- Email: [email protected]
Pathophysiology of neuropathic pain
Pathophysiology of Neuropathic Pain yyy Chris Pasero, MS, RN, FAAN
y
ABSTRACT:
Neuropathic pain is caused by damage to the nervous system. Unlike physiologic pain (also known as nociceptive pain), neuropathic pain is not self-limited and is not as easily treated. The etiologic causes of neuropathic pain are many and varied in their scope. These include infectious agents, metabolic disease, neurodegenerative disease, and physical trauma, among others. Clinically, a high degree of variability exists between patients in their response to treatment. The pathophysiology of neuropathic pain syndromes is complex. However, current research is rapidly expanding our understanding of these syndromes. Numerous cellular mechanisms of pain transmission have been elucidated, and the clinical correlates of these mechanisms are beginning to be recognized. As our knowledge base continues to grow, we anticipate the development of improved treatments for the benefit of our patients with pain. © 2004 by the American Society for Pain Management Nursing
From El Dorado Hills, CA. Address correspondence and reprint requests to Chris Pasero, MS, RN, FAAN, Pain Management Educator and Clinical Consultant, 1252 Clearview Drive, El Dorado Hills, CA 95762. e-mail: [email protected] 1524-9042/$30.00 © 2004 by the American Society for Pain Management Nursing doi:10.1016/j.pmn.2004.10.002
Physiologic pain is caused by normal activation of primary afferent neurons known as nociceptors and a subsequent inflammatory response in the peripheral nervous system after tissue damage. Postoperative pain caused by a surgical incision is one example of physiologic pain. Neuropathic pain, on the other hand, is thought to arise from abnormal physiology of the peripheral or central nervous systems and may be unrelated to ongoing tissue damage or inflammation (Dworkin et al., 2003). Some patients with neuropathic pain may have severe pain without clinical signs of nerve injury, whereas others may have significant nerve injury with no pain. In addition, neuropathic pain may be precipitated by a relatively minor physical insult, and the severity of pain may be much greater than the extent of damage might suggest. The reasons for these phenomena are unclear. The prevalence of neuropathic pain is still unknown. Current estimates are that 1.5% of individuals in the United States and 1% of those in the United Kingdom experience some form of neuropathic pain (Chong & Bajwa, 2003). These rates are considered underestimates because neuropathic pain is often not recognized or reported as such in relation to many disease conditions. Certain individuals are more likely to be affected by neuropathic pain than the general population, for example, those with diabetes, herpes zoster, or spinal cord injury. Postherpetic neuralgia (PHN) and painful diabetic neuropathy (PDN) are two types of neuropathic pain commonly seen in the elderly population. It is estimated that in the United States, up to 1 million people have PHN (Bowsher, 1999) and 3 million have PDN (Schmader, 2002). Pain Management Nursing, Vol 5, No 4, suppl 1 (December), 2004: pp 3-8
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Chris Pasero
NOCICEPTION Nociception is the term used to describe normal pain transmission and sensation. Pain is the result and conscious experience of nociception (Portenoy & Kanner, 1996). A basic understanding of nociception is necessary to understand the mechanisms involved in the development and maintenance of neuropathic pain. Nociception is often discussed as four processes: transduction, transmission, modulation, and perception. An overview of these processes is presented below. Transduction, the first process of nociception, begins in the periphery (skin, subcutaneous tissue, visceral or somatic structures) where primary afferent neurons (free nerve endings) called nociceptors are widely distributed. Nociceptors respond to mechanical, thermal, or chemical noxious stimuli. Tissue damage occurs when tissues are exposed in sufficient quantity to these stimuli. This damage induces the release of a number of substances (e.g., prostaglandins, bradykinin, and substance P) that facilitate the transmission of pain from the periphery to the spinal cord (Pasero, Paice, & McCaffery, 1999). Simply put, transduction is the cellular process by which noxious stimuli are changed into the electrical energy necessary to transmit pain (Fine & Ashburn, 1998). Transmission of the pain impulse along the nociceptor fibers (nerve axons) begins when transduction is complete. Two types of nociceptor fibers, C-fibers and A-␦ fibers, transmit pain from the site of transduction (periphery) to the spinal cord. C-fibers are unmyelinated, small-diameter, slow-conducting fibers, which transmit pain that is poorly localized, dull, and aching. A-␦ fibers are thinly myelinated, large-diameter, fast-conducting fibers, which transmit well-localized sharp pain. During the first segment of transmission, the impulse is carried along nociceptor fibers in an ascending fashion to the dorsal horn of the spinal cord. This is followed by transmission from the spinal cord to the brain stem and thalamus. The thalamus, acting as a relay station, sends the impulse to the cortex where it can be processed (Pasero et al., 1999). Modulation (inhibition and alteration) of pain transmission occurs at several locations within the central nervous system (Fine & Ashburn, 1998). The neuronal pathways involved in modulation are often referred to as the descending pain system because they originate in the brain stem and descend to the dorsal horn of the spinal cord (Portenoy & Kanner, 1996). These descending pathways release substances, such as endogenous opioids, serotonin (5HT), and norepinephrine (NE), which can inhibit the transmission of noxious stimuli and produce analgesia (Pasero et al., 1999).
TABLE 1. Characteristics of Physiologic Pain and Neuropathic Pain Physiologic pain ● Caused by activation of nociceptors (e.g., thermal, chemical, mechanical or inflammatory stimuli) ● Warns and protects the individual against injury ● Subsides with time Neuropathic pain ● Caused by damage to the central or peripheral nervous system or both ● Serves no useful purpose ● Is usually sustained and chronic
Perception of pain is the outcome of the neural activity of pain transduction, transmission, and modulation, and is influenced by behavioral and emotional factors (Siddall & Cousins, 1997). It is the subjective experience of pain (Fine & Ashburn, 1998). The perception of pain is thought to occur in the cortical structures (Fine & Ashburn, 1998). However, the exact location in the brain where pain becomes a conscious experience and the reasons individuals vary in their subjective experience of pain are unclear (Pasero et al., 1999).
NEUROPATHIC PAIN Neuropathic pain (also known as pathophysiologic pain) is different from physiologic pain in many ways (Table 1). As described, physiologic pain results from the activation of peripheral nociceptors in acutely injured and inflamed tissue and normally subsides with time; when noxious stimulation ceases, pain also ceases (Backonja, 2003; Beydoun & Backonja, 2003). Neuropathic pain, on the other hand, occurs when the peripheral nervous system, central nervous system, or both are damaged, which results in abnormal processing of sensory input (Dworkin et al., 2003; Pasero et al., 1999). These pathophysiologic changes result in pain that occurs spontaneously or in response to the environment and is usually sustained and chronic (Beydoun & Backonja, 2003; Dworkin et al., 2003). Unlike physiologic pain, which serves to warn and protect individuals from possible or actual injury, neuropathic pain serves no useful purpose (Beydoun & Backonja, 2003; Pasero et al., 1999). The mechanisms underlying neuropathic pain are not completely understood but are considered to be complex, multifactoral, and to evolve over time (Beydoun & Backonja, 2003; Dworkin et al., 2003). There are numerous causes of nervous system injury (Table 2), including exposure to toxins, infection, viruses, meta-
Pathophysiology of Neuropathic Pain
TABLE 2. Examples of Neuropathic Pain Syndromes Peripheral Alcoholic polyneuropathy Chemotherapy-induced neuropathy Complex regional pain syndrome Diabetic peripheral neuropathy Entrapment neuropathies (e.g., carpal tunnel syndrome) HIV sensory neuropathy Neuropathy secondary to tumor infiltration Phantom limb pain Postherpetic neuralgia Postmastectomy pain Radiculopathy (cervical, thoracic, or lumbosacral) Trigeminal neuralgia Central Compressive myelopathy from spinal stenosis HIV myelopathy Multiple sclerosis pain Parkinson disease pain Poststroke pain Spinal cord injury pain Syringomyelia Note: HIV ⫽ human immunodeficiency virus. Adapted from: (1) Dworkin, R.H. (2002). An overview of neuropathic pain: syndromes, signs, and several mechanisms. Clinical Journal of Pain, 18, 343–349. (2) Dworkin, R.H., Backonja, M., Rowbotham, M.C., Allen, R.R., Argoff, C.R., Bennett, et al. (2003). Advances in neuropathic pain. Diagnosis, mechanisms and treatment recommendations. Archives of Neurology, 60, 1524 –1534.
bolic disease, nutritional deficiencies, ischemia, trauma (surgical and nonsurgical), and stroke. Current research studies indicate that neuropathic pain results from cellular changes that occur in both the peripheral and central nervous systems, which result in sensitization to the transmission of pain signals. This ability of neurons throughout the peripheral and central nervous systems to change their structure and function because of nociceptive input is referred to as neuroplasticity (Arnstein, 1997; Byers & Bonica, 2001; Siddall & Cousins, 1997). Clinically, these changes may be related to symptoms of neuropathic pain (Table 3).
PERIPHERAL MECHANISMS After an injury in the peripheral nervous system, chemicals are released from damaged cells and inflammatory cells (e.g., mast cells, lymphocytes) (Siddall & Cousins, 1997). A partial list of these chemicals includes noradrenaline, bradykinin, histamine, prostaglandins, potassium, cytokines, NE, 5HT, and neuropeptides. These cellular mediators act to sensitize nociceptors to further neural input (Nicholson, 2000). This produces changes in the number and location of ion channels— especially sodium ion channels—in in-
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jured nociceptor nerve fibers and their dorsal root ganglia (Beydoun & Backonja, 2003). As a result, the threshold for depolarization is lowered and spontaneous discharges known as ectopic discharges can occur in abnormal locations. Consequently, the response of nociceptors to thermal and mechanical stimuli is increased, a phenomenon known as peripheral sensitization (Beydoun & Backonja, 2003; Nicholson, 2000). In some disease processes, nerve demyelination from diminished blood supply may also contribute to the production of ectopic discharges along the nerve fiber (Siddall & Cousins, 1997). Under normal conditions, adjacent nerve fibers are isolated from one another (Amir & Devor, 1996; Patil & Campbell, 2001). However, persistent neural activity and changes that occur because of nerve injury can cause chemically mediated electrical connections between injured nerve fibers and nearby uninjured fibers. It is thought that this transmission, known as ephaptic conduction (“cross excitation” or “cross talk”), causes nonpainful stimuli to evoke activity in these normally “silent” nociceptors and thereby produce pain (Bridges, Thompson, & Rice, 2001; Patil & Campbell, 2001; Siddall & Cousins, 1997). Hyperalgesia (an increased sensation of pain in response to a normally painful stimulus) is sometimes seen clinically in patients with pain. Currently, it is thought that peripheral sensitization, mediated through C-fiber primary afferent neurons, is the mechanism responsible for hyperalgesia (Byers & Bonica, 2001). These changes are sometimes evident as spontaneous pain in the clinical setting (Siddall & Cousins, 1997; Woolf & Chong, 1993). Sensations of burning pain may be the result of continuous discharge in C-fibers, whereas dysesthesias (unpleasant abnormal sensations) and paresthesias (abnormal sensations) may arise from intermittent spontaneous discharges in A-␦ or A- fibers (Rowbotham & Petersen, 2001). Another peripheral mechanism undergoing extensive research is sympathetic sensory coupling (Attal, 2000; Bridges et al., 2001). It has been noted in clinical practice that neuropathic pain in a small subset of patients seems to be dependent on the sympathetic nervous system (e.g., complex regional pain syndrome type 1). This is sometimes referred to as sympathetically maintained pain. Although not completely understood in terms of when and why this occurs, an abnormal connection between the sympathetic nervous system and the sensory nervous system may be the underlying cause of this type of pain (Bridges et al., 2001). Several drugs that are effective for neuropathic pain act by modulation of sodium channels, which suppress ectopic discharges that contribute to peripheral sensitization. These include certain anticonvulsant
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Chris Pasero
TABLE 3. Possible Mechanisms of Neuropathic Pain Peripheral mechanisms ● Peripheral sensitization initiated by release of chemicals from damaged cells and inflammatory cells (e.g., bradykinin, prostaglandins, 5HT, NE, leukotrienes, cytokines) ● Ion channels are altered as to their number and location (e.g., sodium, calcium channels) - lowered threshold for depolarization - ectopic and spontaneous discharges occur - increased responsiveness to mechanical and chemical stimuli ● Collateral sprouting of primary afferent neurons ● Recruitment of “silent” nociceptors ● Coupling between the sympathetic nervous system and sensory nervous system ● Clinical correlates include hyperalgesia, burning pain, dysesthesias, paresthesias Central mechanisms ● Initiated by tachykinin and neurotransmitter release from peripheral nociceptors (e.g., substance P, neurokinin A, glutamate, calcitonin gene-related peptide, gamma-aminobutyric acid)-NMDA receptor is activated ● Intracellular calcium is increased ● “Wind-up” occurs in spinal dorsal horn neurons - lower activation threshold - increased response to stimuli - larger receptive field ● Ephaptic conduction (“cross excitation” or “cross talk”) occurs between neurons ● Neuronal reorganization occurs (sprouting of spinal cord neurons into new locations) ● Central disinhibition ● Clinical correlates include allodynia, secondary hyperalgesia, sympathetically maintained pain Note: 5HT ⫽ 5-hydroxytryptamine (serotonin); NE ⫽ norepinephrine; NMDA ⫽ N-methyl-D-aspartate.
drugs (e.g., carbamazepine, oxcarbazepine), local anesthetics (e.g., lidocaine, mexiletine), and tricyclic antidepressants (e.g., desipramine, nortriptyline) (Beydoun & Backonja, 2003).
CENTRAL MECHANISMS Peripheral mechanisms alone cannot explain all of the characteristics of neuropathic pain; central mechanisms play a critical role as well (Attal, 2000). A key process known as central sensitization, which is the abnormal hyperexcitability of central nociceptor neurons, is thought to occur in the spinal cord because of peripheral injury and the release of tachykinins and neurotransmitters. Tachykinins include the neuropeptides substance P and neurokinin A (Beydoun & Backonja, 2003). Neurotransmitters include glutamate, calcitonin gene-related peptide, and ␥-aminobutyric acid (GABA). Prolonged release and binding of these substances to neural receptors activate the N-methyl-D-aspartate (NMDA) receptor, which causes an increase in intracellular calcium levels (Siddall & Cousins, 1997). The increase in calcium levels is believed to occur through N-type calcium channels (Xiao & Bennett, 1995), one of several calcium channels in the central nervous system, and is considered important to the maintenance of central sensitization (Bridges et al., 2001; Nicholson, 2000). These changes, in turn,
lead to a series of biochemical reactions in dorsal horn neurons. The threshold for activation is lowered, the response to stimuli is increased (in both magnitude and duration), and the size of the receptive field is enlarged (a greater area on the neuron surface is available to receive stimuli) (Beydoun & Backonja, 2003). Collectively, these changes result in a phenomenon known as “wind-up,” an increased excitability and sensitivity of spinal cord neurons. Another central mechanism thought to contribute to the development and maintenance of neuropathic pain is called central disinhibition, which occurs when control mechanisms along inhibitory (modulatory) pathways are lost or suppressed. This, in turn, causes abnormal excitability of central neurons (Attal, 2000; Bridges et al., 2001). Clinically, central sensitization and disinhibition, together with peripheral changes, are believed to account for allodynia, a feature of some neuropathic pain states (e.g., PHN) (Bridges et al., 2001; Woolf, 1983). Allodynia is a clinical term that describes pain due to a stimulus that does not normally provoke pain (e.g., the friction of clothing rubbing against the skin). Normally, A- fibers produce the sensation of touch when stimulated. However, these same fibers can produce the sensation of intense pain in some individuals with neuropathic pain (Dworkin, 2002; Nicholson, 2000). Several theories cur-
Pathophysiology of Neuropathic Pain
rently exist to explain allodynia. A lower threshold for sensory input in central neurons may play a role (Siddall & Cousins, 1997; Bridges et al., 2001), as well as a decrease in the central inhibition of nociceptive input (Bridges et al., 2001; Meyer, Campbell, & Raja, 1985). Other abnormalities in neuron organization may also occur. For example, after a peripheral nerve injury, lowthreshold mechanoreceptors have been shown to sprout from deep laminae of the spinal cord, forming synapses in more superficial laminae (laminae I and II) of the dorsal horn (Attal, 2000; Beydoun & Backonja, 2003; Woolf, Shortland, & Coggeshall, 1992). Potentially, this might contribute to an increased sensitivity to pressure (i.e., mechanical allodynia). As previously mentioned, hyperalgesia, or increased sensitivity to stimuli that are normally painful, is common in individuals with pain. Two types of hyperalgesia are frequently described—primary hyperalgesia, which is increased pain and sensitivity at the site of injury; and secondary hyperalgesia, which is increased sensitivity and pain in uninjured tissue that surrounds the site of injury. Whereas primary hyperalgesia is thought to be the result of peripheral changes that occur after tissue damage, secondary hyperalgesia, as with allodynia, is thought to result from events that occur within the dorsal horn of the spinal cord after injury (Byers & Bonica, 2001; Siddall & Cousins, 1997). Several drugs used to treat neuropathic pain have effects in the central nervous system on the levels of calcium, 5HT, and NE, all of which may be important in the central modulation of nociceptive input. Ziconotide is a drug that is administered intrathecally, which specifically antagonizes the N-type calcium channel and can produce pain relief in some patients with neuropathic pain. The anticonvulsant drugs carbamazepine, oxcarbazepine, levetiracetam, and lamotrigine also inhibit N-type calcium channels. In addition, oxcarbazepine and lamotrigine modulate sodium channels. The exact mechanism of analgesic action of gabapentin is unknown. However, research shows that although it does not modify sodium channels, gabapentin does interact with neuronal calcium channels (Nicholson, 2000; Rowbotham & Petersen, 2001; Sindrup & Jensen, 1999). Lidocaine, which is administered both topically and systemically, is a sodium channel blocker that alters membrane permeability. Tricyclic antidepressants are often prescribed for neuropathic pain and may act both peripherally and centrally. Peripherally, they are believed to modulate sodium channels and, centrally, neurotransmitter levels (e.g., 5HT, NE). Opioids act primarily through central
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mechanisms and have a variety of effects, including closure of calcium channels, which reduces the release of key neurotransmitters involved in the transmission of pain (e.g., substance P, NE, 5HT, glutamate). Tramadol, a synthetic analgesic, inhibits both 5HT and NE reuptake and has opioid agonist properties as well (Beydoun & Backonja, 2003).
CONCLUSIONS Our current understanding of neuropathic pain suggests that sensitization mechanisms, both central and peripheral, may contribute to the generation of spontaneous and evoked pain, including hyperalgesia and allodynia (Lynch, Clark, & Sawynok, 2003). Several cellular processes contribute to the pathogenesis of neuropathic pain. It is thought that different mechanisms are involved in painful (e.g., hyperalgesia, allodynia) and nonpainful responses (e.g., dysesthesias, paresthesias) to different stimuli. Namely, C-fibers and A-␦ fibers are normally activated by painful stimuli, whereas A- fiber mechanoreceptors are normally activated by nonpainful mechanical stimuli. Normally, peripheral and central sensitization phenomena dissipate as tissue heals and inflammation subsides. However, when changes in primary afferent function persist after disease or injury of the nervous system, these processes may continue and result in neuropathic pain. In clinical practice, a large variability exists among patients with neuropathic pain. Two patients with the same diagnosis may show different physical findings and symptoms and may have different individual responses to drug treatment. Conversely, two patients with different diagnoses may respond to the same drug. For example, in two patients with PHN, one patient may have spontaneous burning pain, caused by peripheral sensitization, and another patient may have mechanical allodynia, caused by central reorganization. It would be expected that these two patients each require a different drug for treatment. On the other hand, two patients— one with PHN (caused by a virus) and one with PDN (caused by ischemia)—might both have spontaneous burning pain. It is possible that these two patients would respond to the same drug. The multiple mechanisms and mediators involved in the pathogenesis of neuropathic pain indicate many possible treatment targets. Our current understanding is evolving and suggests that different pain mechanisms may explain the variability seen among patients.
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REFERENCES Amir, R., & Devor, M. (1996). Chemically mediated cross excitation in rat dorsal root ganglia. Journal of Neuroscience, 16, 4733-4741. Arnstein, P. (1997). A neuroplastic phenomenon: A physiologic link between chronic pain and learning. Journal of Neuroscience Nursing, 29, 179-186. Attal, N. (2000). Chronic neuropathic pain: Mechanisms and treatment. Clinical Journal of Pain, 16, S118-S130. Backonja, M-M. (2003). Defining neuropathic pain. Anesthesia and Analgesia, 97, 785-790. Beydoun, A., & Backonja, M-M. (2003). Mechanistic stratification of antineuralgic agents. Journal of Pain and Symptom Management, 25, S18-S30. Bowsher, D. (1999). The lifetime occurrence of herpes zoster and prevalence of postherpetic neuralgia: A retrospective survey in an elderly population. European Journal of Pain, 3, 335-342. Bridges, D., Thompson, S. W. N., & Rice, A. S. C. (2001). Mechanisms of neuropathic pain. British Journal of Anaesthesia, 87, 12-26. Byers, M. R., & Bonica, J. J. (2001). Peripheral pain mechanisms and nociceptor plasticity. In J. D. Loeser, S. H. Butler, R. C. Chapman, & D. C. Turk (Eds.), Bonica’s management of pain (3rd ed., pp. 26-72). Philadelphia: Lippincott Williams & Wilkins. Chong, M. S., & Bajwa, Z. H. (2003). Diagnosis and treatment of neuropathic pain. Journal of Pain and Symptom Management, 25, S4-S11. Dworkin, R. H. (2002). An overview of neuropathic pain: Syndromes, signs, and several mechanisms. Clinical Journal of Pain, 18, 343-349. Dworkin, R. H., Backonja, M., Rowbotham, M. C., Allen, R. R., Argoff, C. R., Bennett, et al. (2003). Advances in neuropathic pain. Diagnosis, mechanisms and treatment recommendations. Archives of Neurology, 60, 1524-1534. Fine, P. G., & Ashburn, M. A. (1998). Functional neuroanatomy and nociception. In M. A. Ashburn & L. J. Rice (Eds.), The management of pain. (pp. 1-16). New York: Churchill Livingstone. Lynch, M. E., Clark, A. J., & Sawynok, J. (2003). A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain. Clinical Journal of Pain, 19, 323-328. Meyer, R. A., Campbell, J. N., & Raja, S. N. (1985). Peripheral neural mechanisms of cutaneous hyperalgesia. In H. L. Fields, R. S. Dubner, & F. Cervero (Eds.), Advances
in pain research and therapy, Vol. 9. (pp. 53-71). New York: Raven. Nicholson, B. (2000). Gabapentin use in neuropathic pain syndromes. Acta Neurologica Scandinavica, 101, 359-371. Pasero, C., Paice, J., & McCaffery, M. (1999). Basic mechanisms underlying the causes and effects of pain. In M. McCaffery & C. Pasero, Pain: clinical manual (2nd ed., pp. 18-34). St. Louis, MO: Mosby. Patil, P. G., & Campbell, J. N (2001). Lesions of primary afferents and sympathetic efferents as treatments for pain. In J. D. Loeser, S. H. Butler, R. C. Chapman, & D. C. Turk (Eds.), Bonica’s management of pain (3rd ed., pp. 20112022). Philadelphia: Lippincott Williams & Wilkins. Portenoy, R. K., & Kanner, R. M. (1996). Definition and assessment of pain. In R. K. Portenoy & R. M. Kanner (Eds.), Pain management: theory and practice (pp. 3-18). Philadelphia: F. A. Davis. Rowbotham, M. C., & Petersen, K. L. (2001). Anticonvulsants and local anesthetic drugs. In J. D. Loeser, S. H. Butler, R. C. Chapman, & D. C. Turk (Eds.), Bonica’s management of pain (3rd ed., pp. 1727-1735). Philadelphia: Lippincott Williams &; Wilkins. Schmader, K. E. (2002). Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy. Clinical Journal of Pain 18, 350-354. Siddall, P. J., & Cousins, M. J. (1997). Spine update: Spinal pain mechanisms. Spine, 22, 98-104. Sindrup, S. H., & Jensen, T. S. (1999). Efficacy of pharmacological treatments of neuropathic pain: An update and effect related to mechanism of drug action. Pain, 83, 389-400. Woolf, C. J. (1983). Evidence for central component of post-injury pain. Nature, 306, 686-688. Woolf, C. J., & Chong, M-S. (1993). Preemptive analgesia: Treating postoperative pain by preventing the establishment of central sensitization. Anesthesia and Analgesia, 77, 1-18. Woolf, C. J., Shortland, P., & Coggeshall, E. (1992). Peripheral nerve injury triggers central sprouting of myelinated afferents. Nature, 355, 75-78. Xiao, W. H., & Bennett, G. J. (1995). Synthetic omegaconopeptides applied to the site of injury suppress neuropathic pain in rats. Journal of Pharmacology and Experimental Therapeutics, 274, 666-672.
y
ABSTRACT:
Neuropathic pain is caused by damage to the nervous system. Unlike physiologic pain (also known as nociceptive pain), neuropathic pain is not self-limited and is not as easily treated. The etiologic causes of neuropathic pain are many and varied in their scope. These include infectious agents, metabolic disease, neurodegenerative disease, and physical trauma, among others. Clinically, a high degree of variability exists between patients in their response to treatment. The pathophysiology of neuropathic pain syndromes is complex. However, current research is rapidly expanding our understanding of these syndromes. Numerous cellular mechanisms of pain transmission have been elucidated, and the clinical correlates of these mechanisms are beginning to be recognized. As our knowledge base continues to grow, we anticipate the development of improved treatments for the benefit of our patients with pain. © 2004 by the American Society for Pain Management Nursing
From El Dorado Hills, CA. Address correspondence and reprint requests to Chris Pasero, MS, RN, FAAN, Pain Management Educator and Clinical Consultant, 1252 Clearview Drive, El Dorado Hills, CA 95762. e-mail: [email protected] 1524-9042/$30.00 © 2004 by the American Society for Pain Management Nursing doi:10.1016/j.pmn.2004.10.002
Physiologic pain is caused by normal activation of primary afferent neurons known as nociceptors and a subsequent inflammatory response in the peripheral nervous system after tissue damage. Postoperative pain caused by a surgical incision is one example of physiologic pain. Neuropathic pain, on the other hand, is thought to arise from abnormal physiology of the peripheral or central nervous systems and may be unrelated to ongoing tissue damage or inflammation (Dworkin et al., 2003). Some patients with neuropathic pain may have severe pain without clinical signs of nerve injury, whereas others may have significant nerve injury with no pain. In addition, neuropathic pain may be precipitated by a relatively minor physical insult, and the severity of pain may be much greater than the extent of damage might suggest. The reasons for these phenomena are unclear. The prevalence of neuropathic pain is still unknown. Current estimates are that 1.5% of individuals in the United States and 1% of those in the United Kingdom experience some form of neuropathic pain (Chong & Bajwa, 2003). These rates are considered underestimates because neuropathic pain is often not recognized or reported as such in relation to many disease conditions. Certain individuals are more likely to be affected by neuropathic pain than the general population, for example, those with diabetes, herpes zoster, or spinal cord injury. Postherpetic neuralgia (PHN) and painful diabetic neuropathy (PDN) are two types of neuropathic pain commonly seen in the elderly population. It is estimated that in the United States, up to 1 million people have PHN (Bowsher, 1999) and 3 million have PDN (Schmader, 2002). Pain Management Nursing, Vol 5, No 4, suppl 1 (December), 2004: pp 3-8
4
Chris Pasero
NOCICEPTION Nociception is the term used to describe normal pain transmission and sensation. Pain is the result and conscious experience of nociception (Portenoy & Kanner, 1996). A basic understanding of nociception is necessary to understand the mechanisms involved in the development and maintenance of neuropathic pain. Nociception is often discussed as four processes: transduction, transmission, modulation, and perception. An overview of these processes is presented below. Transduction, the first process of nociception, begins in the periphery (skin, subcutaneous tissue, visceral or somatic structures) where primary afferent neurons (free nerve endings) called nociceptors are widely distributed. Nociceptors respond to mechanical, thermal, or chemical noxious stimuli. Tissue damage occurs when tissues are exposed in sufficient quantity to these stimuli. This damage induces the release of a number of substances (e.g., prostaglandins, bradykinin, and substance P) that facilitate the transmission of pain from the periphery to the spinal cord (Pasero, Paice, & McCaffery, 1999). Simply put, transduction is the cellular process by which noxious stimuli are changed into the electrical energy necessary to transmit pain (Fine & Ashburn, 1998). Transmission of the pain impulse along the nociceptor fibers (nerve axons) begins when transduction is complete. Two types of nociceptor fibers, C-fibers and A-␦ fibers, transmit pain from the site of transduction (periphery) to the spinal cord. C-fibers are unmyelinated, small-diameter, slow-conducting fibers, which transmit pain that is poorly localized, dull, and aching. A-␦ fibers are thinly myelinated, large-diameter, fast-conducting fibers, which transmit well-localized sharp pain. During the first segment of transmission, the impulse is carried along nociceptor fibers in an ascending fashion to the dorsal horn of the spinal cord. This is followed by transmission from the spinal cord to the brain stem and thalamus. The thalamus, acting as a relay station, sends the impulse to the cortex where it can be processed (Pasero et al., 1999). Modulation (inhibition and alteration) of pain transmission occurs at several locations within the central nervous system (Fine & Ashburn, 1998). The neuronal pathways involved in modulation are often referred to as the descending pain system because they originate in the brain stem and descend to the dorsal horn of the spinal cord (Portenoy & Kanner, 1996). These descending pathways release substances, such as endogenous opioids, serotonin (5HT), and norepinephrine (NE), which can inhibit the transmission of noxious stimuli and produce analgesia (Pasero et al., 1999).
TABLE 1. Characteristics of Physiologic Pain and Neuropathic Pain Physiologic pain ● Caused by activation of nociceptors (e.g., thermal, chemical, mechanical or inflammatory stimuli) ● Warns and protects the individual against injury ● Subsides with time Neuropathic pain ● Caused by damage to the central or peripheral nervous system or both ● Serves no useful purpose ● Is usually sustained and chronic
Perception of pain is the outcome of the neural activity of pain transduction, transmission, and modulation, and is influenced by behavioral and emotional factors (Siddall & Cousins, 1997). It is the subjective experience of pain (Fine & Ashburn, 1998). The perception of pain is thought to occur in the cortical structures (Fine & Ashburn, 1998). However, the exact location in the brain where pain becomes a conscious experience and the reasons individuals vary in their subjective experience of pain are unclear (Pasero et al., 1999).
NEUROPATHIC PAIN Neuropathic pain (also known as pathophysiologic pain) is different from physiologic pain in many ways (Table 1). As described, physiologic pain results from the activation of peripheral nociceptors in acutely injured and inflamed tissue and normally subsides with time; when noxious stimulation ceases, pain also ceases (Backonja, 2003; Beydoun & Backonja, 2003). Neuropathic pain, on the other hand, occurs when the peripheral nervous system, central nervous system, or both are damaged, which results in abnormal processing of sensory input (Dworkin et al., 2003; Pasero et al., 1999). These pathophysiologic changes result in pain that occurs spontaneously or in response to the environment and is usually sustained and chronic (Beydoun & Backonja, 2003; Dworkin et al., 2003). Unlike physiologic pain, which serves to warn and protect individuals from possible or actual injury, neuropathic pain serves no useful purpose (Beydoun & Backonja, 2003; Pasero et al., 1999). The mechanisms underlying neuropathic pain are not completely understood but are considered to be complex, multifactoral, and to evolve over time (Beydoun & Backonja, 2003; Dworkin et al., 2003). There are numerous causes of nervous system injury (Table 2), including exposure to toxins, infection, viruses, meta-
Pathophysiology of Neuropathic Pain
TABLE 2. Examples of Neuropathic Pain Syndromes Peripheral Alcoholic polyneuropathy Chemotherapy-induced neuropathy Complex regional pain syndrome Diabetic peripheral neuropathy Entrapment neuropathies (e.g., carpal tunnel syndrome) HIV sensory neuropathy Neuropathy secondary to tumor infiltration Phantom limb pain Postherpetic neuralgia Postmastectomy pain Radiculopathy (cervical, thoracic, or lumbosacral) Trigeminal neuralgia Central Compressive myelopathy from spinal stenosis HIV myelopathy Multiple sclerosis pain Parkinson disease pain Poststroke pain Spinal cord injury pain Syringomyelia Note: HIV ⫽ human immunodeficiency virus. Adapted from: (1) Dworkin, R.H. (2002). An overview of neuropathic pain: syndromes, signs, and several mechanisms. Clinical Journal of Pain, 18, 343–349. (2) Dworkin, R.H., Backonja, M., Rowbotham, M.C., Allen, R.R., Argoff, C.R., Bennett, et al. (2003). Advances in neuropathic pain. Diagnosis, mechanisms and treatment recommendations. Archives of Neurology, 60, 1524 –1534.
bolic disease, nutritional deficiencies, ischemia, trauma (surgical and nonsurgical), and stroke. Current research studies indicate that neuropathic pain results from cellular changes that occur in both the peripheral and central nervous systems, which result in sensitization to the transmission of pain signals. This ability of neurons throughout the peripheral and central nervous systems to change their structure and function because of nociceptive input is referred to as neuroplasticity (Arnstein, 1997; Byers & Bonica, 2001; Siddall & Cousins, 1997). Clinically, these changes may be related to symptoms of neuropathic pain (Table 3).
PERIPHERAL MECHANISMS After an injury in the peripheral nervous system, chemicals are released from damaged cells and inflammatory cells (e.g., mast cells, lymphocytes) (Siddall & Cousins, 1997). A partial list of these chemicals includes noradrenaline, bradykinin, histamine, prostaglandins, potassium, cytokines, NE, 5HT, and neuropeptides. These cellular mediators act to sensitize nociceptors to further neural input (Nicholson, 2000). This produces changes in the number and location of ion channels— especially sodium ion channels—in in-
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jured nociceptor nerve fibers and their dorsal root ganglia (Beydoun & Backonja, 2003). As a result, the threshold for depolarization is lowered and spontaneous discharges known as ectopic discharges can occur in abnormal locations. Consequently, the response of nociceptors to thermal and mechanical stimuli is increased, a phenomenon known as peripheral sensitization (Beydoun & Backonja, 2003; Nicholson, 2000). In some disease processes, nerve demyelination from diminished blood supply may also contribute to the production of ectopic discharges along the nerve fiber (Siddall & Cousins, 1997). Under normal conditions, adjacent nerve fibers are isolated from one another (Amir & Devor, 1996; Patil & Campbell, 2001). However, persistent neural activity and changes that occur because of nerve injury can cause chemically mediated electrical connections between injured nerve fibers and nearby uninjured fibers. It is thought that this transmission, known as ephaptic conduction (“cross excitation” or “cross talk”), causes nonpainful stimuli to evoke activity in these normally “silent” nociceptors and thereby produce pain (Bridges, Thompson, & Rice, 2001; Patil & Campbell, 2001; Siddall & Cousins, 1997). Hyperalgesia (an increased sensation of pain in response to a normally painful stimulus) is sometimes seen clinically in patients with pain. Currently, it is thought that peripheral sensitization, mediated through C-fiber primary afferent neurons, is the mechanism responsible for hyperalgesia (Byers & Bonica, 2001). These changes are sometimes evident as spontaneous pain in the clinical setting (Siddall & Cousins, 1997; Woolf & Chong, 1993). Sensations of burning pain may be the result of continuous discharge in C-fibers, whereas dysesthesias (unpleasant abnormal sensations) and paresthesias (abnormal sensations) may arise from intermittent spontaneous discharges in A-␦ or A- fibers (Rowbotham & Petersen, 2001). Another peripheral mechanism undergoing extensive research is sympathetic sensory coupling (Attal, 2000; Bridges et al., 2001). It has been noted in clinical practice that neuropathic pain in a small subset of patients seems to be dependent on the sympathetic nervous system (e.g., complex regional pain syndrome type 1). This is sometimes referred to as sympathetically maintained pain. Although not completely understood in terms of when and why this occurs, an abnormal connection between the sympathetic nervous system and the sensory nervous system may be the underlying cause of this type of pain (Bridges et al., 2001). Several drugs that are effective for neuropathic pain act by modulation of sodium channels, which suppress ectopic discharges that contribute to peripheral sensitization. These include certain anticonvulsant
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Chris Pasero
TABLE 3. Possible Mechanisms of Neuropathic Pain Peripheral mechanisms ● Peripheral sensitization initiated by release of chemicals from damaged cells and inflammatory cells (e.g., bradykinin, prostaglandins, 5HT, NE, leukotrienes, cytokines) ● Ion channels are altered as to their number and location (e.g., sodium, calcium channels) - lowered threshold for depolarization - ectopic and spontaneous discharges occur - increased responsiveness to mechanical and chemical stimuli ● Collateral sprouting of primary afferent neurons ● Recruitment of “silent” nociceptors ● Coupling between the sympathetic nervous system and sensory nervous system ● Clinical correlates include hyperalgesia, burning pain, dysesthesias, paresthesias Central mechanisms ● Initiated by tachykinin and neurotransmitter release from peripheral nociceptors (e.g., substance P, neurokinin A, glutamate, calcitonin gene-related peptide, gamma-aminobutyric acid)-NMDA receptor is activated ● Intracellular calcium is increased ● “Wind-up” occurs in spinal dorsal horn neurons - lower activation threshold - increased response to stimuli - larger receptive field ● Ephaptic conduction (“cross excitation” or “cross talk”) occurs between neurons ● Neuronal reorganization occurs (sprouting of spinal cord neurons into new locations) ● Central disinhibition ● Clinical correlates include allodynia, secondary hyperalgesia, sympathetically maintained pain Note: 5HT ⫽ 5-hydroxytryptamine (serotonin); NE ⫽ norepinephrine; NMDA ⫽ N-methyl-D-aspartate.
drugs (e.g., carbamazepine, oxcarbazepine), local anesthetics (e.g., lidocaine, mexiletine), and tricyclic antidepressants (e.g., desipramine, nortriptyline) (Beydoun & Backonja, 2003).
CENTRAL MECHANISMS Peripheral mechanisms alone cannot explain all of the characteristics of neuropathic pain; central mechanisms play a critical role as well (Attal, 2000). A key process known as central sensitization, which is the abnormal hyperexcitability of central nociceptor neurons, is thought to occur in the spinal cord because of peripheral injury and the release of tachykinins and neurotransmitters. Tachykinins include the neuropeptides substance P and neurokinin A (Beydoun & Backonja, 2003). Neurotransmitters include glutamate, calcitonin gene-related peptide, and ␥-aminobutyric acid (GABA). Prolonged release and binding of these substances to neural receptors activate the N-methyl-D-aspartate (NMDA) receptor, which causes an increase in intracellular calcium levels (Siddall & Cousins, 1997). The increase in calcium levels is believed to occur through N-type calcium channels (Xiao & Bennett, 1995), one of several calcium channels in the central nervous system, and is considered important to the maintenance of central sensitization (Bridges et al., 2001; Nicholson, 2000). These changes, in turn,
lead to a series of biochemical reactions in dorsal horn neurons. The threshold for activation is lowered, the response to stimuli is increased (in both magnitude and duration), and the size of the receptive field is enlarged (a greater area on the neuron surface is available to receive stimuli) (Beydoun & Backonja, 2003). Collectively, these changes result in a phenomenon known as “wind-up,” an increased excitability and sensitivity of spinal cord neurons. Another central mechanism thought to contribute to the development and maintenance of neuropathic pain is called central disinhibition, which occurs when control mechanisms along inhibitory (modulatory) pathways are lost or suppressed. This, in turn, causes abnormal excitability of central neurons (Attal, 2000; Bridges et al., 2001). Clinically, central sensitization and disinhibition, together with peripheral changes, are believed to account for allodynia, a feature of some neuropathic pain states (e.g., PHN) (Bridges et al., 2001; Woolf, 1983). Allodynia is a clinical term that describes pain due to a stimulus that does not normally provoke pain (e.g., the friction of clothing rubbing against the skin). Normally, A- fibers produce the sensation of touch when stimulated. However, these same fibers can produce the sensation of intense pain in some individuals with neuropathic pain (Dworkin, 2002; Nicholson, 2000). Several theories cur-
Pathophysiology of Neuropathic Pain
rently exist to explain allodynia. A lower threshold for sensory input in central neurons may play a role (Siddall & Cousins, 1997; Bridges et al., 2001), as well as a decrease in the central inhibition of nociceptive input (Bridges et al., 2001; Meyer, Campbell, & Raja, 1985). Other abnormalities in neuron organization may also occur. For example, after a peripheral nerve injury, lowthreshold mechanoreceptors have been shown to sprout from deep laminae of the spinal cord, forming synapses in more superficial laminae (laminae I and II) of the dorsal horn (Attal, 2000; Beydoun & Backonja, 2003; Woolf, Shortland, & Coggeshall, 1992). Potentially, this might contribute to an increased sensitivity to pressure (i.e., mechanical allodynia). As previously mentioned, hyperalgesia, or increased sensitivity to stimuli that are normally painful, is common in individuals with pain. Two types of hyperalgesia are frequently described—primary hyperalgesia, which is increased pain and sensitivity at the site of injury; and secondary hyperalgesia, which is increased sensitivity and pain in uninjured tissue that surrounds the site of injury. Whereas primary hyperalgesia is thought to be the result of peripheral changes that occur after tissue damage, secondary hyperalgesia, as with allodynia, is thought to result from events that occur within the dorsal horn of the spinal cord after injury (Byers & Bonica, 2001; Siddall & Cousins, 1997). Several drugs used to treat neuropathic pain have effects in the central nervous system on the levels of calcium, 5HT, and NE, all of which may be important in the central modulation of nociceptive input. Ziconotide is a drug that is administered intrathecally, which specifically antagonizes the N-type calcium channel and can produce pain relief in some patients with neuropathic pain. The anticonvulsant drugs carbamazepine, oxcarbazepine, levetiracetam, and lamotrigine also inhibit N-type calcium channels. In addition, oxcarbazepine and lamotrigine modulate sodium channels. The exact mechanism of analgesic action of gabapentin is unknown. However, research shows that although it does not modify sodium channels, gabapentin does interact with neuronal calcium channels (Nicholson, 2000; Rowbotham & Petersen, 2001; Sindrup & Jensen, 1999). Lidocaine, which is administered both topically and systemically, is a sodium channel blocker that alters membrane permeability. Tricyclic antidepressants are often prescribed for neuropathic pain and may act both peripherally and centrally. Peripherally, they are believed to modulate sodium channels and, centrally, neurotransmitter levels (e.g., 5HT, NE). Opioids act primarily through central
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mechanisms and have a variety of effects, including closure of calcium channels, which reduces the release of key neurotransmitters involved in the transmission of pain (e.g., substance P, NE, 5HT, glutamate). Tramadol, a synthetic analgesic, inhibits both 5HT and NE reuptake and has opioid agonist properties as well (Beydoun & Backonja, 2003).
CONCLUSIONS Our current understanding of neuropathic pain suggests that sensitization mechanisms, both central and peripheral, may contribute to the generation of spontaneous and evoked pain, including hyperalgesia and allodynia (Lynch, Clark, & Sawynok, 2003). Several cellular processes contribute to the pathogenesis of neuropathic pain. It is thought that different mechanisms are involved in painful (e.g., hyperalgesia, allodynia) and nonpainful responses (e.g., dysesthesias, paresthesias) to different stimuli. Namely, C-fibers and A-␦ fibers are normally activated by painful stimuli, whereas A- fiber mechanoreceptors are normally activated by nonpainful mechanical stimuli. Normally, peripheral and central sensitization phenomena dissipate as tissue heals and inflammation subsides. However, when changes in primary afferent function persist after disease or injury of the nervous system, these processes may continue and result in neuropathic pain. In clinical practice, a large variability exists among patients with neuropathic pain. Two patients with the same diagnosis may show different physical findings and symptoms and may have different individual responses to drug treatment. Conversely, two patients with different diagnoses may respond to the same drug. For example, in two patients with PHN, one patient may have spontaneous burning pain, caused by peripheral sensitization, and another patient may have mechanical allodynia, caused by central reorganization. It would be expected that these two patients each require a different drug for treatment. On the other hand, two patients— one with PHN (caused by a virus) and one with PDN (caused by ischemia)—might both have spontaneous burning pain. It is possible that these two patients would respond to the same drug. The multiple mechanisms and mediators involved in the pathogenesis of neuropathic pain indicate many possible treatment targets. Our current understanding is evolving and suggests that different pain mechanisms may explain the variability seen among patients.
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