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CHAPTER 2
Richard A. Pertes, DDS
Harold V. Cohen, DDS
The mechanisms involved in nociceptive transmission are fundamentally different from the mechanisms
for neuropathic pain. The nociceptive transmission system is concerned with responses to noxious stimuli
and involves an intact and normally functioning nervous sytem. In contrast, neuropathic pain does not
need a noxious stimulus but does require the presence of nerve injury or abnormal function in the
peripheral or central nervous systems. In other words, nociceptive pain requires activation of nociceptors
while neuropathic pain does not. Nevertheless, while the mechanisms involved in nociceptive and
neuropathic pain differ, they do have some features in common.
MECHANISM OF SOMATIC (NOCICEPTIVE) PAIN
Fields has divided the processing of pain from its origin as a stimulus from a tissue injury to the subjective
experience of pain into the following four steps:
Transduction: The process where a noxious stimulus is converted to electrical activity (nerve impulse) in
the appropriate sensory nerve ending.
Transmission: The process of transmitting the nerve impulse to the cerebral cortex can be divided into
three major stages: 1) the transmission of the nerve impulse from the site of transduction to terminals in
the trigeminal brain stem complex (spinal cord); 2) neuronal relays from the trigeminal brain stem complex
to other brain stem areas and the thalamus; and 3) reciprocal connections between the thalamus and
cerebral cortex.
Modulation: This process is concerned with modifying neural activity leading to control over the pain
transmission neurons. This can result in reduction or enhancement of the nociceptive signal to the higher
centers of the brain.
Perception: The subjective response of suffering and pain behavior that results when pain information is
received in the higher centers of the brain.
TRANSDUCTION
Nerve cells generate an electrical signal or nerve impulse to transmit information. When a noxious
stimulus acts on a nociceptor located at the peripheral end of a primary afferent neuron, various physical
and chemical stimuli are converted into a nerve impulse through the process of transduction. This
electrical nerve impulse is known as an action potential.
The Action Potential:
Action potentials are created through the process of depolarization. To understand this process, it is
necessary to have a basic knowledge about the physiology of nerve cells.
A nerve cell is bounded by membranes composed of bilayers of lipoprotein. At rest, an electrical charge is
maintained across the external and internal surfaces of the cell. This charge, known as the resting
membrane potential, is maintained by the presence of sodium (Na+) and chloride (Cl-) ions on the
outside, and potassium (K+) ions on the inside of the cell. This ratio results in the nerve cell being
positively (+) charged on the outside and negatively (-) charged on the inside. Because the outside of the
cell is arbitrarily designated at zero, the inside of the cell is a negative number.
Spanning the cell membrane are various channels that are selectively permeable to ions. When a noxious
stimulus acts at the peripheral end of an axon, Na channels open to allow an influx of Na into the cell.
Following this, K channels open permitting an efflux of K from the cell. The net result is a reversal of the
nerve membrane polarity, making it more positively charged than the resting membrane potential. This
process is known as depolarization. An action potential will only occur when the membrane potential
reaches a certain critical level called the threshold potential. The action potential or nerve impulse is
then propagated along the length of the axon.
For a noxious stimulus to generate an action potential in an A-Delta or C-fiber, it must be of sufficient
strength to reach the threshold potential. If this critical level is not reached, a nociceptive impulse signal
will not be created. Firing frequency is directly related to the intensity of the stimulus. Under normal
physiologic conditions, a strong, sustained pinch will reach the threshold potential and generate an action
potential while a light pinch will not. However, if the nociceptor has been sensitized by trauma or ongoing
inflammation (nociceptor sensitization), its firing threshold potential may be reduced to a level that
allows a relatively innocuous stimulus such as light touch, to generate pain. When this occurs, the
condition is known as allodynia.
Drugs that block the sodium channel preventing the influx of Na ions into the cell are known as sodium
channel blockers. Without an influx of Na ions into the cell, an action potential cannot be created despite
the presence of a noxious stimulus. In clinical practice, injecting a local anesthetic (e.g., lidocaine,
bupivacaine) can prevent the creation of a potentially pain-producing action potential. In a similar manner,
carbamazepine (Tegretol), the drug of choice for management of trigeminal neuralgia, exerts its effect by
preventing an influx of Na ions into the cell. Interestingly, carbamazepine appears to act only on
hyperactive Na channels and not on normal Na channels. Otherwise, carbamazepine would disrupt
normal impulse transmission throughout the body.
Hyperpolarization:
An action potential represents a transient change in the resting membrane potential of a neuron.
Following an action potential is a brief period of hyperpolarization during which the resting membrane
potential of most nerve cells becomes notably negative. This occurs because of inactivation of Na
channels, an influx of negative chloride ions, and continued efflux of K ions. When hyperpolarization
occurs, the cell is in a refractory period and no action potential can be generated. Within a very short
time, the cell repolarizes to its resting membrane potential.
Drugs such as the benzodiazepines and barbiturates can initiate hyperpolarization. The benzodiazepines
bind at specific receptor sites on the nerve membrane increasing its affinity for the neurotransmitter
gamma-amino-butyric acid (GABA) secreted by interneurons. The increased GABA binding allows more
chloride ions to enter the nerve cell, making the inside more negative and leading to hyperpolarization.
Neurochemistry of Transduction:
Following tissue injury, various inflammatory compounds released at peripheral nerve endings activate
primary afferent fibers. The primary inflammatory mediator is the polypeptide bradykinin (BK) which is
released from plasma proteins. Cell wall injury also results in the release of arachidonic acid that is
processed by various enzyme systems to produce two additional inflammatory mediators, prostaglandins
and leukotrienes. BK acts synergistically with these two inflammatory mediators, as well as histamine and
serotonin, to increase plasma extravasation and edema. While plasma extravasation replenishes the
supply of inflammatory mediators to create a feedback mechanism, it also helps to repair tissue damage
by encouraging lymphatic and venous drainage of inflammatory mediators.
Fig 1. Relationship between inflammatory mediators that develops during course of inflammation. From
Hargreaves et al. Orofacial pain: Peripheral mechanisms. In Fricton JR and Dubner RB (eds): Orofacial
Pain and Temporomandibular Disorders. New York: Raven Press, 1995: 36. Reprinted with permission.
Neurotrophins, such as nerve growth factor (NGF), play an important role in the inflammatory process by
activating mast cells. Mast cells release histamine and serotonin, which indirectly contribute to nociceptor
sensitization, an important process in pain amplification. Inflammatory mediators, including NGF, also
encourage the release of the neuropeptides, substance P and CGRP, which are synthesized in the cell
bodies of primary afferent neurons (C-fibers). The release of these algogenic substances at the peripheral
injury site is referred to as neurogenic inflammation. Substance P and CGRP can be transported
through an axon transport system to the CNS (orthodromically), or away from the CNS toward the
periphery opposite to the direction of normal impulses (antidromically), where they act to increase the
inflammatory response. The sympathetic nervous system also has a role in inflammation through the
release of norepinephrine (NE) from sympathetic postganglionic efferent fibers. NE encourages vascular
permeability and plasma extravasation which increases the release of inflammatory mediators.
TRANSMISSION
The process of transmission involves propagation of the action potential from the site of transduction to
second order neurons in the subnucleus caudalis located in the trigeminal brain stem complex. At that
point another action potential is initiated which travels to higher centers in the brain. Action potentials
frequently travel long distances. By increasing the diameter of an axon, conduction velocity of an action
potential is increased. Similarly, wrapping the axonal membrane in myelin increases the flow of an action
potential. This insulates the axon and reduces the ability of the current to leak out of the axon. At gaps in
the myelin wrapping (known as the nodes of Ranvier), action potentials are generated which actively
serve to push the current along the length of the axon.
The Synapse:
Communications between neurons occur at a synapse. This serves as a relay point enabling neurons to
transmit information from one neuron to another. The synapse is actually a minute fluid-filled gap
interposed between a presynaptic neuron and a postsynaptic neuron. There are two main types of
synapse: electrical and chemical. Electrical synapses permit electric current to flow directly from one
neuron to another in either direction. In the human CNS, most synapses are chemical with only a few
electrical synapses; chemical signaling can only go from a presynaptic neuron to a postsynaptic neuron.
Chemical synapsis requires the presence of a chemical neurotransmitter to act as a messenger between
the communicating neurons.
A single CNS neuron is capable of receiving thousands of connections from other neurons All synapses
between sensory nerves occur within the CNS. When a synapse occurs outside the CNS, it is abnormal
and referred to as an ephapse.
Second Order Neurons:
Once the nociceptive signal is generated, it heads toward its first connection with second order neurons in
the subnucleus caudalis where another action potential is initiated thereby sending the nociceptive
information to higher CNS centers. These second order neurons are mainly wide dynamic range (WDR)
neurons which respond to both noxious and non-noxious stimuli, and nociceptive specific (NS) neurons
which respond to only noxious stimuli. Additionally, there are low threshold mechanoreceptor (LTM)
neurons which respond to non-noxious stimuli.
WDR neurons are the most predominant type of nociceptive neuron in the subnucleus caudalis and
routinely receive input from myelinated A-beta and A-delta fibers as well as unmyelinated C-fibers.
Because non-nociceptive stimuli and excitatory input from nociceptive primary afferents in the skin,
muscle and visceral organs converge on WDR neurons, they are able to respond to a wide range of
stimulus intensities. When WDR neurons are activated by painful stimuli, they may become sensitized
(central sensitization) leading to an expansion of receptive fields and radiation (spreading) of pain.
Interneuronal networks are also activated at the level of subnucleus caudalis. These interneurons are
responsible for transmitting nociceptive information to neurons that project to the brain (projection
neurons). They also pass information to reflex motoneurons resulting in reflex responses to nociception.
When pain perception occurs, the body responds by protecting itself from further tissue injury through
various adaptive physiological responses. An increase in excitability of trigeminal neurons results in
enhanced sensory function to produce phenomena such as hyperalgesia and allodynia. Hyperalgesia is
defined as an increased response to a stimulus that is normally painful; allodynia is a painful response to
a non-noxious stimulus that ordinarily would not be expected to cause pain.
These pain facilitatory responses make the individual more aware of the situation and encourage
responses to guard and immobilize the injured part and protect it from additional injury. But under certain
circumstances, the brain can go into a survival mode completely suppressing pain transmission and
perception through the activation of intrinsic pain inhibitory systems. Common examples of this include
a soldier’s ability to carry on with his/her duties in battle despite being wounded, or an athlete continuing
to compete even while injured.
MODULATION
As the nociceptive neural impulse travels along the neuraxis to higher centers, it is subject to various
modulatory influences that can change it; these changes can be either excitatory or inhibitory. In an effort
to explain the complexity of pain modulation, Melzack and Wall formulated the gate control theory in
1965. At the time, this theory was unique and represented a significant breakthrough in traditional
thinking. Although the gate control theory has been modified over the years, the basic concept has
withstood the test of time.
Gate Control Theory:
Basically, this hypothesis proposes that neural mechanisms in the subnucleus caudalis (spinal dorsal
horn) act like a gate to increase or decrease the transmission of nerve impulses from the periphery to the
brain. This gate defines an area that is the terminus for large numbers of primary afferent fibers, multiple
interneurons, and descending fibers from higher CNS centers.
When the nociceptive signal arrives at the gate, it is subject to modulation by descending neuronal
signals from cortical areas that act to amplify or reduce the intensity of the nociceptive signal coming from
the periphery. Complex interactions between myelinated and unmyelinated primary afferent neurons also
occur at this level to modify the nociceptive impulse. Whether this action potential continues on to
trigeminothalamic (spinothalamic) pathways unimpeded, dampened or extinguished will be determined by
the sum of the actions of excitatory and inhibitory neurotransmitters acting at the synapse of first order
neurons with second order neurons, NS and WDR.
Fig 2. The description of this area as a "gate" symbolizes the net result of excitatory and inhibitory
influences acting on the second order neuron or transmission cell (T). Multiple neurotransmitters act on
the T cell and determine the fate of the nociceptive signal. If the nociceptive signal is not inhibited, it will
"pass through the gate" for transmission to higher centers; if interacting neurons cancel the nociceptive
signal, it will not pass through the gate.
M represents a rapidly conducting non-nociceptive myelinated axon; I is an inhibitory interneuron whose
activity inhibits the T cell; U represents an unmyelinated, nociceptor C-fiber which has an excitatory effect
on the T cell. Also, when the inhibitory neuron I is stimulated by the non-nociceptive myelinated fiber M, it
releases inhibitory neurotransmitters onto the T cell and stops the nociceptive signal. From Fields HL.
Pain, New York: McGraw-Hill, 1987. Reprinted with permission.
In summary, the mechanism of the gate is influenced by nerve impulses that descend from the brain as
well as impulses ascending from the periphery. While large afferent fiber input tends to close the gate and
inhibit transmission, small fiber afferent activity generally opens the gate and facilitates transmission.
What does this mean clinically? An example is the typical effect of rubbing a painful area following trauma
to reduce pain. The rubbing is non-noxious and is mediated by A-beta fibers, which stimulate an inhibitory
interneuron to reduce pain transmission. The pain relieving effects of transcutaneous electrical nerve
stimulation (TENS) can also be explained in terms of the gate control theory based on the analgesic
effect of stimulating non-nociceptive, myelinated, cutaneous A-beta fibers.
Descending Pain Modulating System:
When the source of modulation is from the higher centers of the brain, the various pathways involved are
known collectively as the descending pain modulating system. It derives its name from the fact that
neurons originating in the brain stem descend to exert their influence at the level of the subnucleus
caudalis and the dorsal horn of the spinal cord. These fibers release various substances that alter the
transmission of nociceptive information and produce analgesia. If the nociceptive information does not
reach the cortex, there is no perception or experience of pain.
Fig 3. The descending pain modulating system Complex modulatory effects occur at each of the sites
shown including the dorsal horn (subnucleus caudalis). From Purvis D, Augustine CJ, Fitzpatrick D et al.
Neuroscience. Sunderland MA: Sinauer Associates, 1997: 175. Reprinted with permission.
These descending mechanisms are important for they provide the neural network that permits cognitive,
emotional, and attentive aspects of the pain experience to influence nociceptive pain transmission. The
descending pain modulating system is complex and not well understood. What is clear, however, is that
various pharmacological agents, physiological processes, and psychological interventions can activate an
endogenous pain inhibitory system.
This modulating system consists of three major components in the brain stem: the periaqueductal gray
area located in the midbrain, the raphe magnus in the medulla, and an endogenous opioid system.
Modulation is achieved through inhibiting the release of neurotransmitters from primary afferent neurons
or by inhibiting the activation of second order neurons in the subnucleus caudalis.
Periaqueductal Gray Connections (PAG):
When the ascending nociceptive signal interconnects with a midbrain area, the PAG, inhibition can occur
at this level. Of even more significance is the fact that the PAG activates descending pathways to reduce
the nociceptive signal at its first synapse in the subnucleus caudalis (spinal dorsal horn). From the PAG,
pathways descend to various nuclei in the medulla causing the release of the inhibitory monamines,
serotonin (5-HT) and norepinephrine (NE). The main source of 5-HT is the nucleus raphe magnus; the
locus ceruleus serves as the main source of NE. Direct stimulation of the nucleus raphe magnus in the
medulla also evokes the release of 5-HT. Animal studies have demonstrated that these areas, as well as
the spinal tract of the trigeminal complex, also produced analgesia when stimulated by exogenous
opioids. This led to the discovery of an endogenous opioid system.
Endogenous Opioid Pain Inhibitory System:
Although various endogenous processes may prevent the action potential from synapsing with second
order neurons in the trigeminal sensory complex, the most important intrinsic mechanism is the
endogenous opioid system. The endogenous opioid peptides are naturally occurring pain-dampening
neurotransmitters that are part of the body’s internal pain control system. These endogenous opioids are
released after nociceptive stimuli and include the enkephalins, dynorphins, and beta-endorphin related
peptides. Their properties are comparable to the exogenous opioids, such as morphine and codeine.
Opioid peptides and their receptors are located presynaptically and postsynaptically on second order
neurons in the subnucleus caudalis (substantia gelatinosa of the spinal dorsal horn), as well as on several
other levels of the descending inhibitory system. Opioid receptors have also been found on peripheral
terminals of primary afferent neurons and cells of the immune system. All opioids achieve their analgesic
effect by reducing or inhibiting nociceptive transmission through preventing the release of the excitatory
neurotransmitter, substance P, from the primary afferent nerve terminal. In contrast to serotonin and
norepinephrine, which act to alleviate chronic pain, the opioids are effective primarily in acute pain
conditions.
It should be noted that other important modulatory processes use the neurotransmitters, gamma
aminobutyric acid (GABA) and glycine. In contrast to the endogenous opioid system, GABA does not act
by inhibiting the release of substance P. Rather, it causes chloride to enter the nociceptive-conducting
axon resulting in hyperpolarization of the neuronal membrane and inhibition of the nociceptive axon
potential.
Other Modulatory Areas:
Further modulation of the ascending nociceptive signal can also take place at higher levels through a
complex series of interactions between the thalamus, hypothalamus, limbic, and cortical regions. This is
accomplished by the brain stem reticular formation, a diffuse network of cell bodies located in the
medulla, pons, and midbrain with extensive interconnections to the spinal cord, thalamus, hypothalamus,
limbic system, and perhaps the cortex.
The reticular formation exerts its influence on ascending nociceptive signals and its action can be either
excitatory or inhibitory. The reticular formation is probably responsible for the general arousal caused by
pain and for the "fight or flight" reaction to a threatening situation. Reciprocal connections between the
reticular formation and the limbic system are also believed to play an important role in the motivationalaffective dimension of pain.
PERCEPTION
Perception is the end point of neural activity of nociceptive information. When this information reaches the
brain, it becomes a conscious experience. The transmission of sensory information from the periphery to
the brain is known as the sensory-discriminative component of pain. While it is still unclear which neural
systems are exactly responsible for integrating and acting on this information being transmitted to the
brain, it is apparent that areas in the somatosensory cortex are primarily involved.
But pain is not merely the end product of pain transmission; there is also a motivational-affective aspect
to pain. Because pain has a definite unpleasant quality, it overwhelms almost all other considerations and
demands immediate attention to stop the pain. It is the motivational-affective component that drives the
individual into activity to stop the pain as quickly as possible.
Pain is a highly personal experience that varies with the individual. It has been suggested that there is
also a cognitive-evaluative dimension to pain that affects both the sensory-discriminative and
motivational-affective components of pain. Cognitive activities such as cultural learning, anxiety, the
meaning of the situation attending the pain, attention paid to the pain and suggestion all profoundly affect
the pain experience. To reduce the sensory and affective components of pain, various cognitivebehavioral techniques such as relaxation training, guided imagery and distraction have been employed
with varying degrees of success.
TISSUE INJURY
When peripheral tissue damage occurs, an inflammatory response is evoked. Common signs include
edema, pain, erythema and loss of function. Another result of tissue damage is hyperalgesia which is
defined as an increased response to a stimulus that is normally painful. Hyperalgesia can be separated
into two basic types: inflammatory hyperalgesia, which follows peripheral damage to somatic tissues,
and neuropathic hyperalgesia, which arises as a consequence of nerve damage in addition to somatic
tissue injury. Allodynia, described as a painful response to a stimulus that is not normally painful, such as
light touch, is considered a subset of hyperalgesia.
Both somatic (inflammatory) pain and neuropathic pain have some features in common -- hyperalgesia,
allodynia and ongoing spontaneous pain. Although our understanding of the pathophysiologic
mechanisms behind the production of pain following injury is still lacking, it is evident that the pain of both
inflammatory and neuropathic hyperalgesia involves altered processing in the CNS as well as changes at
the site of injury. Because hyperalgesia is commonly found in many orofacial pain conditions,
understanding the mechanisms involved is important from both a diagnostic and therapeutic viewpoint.
Inflammatory Hyperalgesia:
Hyperalgesia is usually classified as either primary or secondary. Primary hyperalgesia is restricted to the
area immediately adjacent to the site of injury and occurs because of increased sensitivity in peripheral
nociceptors, referred to as peripheral or nociceptor sensitization. The affected nociceptors not only
show an increased response to noxious stimuli, they also exhibit spontaneous pain and lowered
thresholds to both noxious and non-noxious stimuli. In allodynia, second order neurons become reactive
to light touch mediated through normally non-painful A-beta fibers. This is attributed to a lowered firing
threshold of peripheral nociceptive nerve endings and to central changes.
Peripheral (Nociceptor) Sensitization:
Sensitization of nociceptors is due to the action of various inflammatory mediators that are synthesized
and released at the site of injury following tissue damage. These inflammatory substances cause lowering
of the threshold for depolarization of the nociceptor. This results in increased nociceptor reactivity to
mechanical, chemical or thermal stimuli in the primary zone of injury known as primary hyperalgesia. By
providing a signal to immobilize the injured part, nociceptor sensitization serves as a defense mechanism
to protect the injured tissue from further damage.
The process of neurogenic inflammation plays a primary role in peripheral sensitization. Neurogenic
inflammation is a basic pain mechanism involving the release of two prominent mediators of pain from the
afferent nerve cell bodies of C-fibers in the trigeminal ganglion: the neuropeptides substance P and
CGRP. When these neurotransmitters are transported to the peripheral endings of nerve terminals, they
cause sensitization of primary afferent nociceptors. Neurogenic inflammation is also important in the
central processing of nociceptive information and is involved in the pathogenesis of neuropathic pain,
migraine headaches and musculoskeletal pain disorders.
Another factor in receptor sensitization is the awakening of otherwise "sleeping or silent" nociceptors.
Normally, these afferent nerve fibers are inactive and do not respond to mechanical stimuli. However,
following tissue injury, they can become active and respond to relatively innocuous mechanical stimuli
thereby adding to the nociceptive input to the CNS.
Secondary hyperalgesia refers to increased sensitivity to stimulation in an area that spreads away from
the injury site. The zone of secondary hyperalgesia is considered to be a CNS response to protect the
original site of injury. In contrast to primary hyperalgesia (which is mainly due to peripheral sensitization),
secondary hyperalgesia is caused by increased excitability in trigeminal second order neurons known as
central sensitization.
Central Sensitization:
Following a marked increase in nociceptor stimulation or nerve damage, structural and functional
changes occur in the trigeminal brain stem complex, specifically involving second order neurons. These
central physiologic changes are referred to as central neuroplasticity and primarily affect WDR second
order neurons in the subnucleus caudalis. An important result of this reorganization in CNS nociceptive
pathways is the development of central sensitization or hyperexcitability to afferent stimuli by second
order neurons.
Neurogenic inflammation is also prominent in the development of central sensitization. Both substance P
and CGRP, along with other neuropeptides, neurokinin A and somatostatin, can also be transported
centrally via unmyelinated afferent C-fibers (axon reflex) to second order neurons in the subnucleus
caudalis. Here these neurochemicals have been implicated in triggering central neuroplasticity and
central sensitization following tissue injury or noxious stimulation.
Activation of N-methyl d-aspartate (NMDA) receptors is one of the primary mechanisms involved in
central sensitization. Not only is pain increased when nociceptive impulses reach second order neurons,
but even a weak stimulus such as light touch is able to trigger a painful response for a brief period of time
(allodynia). Central sensitization has multiple other effects in addition to allodynia and secondary
hyperalgesia; it can cause increased spontaneous activity and expanded receptive fields. An enhanced
receptor field represents the ability of second order neurons to respond to a wider area of peripheral
stimulation. (See Fig.4)
Central Sensitization
Another subtype of central sensitization is the phenomenon of "wind-up" in which the response of
trigeminal second order neurons is significantly increased, although the intensity of noxious stimulus
remains the same. Wind-up results from repetitive C-fiber activity and represents facilitation of pain and
sensitization of WDR neurons. The mechanism responsible for wind-up is thought to be due to the
release of the excitatory neurotransmitter glutamate and its action on NMDA receptors. Hyperpathia, a
common disorder seen in neuropathic pain particularly when there is a loss of nerve fibers, can also result
from central sensitization. Hyperpathia is expressed clinically as an explosive pain response when the
stimulus intensity exceeds sensory threshold.
In summary, both somatic tissue injury and nerve injury can lead to peripheral and central sensitization.
Both types of injury produce an increased neuronal barrage reaching the CNS and cause increased
depolarization or excitation by excitatory amino acids at NMDA receptor sites. This can lead to an
expanded receptive field, hyperexcitability of second order neurons resulting in hyperalgesia and
allodynia and increased pain. If the injury is excessive, hyperexcitability and/or depolarization can cause
loss of inhibitory mechanisms with more pain and a larger receptive field. Central sensitization is
increased after a deep tissue injury of muscle or viscera.
MECHANISMS OF NEUROPATHIC PAIN
Neuropathic pain is one of the most challenging and complex pain syndromes. It results from an
abnormality in one or more components of the nervous system i.e., peripheral, central or autonomic.
These disorders comprise a group of subtypes precipitated by neural injury or disease that can result in a
neuropathic pain problem, a sensory deficit or both. In contrast to somatic (nociceptive) pain, which is
related to noxious stimulation, neuropathic pain does not require the presence of a noxious stimulus and
does not serve as a warning signal to the body. As previously stated, while the mechanisms involved in
somatic pain differ from those in neuropathic pain, they nevertheless share some features in common.
Neuropathic pain is complex. It is not unusual to find more than one distinct pain mechanism involved in
an individual patient with neuropathic pain. Even patients with similar symptoms may have different
underlying mechanisms. Management of neuropathic pain is based on matching specific treatments to
different pain-generating mechanisms. But despite the growing body of knowledge on neuropathic pain
mechanisms, some patients still do not respond to current treatment protocols.
Five main mechanisms have been identified in peripheral nerve injury: 1) nerve compression, 2) neuroma
formation, 3) neurogenic inflammation, 4) sympathetic nervous system involvement, and 5)
deafferentation. Although these mechanisms have been separated for purposes of discussion, it should
be noted they are often intertwined.
1. Nerve Compression:
When a peripheral nerve is subjected to compression or stretching, the injury may result in either
neuropathic pain or a sensory deficit. Compression of a nerve will initially cause inflammation and edema
leading to nerve degeneration. The extent of nerve degeneration depends upon the magnitude and
duration of the compression with both mechanical deformation and ischemic factors playing a role.
The most important local pathological change to the nerve is loss of the myelin covering at the site of
injury (segmental demyelination). Only myelinated fibers are affected by segmental demyelination; no
damage occurs to unmyelinated C-fibers. The large myelinated A-alpha and A-beta fibers are affected
first, followed by the smaller A-delta fibers. Although the axon is still able to conduct nerve impulses,
altered cell membrane physiology at the point of demyelination (reorganization of sodium channels) may
allow the electrical impulse to "leak out" and become a source of ectopic impulse generation. In other
words, the injury site can acquire the abnormal capability of generating nerve impulses on its own. No
external stimulus is necessary; the nerve just depolarizes.
Because the nerve has lost its protective insulation, the points of demyelination may also permit the nerve
to be abnormally influenced by activity in adjacent axons. This "cross-talk" between neighboring axons is
termed "ephapsis" and may account for the spread of abnormal sensations from the original site of
ectopic impulses.
Vascular compression of a trigeminal nerve root has been suggested as an important etiologic factor in
trigeminal neuralgia. Research has shown that when impulses evoked by light tactile stimuli arrive at a
point of demyelination, ectopic impulses are generated. Both ectopic impulse generation and ephaptic
transmission contribute to the paroxysmal bursts of discharges seen in trigeminal neuralgia. Nerve
compression pain can also be continuous with associated allodynia and hyperalgesia, or may be
expressed as paresthesia (an abnormal sensation) and dysesthesia (an uncomfortable abnormal
sensation).
The plaques of multiple sclerosis can also cause demyelination. This may account for the sensory
abnormalities and bursts of paroxysmal pain associated with this disorder. Unless the demyelination
process is prolonged or is caused by a progressive systemic disease such as multiple sclerosis, it is
usually reversible. This reversibility is the basis for the neurosurgical procedure of vascular
decompression and is frequently employed to relieve the pain of trigeminal neuralgia.
2. Neuroma Formation:
When a nerve is severed, new extensions will sprout from the end of the severed nerve in an attempt to
regenerate and reconnect with the peripheral structure it innervated. If the connective tissue sheath
covering the nerve (Schwann cell tube) is still intact, axonal sprouts will enter it and use the sheath as a
mechanical guide for reconnection. This attempt at regeneration will probably be successful. But if the
sheath is severely damaged and not available, these nerve sprouts will be unable to find the correct path
for reconnection with the distal part of the nerve. Instead they will interdigitate and wind up in a mass of
tangled, disorganized tissue known as a neuroma. Although full sectioning of the nerve is the usual
scenario for neuroma formation, partial severance of a nerve can also cause a neuroma, i.e., a neuromain-continuity. Microneuromas can form even after seemingly minor trauma such as a skin incision.
The area of sprouting and the neuroma are exceedingly sensitive to mechanical disturbances. This
phenomenon is known as Tinel’s sign -- a light tapping of the tip of a regenerating peripheral nerve
causing tingling. Any movement that stretches or compresses the nerve may cause shooting pains in the
area of the neuroma. The pain arising from a neuroma is described as continuous with occasional bursts
of sharp, shooting pain.
Because the neuroma involves a somatic sensory neuron, the pain can be temporarily blocked with local
anesthesia. Not only is the area of the regenerating sprout abnormally sensitive but the cell bodies from
which they arise may also be damaged and extremely sensitive. Both neuroma sprouts and cell bodies
are able to depolarize readily causing an ectopic discharge of impulses resulting in spontaneous pain.
Neuromas can also become sensitized to adrenergic substances released by the sympathetic nervous
system (SMP). This sensitivity is due to an up-regulation in the number of adrenergic receptors on the
sprouting nerve terminals. It may account for exaggerated pain responses to heat and cold and increased
pain during periods of emotional stress when there is an increase in norepinephrine. Unless a neuroma is
surgically excised, it can persist as a continuous source of pain.
3. Neurogenic Inflammation:
The process of neurogenic inflammation is important in both somatic and neuropathic pain mechanisms
and was previously discussed.
4. Sympathetically Maintained Pain (SMP):
A proposed mechanism for neuropathic pain involves sympathetic efferent (postganglionic) activation of
primary afferent nociceptors. In the orofacial region, unmyelinated sympathetic postganglionic fibers,
whose cell bodies are in the superior cervical ganglion in the sympathetic chain, travel along with primary
nociceptive afferents. Normally, the sympathetic nervous system is not involved in nociceptive
transmission and sympathetic fibers are able to release norepinephrine (NE) at synapses into tissues
without inducing pain. However, in certain types of nerve injuries, changes can occur in primary afferent
receptors causing them to become sensitive to these same adrenergic substances. Sympathetic
stimulation now results in pain. Because this pain depends on efferent input from the sympathetic system,
it is referred to as sympathetically maintained pain (SMP). If the sympathetic nervous system is not
involved, the pain is termed sympathetically independent pain (SIP).
Currently, the term complex regional pain disorder (CRPS) has been suggested to replace previously
used terms thought to be related to SMP, such as causalgia and reflex sympathetic dystrophy. Because
CRPS primarily involves the extremities, the term SMP will be used throughout this syllabus for orofacial
pain maintained by the sympathetic nervous system.
Diagnosis of SMP depends upon achieving a significant decrease in pain (>60%) by blocking sympathetic
efferent innervation of the affected area to prevent the release of norepinephrine from sympathetic
terminals. In the head and neck area, this can be accomplished by blocking the cervical sympathetic
(stellate) ganglion. Another technique using intravenous infusion with phentolamine (an alpha
adrenoreceptor blocking agent), is also used extensively in the diagnosis of SMP. When either technique
of sympathetic blockade fails to reduce the level of pain, the pain can be assumed to be independent of
the sympathetic nervous system.
The pain associated with SMP can be continuous with an aching, burning quality that is sometimes
accompanied by a continuing background discomfort, or it can occur spontaneously. Patients with SMP
exhibit hypersensitivity to even mild cooling stimuli (cooling hyperalgesia). However, caution is advised in
using this sign as a specific marker for SMP since 50% of SIP patients also show an increased response
to cold.
The mechanism of SMP is unclear and several hypotheses have been offered to explain clinical
observation. One theory suggests that an up-regulation in alpha receptors along mechanoreceptors and
blood vessels is responsible for the increased sensitivity to NE that can result in pain. Another concept
states that when a nerve is severed, "ephaptic coupling" between sympathetic efferents and sensory
afferent fibers may occur. This coupling appears to be chemically mediated and occurs when NE
released from sympathetic endings acts on adrenoreceptors in afferent neurons. Sympathetic blockade
stops the release of NE and causes nociceptor activation to cease.
Management of SMP may involve a series of sympathetic blocks leading to down- regulation (decrease)
of adrenoreceptors, thereby inducing long-term elimination of SMP. In cases of SMP that are refractory to
sympathetic blocks, a surgical sympathectomy may be recommended.
5. Deafferentation Pain:
Deafferentation refers to the partial or total loss of a sensory nerve supply to a particular body area.
Normally, when the sensory supply to an area is compromised, one would expect a decrease in sensation
and a loss in ability to perceive pain. However, in some cases involving nerve injury, a paradoxical
condition arises; there is pain in an area of decreased sensation. When this occurs, the pain is termed
deafferentation pain.
Any type of injury to the somatosensory system can be complicated by deafferentation pain and can arise
from central lesions as well as a peripheral nerve injury. Several various chronic pain conditions have
been attributed to the process of deafferentation, including atypical odontalgia (phantom tooth pain,
trigeminal deafferentation pain) and some central pain syndromes such as thalamic pain.
The mechanisms involved in deafferentation pain are complex and not completely understood. In many
chronic orofacial pain conditions or sensory disorders, the primary initiating factor is a peripheral
deafferentation injury. While both peripheral and central mechanisms are involved, the main underlying
mechanism for deafferentation pain is central neuroplasticity and the development of central sensitization.
Even mild forms of peripheral deafferentation following a tooth extraction or pulp extirpation can cause
central sensitization and result in deafferentation pain. To prevent the occurrence of deafferentation pain
following a surgical procedure in the orofacial area, and indeed anywhere in the body, a local anesthetic
should be administered even when a general anesthetic is used. This concept of preventive therapy is
known as preemptive analgesia. It implies that when an analgesic is given prior to any noxious
stimulation, subsequent pain can be prevented or reduced.
Preemptive Analgesia:
Although a general anesthetic eliminates the perception of pain by preventing nociceptive impulses from
reaching higher CNS centers, it will still allow pain signals to reach second order neurons. Animal studies
have shown that when pain impulses are prevented from reaching second order neurons, the incidence of
deafferentation pain is decreased. The objective of preemptive analgesia is to eliminate or reduce
nociceptive input during, or immediately following, an invasive procedure. When nerve tissue is damaged,
a variety of inflammatory biochemicals are released which can stimulate and sensitize nociceptors and
cause an increased barrage of afferent signals going to the CNS. This increase in afferent impulses can
result in central neuroplasticity and central sensitization and may lead to deafferentation pain. Preemptive
analgesia also includes the use of preoperative and postoperative opioids and NSAIDs as well as
regional local anesthetics.
On a peripheral level, several theories have been offered to account for part of the deafferentation pain
process. These include an increase in afferent input from the trigeminal ganglion in response to
peripheral nerve injury. Ectopic pain impulses arising from neuroma formation may also contribute to
deafferentation pain. Related to neuroma formation, sprouts can become sensitive to norepinephrine
generated by activity of sympathetic efferent (postganglionic) fibers. This introduces the concept that
some clinical conditions caused by deafferentation may be sympathetically mediated. Another factor
contributing to deafferentation pain may be a reduction in inhibitory input to the trigeminal brain stem
complex. This can result in a net increase in excitation of second order neurons.
Neuromatrix Theory of Melzack:
Finally, it is possible that deafferentation may be genetically related. Melzack, who formulated the gate
control theory, suggests that there is a genetically built-in neuromatrix composed of a widely distributed
neural network that includes somatosensory, limbic and thalamocortical components. (Melzack, 1993)
According to Melzack, this neuromatrix carries with it patterns for perceiving the body and its parts and
the various qualities we feel. It is built into the brain by genetic specification but can be modified by
experience, sensory inputs and the body’s stress system. Chronic pain related to deafferentation is
determined not only by sensory stimulation during the discomfort but also by brain processing. The brain
generates the experience of the body and sensory inputs merely modulate that experience but do not
directly cause it.
Chemical and Injection Nerve Injury:
In addition to the mechanisms discussed, peripheral nerve damage can occur as a result of exposure to
chemical agents used during various dental procedures such as endodontic therapy or packing of a dry
socket. The extent of nerve injury following use of a chemical is dependent upon the depth of penetration
of the chemical into the nerve, toxicity of the chemical, and duration of exposure to the chemical.
Sometimes only a brief exposure to a chemical is enough to cause nerve injury. An inflammatory
response in the affected nerve usually begins after chemical exposure which, in the case of an
intraosseous nerve, may result in edema, ischemia and nerve compression. Symptoms may include
abnormal touch and vibratory perception.
Penetration of a nerve trunk by a needle can cause paresthesia or anesthesia (loss of sensation) in the
distribution of the affected nerve. In dental practice, the potential for nerve injection injury exists mostly
with the larger peripheral trigeminal branches such as the inferior alveolar, lingual, mental and infraorbital
nerves. Fortunately, the incidence of reported nerve injury from nerve injection is relatively low compared
to the large number of blocks administered on a routine basis.
The mechanism involved is probably a form of compression neuropathy. Symptoms may vary from a
shock-like sensation associated with penetration of the lingual nerve during inferior alveolar nerve block,
to a longer-lasting paresthesia resulting from compression of the mental nerve. A nerve injection injury
usually results in minimal nerve injury with no long-lasting structural and physiological alteration.
PAIN AND STRESS
No discussion on pain mechanisms would be complete without mention of the role of the stress system in
pain. When tissue injury occurs, the brain’s homeostatic regulatory system is disrupted. This induces
"stress" and initiates a complex series of events to reinstate homeostasis. If the injury is severe enough,
the whole sympathetic nervous system is activated through the release of norepinephrine. Concurrently,
the hypothalamic-pituitary-adrenal (HPA) system is activated which results in the release of cortisol from
the adrenal cortex. Although cortisol is an essential hormone that is necessary for survival after injury, it
can also be destructive. Prolonged output can cause myopathy, weakness and neural degeneration of the
hippocampus, a part of the brain involved in learning and memory. Cortisol can also suppress the
immune system which may account for the fact that many autoimmune diseases (e.g., rheumatoid
arthritis, scleroderma) are also classified as pain disorders.
Melzack, who gave us the gate control theory and the neuromatrix concept, has proposed an interesting
hypothesis on the complex relationship between stress, the autoimmune system and pain. (Melzack,
1999) He proposed that some forms of chronic pain could be due to the cumulative destructive effects of
cortisol on muscle, bone and neural tissue as well as the immune system. While cortisol by itself may not
directly cause these problems, it may enable other contributing factors such as psychological stress,
genetic factors and sex-related hormones to produce them. In his opinion, investigation of these factors
may provide valuable clues for understanding some of the more terrible chronic pain syndromes.
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Suggested Reading
Merrill RL. Orofacial pain mechanisms and their clinical application. Dent Clin N Amer 1997; 41:167-188.
Purvis D, Augustine CJ, Fitzpatrick D et al. Neuroscience. Sunderland MA: Sinauer Associates, 1997.
Ren K, Dubner R. Central nervous system plasticity and persistent pain. J Orofacial Pain 1999; 13:155163.