1. Pathophysiology of Pain

2. Nociception
The detection of tissue damage by specialized transducers connected to A-delta and C-fibers
Nociception has been defined by Loeser (2000) as “the detection of tissue damage by specialized transducers connected to A-delta and C-fibers.”
Anatomically, this process occurs predominantly peripherally and involves the nociceptor neurons, which terminate in the dorsal horn of the spinal cord.
Nociceptors are the primary afferent neurons with specific nerve endings that can distinguish between noxious (thermal, chemical, and mechanical) and innocuous events, and can initially transmit this information centrally to the spinal cord.

3. Pain
An unpleasant sensory and emotional experience which we primarily associate with tissue damage or describe in terms of such damage, or both
Pain is “the perception of a noxious stimulus that begins in the dorsal horn and involves the entire spinal cord and brain.”
The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience which we primarily associate with tissue damage or describe in terms of such damage, or both.”
Pain can be described in terms of sensory, emotional, and cognitive components. These 3 components of pain are reflected in the mechanisms of the transmission and modulation of painful stimuli. Such mechanisms are mediated through the nociceptor neurons, the spinal cord processes, and the cerebral or brain processes.
Many different taxonomies exist for the classification of pain. In the clinical setting, a physician must infer the pathophysiology of a pain syndrome from his or her patient’s clinical evaluation. The most common of these inferred pathophysiologies may be described as nociceptive, neuropathic, and mixed.
For more information, please see Pain Assessment.

4. Classification of Pain Nociception
Proportionate to the stimulation of the nociceptor
When acute
Physiologic pain
Serves a protective function
Normal pain
Pathologic when chronic
Pain is termed “nociceptive” when the clinical evaluation suggests that it is sustained primarily by the nociceptive system.
Nociceptive pain is pain that is proportionate to the degree of actual tissue damage. A more severe injury results in a pain that is perceived to be greater than that caused by a less severe injury.
Such pain serves a protective function. Sensing a noxious stimulus, a person behaves in certain ways to reduce the injury and promote healing (eg, pulling his finger away from a hot object). This “good” pain serves a positive function.
Some examples of nociceptive pain are acute burns, bone fracture, and other somatic and visceral pains.

5. Classification of Pain: Neuropathic Pain
Sustained by aberrant processes in PNS or CNS
Disproportionate to the stimulation of nociceptor
Serves no protective function
Pathologic pain
Neuropathic pain occurs through central nervous system (CNS) changes, such as the processes of “wind-up” phenomenon and central sensitization that can occur in patients with a prolonged exposure to noxious stimuli or nerve injury, or through peripheral nervous system (PNS) changes, such as neuroma formation. It is disproportionate to the degree of tissue damage; it can occur without nociception.
Also called neurogenic pain, neuropathic pain occurs when pathophysiologic changes become independent of the inciting event, thus serving no protective function.
Neuropathic pain does not serve a positive function for the overall health of the person.
Some examples of neuropathic pain are painful diabetic and other peripheral neuropathies, deafferentation and sympathetically-maintained pains, and nerve inflammation, compression, or laceration.
For more information, please see Pain Assessment and Neuropathic Pain.

6. Classification of Pain: Mixed Pain
Nociceptive components
Neuropathic components
Examples
Failed low-back-surgery syndrome
Complex regional pain syndrome
In a given patient, components of continued nociceptive pain may coexist with a component of neuropathic pain. Patients with persistent back and leg pain following lumbar spine surgery (failed low-back-surgery syndrome) represent a common example. Some patients with complex regional pain syndrome (reflex sympathetic dystrophy or causalgia) may develop painful complications that are nociceptive (eg, joint ankylosis, myofascial pain) and that coexist with the underlying neuropathic pain.

7. Classification of Pain: Idiopathic Pain
No underlying lesion found yet, despite investigation
Pain disproportionate to the degree of clinically discernible tissue injury
Idiopathic pain may be defined as pain that persists without any identifiable organic lesions or as pain that is disproportionate to the degree of tissue damage.

8. Normal Central Pain Mechanisms

9. Peripheral and Central Pathways for Pain
Ascending Tracts
Descending Tracts
Cortex
Thalamus
Midbrain
Pons
The physiology of normal pain transmission involves some basic concepts that are necessary to understand the pathophysiology of abnormal or nonphysiologic pain. These include the concept of transduction of the first-order afferent neuron nociceptors. The nociceptor neurons have specific receptors that respond to specific stimuli if a specific degree of amplitude of the stimulus is applied to the receptor in the periphery. If sufficient stimulation of the receptor occurs, then there is a depolarization of the nociceptor neuron.
The nociceptive axon carries this impulse from the periphery into the dorsal horn of the spinal cord to make connections directly, and indirectly, through spinal interneurons, with second-order afferent neurons in the spinal cord.
The second-order neurons can transmit these impulses from the spinal cord to the brain. Second-order neurons ascend mostly via the spinothalamic tract up the spinal cord and terminate in higher neural structures, including the thalamus of the brain.
Third-order neurons originate from the thalamus and transmit their signals to the cerebral cortex.
Evidence exists that numerous supraspinal control areas—including the reticular formation, midbrain, thalamus, hypothalamus, the limbic system of the amygdala and the cingulate cortex, basal ganglia, and cerebral cortex—modulate pain. Neurons originating from these cerebral areas synapse with the neuronal cells of the descending spinal pathways, which terminate in the dorsal horn of the spinal cord.
Medulla
Spinal Cord

10. Pain-Inhibitory and Pain-Facilitatory Mechanisms Within the Dorsal Horn
A-BETA
A-DELTA C
_ _ +
Neuronal circuitry
within the dorsal horn.
Primary afferent neuron
axons synapse onto
spinothalamic neurons
and onto inhibitory and
excitatory neurons.
Several types of primary afferent neurons synapse on neurons of origin of central pain-related pathways, including neurons of the spinothalamic tract (STT).
These include tactile mechanoreceptive neurons that have myelinated A-beta axons and have rapid conduction velocities (>30 m/sec). They synapse onto dorsal horn STT neurons and onto inhibitory interneurons. The latter inhibit the STT neurons soon after the STT neurons are briefly excited by impulses in A-beta axons.
They also include the A-delta and C-fibers. These primary afferent fibers have what are called nociceptors at their distal ends, which respond to specific types of external (eg, the skin) or internal, such as visceral organs, (eg, the liver) sensory stimuli. The cell bodies of these A-delta and C-fiber neurons are located in the dorsal root ganglia, external to the spinal cord. The A-delta fibers are small, lightly myelinated neurons, which conduct impulses for the sensory modalities of touch, pressure, pain, and temperature. These fibers have conduction velocities of 3 to 30 m/sec. The C-fibers are unmyelinated neurons that conduct impulses carrying pain and temperature sensory information from their nerve endings. The C-fibers conduct impulses with velocities of 0.3 to 1.5 m/sec.
There are interactions between pain-inhibitory and pain-facilitatory mechanisms within the dorsal horn. The magnitude of pain depends partly on the balance between these inhibitory and facilitatory mechanisms.
Inhibitory mechanism: Responses of STT neurons to nociceptive stimuli can be inhibited by repetitive stimulation of primary A-beta mechanoreceptive neurons. This is mediated through presynaptic inhibition in the substantia gelatinosa of the dorsal horn. This inhibition is what occurs during transcutaneous electrical nerve stimulation (TENS) and dorsal column stimulation, both clinically therapeutic interventions for patients with pain. Descending pathways from areas rostral in the CNS also can inhibit STT neurons.
Facilitatory mechanism: Responses of STT neurons to nociceptive stimuli can be facilitated if they have been subjected to long-term excessive impulse input from C-fiber nociceptive neurons (sensitization). This long-term excessive input can be caused by chronic inflammation or other chronic noxious stimulation of C-fibers. Descending facilitatory mechanisms also exist.
STT NEURON +
+ +
TO BRAIN

11. Rating of First and Second Pain Intensity
When a single brief nociceptive stimulus is applied to the hand or foot, the resultant experience is often that of a first pricking pain. This “first” pain is followed 1 to 1.5 seconds later (depending on conduction distance) by a “second” subsequent burning, throbbing, or aching pain.
Similar to the double-pain phenomenon, synchronous stimulation of A-delta and C-fiber afferents reliably evokes a brief latency high-frequency impulse discharge, followed by a long latency discharge in the same STT neuron. This is explained by the C-fiber’s slower conduction velocity of impulses.
Graph A is a plot of the impulses evoked in a dorsal horn spinothalamic neuron at different times after 1 electrical activation of A and C axons of the sural nerve of a monkey. Note the double response that is related to differences in conduction velocity of the 2 axon groups (A vs C).
Graph B is an instant analogue rating of “first” and “second” pain in human subjects, also associated with A and C axon stimulation. Note the similarity to graph A.
Both A-delta and C nociceptive afferents directly excite STT dorsal horn neurons. Differences in conduction velocity between these 2 types of afferent axons give rise to a double response both in STT neurons and to the “first” and “second” pain in humans. The A-delta fibers, which conduct impulses at a much faster velocity than the C-fibers, is the explanation for the A-delta fiber attributed to the “first” pain response. The “second” pain shortly follows the “first” pain, as this “second” pain is more slowly conducted via unmyelinated C-fiber.
Adapted with permission from Cooper BY, et al. Pain. 1986;24:103 and from Lee KH, et al. In: Fields HL, Dubner R, Cervero F, eds. Proceedings of the Fourth World Congress on Pain. New York, NY: Raven Press; 1985:204.

12. Mechanisms of Pathologic Pain

13. Mechanisms of Pathologic Pain: General Considerations
Pain-processing mechanisms function abnormally
Examples: neuropathic pain syndromes
Nociception is sustained by chronic injury
Example: arthritis
Pathologic pain occurs when prolonged nociception continues to drive pain that outlasts its physiologic usefulness (as a signal to avoid harm and promote healing) and when pain-processing mechanisms themselves function abnormally. The latter occur in neuropathic pain syndromes, such as postherpetic neuralgia and central pain due to stroke.
Pathophysiologic mechanisms include both peripheral and central processes. These mechanisms occur during both prolonged nociceptive pain and neuropathic pain.
For more information, please see Neuropathic Pain.

14. Mechanisms of Pathophysiologic Pain: Peripheral Processes
 Injured or diseased nerve(s)
Growth of axonal sprouts
Formation of ectopic foci
A common peripheral source of pathophysiologic pain involves injured or diseased nerves.
Damaged nerves often grow axonal sprouts in which receptors to norepinephrine proliferate. These sprouts become highly sensitive to norepinephrine and thus to sympathetic nerve discharge. The nerves develop active sodium channels that become the sites of tonic impulse generation, known as ectopic foci.
These tonic impulses occur in primary nociceptive axons in the absence of a tonic nociceptive stimulus (eg, intense heat).
This abnormal tonic-impulse–input in nociceptors leads to central sensitization, an important concept in the pathophysiology of chronic pain.

15. Mechanisms of Pathophysiologic Pain: Central Sensitization Processes
Repeated impulse activity in C nociceptive neurons produces sensitization of STT neurons over time
Sensitization of STT neurons leads to
Increased spontaneous impulse activity
Enhanced responses to impulses in nociceptive and non-nociceptive primary afferents
Causes hyperalgesia, allodynia, and spontaneous pain
Constant and/or intense bombardment of impulses from nociceptive afferents, particularly C nociceptive afferents, may lead to sensitization of dorsal horn neurons.
Sensitization of dorsal horn neurons leads to increased spontaneous impulse activity and their enhanced responses to impulses in nociceptive and even non-nociceptive primary afferents.
The consequences are hyperalgesia, allodynia, and spontaneous pain.

16. Temporal summation of second pain (second pain summation is a result of repeated input from C-fiber).
Temporal summation of responses of a dorsal horn (STT) neuron to repeated C-fiber stimulation and the effects of the NMDA-receptor antagonist ketamine.
Experiments on STT neurons and “first” and “second” pain provide clues to understanding the modulatory mechanisms of pain.
The top graph reflects the mean ratings of subjects to second pain that is evoked repeatedly by individual stimuli, heat pulses, that elicit first and second pain. The numbers on the x-axis refer to the stimulus number within a series of such heat pulses; the broken lines indicate the condition where first pain is selectively blocked, and the solid lines indicate the condition where first pain is intact.
The graph shows that the perceived magnitude of second pain increases throughout a series of heat pulses (repeated at least once every 3 seconds). This progressive increase is a result of NMDA-receptor activation in the dorsal horn. The bottom graph shows why this occurs.
This slow temporal summation can be evoked only by C nociceptive afferent stimulation and is never evoked by stimulation of A-beta afferents in pain-free individuals.
Both the magnitude of second pain and that of the long latency impulse discharge increase after blockade of impulses in A-fiber afferents. This enhancement is likely to be related to the reduction of the inhibitory influence of low-threshold A-beta mechanoreceptive afferents and is highly relevant to some forms of abnormal pain.
Repeated artificial stimulation of C afferents mimics the tonic impulse discharge that occurs in these afferents during inflammation and after some forms of nerve injury.
Both temporal summation of second pain and the temporal summation of responses of STT neurons to repeated C-afferent stimulation can be blocked pharmacologically. Thus the “wind-up” phenomenon can be abolished by the presence of a pharmacologic antagonist to the N-methyl-D-aspartate (NMDA) receptor, a receptor that resides on the neuronal membrane of STT neurons.
This temporal summation or “wind-up” is a key to understanding mechanisms of central sensitization and central hyperalgesia and allodynia.
Reproduced with permission from Price DD, et al. In: Fields HL, Liebeskind JC, eds. Pharmacological Approaches to the Treatment of Chronic Pain: New Concepts and Critical Issues. Seattle, Wash: IASP Press; 1994:66.

17. Mechanism of Central Sensitization Associated With Tonic C Nociceptor Input
A-BETA
A-DELTA C
Tonic activity in C nociceptors
_ _ + +
STT NEURON +
+ +
Enhanced postsynaptic effects by NMDA-receptor sensitization
Central sensitization depends on tonic activity in primary nociceptors (top right) and NMDA-receptor sensitization.
Activation of primary C nociceptive afferents leads to the release of excitatory amino acids such as glutamate and aspartate. These excitatory amino acids simultaneously bind to different types of postsynaptic receptors on the membranes of STT neurons with the following consequences:
Glutamate/aspartate activation of the AMPA receptor leads to brief depolarization (100–200 milliseconds), often with action potentials in STT neurons.
Glutamate/aspartate activation of the NMDA receptor leads to long duration depolarization (1–2 seconds). Release of substance P, a peptide released from C nociceptive afferent neurons, adds to the long-term depolarization produced by glutamate/aspartate activation of NMDA receptors.
Repeated impulses from C nociceptive afferents leads to temporal summation of responses in STT neurons if the interval between the peripheral C impulses is about 2 seconds or less.
This temporal summation can occur because of the long-duration depolarization produced by NMDA-receptor activation.
The slow temporal summation leads to a steady depolarization and an increased responsiveness of the STT neuron to all of its primary afferent inputs. These input impulses are transmitted via A-beta, A-delta, and C-fiber axons. This increased responsiveness of the STT neurons is referred to as sensitization. Thus, even previously non-noxious stimuli such as light touch now may be perceived as pain.
Slow temporal summation and sensitization can occur if there is a steady flow of nerve impulses coming into the spinal cord from C nociceptive neurons, for example, during inflammation and after some types of nerve injury. + + + +
TO BRAIN

18. Intracellular  Mechanisms of Sensitization
This figure details the biochemical mechanism of central sensitization.
Central sensitization within the dorsal horn is related to an excitatory cascade triggered by continuous impulse input from the C-nociceptive afferents.
Features of this cascade include:
Ongoing C-fiber nociceptive peripheral nerve impulse input (such as that which occurs during inflammation or nerve injury).
Repeated NMDA receptor (NMDA-R) activation follows C-fiber release of glutamate and its binding to the NMDA receptor of the membrane of a STT neuron. This NMDA activation, along with substance P release, results in a buildup of intracellular calcium ion (Ca++).
A Ca++-induced protein kinase C (PKC) activation, the translocation of this activated PKC from the cytoplasm to the plasma membrane, leads to PKC-induced sensitization of the NMDA receptor via phosphorylation of NMDA receptor proteins. It also leads to reduced sensitivity of the opioid receptor.
This mechanism represents a positive-feedback loop wherein continuous release of glutamate/aspartate onto NMDA receptors of STT neurons ultimately leads to the sensitization of those very same NMDA receptors.
The STT neuron then becomes hyperresponsive to input from primary nociceptive neurons and to peripheral painful stimuli (eg, intense heat, pinch, etc). STT hyper-responsiveness leads to hyperalgesia (pain that is more intense than normal) or allodynia (pain resulting from a normally nonpainful stimulus such as touch). These reflect central hyperalgesia and allodynia, which can result in continuous pain being perceived by a patient.
Reproduced with permission from Mao J, et al. Pain. 1995;61:361.

19. Loss of Inhibitory Interneuron FunctionC
A-BETA
A-DELTA
Tonic activity in C nociceptors
_ _ +
STT NEURON +
+ +
Enhanced postsynaptic effects by NMDA-receptor sensitization
Under normal conditions, repetitive stimulation of A-beta mechanoreceptive afferents initially excites and then inhibits dorsal horn STT neurons (via interposed interneurons releasing GABA or enkephalin).
In addition to the mechanisms of sensitization, inhibitory interneurons sometimes stop functioning during severe conditions of neuropathic pain. This is hypothesized to result from denervation of input from A-beta afferent (deafferentation) or glutamate excitotoxicity.
The loss of inhibitory mechanisms that normally limit the excitation of STT neurons results in enhancement of STT neurons to peripheral stimuli.
This mechanism enhances the severity of the pain perceived by a patient and may cause allodynia/hyperalgesia. + + + +
TO BRAIN

20. Brain-to-Spinal-Cord Modulation of Pain

21. Pain Modulation Mechanisms
Brain centers/pathways that descend to the spinal cord and modulate pain
“Tail-flick test”
“Off-cells” inhibit transmission of pain-related information to the brain
“On-cells” facilitate transmission of pain-related signals to the brain
Brain centers and pathways exist that descend to the spinal cord and amplify or inhibit the transmission of pain-related signals.
An experimental model of rats was used to perform the “tail-flick test” as evidence supportive of this facilitatory modulation mechanism.
In 1985, it was found by Fields and colleagues that 1 group of cells in the rostral ventromedial medulla would stop and reduce their spontaneous firing rate immediately prior to the rat’s moving its tail away from a noxious heat stimulus. These cells were called the “off-cells.” Another group of cells in this same area of the medulla demonstrated a burst and increased rate of discharge firing immediately before the tail-flick in response to a heat stimulus; these cells were called the “on-cells.”
“On-cells” are thought to facilitate transmission of pain-related information to the brain, while “off-cells” are thought to inhibit the transmission of pain-related information to the brain.

22. Pathophysiology of Pain: Conclusion
Neuronal plasticity
Nociceptor, spinal cord, brain
Pain-facilitatory and pathophysiologic mechanisms
Wind-up phenomenon
Central sensitization
Modulating mechanisms
Ascending
Descending
Understanding of the pathophysiology of pain involves the concepts of neuronal plasticity at the levels of the nociceptor neurons, spinal cord, and brain. These concepts include modulatory effects at the nociceptor, sympathetically-mediated pain, the “wind-up” phenomenon, central sensitization, and descending and ascending central modulatory mechanisms for the perception of pain as well as the related pain motivations and behaviors.
A proposed natural history of pain for an individual has many variables that lead to the patient’s recovering fully or experiencing chronic pain. Some of these variables or conditions include the chronicity of noxious stimulation, partial recovery, repetitive/new injury, stress, and sympathetically-mediated pain mechanisms.
Numerous modulatory mechanisms for pain have been postulated, which control the degree of pain perceived and the emotional and behavioral phenomena associated with a patient’s pain experience. These numerous mechanisms take place at all levels of the nervous system—peripheral nerve, spinal cord, and brain.
Despite great advances in unraveling the complexities of the pathophysiology of pain, much remains to be discovered that will hopefully lead to better therapies.

23. Suggested Reading
Adam RD, Victor M, Ropper AH. Pain. In: Adam RD, Victor M, Ropper AH, eds. Principles of Neurology. 6th ed. New York, NY: McGraw-Hill; 1997:
Bennett RM. Emerging concepts in the neurobiology of chronic pain: evidence of abnormal sensory processing in fibromyalgia. Mayo Clin Proc. 1999;74:
Cooper BY, Vierck CJ Jr, Yeomans DC. Selective reduction of second pain sensations by systemic morphine in humans. Pain. 1986;24:
Fields HL, Price DD. Toward a neurobiology of placebo analgesia. In: Harrington A, ed. The Placebo Effect. An Interdisciplinary Exploration. Cambridge, Mass: Harvard University Press; 1997:
Galer BS, Dworkin RH. Pathophysiology of neuropathic pain. In: Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain. Minneapolis, Minn: Healthcare Information Programs, a division of McGraw-Hill Healthcare Information; 2000:33-36.
Gilman S, Newman SW. Manter and Gatz’s Essentials of Clinical Neuroanatomy and Neurophysiology. 7th ed. Philadelphia, Pa: F.A. Davis Company; 1987.
Hooshmand H. Pathophysiology of the sympathetic system. In: Hooshmand H, ed. Chronic Pain: Reflex Sympathetic Dystrophy. Prevention and Management. Boca Raton, Fla: 1993:33-55.
Loeser JD. Pain and suffering. Clin J Pain. 2000;16(suppl):S2-S6.
Loeser JD, Butler SH, Chapman CR, Turk DC, eds. Bonica’s Management of Pain. 3rd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001.
Mao J, Price DD, Mayer DJ. Experimental mononeuropathy reduces the antinociceptive effects of morphine: implications for common intracellular mechanisms involved in morphine tolerance and neuropathic pain. Pain. 1995;61:
Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. Philadelphia, Pa: F.A. Davis Company; 1996.
Price DD, Mao J, Mayer DJ. Central neural mechanisms of normal and abnormal pain states. In: Fields HL, Liebeskind JC, eds. Pharmacological Approaches to the Treatment of Chronic Pain: New Concepts and Critical Issues. Seattle, Wash: IASP Press; 1994: Progress in Pain Research and Management, Vol 1.
Roberts WJ. A hypothesis on the physiological basis for causalgia and related pains. Pain. 1986;24:
Shealy CN, Cady RK. Historical perspective on pain management. In: Weiner RS, ed. Pain Management: A Practical Guide for Clinicians. 5th ed. Boca Raton, Fla: St. Lucie Press; 1998:7-15.
Urban MO, Gebhart GF. Central mechanisms of pain. Med Clin North Am. 1999;83: