When Does Acute Pain Become Chronic?

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Thus, in terms of central sensitization, the spinal cord junction of pain processing is an important crossroad receiving input from peripheral neurones, interneurones, astrocytes and microglia, and descending modulatorycontrols.

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 neurones sending the signal to the cerebral cortex where nociception is finally perceived as pain. Each process is controlled by a distinct set of proteins amenable to a wide variety of therapeutic interventions, some of which will be briefly reviewed below.

Being free nerve endings, nociceptors are essentially chemosensors, and react to cellular damage by responding to a wide range of molecules that include, but are not limited to, ATP, NGF, TNF-α, bradykinin, prostaglandin E2, serotonin, and protons (H+), being released by such cells as epithelial cells, mast cells, and macrophages. Given the abundance of ligands, and voltage gated ion channels, nociceptive transmission involves more than one voltage or ligand gated channel. 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 CGRP which will affect capillaries. Following tissue damage increases in the density of several transducers as well as phosphorylation of these tranducers, and activation of receptors such as TRPV1, results in an increased channel activity and sensitivity to noxious stimuli. For example, changes in the expression, trafficking, and redistribution of Na+ channels, after inflammation or nerve injury, are considered to account for unstable oscillations of membrane potential, abnormal firing, and the generation of ectopic activity in afferent nerves[9-11].

In addition, damaged neurones can begin to generate ongoing spontaneous ectopic acitivity, through accumulation and clustering of Na+ channels, and exhibit ephaptic transmission both between peripheral fibres and their cell bodies within the dorsal root ganglion. Moreover, along with changes within nociceptive fibres, sympathetic efferents become able to activate nociceptive fibres via poorly characterized α-adrenoceptors. In relation to this generation of spontaneous activity, the NaV 1.8 channel is thought to play a key role, because the knockdown of this receptor in mice produces a marked reduction in abnormal responsiveness.[12-13].Understanding this ability to sensitize, and the endogenous mediators and factors that contribute to sensitization in a synergistic fashion, though different among the various pain conditions such as inflammation or nerve injury, may provide us with a better understanding of how acute pain may transition to a chronic physiologic pain state. It is the hope that by blocking these receptors, acute pain will be attenuated or not develop at all, or, if a chronic pain state has already developed, that blockage of these receptors can ameliorate or even reverse such a pathophysiologic state.

However, it is important to note that the stimuli adequate for activation of nociceptors appearto 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 potassium channel [14]. Similar mechanisms of a decrease, or increase, in a specific ligand gated or voltage gated channel havebeen found in the sensitization process of other specific tissues [15-23]. Furthermore, so-called “sleeping” nociceptors can become activated after exposure to inflammation and other endogenous mediators, that .

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Neuroplasticity

Neuroplasticity, or the physical remodeling of neuronal cytoarchitecture, occurs shortly after the onset of persistent acute pain and forms the connection between acute pain transforming into a chronic pain state. As a result of a peripheral lesion that persistently generates pain impulses to the spinal cord, inhibitory interneurones, that are responsible for modulating painful nerve transmission impulses eventually die. Furthermore, glial cells remodel neuronal synapses to intensify nociceptive transmission. Lastly, these pain transmitting neurones become more sensitive, react more intensely to stimuli, and grow more connections to second order nerves 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 centers [24].

Whereas primary hyperalgesia occurs in the periphery, secondary hyperalgesia occurs within the CNS, and is the precedent to the formation of longer term central sensitization changes. Most of the treatments employed to treat postoperative pain have only slight analgesic effects on secondary hyperalgesia. Since secondary hyperalgesia is felt to be a source for chronic postsurgical pain, developing agents to better treat secondary hyperalgesia may prove to be not only more effective in preventing chronic postsurgical pain, but also acute post-operative pain[25-26].

What Kind of Acute Pain? Post-op, Trauma, and Neuropathic

In general, when looking at post-procedural pain, the factors 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 related factors include the type of anaesthesia administered (general vs. regional technique), surgical approach including the ability to identify and avoid nerves in the region or resultant nerve injury when not possible. Additional surgical factors include the postoperative period and the resultant type of pain treatment and duration, and full assessments of the pain, its consequences, and neurophysiologic examination. [27-29].

Post-Procedural Pain (PPP) and Trauma Pain

The mechanisms of PPP and chronic post surgical pain (CPSP) are complex and poorly understood. After surgical intervention, patients experience ongoing pain, or are sensitive to incidental, normally nonpainful stimulation. This period of time varies, however, and with uncomplicated wound healing, this pain progressively attenuatesand disappears. The patient population with a persistent post surgical pain experience, deep pain or referred pain that lasts months or years, has a reported incidence between 5-50% after diverse surgical

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