1. Pathophysiology

2. Overview

3. Pathophysiological Classification of Pain
Central sensitization/ dysfunctional pain
Multiple pain mechanisms may coexist
(mixed pain)
Nociceptive pain
Somatic
Visceral
Neuropathic pain
Peripheral
Central
Speaker’s Notes
This slide illustrates three broad categories of pain: central sensitization/dysfunctional, neuropathic and nociceptive pain. It should also be noted that many conditions feature more than one type of pain, and are thus termed ‘mixed pain’ states.
Nociceptive pain is an appropriate physiologic response that occurs when specific peripheral sensory neurons (nociceptors) respond to noxious stimuli. Nociceptive pain has a protective role because it elicits reflex and behavioral responses that keep tissue damage to a minimum. Nociceptive pain may be somatic or visceral in origin. Somatic pain, such as gout, osteoarthritis and trauma-induced pain, originates with the musculoskeletal or cutaneous nociceptors and is often well localized. Visceral pain, such as dysmenorrhea or acute pancreatitis, originates in nociceptors located in the hollow organs and smooth muscles; it is often referred.
Neuropathic pain has been defined by the International Association for the Study of Pain as “Pain caused by a lesion or disease of the somatosensory nervous system.” Depending on where the lesion or dysfunction occurs within the nervous system, neuropathic pain can be peripheral in origin (as in painful diabetic peripheral neuropathy and postherpetic neuralgia) or central in origin (for example, neuropathic pain associated with stroke or spinal cord injury).
Central sensitization/dysfunctional pain is defined as “Hypersensitivity of the pain system such that normally innocuous inputs can activate and perceptual responses to noxious inputs are exaggerated, prolonged and spread widely”. Some common examples for this pain type are: fibromyalgia, temporomandibular joint disorder, chronic migraine/tension type headache, interstitial cystitis, irritable bowel syndrome and complex regional pain syndrome.
There are cases in which more than one type of pain pathophysiology exist (mixed pain). For example, in a lumbar herniated disc patient with radiculopathy, it is common to experience both nociceptive/inflammatory pain, felt around the low back area with movement, and neuropathic pain, felt in the distribution territory of the effected root (lower extremity).
References
Freynhagen R, Baron R. The evaluation of neuropathic components in low back pain. Curr Pain Headache Rep 2009; 13(3):
Jensen TS et al. A new definition of neuropathic pain. Pain 2011; 152(10):
Julius D et al. In: McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006.
Ross E. Moving towards rational pharmacological management of pain with an improved classification system of pain. Expert Opin Pharmacother 2001; 2(1):
Webster LR. Breakthrough pain in the management of chronic persistent pain syndromes. Am J Manag Care 2008; 14(5 Suppl 1):S
Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011; 152(3 Suppl):S2-15.
Freynhagen R, Baron R. Curr Pain Headache Rep 2009; 13(3):185-90; Jensen TS et al. Pain 2011; 152(10):2204-5; Julius D et al. In: McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006; Ross E. Expert Opin Pharmacother 2001; 2(1): ; Webster LR. Am J Manag Care 2008; 14(5 Suppl 1):S116-22; Woolf CJ. Pain 2011; 152(3 Suppl):S2-15.

4. What is neuropathic pain?
Pain caused by a lesion or disease of the somatosensory nervous system
Peripheral Neuropathic Pain
Pain caused by a lesion or disease of the peripheral somatosensory nervous system
Central Neuropathic Pain
Pain caused by a lesion or disease of the central somatosensory nervous system
Speaker’s Notes
The International Association for the Study of Pain (IASP)’s definition of neuropathic pain as “Pain caused by a lesion or disease of the somatosensory nervous system”
Note: Neuropathic pain is a clinical description (and not a diagnosis) which requires a demonstrable lesion or a disease that satisfies established neurological diagnostic criteria. The term lesion is commonly used when diagnostic investigations (e.g. imaging, neurophysiology, biopsies, lab tests) reveal an abnormality or when there was obvious trauma. The term disease is commonly used when the underlying cause of the lesion is known (e.g. stroke, vasculitis, diabetes mellitus, genetic abnormality). Somatosensory refers to information about the body per se including visceral organs, rather than information about the external world (e.g., vision, hearing, or olfaction). The presence of symptoms or signs (e.g., touch-evoked pain) alone does not justify the use of the term neuropathic. Some disease entities, such as trigeminal neuralgia, are currently defined by their clinical presentation rather than by objective diagnostic testing. Other diagnoses such as postherpetic neuralgia are normally based upon the history. It is common when investigating neuropathic pain that diagnostic testing may yield inconclusive or even inconsistent data. In such instances, clinical judgment is required to reduce the totality of findings in a patient into one putative diagnosis or concise group of diagnoses.
Depending on where the lesion or dysfunction occurs in the somatosensory nervous system, neuropathic pain can be peripheral or central in origin. Causes of peripheral neuropathic pain include post-surgical and post-traumatic nerve injury, diabetic peripheral neuropathy, postherpetic neuralgia etc. Causes of central neuropathic pain are: post-stroke pain, multiple sclerosis and spinal cord injuries, etc.
Reference
International Association for the Study of Pain. IASP Taxonomy, Changes in the 2011 List. Available at: Accessed: July 15, 2013.
International Association for the Study of Pain. IASP Taxonomy, Changes in the List. Available at: Accessed: July 15, 2013.

5. Nociceptive vs. Neuropathic Pain
Usually aching or throbbing and well-localized
Usually time-limited (resolves when damaged tissue heals), but can be chronic
Generally responds to conventional analgesics
Pain often described as tingling, shock-like, and burning – commonly associated with numbness
Almost always a chronic condition
Responds poorly to conventional analgesics
Speaker’s Notes
With nociceptive pain, the painful region is typically localized to the site of injury and the pain is often described as throbbing, aching or pressure-like. Nociceptive pain is usually time limited and resolves when the damaged tissue heals (e.g., bone fractures, burns, and bruises). Although nociceptive pain is generally self-limiting, it can be chronic, as in osteoarthritis. Treatment with conventional analgesics is usually appropriate.
Neuropathic pain is frequently described as a ‘shooting’, ‘electric shock-like’ or burning’ pain, commonly associated with ‘tingling’ and/or ‘numbness’. The painful region may not necessarily be the same as the site of injury. Pain occurs in the neurological territory of the affected structure (nerve, root, spinal cord, brain). In peripheral neuropathic pain, it is in the territory of the affected nerve or nerve root. In central neuropathic pain, it is related to the site of the lesion in the spinal cord or brain. Neuropathic pain is almost always a chronic condition and responds poorly to conventional analgesics.
References
Dray A. Neuropathic pain: emerging treatments. Br J Anaesth 2008; 101(1):48-58.
Felson DT. Developments in the clinical understanding of osteoarthritis. Arthritis Res Ther 2009; 11(1):203.
International Association for the Study of Pain. IASP Taxonomy. Available at: pain.org/AM/Template.cfm?Section=Pain_Definitions. Accessed: July 15, 2013.
McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006.
Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011; 152(3 Suppl):S2-15.
Dray A. Br J Anaesth 2008; 101(1):48-58; Felson DT. Arthritis Res Ther 2009; 11(1):203; International Association for the Study of Pain. IASP Taxonomy. Available at: Accessed: July 15, 2013; McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006; Woolf CJ. Pain 2011; 152(3 Suppl):S2-15.

6. Neuropathic Pain Is Characterized by Changes in Pain Response to Painful Stimuli10 8 6 4 2
Hyperalgesia
(increased response to a stimulus that is normally painful)
Normal
pain response
Pain intensity
Allodynia
(pain due to stimulus that does not normally provoke pain)
Injury
Response after injury
Speaker’s Notes
This animated slide illustrates what happens to pain response following nerve injury.
Left-click or arrow down in presentation mode to show the next item in the animation sequence. Please wait for the animation to finish running before clicking for the next item:
The normal pain response curve (that appears with upon first showing slide) shows zero pain intensity with lower intensity stimuli (e.g., light touch does not normally elicit pain; it is an innocuous stimuli. As stimulus intensity increases (e.g., squeezing or pinching harder), one begins to feel pain with increasing intensity.
Following nerve injury, the pain response curve shifts to the left.
The dotted line representing a fixed stimulus intensity bisects both pain response curves. In the normal pain response, this level of stimulus would cause a low level of pain. With a left shift of the response curve following injury, this same level of stimulus would cause a much higher level of pain.
This is the definition of “hyperalgesia”, a heightened response to a stimulus that would normally evoke pain.
Normally innocuous stimuli (blue shaded region) now become painful. This is the definition of “allodynia”, a painful response to a stimulus that is not normally painful.
Reference
Gottschalk A et al. New concepts in acute pain therapy: preemptive analgesia. Am Fam Physician 2001; 63(10):
Stimulus intensity
Adapted from: Gottschalk A et al. Am Fam Physician 2001; 63(10):

7. Etiology

8. Neuropathic Pain Conditions May Affect Various Parts of the Somatosensory Nervous System
Lumbar Radiculopathy1
Carpal Tunnel Syndrome2
Diabetic Peripheral Neuropathy3
Speaker’s Notes
This slide depicts the different regions of the body that may be affected by neuropathic pain caused by different conditions. Lumbar radiculopathy caused by a herniated disc results in pain that radiates down the leg into the calf and foot.1 Carpal tunnel syndrome gives rise to pain in the upper arm distal to the lesion in the nerve, commonly manifesting in the forearm and radiating to the fingers.2 Pain associated with diabetic peripheral neuropathy typically occurs distally (in a stocking distribution) in the feet and lower legs, and sometimes occurs in the hands (in a glove distribution).3
References
Freynhagen R, Baron R. The evaluation of neuropathic components in low back pain. Curr Pain Headache Rep 2009; 13(3):
Michelsen H, Posner MA. Medical history of carpal tunnel syndrome. Hand Clin 2002; 18(2):
Perkins T, Morgenlander JC. Endocrinologic causes of peripheral neuropathy. Pins and needles in a stocking-and-glove pattern and other symptoms. Postgrad Med 1997; 102(3):81-2, 90-2,
Freynhagen R, Baron R. Curr Pain Headache Rep 2009; 13(3):185-90;
Michelsen H, Posner MA. Hand Clin 2002; 18(2):257-68;
Perkins T, Morgenlander JC. Postgrad Med 1997; 102(3):81-2, 90-2, 8

9. Neuropathic Pain Has a Wide Variety of Etiologies
Shingles
Diabetic neuropathy
Speaker’s Notes
This slide lists some of the most commonly encountered peripheral and central causes of neuropathic pain.
Any type of peripheral nerve or root injury may lead to neuropathic pain: traumas, entrapments (like carpal tunnel syndrome), postsurgical iatrogenic nerve lesions, amputations, radiculopathies, etc. Metabolic disturbances may also cause neuropathies associated with neuropathic pain, most notably diabetes mellitus but also uremia and hypothyroidism. Infections such as human immunodeficiency virus (HIV) may also result in peripheral nerve damage. Toxins implicated in peripheral nerve injury include chemotherapeutic agents, lead, organophosphorates and alcohol. Glue sniffing has also been associated with neuropathic pain from peripheral neuropathy. Vascular disorders (polyarteritis nodosa, lupus erythematosus), nutritional deficiencies (niacin, thiamine, pyridoxine), and direct effects of cancer due to metastases and infiltration may also cause peripheral neuropathies leading to neuropathic pain.
Central neuropathic pain may be present in about 8% of stroke patients and in about 28% of patients with multiple sclerosis. Spinal cord lesions and tumors are also known common causes of central neuropathic pain.
References
Baron R et al. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol 2010; 9(8):
McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006.
Nerve trauma
Surgery
Radiculopathy
Baron R et al. Lancet Neurol 2010; 9(8):807-19; McMahon SB, Koltzenburg M. Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006.

10. Complex Regional Pain Syndrome
What is it?
Exaggerated response to trauma, characterized by intense prolonged pain, delayed recovery of function, vasomotor disturbances and trophic changes
Causes are unclear, but may include exaggerated local inflammatory response, nerve injury and involvement of the central and peripheral somatosensory nervous systems
How common is it?
Thought to occur in 1 in 2000 cases of limb trauma
How should it be treated?
Physiotherapy is the mainstay of treatment
Combination of pharmacological agents may be necessary
Speaker’s Notes
As described on this slide, complex regional pain syndrome is one example of a possible mixed pain condition.
Management of this condition may be complex and referral to a specialist is recommended.
Reference
Dowd GS et al. Complex regional pain syndrome with special emphasis on the knee. J Bone Joint Surg Br 2007; 89(3):
Dowd GS et al. J Bone Joint Surg Br 2007; 89(3):

11. Pathophysiology

12. Development of Neuropathic Pain
Nerve damage
Metabolic
Traumatic
Toxic
Ischemic
Hereditary
Compression
Infectious
Immune-related
Etiology
Pathophysiology
Mechanisms
Speaker’s Notes
This slide illustrates the concept that many different underlying causes of neuropathic pain may express as different spontaneous and stimulus-evoked pain symptoms via different pathophysiological mechanisms.
There are many possible causes of neuropathic pain. Neuropathic pain is commonly classified according to the etiological nature of the damage to the somatosensory nervous system or the anatomical distribution of the pain, although the relationship between etiology, mechanisms, and symptoms/signs is highly complex. For instance, the pain caused by diverse diseases may originate through common mechanisms. In addition, one mechanism could be responsible for many different symptoms. Conversely, the same symptom in two patients may be caused by different mechanisms. Furthermore, more than one mechanism can operate in a single patient, and the pattern of mechanisms and symptoms within a single patient may change with time.
No pain pathophysiological mechanism is an inevitable consequence of a particular disease process.
Studies are needed to further define pathophysiological mechanisms of neuropathic pain.
Reference
Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999; 353(9168):
Symptoms
Spontaneous pain
Stimulus-evoked pain
Syndrome
Neuropathic pain
Woolf CJ, Mannion RJ. Lancet 1999; 353(9168):

13. Pathophysiology of Neuropathic Pain
Peripheral mechanisms
Membrane hyperexcitability
Ectopic discharges
Transcriptional changes
Central mechanisms
Hyperexcitability
Sensitization
Peripheral
Central
Neuropathic pain
Loss of inhibitory controls
Speaker’s Notes
Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system is defined as “neuropathic pain”.
This slide illustrates the main mechanisms underlying the development of neuropathic pain.
Peripheral mechanisms of neuropathic pain include membrane hyperexcitability in the nociceptive neurons, ectopic discharges along sensory nerves, which may lead to transcriptional changes in the dorsal root ganglia (peripheral sensitization). Peripheral mechanisms can trigger changes within the central nervous system (central mechanisms) as well.
Central mechanisms in the spinal cord include increased excitability in the dorsal horn neurons, sprouting of non-nociceptive myelinated A-beta-afferents in the dorsal horn that form new connections with the nociceptive neurons in the laminae I and II, and loss of inhibitory controls (disinhibition). Central mechanisms in the supraspinal systems include hyperexcitability and changes in synaptic activity and reorganization within the brainstem nuclei, thalamus and the brain cortex associated with pain matrix (central sensitization).
References
Moisset X, Bouhassira D. Brain imaging of neuropathic pain. Neuroimage 2007; 37(Suppl 1):S80-8.
Scholz J, Woolf CJ. Can we conquer pain? Nat Neurosci 2002; 5(Suppl):
Reorganization
Moisset X, Bouhassira D. Neuroimage 2007; 37(Suppl 1):S80-8; Scholz J, Woolf CJ. Nat Neurosci 2002; 5(Suppl):

14. Peripheral Mechanisms
Mechanisms of Neuropathic Pain
in Diabetic Peripheral Neuropathy
Peripheral Mechanisms
Central Mechanisms
Changes in sodium channel distribution and expression
Changes in calcium channel distribution and expression
Altered neuro-peptide expression
Sympathetic sprouting
Loss of spinal inhibitory control
Altered peripheral blood flow
Axonal atrophy, degeneration or regeneration
Damage to small fibers
Increased glycemic flux
Central sensitization
Changes in the balance of facilitation/inhibition with descending pathways
Increased thalamic vascularity
Speaker’s Notes
This slide lists the known peripheral and central mechanisms resulting in painful diabetic peripheral neuropathy.
Reference
Tesfaye S et al. Mechanisms and management of diabetic painful distal symmetrical polyneuropathy. Diabetes Care 2013; 36(9):
Tesfaye S et al. Diabetes Care 2013; 36(9):

15. Sensory Processing and Neuropathic Pain
Nerve function
Stimulus
Primary afferent
Sensation
Mechanism
Normal
Innocuous
Mechanical Aβ
Normal touch
Normal function
Noxious
Thermal
Chemical
Aδ nociceptor
C nociceptor
Normal sharp pain
Normal burning pain
Decreased
Tactile hypoanesthesia
Decreased transmission of impulses
Heat or cold hypoalgesia
Increased
Dynamic mechanical allodynia
Many theories (e.g., sensitization)
Heat or cold hyperalgesia
Many theories (e.g., wind-up, peripheral sensitization)
Speaker’s Notes
This slide describes sensations in response to innocuous and noxious stimuli under conditions of normal nerve function, decreased nerve function in damaged nerves and increased nerve function in damaged nerves.
When nerves are not damaged and functioning normally, innocuous mechanical stimuli (e.g., rubbing your face) result in transmission by Aβ fibers and the resulting sensation is normal touch. If undamaged nerves are subject to noxious stimuli (e.g. pinprick, burn by a candle or a strong acid), resulting transmission by Aδ nociceptors and C nociceptors, results in sensations of normal sharp and burning pain, respectively.
When nerves are damaged and their function is decreased, innocuous mechanical stimuli result in decreased transmission of impulses along Aβ fibers with resultant tactile hypoanesthesia (little or no feeling). When damaged nerves with decreased function are exposed to noxious stimuli, transmission or impulses along Aδ and C nociceptors is decreased with resultant hyopalgesia (lack of an appropriate painful sensation).
When nerves are damaged and their function is increased, innocuous mechanical stimuli result in dysfunction of Aβ fibers with resultant dynamic mechanical allodynia (a sensation of pain when it is not appropriate). When damaged nerves with increased function are exposed to noxious stimuli result in dysfunction of Aδ and C nociceptors with resultant hyperalgesia (an increased pain response beyond that expected for the level of stimulus).
The precise mechanisms that underlie the dysfunction in damages nerves with increased function are not yet fully understood. However, several theories have been proposed and these include peripheral and central sensitization and wind-up.
Reference
Doubell TP et al. In: Wall PD, Melzack R (eds). Textbook of Pain. 4th ed. Harcourt Publishers Limited; Edinburgh, UK: 1999.
Adapted from: Doubell TP et al. In: Wall PD, Melzack R (eds). Textbook of Pain. 4th ed. Harcourt Publishers Limited; Edinburgh, UK: 1999.

16. Neuropathic Pain: Aβ , Aδ and C Fibers
Characteristic
Aβ fibers
Aδ fibers
C fibers
Diameter
Large
Larger
Small
Myelination
Yes No
Conduction velocity
Rapid
Intermediate
Slow
Activation stimuli
Non-noxious mechanical
Noxious
Speaker’s Notes
One of the vital functions of the somatosensory nervous system is to provide information about the occurrence or threat of injury. Highly specialized sensory neurons provide information to the central nervous system about both the environment and the organism itself. This slide describes the three main types of sensory fibers that may be implicated in the generation of neuropathic pain signs and symptoms. The overall message of the slide is that in neuropathic pain, abnormal sensations may be transmitted along Aβ , Aδ or C fibers.
Nociception (the perception of noxious stimuli) is initiated by stimuli that activate the peripheral receptors of nociceptors, a highly specialized set of sensory neurons that respond only to damaging or potentially stimuli. Nociceptors have unmyelinated (C fibers) or thinly myelinated (Aδ fibers) axons. Aβ fiber mechanoreceptors respond to non-noxious mechanical stimuli, such as touch. Aδ and C fibers nociceptors are usually activated by noxious stimuli. Activated Aδ fibers transmit sharp pain, while activated C fibers are responsible for secondary pain, which is usually described as aching or burning. All three types of sensory fibers may be involved in the production of neuropathic pain.
References
Dworkin RH. An overview of neuropathic pain: syndromes, symptoms, signs, and several mechanisms. Clin J Pain 2002; 18(6):343-9.
Raja SN et al. In: Wall PD, Melzack R (eds). Textbook of Pain. 4th ed. Harcourt Publishers Limited; Edinburgh, UK: 1999.
Dworkin RH. Clin J Pain 2002; 18(6):343-9; Raja SN et al. In: Wall PD, Melzack R (eds). Textbook of Pain. 4th ed. Harcourt Publishers Limited; Edinburgh, UK: 1999.

17. Mechanisms of Neuropathic Pain
Nerve lesion/disease
Central sensitization
Brain
Loss of inhibitory control
Descending modulation
Nerve lesion/disease
Ectopic discharge
Speaker’s Notes
This slide illustrates the main mechanisms underlying the development of neuropathic pain. Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system is defined as “neuropathic pain”.
Peripheral mechanisms of neuropathic pain include membrane hyperexcitability in the nociceptive neurons, ectopic discharges along sensory nerves, which may lead to transcriptional changes in the dorsal root ganglia (peripheral sensitization). Peripheral mechanisms can trigger changes within the central nervous system (central mechanisms) as well.
Central mechanisms in the spinal cord include increased excitability in the dorsal horn neurons, sprouting of non-nociceptive myelinated A-beta-afferents in the dorsal horn that form new connections with the nociceptive neurons in the laminae I and II, and loss of inhibitory controls (disinhibition). Central mechanisms in the supraspinal systems include hyperexcitability and changes in synaptic activity and reorganization within the brainstem nuclei, thalamus and the brain cortex associated with pain matrix (central sensitization).
References
Gilron I et al. Neuropathic pain: a practical guide for the clinician. CMAJ 2006; 175(3):
Jarvis MF, Boyce-Rustay JM. Neuropathic pain: models and mechanisms. Curr Pharm Des 2009; 15(15):
Scholz J, Woolf CJ. Can we conquer pain? Nat Neurosci 2002; 5(Suppl):
Nerve lesion/disease
Central sensitization
Peripheral sensitization
Nociceptive afferent fiber
Spinal cord
Gilron I et al. CMAJ 2006; 175(3):265-75; Jarvis MF, Boyce-Rustay JM. Curr Pharm Des 2009; 15(15):1711-6; Scholz J, Woolf CJ. Nat Neurosci 2002; 5(Suppl):

18. Nociceptive afferent fiber
Ectopic Discharges
Nerve lesion induces hyperactivity due to changes in ion channel function.
Perceived pain
Nerve lesion
Descending modulation
Ascending input
Speaker’s Notes
This slide contains an animation illustrating the consequences of ectopic discharges from a damaged or diseased nociceptive afferent fiber. Clicking on this slide will cause subsequent components of this animation to run automatically:
The equilibrium between ion channels (e.g., sodium and potassium) in the axonal membrane of damaged or diseased neurons becomes altered.
This may result in hyperexcitability causing impulse “over-firing” – also known as ectopic discharges.
Such ectopic discharges may occur spontaneously or may be evoked by mechanical stimuli (e.g., touch, pressure).
References
England JD et al. Sodium channel accumulation in humans with painful neuromas. Neurology 1996; 47(1):272-6.
Ochoa JL, Torebjörk HE. Paraesthesiae from ectopic impulse generation in human sensory nerves. Brain 1980; 103(4):
Taylor BK. Spinal inhibitory neurotransmission in neuropathic pain. Curr Pain Headache Rep 2009; 13(3):
Sukhotinsky I et al. Key role of the dorsal root ganglion in neuropathic tactile hypersensibility. Eur J Pain 2004; 8(2):
Nociceptive afferent fiber
Spinal cord
Ectopic discharges
England JD et al. Neurology 1996;47(1):272-6; Ochoa JL, Torebjörk HE. Brain 1980; 103(4):835-53; Sukhotinsky I et al. Eur J Pain 2004; 8(2):135-43; Taylor BK. Curr Pain Headache Rep 2009; 13(3):208-14;

19. Ectopic Discharges Sodium channel expression increased
Primary excitatory afferent nerve fiber
Speaker’s Notes
This slide illustrates the concept that after nerve injury, membrane hyperexcitability may develop at different sites.
The ability of nerve fibers to conduct impulses is mainly related to the normal interplay between sodium and potassium channels in the axonal membrane of the neuron. After nerve injury, many changes will occur that will alter this normal equilibrium, leading to conduction failure (the cause of negative symptoms, e.g., numbness), and frequently also to hyperexcitability (a cause of positive symptoms, e.g., tingling).
Regenerating fibers from parent axons in damaged nerves are highly excitable. It has been demonstrated that these fibers develop with an abnormally high number of sodium channels, which may result in ectopic discharges (i.e., repetitive firing capability in the region of the nerve injury). Ectopic discharges may be spontaneous or evoked by mechanical or chemical stimuli.
Depending on the sensory modality of the ectopically active fiber, different sensations will be felt. For example, ectopic activity in Aβ touch fibers will lead to the experience of tactile paresthesias or dysesthesias On the other hand, ectopic activity in Aδ or C nociceptors will induce pain of different qualities (sharp-pricking or burning-aching pain).
Ectopic discharges may also occur in other parts of injured axons. For example, ectopic discharges may appear in damaged or demyelinated segments of injured fibers. Moreover, the body of the damaged neuron, located in the dorsal root ganglion, may also engage in spontaneous ectopic discharges, even if the original injury took part in a distal segment of the axon.
References
England JD et al. Sodium channel accumulation in humans with painful neuromas. Neurology 1996; 47(1):272-6.
Ochoa JL, Torebjörk HE. Paraesthesiae from ectopic impulse generation in human sensory nerves. Brain 1980; 103(4):
Sukhotinsky I et al. Key role of the dorsal root ganglion in neuropathic tactile hypersensibility. Eur J Pain 2004; 8(2):
Taylor BK. Pathophysiologic mechanisms of neuropathic pain. Curr Pain Headache Rep 2001; 5(2):
Conduction frequency amplified
England JD et al. Neurology 1996; 47(1):272-6; Ochoa JL, Torebjörk HE. Brain 1980; 103(4):835-53;
Sukhotinsky I et al. Eur J Pain 2004; 8(2):135-43; Taylor BK. Curr Pain Headache Rep 2001; 5(2):

20. Peripheral Sensitization
Primary afferent nerve fibers
Dorsal horn neurons
NGF
NGF
Neuropeptide release
NGF
NGF
Speaker’s Notes
This diagram shows how nociceptor stimulation can lead to the sensitization of peripheral nerve terminals.
The perception of pain in response to innocuous stimuli may be, in part, attributed to peripheral sensitization. Peripheral sensitization lowers the activation threshold of both damaged nerve fibers and undamaged neighboring nerve fibers.
When certain types of nociceptors are stimulated, the action potentials travel orthodromically towards the central nervous system, but also antidromically, to invade all the peripheral terminal branches of the neuron (a phenomenon called “axon reflex”). This antidromic invasion of the terminal branches will induce the release of inflammatory mediators, causing neurogenic inflammation that will, in turn, sensitize nearby nociceptors.
Antidromic activity can rigger the release of excitatory neuropeptides, such as substance P and calcitonin-gene-related peptide. These neuropeptides may lead to the sensitization of the peripheral sensory terminals of injured and neighbouring uninjured fibers. Therefore, spontaneous activity (neuropeptide release) in primary afferents can produce peripheral sensitization in injured and uninjured adjacent neurons.
Partial denervation also increases relative concentrations of nerve growth factor (NGF) for intact cells. Nerve growth factor is found in a variety of peripheral tissues. It attracts neurites to the tissues by chemotropism, where they form synapses. The successful neurons are then protected from neuronal death by continuing supplies of nerve growth factor.
References
Ørstavik K et al. Pathological C-fibres in patients with a chronic painful condition. Brain 2003; 126(Pt 3):
Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999; 353(9168):
Innocuous stimulus
PAIN
Ørstavik K et al. Brain 2003; 126(Pt 3):567-78; Woolf CJ, Mannion RJ. Lancet 1999; 353(9168):

21. Central Sensitization
After nerve injury, increased input to the dorsal horn can induce central sensitization.
Perceived pain
Nerve lesion
Descending modulation
Ascending input
Abnormal discharges induce central sensitization
Nociceptive afferent fiber
Intact tactile fiber
Perceived pain (allodynia)
Speaker’s Notes
This slide contains an animated build to show that central sensitization involves changes at the level of the dorsal horn neurons. Clicking on this slide will cause subsequent components of the build to appear automatically.
Under normal conditions, activation of tactile fibers is unable to stimulate dorsal horn nociceptive neurons, therefore tactile stimuli are perceived as non-painful.
Under pathological conditions, abnormal ectopic discharges from damaged or diseased nociceptors induce central sensitization of spinal dorsal horn neurons. Consequently, activation of tactile fibers is now sufficient to activate dorsal horn nociceptive neurons. Therefore, stimuli normally perceived as non-painful are now perceived as pain (e.g., allodynia).
References
Campbell JN, Meyer RA. Mechanisms of neuropathic pain. Neuron 2006; 52(1):77-92.
Gottschalk A, Smith DS. New concepts in acute pain therapy: preemptive analgesia. Am Fam Physician 2001; 63(10)
Henriksson KG. Fibromyalgia–from syndrome to disease: overview of pathogenetic mechanisms. J Rehabil Med 2003; 41(Suppl):89-94.
Larson AA et al. Changes in the concentrations of amino acids in the cerebrospinal fluid that correlate with pain in patients with fibromyalgia: implications for nitric oxide pathways. Pain 2000; 87(2):
Marchand S. The physiology of pain mechanisms: from the periphery to the brain. Rheum Dis Clin North Am 2008; 34(2):
Rao SG. The neuropharmacology of centrally-acting analgesic medications in fibromyalgia. Rheum Dis Clin North Am 2002; 28(2):
Staud R. Biology and therapy of fibromyalgia: pain in fibromyalgia syndrome. Arthritis Res Ther 2006; 8(3):
Staud R, Rodriguez ME. Mechanisms of disease: pain in fibromyalgia syndrome. Nat Clin Pract Rheumatol 2006; 2(2):90-8.
Vaerøy H et al. Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis. Pain 1988; 32(1):21-6.
Woolf CJ et al. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med 2004; 140(6):
Tactile stimuli
Descending modulation
Ascending input
Adapted from: Campbell JN, Meyer RA. Neuron 2006; 52(1):77-92; Gottschalk A, Smith DS. Am Fam Physician 2001; 63(10) ; Henriksson KG. J Rehabil Med 2003; 41(Suppl):89-94; Larson AA et al. Pain 2000; 87(2):201-11; Marchand S. Rheum Dis Clin North Am 2008; 34(2): ; Rao SG. Rheum Dis Clin North Am 2002; 28(2):235-59; Staud R. Arthritis Res Ther 2006; 8(3):208-14; Staud R, Rodriguez ME. Nat Clin Pract Rheumatol 2006; 2(2):90-8; Vaerøy H et al. Pain 1988; 32(1):21-6; Woolf CJ et al. Ann Intern Med 2004; 140(6):

22. Central Sensitization
Ca2+ channel
Presynaptic
Ca2+ ion
Believed to result from excessive release of 2 important neurotransmitters:
Substance P
Glutamate
Speaker’s Notes
Central sensitization is believed to be the underlying cause of amplified pain perception that results from dysfunction in the central nervous system (CNS).1,2
The damaged nerve fibers that cause pain can produce abnormal nerve activity that triggers central sensitization.1 This theory may explain the amplified pain perception that results from dysfunction in the CNS.2
Central sensitization is thought to result from excessive release of two important neurotransmitters – substance P and glutamate. Release of these transmitters is thought to be mediated by voltage-gated calcium channels on the presynaptic membrane.3
References
Costigan M et al. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci 2009; 32:1-32.
Staud R. Biology and therapy of fibromyalgia: pain in fibromyalgia syndrome. Arthritis Res Ther 2006; 8(3):
Costigan M et al. In: Siegel GJ et al (eds). Basic Neurochemistry: Molecular,
Cellular and Medical Aspects. 7th ed. Elsevier Academic Press; Burlington, MA: 2006.
Postsynaptic
Neurotransmitters
Costigan M et al. Annu Rev Neurosci 2009; 32:1-32; Costigan M et al. In: Siegel GJ et al (eds). Basic Neurochemistry: Molecular,
Cellular and Medical Aspects. 7th ed. Elsevier Academic Press; Burlington, MA: 2006; Staud R. Arthritis Res Ther 2006; 8(3):

23. Central Sensitization after Nerve Injury
No pain
NORMAL
Innocuous
stimulus
Speaker’s Notes
This slide shows how central sensitization can result from increased nociceptor drive or disinhibition after nerve injury.
In the top visual, which represents normal sensory function, activation of the Aβ mechanoreceptors by low threshold mechanical stimuli is unable to activate dorsal horn pain pathways.
In the bottom visual, increased nociceptor drive leads to central sensitization of dorsal horn neurons wide dynamic range neurons. Aβ fiber input is now sufficient to activate these neurons that will transmit to the sensing brain.
These changes manifest as hypersensitivity to pain that spreads from the site of injury and includes tactile Aβ-fiber-mediated allodynia. When nerves are damaged and their function is increased, innocuous mechanical stimuli result in dysfunction of Aβ fibers with resultant dynamic mechanical allodynia (a sensation of pain when it is not appropriate).
Reference
Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999; 353(9168):
PAIN
NERVE INJURY
Woolf CJ, Mannion RJ. Lancet 1999; 353(9168):

24. Central Sensitization
C fiber terminal
GABA Glycine
Glutamate
(+)
PGE2
Inhibitory
Inter-neuron
(-)
NMDA P
Substance P
(-) on
Glycine
receptors
AMPA P
Ca++
PGE2
(+)
(+)
Speaker’s Notes
Peripheral injury can generate pain hypersensitivity in neighboring, uninjured tissues (i.e., “secondary hyperalgesia”) and pain syndrome (diffuse muscle and joint pain, fever, lethargy and anorexia). This is caused by increased neuronal excitability in spinal cord or “central sensitization”.
Repeated activation of C-fiber nociceptors and peripheral inflammation can also lead to central sensitization:
Releases glutamate neurotransmitter at synapses with dorsal horn
Glutamate stimulates AMPA receptor linked sodium channel
Opened sodium channel allows influx of sodium
Depolarization suppresses magnesium ion inhibition of NMDA receptor-linked calcium channels
Influx of calcium ions from opened NMDA channel activates cascade of signals:
Increasing neuron excitability
Suppressing effects of inhibitory interneurons
Other chemical messengers including substance P and prostaglandins potentiate this effect
Reference
Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000; 288(5472):
PKC
(+)
Na+
PGE2
Dorsal horn neuron
PGE2
COX-2
induction
AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA = γ-aminobutyric acid; NMDA = N-methyl-D-aspartate; prostaglandin E; PKC = protein kinase C
Woolf CJ, Salter MW. Science 2000; 288(5472):

25. Central Sensitization
C fiber terminal
Inhibitory
inter-neuron
cell death
GABA Glycine
Glutamate
(+)
PGE2
(-)
NMDA P
Substance P
(-) on
Glycine
receptors
AMPA P
Ca++
PGE2
(+)
(+)
Speaker’s Notes
This slide contains an animation sequence: left click or arrow down in presentation mode to show next numbered item. Please wait for the animation to complete running before clicking on the next item.
The sequence is as follows:
Inhibitory inter-neurons (including those using endogenous opioid transmitters) die (disappear), and are replaced by text “Inhibitory inter-neuron cell death”
Animation skips to next slide – make one additional left click or arrow down and the animation will automatically run until completion
Formation of aberrant excitatory synapses between A-fibers (instead of normal C fibers) and the dorsal horn
New afferent neuron appears from top left, NMDA and AMDA receptors appear on dorsal horn; glutamate transmitters are released from new afferent neuron, bind to AMDA and NMDA receptors, opening associated calcium channels which stimulate PKC enzymes to phosphorylate NMDA and AMDA receptors – further opening their associated calcium channels
The result is a long-lasting increase in neuron sensitivity, leading to chronic neuropathic pain, often resistant to opioids.
Reference
Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000; 288(5472):
PKC
(+)
Na+
PGE2
Dorsal horn neuron
PGE2
COX-2
induction
AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA = γ-aminobutyric acid; NMDA = N-methyl-D-aspartate; prostaglandin E; PKC = protein kinase C
Woolf CJ, Salter MW. Science 2000; 288(5472):

26. Central Sensitization
New A fiber forming synapse
C fiber terminal
Inhibitory
inter-neuron
cell death
Glutamate
(+)
PGE2 P
NMDA P
AMPA P
Substance P
Dorsal horn neuron
AMPA P
Ca++
(+)
Loss of inhibitory
effects of inter-neurons
(+)
Establishment of aberrant excitatory
synaptic
connection
Speaker’s Notes
This slide contains an animation sequence continued from the previous slide. The animation should “play” automatically from the previous slide.
Reference
Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000; 288(5472):
PKC
(+)
Na+
PGE2
Dorsal horn neuron
PGE2
COX-2
induction
AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA = γ-aminobutyric acid; NMDA = N-methyl-D-aspartate; prostaglandin E; PKC = protein kinase C
Woolf CJ, Salter MW. Science 2000; 288(5472):

27. Loss of Inhibitory Control: Disinhibition
Brain
Pain treatment options
α2δ ligands
Antidepressants
Perception
Exaggerated
pain perception X
Noxious stimuli
Descending modulation X
Ascending input
Speaker’s Notes
This slide illustrates how nervous system injury can reduce inhibition in the dorsal horn through various mechanisms.
Stimulation of inhibitory interneurons located in the dorsal horn of the spinal cord releases neurotransmitters such as gamma-aminobutyric acid (GABA) and glycine, which have the effect of reducing synaptic transmission of sensory impulses.
Inhibitory mechanisms that arise from descending pathways from the brain are mediated by endogenous opioids or neurotransmitters, such as serotonin and noradrenaline. This inhibitory system prevents overstimulation. 
Experimental peripheral nerve injuries in animals have been associated with decreased GABA and glycine levels. In addition, GABA receptors and opioid receptors are down-regulated following nerve injury.
It has been hypothesized that if inhibitory controls are lost or impaired, then excitatory mechanisms may dominate, allowing dorsal horn neurons to fire in an exaggerated way in response to noxious input which may eventually result in an increased pain perception. In chronic pain states there is increasing deficit of descending inhibition.
References
Attal N, Bouhassira D. Mechanisms of pain in peripheral neuropathy. Acta Neurol Scand Suppl 1999; 173:12-24.
Doubell TP et al. In: Wall PD, Melzack R (eds). Textbook of Pain. 4th ed. Harcourt Publishers Limited; Edinburgh, UK: 1999.
Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999; 353(9168):
Transmission
Transduction
Nociceptive afferent fiber
Spinal cord
Attal N, Bouhassira D. Acta Neurol Scand 1999; 173:12-24; Doubell TP et al. In: Wall PD, Melzack R (eds). Textbook of Pain. 4th ed. Harcourt Publishers Limited; Edinburgh, UK: 1999; Woolf CJ, Mannion RJ. Lancet 1999; 353(9168):

28. Loss of Inhibitory Controls
Dorsal horn neuron
Descending
Local To
brain
Normal
Descending
Innocuous or noxious stimulus
Local
Speaker’s Notes
This slide illustrates how nervous system injury can reduce inhibition in the dorsal horn through various mechanisms.
Stimulation of inhibitory interneurons located in the dorsal horn of the spinal cord releases neurotransmitters such as gamma-aminobutyric acid (GABA) and glycine, which have the effect of reducing synaptic transmission of sensory impulses.
Inhibitory mechanisms that arise from descending pathways from the brain are mediated by endogenous opioids or neurotransmitters, such as serotonin and noradrenaline. This inhibitory system prevents overstimulation. 
Experimental peripheral nerve injuries in animals have been associated with decreased GABA and glycine levels. In addition, GABA receptors and opioid receptors are downregulated following nerve injury.
It has been hypothesized that if inhibitory controls are lost or impaired, then excitatory mechanisms may dominate, allowing dorsal horn neurons to fire in an exaggerated way in response to noxious input which may eventually result in an increased pain perception.
References
Attal N, Bouhassira D. Mechanisms of pain in peripheral neuropathy. Acta Neurol Scand 1999; 173:12-24.
Doubell TP et al. In: Wall PD, Melzack R (eds). Textbook of Pain. 4th ed. Harcourt Publishers Limited; Edinburgh, UK: 1999.
Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999; 353(9168):
Exaggerated pain response To
brain
Injured
Spontaneous firing
Attal N, Bouhassira D. Acta Neurol Scand 1999; 173:12-24; Doubell TP et al. In: Wall PD, Melzack R (eds). Textbook of Pain. 4th ed. Harcourt Publishers Limited; Edinburgh, UK: 1999; Woolf CJ, Mannion RJ. Lancet 1999; 353(9168):

29. Summary

30. Pathophysiology: Summary
Neuropathic pain is pain caused by a lesion or disease of the somatosensory system
It is characterized by positive and negative sensory symptoms
Peripheral and central mechanisms mediate neuropathic pain independent of etiology
Hyperexcitability
Sensitization
Loss of inhibitory controls
Speaker’s Notes
This slide can be used to summarize the key messages of this section.