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When does acute pain become chronic?

2010; Elsevier BV; Volume: 105; Linguagem: Inglês

10.1093/bja/aeq323

1471-6771

Christopher Voscopoulos, Mark J. Lema,

Pain Management and Opioid Use

SummaryThe transition from acute to chronic pain appears to occur in discrete pathophysiological and histopathological steps. Stimuli initiating a nociceptive response vary, but receptors and endogenous defence mechanisms in the periphery interact in a similar manner regardless of the insult. Chemical, mechanical, and thermal receptors, along with leucocytes and macrophages, determine the intensity, location, and duration of noxious events. Noxious stimuli are transduced to the dorsal horn of the spinal cord, where amino acid and peptide transmitters activate second-order neurones. Spinal neurones then transmit signals to the brain. The resultant actions by the individual involve sensory-discriminative, motivational-affective, and modulatory processes in an attempt to limit or stop the painful process. Under normal conditions, noxious stimuli diminish as healing progresses and pain sensation lessens until minimal or no pain is detected. Persistent, intense pain, however, activates secondary mechanisms both at the periphery and within the central nervous system that cause allodynia, hyperalgesia, and hyperpathia that can diminish normal functioning. These changes begin in the periphery with upregulation of cyclo-oxygenase-2 and interleukin-1β-sensitizing first-order neurones, which eventually sensitize second-order spinal neurones by activating N-methyl-d-aspartic acid channels and signalling microglia to alter neuronal cytoarchitecture. Throughout these processes, prostaglandins, endocannabinoids, ion-specific channels, and scavenger cells all play a key role in the transformation of acute to chronic pain. A better understanding of the interplay among these substances will assist in the development of agents designed to ameliorate or reverse chronic pain. The transition from acute to chronic pain appears to occur in discrete pathophysiological and histopathological steps. Stimuli initiating a nociceptive response vary, but receptors and endogenous defence mechanisms in the periphery interact in a similar manner regardless of the insult. Chemical, mechanical, and thermal receptors, along with leucocytes and macrophages, determine the intensity, location, and duration of noxious events. Noxious stimuli are transduced to the dorsal horn of the spinal cord, where amino acid and peptide transmitters activate second-order neurones. Spinal neurones then transmit signals to the brain. The resultant actions by the individual involve sensory-discriminative, motivational-affective, and modulatory processes in an attempt to limit or stop the painful process. Under normal conditions, noxious stimuli diminish as healing progresses and pain sensation lessens until minimal or no pain is detected. Persistent, intense pain, however, activates secondary mechanisms both at the periphery and within the central nervous system that cause allodynia, hyperalgesia, and hyperpathia that can diminish normal functioning. These changes begin in the periphery with upregulation of cyclo-oxygenase-2 and interleukin-1β-sensitizing first-order neurones, which eventually sensitize second-order spinal neurones by activating N-methyl-d-aspartic acid channels and signalling microglia to alter neuronal cytoarchitecture. Throughout these processes, prostaglandins, endocannabinoids, ion-specific channels, and scavenger cells all play a key role in the transformation of acute to chronic pain. A better understanding of the interplay among these substances will assist in the development of agents designed to ameliorate or reverse chronic pain. Key points•The transition from acute to chronic pain occurs in discrete pathophysiological steps involving multiple signalling pathways.•The duration and intensity of the initial stimulus leads to both peripheral and central sensitization that synergistically exacerbate pain perception.•A multimodal therapeutic approach is best suited to target the complex mechanisms leading to the transition from acute to chronic pain. •The transition from acute to chronic pain occurs in discrete pathophysiological steps involving multiple signalling pathways.•The duration and intensity of the initial stimulus leads to both peripheral and central sensitization that synergistically exacerbate pain perception.•A multimodal therapeutic approach is best suited to target the complex mechanisms leading to the transition from acute to chronic pain. Pain-related problems account for up to 80% of visits to physicians. The epidemiological significance of chronic pain after surgery is enormous.1Schmitt P Rehabilitation of chronic pain: A multi-disciplinary approach.J Rehabil. 1985; 51: 72Google Scholar The prevalence of chronic pain can range from 10.1% to 55.2% of the populations studied.2Harstall C How prevalent is chronic pain?.IASP Pain Clinical Updates. 2003; XI: 1-4Google Scholar Current theories propose that a prolonged experience of acute pain in which long-standing changes are seen within and external to the central nervous system (CNS) creates chronic pain with a histological and pathological basis.3Ready L The interface between acute and chronic pain.in: The Management of Pain. Churchill Livingstone, New York1998Google Scholar Furthermore, chronic pain development after surgery likely occurs as a result of complex biochemical and pathophysiological mechanisms that differ in type among different surgical procedures. This article focuses on how postoperative, traumatic, and neuropathic nociception are generated and inter-related, with the goal of providing a deeper understanding of how long-term pain develops so that we can prevent and treat it more effectively, in the hope of stimulating more research and inquiry. The generation of acute surgical pain can be summarized in the following way. Surgery-associated tissue injury is interpreted neuraxially in the same way as trauma-associated injury. Pain sensation varies according to the intensity, quality, and duration of stimuli. Surgery sets off a cascade of inter-related events designed to fight infection, limit further damage, and initiate repair. It involves nociception, inflammation, and nerve cell remodelling. Pro-inflammatory cytokines, chemokines, and neurotrophins induce both peripheral and central nerve sensitization to heighten pain awareness in order to limit further injury to the affected area. In the generation of pain, multiple pain systems are known to be activated. It is the activation of nociceptors in the periphery, and their ongoing activation, through processes such as peripheral and ultimately central sensitization, that underlies one mechanism of the transition to the chronic pain state. Nociceptors are free nerve endings, with no extracellular matrix capsule or epithelial cell adjoined to the neurone, and respond to stimuli that damage or threaten to damage tissue.4Kruger L Kavookjian A Kumazawa T Light A Mizumura K Nociceptor structural specialization in canine and rodent testicular ‘free’ nerve endings.J Comp Neurol. 2003; 463: 197-211Crossref PubMed Scopus (0) Google Scholar Nociceptors are present in skin, muscle, joints, and viscera, with varying degrees of density. It is this density of population that allows for differential sensory ability, for example, the difference between the finger tip and the back.5Gold M Gebhart G Peripheral pain mechanisms and nociceptor sensitization.in: Fishman S Ballantyne JC Rathmell JP Bonica’s Pain Management. 4th Edn. Lippincott Williams & Wilkins (LWW), 2010: 25-34Google Scholar Nociceptors are the primary afferent terminals of nerves that generate impulses to the spinal cord, and are categorized by their receptive modality and by their response to that stimulus.5Gold M Gebhart G Peripheral pain mechanisms and nociceptor sensitization.in: Fishman S Ballantyne JC Rathmell JP Bonica’s Pain Management. 4th Edn. Lippincott Williams & Wilkins (LWW), 2010: 25-34Google Scholar A-δ fibres are fast-conducting myelinated nerves activated by heat by mechanothermal receptors and high-threshold mechanoreceptors. The degree of the stimulus is translated into a proportional intensity of firing.6Gold M Ion channels: recent advances and clinical applications.in: Flor H Kaslo E Dostrovsky JO Proceedings of the 11th World Congress on Pain. IASP Press, Seattle2006: 73-92Google Scholar In contrast, C-fibres are non-myelinated, slow-conducting, fibres with receptive fields smaller than those of A-δ nociceptors. In the non-sensitized state, they have higher thresholds for activation when compared with A-δ fibres or A-β fibres. These fibres represent the majority of peripheral nociceptors, and most are of the C-polymodal neurone type.5Gold M Gebhart G Peripheral pain mechanisms and nociceptor sensitization.in: Fishman S Ballantyne JC Rathmell JP Bonica’s Pain Management. 4th Edn. Lippincott Williams & Wilkins (LWW), 2010: 25-34Google Scholar Like A-δ fibres, C-fibres respond to thermal and mechanical stimulation. Unlike A-δ fibres, they also respond to chemical stimuli, and produce sensation consistent with itching.6Gold M Ion channels: recent advances and clinical applications.in: Flor H Kaslo E Dostrovsky JO Proceedings of the 11th World Congress on Pain. IASP Press, Seattle2006: 73-92Google Scholar A-β fibres are of large diameter and highly myelinated, and convey only proprioception and touch. Nociceptors are either specific to the type of noxious stimuli, such as mechanical pressure, cold, or hot, or are polymodal nociceptors that respond to mechanical, thermal, and chemical stimuli. Polymodal nociceptors are the most abundant type.6Gold M Ion channels: recent advances and clinical applications.in: Flor H Kaslo E Dostrovsky JO Proceedings of the 11th World Congress on Pain. IASP Press, Seattle2006: 73-92Google Scholar By varying both in their threshold to stimuli and their rate of firing to the dorsal horn, action potential processing into the CNS can span a wide range of pain perceptions, both in quality and intensity. Also, by responding differently to stimuli, these nociceptors encode a wide range of sensory phenomena. When a polymodal nociceptor becomes sensitized, it is sensitized to all modalities it conveys.5Gold M Gebhart G Peripheral pain mechanisms and nociceptor sensitization.in: Fishman S Ballantyne JC Rathmell JP Bonica’s Pain Management. 4th Edn. Lippincott Williams & Wilkins (LWW), 2010: 25-34Google Scholar A-δ and C-fibre innervation of the dorsal horn terminates superficially in laminae I–II with a few connections to deeper laminae, whereas A-β fibres predominantly terminate in laminae III–VI.7Todd AJ Anatomy of primary afferents and projection neurones in the rat spinal dorsal horn with particular emphasis on substance P and the neurokinin 1 receptor.Exp Physiol. 2002; 87: 245-249Crossref PubMed Scopus (112) Google Scholar Centrally, within the laminae of the dorsal horn, receiving neurones are specific to either A-δ and C-fibre input, to A-β input, or are wide dynamic range neurones receiving input from all three. These second-order neurone connections can be influenced by both excitatory glutamatergic and inhibitory GABAergic interneurones, or by astrocytes and microglia, particularly under pathological states. Within lamina I, approximately 80% of these cells express the neurokinin 1 receptor for substance P. These cells project to the thalamus, periaqueductal grey (PAG), and the parabrachial area. Hence, lamina I cells play a strong role in processing spinal input to inhibitory and facilitatory descending pathways from higher CNS centres.7Todd AJ Anatomy of primary afferents and projection neurones in the rat spinal dorsal horn with particular emphasis on substance P and the neurokinin 1 receptor.Exp Physiol. 2002; 87: 245-249Crossref PubMed Scopus (112) Google Scholar The CNS can alter the afferent nociceptive information it receives by a descending or modulatory system. This system arises out of several regions of the CNS, including the somatosensory cortex, hypothalamus, PAG, pons, lateral tegmental area, and raphe magnus. These structures communicate with laminae I and V via the dorsolateral funiculus. Stimulation of these areas, or of their common outlet path via the dorsolateral funiculus, inhibits nociceptive impulses promoting an analgesic effect.8Pubols LM Simone DA Bernau NA Atkinson JD Anesthetic blockade of the dorsolateral funiculus enhances evoked activity of spinal cord dorsal horn neurons.J Neurophysiol. 1991; 66: 140-152Crossref PubMed Scopus (14) Google Scholar Descending inhibition largely involves the release of norepinephrine in the dorsal horn from the locus coeruleus, acting at α2-adenoceptors, to inhibit primary afferent terminals and suppress firing of projection neurones.9Millan MJ Descending control of pain.Prog Neurobiol. 2002; 66: 355-474Crossref PubMed Scopus (1756) Google Scholar 10D’Mello R Dickenson AH Spinal cord mechanisms of pain.Br J Anaesth. 2008; 101: 8-16Crossref PubMed Scopus (175) Google Scholar Descending facilitatory pathways, primarily involving a serotonergic mechanism, are also involved and appear to play a greater role in the development of chronic pain.11McCleane GJ Suzuki R Dickenson AH Does a single intravenous injection of the 5HT3 receptor antagonist ondansetron have an analgesic effect in neuropathic pain? A double-blinded, placebo-controlled cross-over study.Anesth Analg. 2003; 97: 1474-1478Crossref PubMed Google Scholar Thus, in terms of central sensitization, the spinal cord is an important pain processing crossroad receiving input from peripheral neurones, interneurones, astrocytes and microglia, and descending modulatory controls. Five events are needed for a nociceptor to relay pain information to the CNS; signal transduction, action potential generation, transmission of the action potential to the CNS, second-order neurone activation to transmit the signal to the thalamus, and third-order neurone transmission of the signal to the cerebral cortex, where the nociceptive stimulus is perceived as pain. Each process is controlled by a distinct set of receptor proteins amenable to a wide variety of therapeutic interventions, some of which will be briefly reviewed below. As free nerve endings, nociceptors are chemosensors that react to cellular damage by responding to a wide range of inflammatory molecules. These include adenosine-5’-triphosphate (ATP), nerve growth factor (NGF), tumour necrosis factor-alpha (TNF-α), bradykinin, prostaglandin E2, serotonin, and protons (H+), which are released by epithelial cells, mast cells, macrophages, etc.5Gold M Gebhart G Peripheral pain mechanisms and nociceptor sensitization.in: Fishman S Ballantyne JC Rathmell JP Bonica’s Pain Management. 4th Edn. Lippincott Williams & Wilkins (LWW), 2010: 25-34Google Scholar Given the abundance of ligands and voltage-gated ion channels, nociceptive transmission involves multiple rather than only one voltage- or ligand-gated channels. Nociceptors are also capable of amplifying local inflammation by releasing such compounds as substance P, which can activate local mast cells and cause vasodilation by the release of calcitonin gene-related peptide (CGRP). After tissue damage, increased density of several transducers, phosphorylation of these tranducers, and activation of receptors such as transient receptor potential type V1 (TRPV1) results in an increased channel activity and sensitivity to noxious stimuli (sensitization). For example, changes in the expression, trafficking, and distribution of Na+ channels after inflammation or nerve injury contribute to unstable oscillations of membrane potential, abnormal firing, and the generation of ectopic activity in afferent nerves.12Dray A Neuropathic pain: emerging treatments.Br J Anaesth. 2008; 101: 48-58Crossref PubMed Scopus (0) Google Scholar, 13Devor M Sodium channels and mechanisms of neuropathic pain.J Pain. 2006; 7: S3-S12Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, 14Amir R Liu CN Kocsis JD Devor M Oscillatory mechanism in primary sensory neurones.Brain. 2002; 125: 421-435Crossref PubMed Google Scholar In addition to the generation of ongoing spontaneous ectopic activity through the accumulation and clustering of Na+ channels, these neurones can exhibit ephaptic transmission both between peripheral fibres and their cell bodies within the dorsal root ganglion. Along with changes within nociceptive fibres, sympathetic efferents become able to activate nociceptive fibres via poorly characterized α-adrenoceptors.15Wang J Ren Y Zou X Fang L Willis WD Lin Q Sympathetic influence on capsaicin-evoked enhancement of dorsal root reflexes in rats.J Neurophysiol. 2004; 92: 2017-2026Crossref PubMed Scopus (0) Google Scholar In relation to this generation of spontaneous activity, the Nav 1.8 Na+ channel subtype is thought to play a key role. Knockdown of this receptor in mice produces a marked reduction in abnormal responsiveness.16Roza C Laird JM Souslova V Wood JN Cervero F The tetrodotoxin-resistant Na+ channel Nav1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice.J Physiol. 2003; 550: 921-926Crossref PubMed Scopus (0) Google Scholar Understanding the endogenous mediators and factors that contribute to sensitization in a synergistic fashion might provide a better understanding of how acute pain may transition to a chronic physiological pain state (Fig. 1). Blocking these receptors might attenuate or prevent acute pain, or if a chronic pain state has already developed, might ameliorate or even reverse such a pathophysiological state. The stimuli sufficient for the activation of nociceptors appear to be tissue-specific, and tissue damage is not always required. For example, the sensitization process in the masseter muscle has been found to involve a decrease in a specific voltage-gated K+ channel.17Harriott AM Dessem D Gold MS Inflammation increases the excitability of masseter muscle afferents.Neuroscience. 2006; 141: 433-442Crossref PubMed Scopus (0) Google Scholar Similar mechanisms of a decrease, or increase, in specific ligand-gated or voltage-gated channels have been found in the sensitization process of other tissues.18Dang K Lamb K Cohen M Bielefeldt K Gebhart GF Cyclophosphamide-induced bladder inflammation sensitizes and enhances P2X receptor function in rat bladder sensory neurons.J Neurophysiol. 2008; 99: 49-59Crossref PubMed Scopus (0) Google Scholar, 19Sugiura T Dang K Lamb K Bielefeldt K Gebhart GF Acid-sensing properties in rat gastric sensory neurons from normal and ulcerated stomach.J Neurosci. 2005; 25: 2617-2627Crossref PubMed Scopus (0) Google Scholar, 20Flake NM Gold MS Inflammation alters sodium currents and excitability of temporomandibular joint afferents.Neurosci Lett. 2005; 384: 294-299Crossref PubMed Scopus (0) Google Scholar, 21Dang K Bielefeldt K Gebhart GF Gastric ulcers reduce A-type potassium currents in rat gastric sensory ganglion neurons.Am J Physiol Gastrointest Liver Physiol. 2004; 286: G573-G579Crossref PubMed Google Scholar, 22Beyak MJ Ramji N Krol KM Kawaja MD Vanner SJ Two TTX-resistant Na+ currents in mouse colonic dorsal root ganglia neurons and their role in colitis-induced hyperexcitability.Am J Physiol Gastrointest Liver Physiol. 2004; 287: G845-G855Crossref PubMed Scopus (0) Google Scholar, 23Stewart T Beyak MJ Vanner S Ileitis modulates potassium and sodium currents in guinea pig dorsal root ganglia sensory neurons.J Physiol. 2003; 552: 797-807Crossref PubMed Scopus (0) Google Scholar, 24Moore BA Stewart TM Hill C Vanner SJ TNBS ileitis evokes hyperexcitability and changes in ionic membrane properties of nociceptive DRG neurons.Am J Physiol Gastrointest Liver Physiol. 2002; 282: G1045-G1051Crossref PubMed Google Scholar, 25Bielefeldt K Ozaki N Gebhart GF Experimental ulcers alter voltage-sensitive sodium currents in rat gastric sensory neurons.Gastroenterology. 2002; 122: 394-405Abstract Full Text Full Text PDF PubMed Google Scholar, 26Yoshimura N de Groat WC Increased excitability of afferent neurons innervating rat urinary bladder after chronic bladder inflammation.J Neurosci. 1999; 19: 4644-4653Crossref PubMed Google Scholar Additionally, so-called ‘sleeping’ nociceptors can become activated after exposure to inflammation and other endogenous mediators, and might represent as much as 15% of all C-fibres, contributing to a significant increase in peripheral input to the CNS. Neuroplasticity, or the physical remodelling of neuronal cytoarchitecture, occurs shortly after the onset of persistent acute pain and leads to the transition from acute pain into a chronic pain state. As a result of a peripheral lesion that persistently generates pain impulses to the spinal cord, inhibitory interneurones responsible for modulating painful nerve transmission impulses eventually die. Furthermore, glial cells remodel neuronal synapses to intensify nociceptive transmission. These pain-transmitting neurones become more sensitive, react more intensely to stimuli, and grow more connections to second-order neurones within the CNS. In short, this process of neuroplasticity leads to central sensitization in which activity dependent phenotypic changes are seen in the dorsal horn neurones and other CNS structures, including higher centres.27Torebjork HE Lundberg LE LaMotte RH Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans.J Physiol. 1992; 448: 765-780Crossref PubMed Google Scholar Whereas primary hyperalgesia occurs in the periphery, secondary hyperalgesia occurs within the CNS and precedes long-term central sensitization. Most of the treatments for postoperative pain have only minimal analgesic effects on secondary hyperalgesia. As secondary hyperalgesia is felt to be a source for chronic postsurgical pain, developing agents to better treat secondary hyperalgesia might be more effective in preventing chronic postsurgical pain, and treating acute postoperative pain.28Eisenach JC Preventing chronic pain after surgery: who, how, and when?.Reg Anesth Pain Med. 2006; 31: 1-3PubMed Google Scholar 29Apfelbaum JL Chen C Mehta SS Gan TJ Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged.Anesth Analg. 2003; 97: 534-540Crossref PubMed Google Scholar The factors contributing to post-procedural pain can broadly be divided between patient and surgical factors. Patient factors include psychosocial status, pre-existing pain conditions, genetic predisposition to exaggerated pain response, and gender. Surgical factors include the type of anaesthesia administered (general vs regional technique) and surgical approach including the ability to identify and avoid nerve injury when possible. Additional surgical factors include the postoperative period and the type of pain treatment and duration, and full assessments of the pain, its consequences, and neurophysiological examination.30Kehlet H Rathmell JP Persistent postsurgical pain: the path forward through better design of clinical studies.Anesthesiology. 2010; 112: 514-515Crossref PubMed Scopus (0) Google Scholar, 31Granot M Can we predict persistent postoperative pain by testing preoperative experimental pain?.Curr Opin Anaesthesiol. 2009; 22: 425-430Crossref PubMed Scopus (0) Google Scholar, 32Kehlet H Jensen TS Woolf CJ Persistent postsurgical pain: risk factors and prevention.Lancet. 2006; 367: 1618-1625Abstract Full Text Full Text PDF PubMed Scopus (1442) Google Scholar The mechanisms of post-procedural pain and chronic post-surgical pain are complex and poorly understood. Many of the syndromes are, at least in part, neuropathic that result from neuroplastic changes after injury.33Macrae WA Chronic post-surgical pain: 10 years on.Br J Anaesth. 2008; 101: 77-86Crossref PubMed Scopus (338) Google Scholar After surgical intervention, patients experience ongoing pain or are sensitive to incidental, normally non-painful stimulation. This period of time varies, and with uncomplicated wound healing this pain progressively attenuates and disappears. The patient population with persistent post-surgical pain experience deep pain or referred pain that lasts months or years. The International Association for the Study of Pain defined post-procedural pain as a persistent pain state that is apparent more than two months after operation and cannot be explained by other causes. The nature and properties of this pain are poorly characterized, without a distinct transition period from acute to chronic pain. It is unclear whether the chronic condition constitutes merely an extension of perioperative pain.34Scholz J Yaksh TL Preclinical research on persistent postsurgical pain: what we don’t know, but should start studying.Anesthesiology. 2010; 112: 511-513Crossref PubMed Scopus (0) Google Scholar To give an example of the magnitude of the problem, after procedures such as thoracotomy, mastectomy, and amputation, as many as 50–70% of patients continue to experience pain for at least 6 months, with approximately 10% reporting severe pain.32Kehlet H Jensen TS Woolf CJ Persistent postsurgical pain: risk factors and prevention.Lancet. 2006; 367: 1618-1625Abstract Full Text Full Text PDF PubMed Scopus (1442) Google Scholar 35Dworkin RH McDermott MP Raja SN Preventing chronic postsurgical pain: how much of a difference makes a difference?.Anesthesiology. 2010; 112: 516-518Crossref PubMed Scopus (0) Google Scholar, 36Katz J Seltzer Z Transition from acute to chronic postsurgical pain: risk factors and protective factors.Expert Rev Neurother. 2009; 9: 723-744Crossref PubMed Scopus (254) Google Scholar, 37Gartner R Jensen MB Nielsen J Ewertz M Kroman N Kehlet H Prevalence of and factors associated with persistent pain following breast cancer surgery.JAMA. 2009; 302: 1985-1992Crossref PubMed Scopus (282) Google Scholar Post-procedural pain is also common 1 yr after lower abdominal surgery, sternotomy, hysterectomy, and herniorrhaphy with rates of 25% or greater.38Katz 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: 169-174Crossref PubMed Scopus (0) Google Scholar, 39Bruce J Poobalan AS Smith WC Chambers WA Quantitative assessment of chronic postsurgical pain using the McGill Pain Questionnaire.Clin J Pain. 2004; 20: 70-75Crossref PubMed Scopus (0) Google Scholar, 40Kalso E Mennander S Tasmuth T Nilsson E Chronic post-sternotomy pain.Acta Anaesthesiol Scand. 2001; 45: 935-939Crossref PubMed Scopus (0) Google Scholar, 41Bay-Nielsen M Perkins FM Kehlet H Pain and functional impairment 1 year after inguinal herniorrhaphy: a nationwide questionnaire study.Ann Surg. 2001; 233: 1-7Crossref PubMed Scopus (0) Google Scholar, 42Haythornthwaite JA Raja SN Fisher B Frank SM Brendler CB Shir Y Pain and quality of life following radical retropubic prostatectomy.J Urol. 1998; 160: 1761-1764Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 43Gottschalk A Smith DS Jobes DR et al.Preemptive epidural analgesia and recovery from radical prostatectomy: a randomized controlled trial.JAMA. 1998; 279: 1076-1082Crossref PubMed Scopus (0) Google Scholar This problem is not restricted to major surgeries; after minor procedures, approximately 5% of patients suffer severe chronic post-surgical pain.32Kehlet H Jensen TS Woolf CJ Persistent postsurgical pain: risk factors and prevention.Lancet. 2006; 367: 1618-1625Abstract Full Text Full Text PDF PubMed Scopus (1442) Google Scholar The wide variation in the incidence of chronic post-surgical pain is probably owing to differences in surgical techniques, study design, patient populations, and differing definitions of chronic pain.33Macrae WA Chronic post-surgical pain: 10 years on.Br J Anaesth. 2008; 101: 77-86Crossref PubMed Scopus (338) Google Scholar From the perspective of patient’s overall assessments of their health, even low levels of residual pain significantly affect social and physical function. From the perspective of the medical profession, it is encouraging that it is now recognized that ‘chronic pain is the most common and serious long-term problem after repair of an inguinal hernia,’ showing a heightened awareness of this important issue in the last decade.33Macrae WA Chronic post-surgical pain: 10 years on.Br J Anaesth. 2008; 101: 77-86Crossref PubMed Scopus (338) Google Scholar 44Jenkins JT O’Dwyer PJ Inguinal hernias.Br Med J. 2008; 336: 269-272Crossref PubMed Scopus (0) Google Scholar Surgery causes the release of inflammatory and other mediators. Initially, these mediators activate nociceptors, however during persistent pain nociceptors become sensitized. If this persistent pain resolves in the process of normal wound healing, this process of sensitization and facilitation of synaptic transmission to the CNS reverts to normal intrinsic nociceptor activity. For many surgery-related reasons, such as prolonged inflammatory states with the insertion of mesh materials or chronic nerve stretching in bunionectomy, this process of sensitization and facilitation can cause phenotypic and pathophysiological changes in nociceptors. These include changes in gene expression, receptor translocation to the cell membrane, sustained activation of inflammatory and glial cells, and spinal inhibition and facilitation. Once these structural changes occur, chronic pain pathophysiology becomes established. These changes are seen in animal models of incisional injury, which predisposes animals to enhanced pain sensitivity when a second injury is applied several weeks later.34Scholz J Yaksh TL Preclinical research on persistent postsurgical pain: what we don’t know, but should start studying.Anesthesiology. 2010; 112: 511-513Crossref PubMed Scopus (0) Google Scholar 45Walker SM Franck LS