II outer) and Aδ fibers ending in lamina I, and in laminae III to V. Because both C and Aδ fibers terminate in lamina I, in addition to C fiber termination into lamina II, neurons within these laminae respond almost exclusively to noxious inputs10 and are often termed nociceptive specific (NS) or high-threshold neurons.11,12
In addition to these NS neurons, two other classes of sensory spinal neurons make synapse with nociceptive neurons. These cells, the wide dynamic range (WDR) and the multi-receptive (MR) cells, respond to both noxious and non-noxious stimuli with the difference being that WDR cells show a discharge rate that is graded with stimulus intensity whereas the MR cells do not.13,14 The WDR and MR cells in laminae III to V show responses to both cutaneous mechanical and heat stimuli, but rarely show responses from deep tissues, while cells in laminae VI and VII tend to show responses from deep tissue and visceral receptors.
Figure 6–1. Laminae distribution and primary afferent termination within the spinal cord. The histological section on the left is labeled to show the location of the dorsal horn within the spinal cord. In the enlarged segment to the right, the layers of laminae I through VI are outlined. Primary afferent innervation to the various laminae is depicted in the schematic at the bottom. (From: Raja, SN & Dougherty, PM. Anatomy and physiology of somatosensory and pain processing. In HT Benzon, SN Raja, RE Molloy, SS Liu, & SM Fishman (eds). Essentials of Pain Medicine and Regional Anesthesia. 2nd ed. Figure 1-1, pg 3. Philadelphia, USA: Elsevier, Churchill, Livingstone; 2005, with permission.)
Unlike for touch where information ascends ipislaterally up the spinal cord via the dorsal column medial lemniscal system, almost all nociceptive information is transmitted to the contralateral side of the body at the level of primary afferent innervation. There the axons of WDR and NS neurons cross the midline of the spinal cord, gather into bundles and then ascend toward targets in the brainstem and diencephalon via the antereolateral system. This system is further divided into distinct tracts based primarily upon the location of projection neurons within dorsal horn laminae (Figure 6–2). For instance, the axons of WDR and NS cells that make synapse within laminae I and V-VII ascend to the medial thalamus, thus forming the spinothalamic tract.
Figure 6–2. Summary of the central nociceptive pathways. Information ascends from primary afferent fibers via either the dorsal column medial lemniscal column (touch) or the anterolateral system (nociception). Projections of various nociceptive specific tracts are also depicted. (From: Raja, SN & Dougherty, PM. Anatomy and physiology of somatosensory and pain processing. In HT Benzon, SN Raja, RE Molloy, SS Liu, & SM Fishman (eds). Essentials of Pain Medicine and Regional Anesthesia. 2nd ed. Figure 1-4, pg 5. Philadelphia, USA: Elsevier, Churchill, Livingstone; 2005, with permission.)
Within the brain, several areas are especially involved in processing nociceptive information.15 In response to pain, six brain areas are consistently recruited: the primary and secondary somatosensory cortices, the insular cortex, the anterior cingulate cortex, the prefrontal cortex (PFC), and several nuclei of the thalamus. The somatosensory cortices provide information regarding where in the body pain originates, and there is evidence that S2 contains a somatotopic map for nociceptive input. The insular and rostral anterior cingulate cortices are part of the limbic system, and an abundance of literature suggests these brain structures modulate the affective or emotional aspect of pain. The PFC aids not only in making a decision as to what actions should be taken to alter pain, but this part of the brain also is useful in controlling input from the limbic system. Interestingly, some research suggests that the pattern of brain activation changes during chronic pain from more limbic-related activity to significantly more activation in the PFC. Further, thalamic activation tends to be lower in chronic versus acute pain. Finally, other key areas of the brain are involved in the descending modulation of pain, primarily via serotonin-related mechanisms. These areas include the rostral ventromedial medulla, the nucleus raphe magnus, the locus ceruleus, and the periaqueductal gray matter.
Within the periphery, numerous chemicals are released following insult to tissue (Figure 6–3). These chemicals, which can directly activate nociceptors or increase the general excitability of nociceptors, are frequently referred to as an “inflammatory soup.” Following injury, both bradykinin16 and serotonin17 directly activate nociceptors. The neuropeptides histamine, substance P, and calcitonin gene-related peptide (CGRP) are derived from activated nociceptors and produce a variety of responses, including vasodilation and edema. Further, histamine excites polymodal visceral nociceptors and potentiates the responses of nociceptors to bradykinin and heat.18 Eicosanoids, including prostaglandins, thromboxanes, and leukotrienes, directly activate and sensitize afferents.19,20 Nitric oxide (NO) released by damaged afferents can further sensitize nearby neurons, augmenting pain and inflammation.21 Cytokines released by a variety of cells19 can also serve to directly excite and sensitize nociceptive afferent fibers to thermal and mechanical stimuli. Cytokines also lead to increased production of nerve growth factor (NGF),22 which in turn stimulates mast cells to release histamine and serotonin, leading to the aforementioned primary afferent fiber activation and sensitization. Proteinases such as thrombin, trypsin, and tryptase, although not traditionally considered part of the inflammatory soup, are gaining increasing attention as mediators of pain and inflammation.23 Activation of proteinase receptors PAR1 and PAR2, which are located on primary afferent nerve fiber endings, leads to a cascade effect of histamine, substance P, CGRP, prostaglandin, bradykinin, and cytokine release.
Figure 6–3. Summary of the neurochemical mediators in the periphery. Tissue injury provokes the release of numerous chemical mediators of pain. Pro-nociceptive mediators augment pain via multiple mechanisms, including directly activating nociceptors, sensitizing primary afferents, and causing the release of other known mediators. (Adapted from Dougherty, PM & Raja, SN. Neurochemistry of somatosensory and pain processing. In HT Benzon, SN Raja, RE Molloy, SS Liu, & SM Fishman (eds). Essentials of Pain Medicine and Regional Anesthesia 2nd ed., Figure 2-1, pg 8. Philadelphia, USA: Elsevier, Churchill, Livingstone; 2005, with permission.)
In addition to these pro-nociceptive mediators, anti-nociceptive chemicals are also present in the periphery. For instance, opioids, which are known for their analgesic properties, are also a component in inflammatory soup.24 The peripheral terminals of afferent fibers contain receptors for opioids, and the number of receptors is upregulated following tissue injury. Acetylcholine modulates pain primarily via its effects on muscarinic receptors. This is supported by the findings that muscarinic agonists desensitize C-fiber nociceptors to mechanical and heat stimuli.25 Finally, somatostatin (SST) may also serve as an antinociceptive agent. The SST receptor type 2a has been identified in a small percentage of unmyelinated primary afferent fibers,26 and administration of the SST receptor agonist octreotide attenuates bradykinin-induced nociceptor sensitization. SST also inhibits the release of cholecystokinin, which has been shown to have nociceptive properties.
Within the central nervous system, pain is modulated via a host of chemical mediators (Figure 6–4). The amino acids glutamate and aspartate constitute the main excitatory neurotransmitters within the central nervous system. Of particular interest is the glutamate receptor N-methyl-D-aspartate (NMDA). In the spinal cord, the NMDA receptor is recruited only by intense and/or prolonged stimuli, and persistent activation of NMDA receptors leads to sensitization of dorsal horn neurons that includes an increase in receptive field size, decreased activation threshold, and prolonged depolarization. The impact of spinal NMDA-mediated changes will be discussed again in regards to hyperalgesia. In the brain, NMDA receptors are also important for pain27 and are upregulated following injury. This upregulation is associated with augmented sensitivity to inflammatory pain, excessive excitation of the brainstem, and increased expression of the transcription factor c-Fos. A multitude of research implicates c-Fos as an important facilitator of pain. Adenosine triphosphate (ATP) also serves to enhance pain. ATP receptors, especially the P2X family of receptors are present on the central terminals of primary afferent fibers innervating neurons in lamina V and II of the dorsal horn where they function to increase the release of glutamate. Like many other chemical mediators, the effects of ATP are not limited to neurons. The binding of ATP to P2 receptors on microglia activates these cells, which then begin to secrete inflammatory mediators such as cytokines, nerve growth factor, and NO. These factors then serve to sustain pain and inflammation.28
Figure 6–4. Summary of the neurochemical mediators in the spinal cord. As is seen in the periphery, many modulators are present in the spinal cord which work to increase pain transmission. In addition to these factors, nociceptive mediated changes within the spinal cord also include changes to ion channel expression and glial cell activation. These changes play a role in the transition from acute to chronic pain. (Adapted from Dougherty, PM & Raja, SN. Neurochemistry of somatosensory and pain processing. In HT Benzon, SN Raja, RE Molloy, SS Liu, & SM Fishman (eds).Essentials of Pain Medicine and Regional Anesthesia. 2nd ed. Figure 2-2, pg 10. Philadelphia, USA: Elsevier, Churchill, Livingstone; 2005, with permission.)
Substance P and neurokinin A serve as excitatory neuropeptides present in addition to the traditional neurotransmitters.29,30 Activation of neurokinin receptors by either substance P or neurokinin A is an important step in the induction of sensitization and hence the expression of hyperalgesia following cutaneous injury. Spinal release of another peptide, CGRP, has an excitatory effect on WDR neurons, and administration of the CGRP antagonist CGRP8-37 reverses this activity. Interestingly, the role of CGRP released within the brain seems to be antithetic to the peripheral and spinal effects, with release of this peptide within the PAG producing antinociceptive results.
The amino acids glycine and gamma-amino-butyric acid (GABA) are the chief inhibitory neurotransmitters in the somatosensory system. Glycine is the prominent inhibitory neurotransmitter in the spinal cord, especially in local circuit neurons of spinal laminae I, II, and III. Conversely, GABA predominates at higher levels. This is evidenced by the finding that the effects of barbiturates, benzodiazepines and alcohol are mediated by GABA receptors located within the brain. Norepinephrine is another abundant inhibitory neurotransmitter, and it exerts its effects by activating inhibitory GABAergic interneurons and by also inhibiting excitatory interneurons.31 Serotonin, like norepinephrine, is also involved in descending pathways to the spinal dorsal horn, predominately from the midbrain raphe nuclei.32,33 The main inhibitory peptides present in the central nervous system are the opioid peptides, which bind to mu, delta and kappa receptor subtypes found at all levels of the somatosensory system. Opioids modulate pain transmission by hyperpolarizing neurons and by blocking the release of pro-nociceptive mediators, such as glutamate and substance P.
THE DEVELOPMENT OF HYPERALGESIA AND CENTRAL SENSITIZATION
Up to this point, discussion has focused on the more acute effects of tissue injury. Following surgery, patients will experience pain as a result of activation of the nociceptive system. This pain may be brief and directly related to tissue injury, but for 50% of patients, this pain will be present for months, or even years. This section, along with the following section will outline how acute pain can transition to a chronic pain state.
Injury to cutaneous and deep tissue such as that occurring with surgery will result in a state of increased sensitivity to suprathreshold stimuli at the site of injury, termed primary hyperalgesia, as well as in the uninjured skin surrounding the injury, termed secondary hyperalgesia.34 The characteristics and mechanisms of primary and secondary hyperalgesia differ. Within the zone of primary hyperalgesia, the thresholds for both mechanical and thermal stimuli are lowered, but within the area of secondary hyperalgesia, hypersensitivity to mechanical stimuli but not to thermal stimuli is found.35
The driving force of primary hyperalgesia is sensitization of nociceptors.36,37 Here, sensitization refers to a leftward shift of the stimulus-response function that relates magnitude of the neural response to stimulus intensity and is characterized by a decrease in threshold, an augmented response to suprathreshold stimuli, and ongoing spontaneous activity in nociceptors.38-40 Conversely, the driving force of secondary hyperalgesia is sensitization of spinal neurons. Neurophysiological investigations have shown that the characteristics of secondary hyperalgesia are well-explained by properties of dorsal horn neurons after injury.41-43 These neurons display increased responding and expanded receptive fields to a mechanical stimulus following an injury. As outlined above, WDR and NS cells play a key role in transmission of pain, but they appear to have differing roles in secondary hyperalgesia. Unlike NS cells, most WDR dorsal horn neurons are sensitized by a variety of peripheral injuries suggesting that this subtype of neurons are important for the detection and discrimination of tissue damaging stimuli and in the generation of secondary hyperalgesia.44
Finally, neurons in higher CNS areas also show enhanced responses after injury. For example, the responses of neurons in the thalamus and cortex of rats to cutaneous mechanical stimuli have been shown to increase with the induction of both experimental arthritis and experimental neuropathy.45 Similarly, the neuronal activity in the thalamus of humans with chronic pain also show alterations.46,47Although these changes in responses of thalamic and cortical neurons may just reflect changes that have taken place in the primary afferents and spinal cord neurons under each of these conditions, it should be noted that anatomical and neurochemical changes also take place in the thalamus and cortex under each of these conditions.48,49 Thus, neuronal substrates exist to support a third or even fourth component to hyperalgesia.
Unfortunately for many patients, hyperalgesia lasts long after injuries have healed. This may be due in part to the phenomenon of central sensitization whereby dorsal horn neurons show increased excitability as discussed above. Persistent activation of C fibers results in the release of glutamate, which then activates NMDA receptors. These receptors are an imperative part of transmission of pain signals, so much so that NMDA receptor antagonists like ketamine are often used as analgesics in surgical settings. Indeed, presurgical administration of ketamine can block the development of central sensitization and hyperalgesia.
MECHANISMS OF NEUROPATHIC PAIN
Traumatic injury to soft-tissue, bone, and/or nerve leads, in certain cases, to a chronic pain state that is characterized by ongoing pain and hyperalgesia.50,51 Noxious stimuli during thoracic surgery may be acutely conveyed by the intercostal, vagus, and phrenic nerves.52 For example, it is thought that the phrenic nerve is responsible for referred shoulder pain, as it is not ablated by intercostal or epidural analgesia but is treated by phrenic nerve infiltration with lidocaine.53 Although all three nerves are at risk for mediating the development of enduring pain, in thoracic surgery, a majority of ongoing pain may be attributed to direct or indirect intercostal nerve damage.54 The pain attributed to nerve damage is very often persistent and characterized by feelings of burning or numbness that is not responsive to typical analgesics. Intriguingly, in some patients the pain and hyperalgesia are dependent on sympathetic innervation of the affected area (sympathetically maintained pain, SMP55), while in others the pain is independent of the sympathetics (SIP56). Clinically, both SMP and SIP patients often present with similar signs and symptoms.57
Immediately following injury, peripheral nerves show a dramatic increase in activity, but this activity usually resolves within several minutes.58,59 This injury barrage appears to be a very important event in provoking many of the sequelae of nerve injury, as anesthesia of a nerve prior to injury reduces both the severity and duration of the thermal hyperalgesia which later develops.60 Along the same lines, administration an NMDA antagonist reduces the severity of partial nerve injury induced hyperalgesia.61 Once the injury discharges subside, the activity in injured axons changes. Three to five days following nerve transection or partial nerve injury, spontaneous discharges develop in the severed nerves62,63 which then peak at around 14 days after injury. Although this activity slowly tapers to a lower level, altered patterns of activity are sustained for many weeks.
Neurons of the CNS, like primary afferents, also show a large discharge at the time of nerve damage,64 and the time course of the injury discharges observed in the CNS parallels that found in primary afferents. A few days following nerve injury many CNS neurons develop changes in spontaneous activity.64-66 These neurons exhibit a pattern of continuous, regular discharges of high frequency, or they are silent except for sudden high-frequency bursts. Also, higher percentages than normal of these cells respond only to noxious stimuli.
Degenerative changes, such as the loss of inhibitory neurons in the spinal cord67,68 and thalamus69 following peripheral nerve injury are thought to contribute to neuropathic pain as well. Wallerian degeneration of peripheral axons and digestion of lost central neurons activates inflammatory cells, leading to increases in the levels of perineural inflammatory cytokines that can further activate nociceptive neurons and generate pain.70-72 Following the phase of axonal/neuronal degeneration injured neurons will attempt to restore connectivity that is lost to an original innervation target and uninjured neurons will attempt to establish innervation to targets that have become deprived of neural input. As neurons grow, they discharge spontaneously thus increasing signal traffic throughout the somatosensory axis. Changes in transcription factors and other neurochemistry result in altered gene expression in neurons,73 which then can result in widespread changes in cell phenotype, including alteration of cell surface ion channels,74,75 neurotransmitter and neuropeptide receptors,67 surface growth associated proteins,76 and changes in neurotransmitter and neuropeptide content and synaptic release. Finally, the expression of nerve growth factors, which have been shown to directly produce pain when administered to experimental animals, are upregulated with neuronal proliferation.77-79 These factors, in whole or in part, contribute to the long lasting condition of neuropathy.
Throughout this chapter, the mechanisms of pain associated with thoracic surgery have been outlined, and these principles can now be applied to pain relief. For acute pain, analgesic interventions can occur after surgery but with extremely variable success. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly used form of pain relief available. This class of drugs works primarily by inhibiting prostaglandin synthesis and have some success in moderating thoracic pain. However, they are most effective when combined with a form of opioid analgesia. Opioids provide almost immediate, and sometimes complete, analgesia following surgery and are the drug of choice immediately following surgery. These drugs may be administered intravenously, orally, or epidurally.
With so many patients developing chronic pain following thoracic surgery, it is important to apply the principles of chronic pain development to analgesic options. As outlined above, ongoing input to the spinal cord from nociceptors can result in a state of central sensitization. To prevent this occurrence, preemptive analgesia is now often used. While any one intervention has limited success, combining opiates, NSAIDS, and nerve blocks and administering these prior to surgery appears to decrease the incidence of chronic pain.1
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