Theories of pain, like all scientific theories, evolve as result of the accumulation of new

facts as well as leaps of the imagination.1 The gate control theory's most revolutionary
contribution to understanding pain was its emphasis on central neural mechanisms. 2 The
theory forced the medical and biologic sciences to accept the brain as an active system
that filters, selects, and modulates inputs. The dorsal horns, too, are not merely passive
transmission stations but sites at which dynamic activitiesinhibition, excitation, and
modulationoccur. The great challenge ahead of us is to understand how the brain
functions.

A Brief History of Pain

in the 20th Century
The theory of pain we inherited in the 20th century was
proposed
by Descartes 3 centuries earlier. The impact of
Descartes' specificity theory was enormous. It influenced
experiments on the anatomy and physiology of pain up
to the first half of the 20th century (reviewed in Melzack
and Wall3). This body of research is marked by a search for
specific pain fibers and pathways
and a pain center in the
brain. The result was a concept
of pain as a specific, straightthrough
sensory projection system. This rigid anatomy of
pain in the 1950s led to attempts to treat severe chronic pain
by a variety of neurosurgical lesions. Descartes' specificity
theory, then, determined the facts as they were known
up to the middle of the 20th century and even determined
therapy.
Specificity theory proposed that injury activates specific
pain receptors and fibers that, in turn, project pain impulses
through a spinal pain pathway to a pain center in the brain.
The psychological experience of pain, therefore, was virtually
equated with peripheral injury. In the 1950s, there was no room
for psychological contributions to pain, such as attention,
past experience, anxiety, depression, and the meaning of the
situation.
Instead, pain experience was held to be proportional
to peripheral injury or disease. Patients who suffered back
pain without presenting signs of organic disease were often
labeled as psychologically disturbed and were sent to psychiatrists.
The concept, in short, was simple and, not surprisingly,
often failed to help patients who suffered severe chronic pain.
To thoughtful clinical observers, specificity theory
was clearly
wrong.
Several attempts were made to find a new theory. The major
opponent to specificity was labeled pattern theory, but several
different pattern theories were put forth, and they were generally
vague and inadequate (see Melzack and Wall3). However,
seen in retrospect, pattern theories gradually evolved (Fig. 1.1)
and set the stage for the gate control theory. Goldscheider 4 proposed
that central summation in the dorsal horns is one of the
critical determinants of pain. Livingston's 5 theory postulated a
reverberatory circuit in the dorsal horns to explain summation,
referred pain, and pain that persisted long after healing was
completed. Noordenbos'6 theory proposed that large-diameter
fibers inhibited small-diameter fibers, and he even suggested
that the substantia gelatinosa in the dorsal horns plays a major
role in the summation and other dynamic processes described

by Livingston. However, none of these theories

had an explicit Nevertheless, the successive
theoretical
concepts moved the
field in the right direction: into the spinal cord and away from
the periphery as the exclusive
answer to pain. At least the field
of pain was making its way up toward the brain.

Fig. 1.1 Schematic representation of conceptual models of pain mechanisms. A, Specificity theory. Large (L) and
small (S) fibers are assumed to
transmit touch and pain impulses, respectively, in separate, specific, straight-through pathways to touch and
pain centers in the brain. B, Goldscheider's4
summation theory, showing convergence of small fibers onto a dorsal horn cell. The central network projecting
to the central cell represents Livingston's5
conceptual model of reverberatory circuits underlying pathologic pain states. Touch is assumed to be carried by
large fibers. C, Sensory interaction
theory, in which large (L) fibers inhibit () and small (S) fibers excite (+) central transmission neurons. The
output projects to spinal cord neurons,
which are conceived by Noordenbos6 to comprise a multisynaptic afferent system. D, Gate control theory. The
large (L) and small (S) fibers project to
the substantia gelatinosa (SG) and first central transmission (T) cells. The central control trigger is represented
by a line running from the large fiber
system to central control mechanisms, which in turn project back to the gate control system. The T cells project
to the entry cells of the action system.
+, excitation; , inhibition. (From Melzack R: The gate control theory 25 years later: new perspectives on phantom limb
pain. In Bond MR, Charlton JE, Woolf CJ, editors:
Pain research and therapy: proceedings of the VIth World Congress on Pain, Amsterdam, 1991, Elsevier, pp 921.)

The Gate Control Theory of Pain

In 1965, Melzack and Wall2 proposed the gate control theory

of pain. The final model, depicted in Figure 1.1D in the
context
of earlier theories of pain, is the first theory of pain
that incorporated
the central control processes of the brain.
The gate control theory of pain2 proposed that the transmission
of nerve impulses from afferent fibers to spinal cord
transmission (T) cells is modulated by a gating mechanism in
the spinal dorsal horn. This gating mechanism is influenced
by the relative amount of activity in large- and small-diameter
fibers, so that large fibers tend to inhibit transmission (close
the gate), whereas small fibers tend to facilitate transmission
(open the gate). In addition, the spinal gating mechanism is
influenced by nerve impulses that descend from the brain.
When the output of the spinal T cells exceeds a critical level, it
activates the Action Systemthose neural areas that underlie
the complex, sequential patterns of behavior and experience
characteristic of pain.
The theory's emphasis on the modulation of inputs in
the spinal dorsal horns and the dynamic role of the brain in
pain processes had a clinical as well as a scientific impact.
Psychological factors, which were previously dismissed as
reactions to pain, were now seen to be an integral part of
pain processing, and new avenues for pain control by psychological
therapies were opened. Similarly, cutting of nerves and
pathways was gradually replaced by a host of methods to modulate
the input. Physical therapists and other health care professionals
who use a multitude of modulation techniques were
brought into the picture, and transcutaneous electrical nerve

stimulation became an important modality for the treatment

of chronic and acute pain. The current status of pain research
and therapy indicates that, despite the addition of a massive
amount of detail, the conceptual components of the theory
remain basically intact up to the present.

Beyond the Gate

The great challenge ahead of us is to understand brain

function.
Melzack and Casey7 made a start by proposing
that specialized systems in the brain are involved in the
sensorydiscriminative, motivational-affective, and cognitiveevaluative
dimensions of subjective pain experience (Fig. 1.2).
These names for the dimensions of subjective experience
seemed strange when they were coined, but they are now used so
frequently
and seem so logical that they have become part of
our language. So, too, the McGill Pain Questionnaire, which taps
into subjective
experienceone of the functions
of the brain
is the most widely used instrument to measure
pain.810 The
newest version, the Short-Form McGill Pain Questionnaire-2,10
was designed to measure the qualities of both neuropathic and
non-neuropathic pain in research and clinical settings.
In 1978, Melzack and Loeser11 described severe pains in
the phantom body of paraplegic patients with verified total
sections
of the spinal cord and proposed a central pattern
generating mechanism above the level of the section. This
concept, generally
ignored for more than 2 decades, is now
beginning to be accepted. It represents a revolutionary advance:
it did not merely extend the gate; it said that pain could be
generated by brain mechanisms in paraplegic patients in the
absence of a spinal gate because the brain is completely disconnected
from the spinal cord. Psychophysical specificity, in
such a concept,
makes no sense; instead we must explore how
patterns of nerve impulses generated in the brain can give rise
to somesthetic experience.

Phantom Limbs and the Concept

of a Neuromatrix
It is evident that the gate control theory has taken us a long
way. Yet, as historians of science have pointed out, good theories
are instrumental in producing facts that eventually
require a new theory to incorporate them, and this is what
has happened. It is possible to make adjustments to the gate
theory so that, for example, it includes long-lasting activity of
the sort Wall has described (see Melzack and Wall3). However,
one set of observations on pain in paraplegic patients just
does not fit the theory. This does not negate the gate theory,
of course. Peripheral and spinal processes are obviously an
important part of pain, and we need to know more about the
mechanisms of peripheral inflammation, spinal modulation,
midbrain descending control, and so forth. However, the data

on painful phantoms below the level of total spinal section 12,13

indicate that we need to go above the spinal cord and into the
brain.
Note that more than the spinal projection areas in the
thalamus and cortex are meant. These areas are important,
of course, but they are only part of the neural processes that
underlie perception. The cortex, Gybels and Tasker14 made
amply clear, is not the pain center, and neither is the thalamus.
The areas of the brain involved in pain experience and behavior
must include somatosensory projections as well as the
limbic
system. Furthermore, cognitive processes are known to
involve widespread areas of the brain. Despite this increased
knowledge, we do not yet have an adequate theory of how the
brain works.
Melzack's13 analysis of phantom limb phenomena, particularly
the astonishing reports of a phantom body and severe
phantom limb pain in people with a total thoracic spinal cord
section,11 has led to four conclusions that point to a newer
conceptual model of the nervous system. First, because the
phantom limb (or other body part) feels so real, it is reasonable
to conclude that the body we normally feel is subserved
by the same neural processes in the brain as the phantom;
these brain processes are normally activated and modulated
by inputs from the body, but they can act in the absence of
any inputs. Second, all the qualities we normally feel from
the body, including pain, are also felt in the absence of inputs
from the body; from this we may conclude that the origins
of the patterns that underlie the qualities of experience lie in
neural networks in the brain; stimuli may trigger
the patterns
but do not produce them. Third, the body is perceived
as a
unity and is identified
as the self, distinct from other people
and the surrounding world. The experience of a unity of such
diverse feelings, including the self as the point of orientation
in the surrounding
environment, is produced by central
neural
processes
and cannot derive from the peripheral nervous
system
or the spinal cord. Fourth, the brain processes that
underlie the body-self are built in by genetic specification,
although this built-in substrate must, of course, be modified
by experience. These conclusions
provide the basis of the
newer conceptual model12,13,15 depicted in Figure 1.3.

Outline of the Theory

Melzack12,13,15 proposed
that the anatomic substrate of the
body-self is a large, widespread network of neurons that
consists of loops between the thalamus and cortex as well as
between the cortex and limbic system. He labeled the entire
network, whose spatial distribution and synaptic links are
initially
determined genetically and are later sculpted by
sensory

inputs, a neuromatrix. The loops diverge to permit

parallel processing in different components of the neuromatrix
and converge repeatedly to permit interactions among
the output products of processing. The repeated cyclical processing
and synthesis of nerve impulses through the neuromatrix
imparts a characteristic pattern: the neurosignature. The
neurosignature of the neuromatrix is imparted on all nerve
impulse patterns that flow through it; the neurosignature
is produced by the patterns of synaptic connections in the
entire neuromatrix.
All inputs from the body undergo cyclical
processing and synthesis
so that characteristic patterns are
impressed on them in the neuromatrix. Portions of the neuromatrix
are specialized to process information related to major
sensory events (e.g., injury, temperature change, and stimulation
of erogenous tissue) and may be labeled neuromodules
that impress subsignatures on the larger neurosignature.
The neurosignature, which is a continuous output from the
body-self neuromatrix, is projected to areas in the brain
the sentient neural hubin which the stream of nerve
impulses (the neurosignature modulated by ongoing inputs)
is converted into a continually changing stream of awareness.
Furthermore, the neurosignature patterns may also activate
a neuromatrix to produce movement. That is, the signature
patterns bifurcate so that a pattern proceeds to the sentient
neural hub (where the pattern is transformed into the experience
of movement), and a similar pattern proceeds through a
neuromatrix that eventually activates spinal cord neurons to
produce
muscle patterns for complex actions.

The Body-Self Neuromatrix

The body is felt as a unity, with different qualities at different
times. Melzack12,13,15 proposed that the brain mechanism that
underlies the experience also comprises a unified system that
acts as a whole and produces a neurosignature pattern of a
whole body. The conceptualization of this unified brain mechanism
lies at the heart of this theory, and the word neuromatrix
best characterizes it. The neuromatrix (not the stimulus,
peripheral nerves, or brain center) is the origin of the neurosignature;
the neurosignature originates and takes form in
the neuromatrix. Although the neurosignature may be triggered
or modulated by input, the input is only a trigger and
does not produce the neurosignature itself. The neuromatrix
casts its distinctive signature on all inputs (nerve impulse
patterns) that flow through it. Finally, the array of neurons in
a neuromatrix is genetically programmed to perform the specific
function of producing the signature pattern. The final,
integrated neurosignature pattern for the body-self ultimately
produces awareness and action.
The neuromatrix, distributed throughout many areas of the
brain, comprises a widespread network of neurons that generates
patterns, processes information that flows through it, and
ultimately produces the pattern that is felt as a whole body.
The stream of neurosignature output with constantly varying
patterns riding on the main signature pattern produces the
feelings of the whole body with constantly changing qualities.

Conceptual Reasons for a Neuromatrix

It is difficult to comprehend how individual bits of information

from skin, joints, or muscles can all come together to

produce
the experience of a coherent, articulated body. At any
instant in time, millions of nerve impulses arrive at the brain
from all the body's sensory systems, including the proprioceptive
and vestibular systems. How can all this be integrated in
a constantly changing unity of experience? Where does it all
come together?
Melzack12,13,15 conceptualized a genetically built-in neuromatrix
for the whole body. This neuromatrix produces a
characteristic neurosignature for the body that carries with it
patterns for the myriad qualities we feel. The neuromatrix, as
Melzack conceived of it, produces a continuous message that
represents the whole body in which details are differentiated
within the whole as inputs come into it. We start from the top,
with the experience of a unity of the body, and look for differentiation
of detail within the whole. The neuromatrix, then,
is a template of the whole, which provides the characteristic
neural
pattern for the whole body (the body's neurosignature),
as well as subsets of signature patterns (from neuromodules)
that relate to events at (or in) different parts of the body.
These views are in sharp contrast to the classical specificity
theory in which the qualities of experience are presumed
to be inherent in peripheral nerve fibers. Pain is not injury;
the quality
of pain experiences must not be confused with the
physical
event of breaking skin or bone. Warmth and cold
are not out there; temperature changes occur out there,
but the qualities of experience must be generated by structures
in the brain. Stinging, smarting, tickling, and itch have
no external equivalents; the qualities are produced by builtin
neuromodules whose neurosignatures innately produce the
qualities.
We do not learn to feel qualities of experience: our brains
are built to produce them. The inadequacy of the traditional
peripheralist view becomes especially evident when we consider
paraplegic patients with high-level complete spinal
breaks. In spite of the absence of inputs from the body, virtually
every quality of sensation and affect is experienced. It
is known that the absence of input produces hyperactivity
and abnormal firing patterns in spinal cells above the level of
the break,11 but how, from this jumble of activity, do we get
the meaningful experience of movement, the coordination of
limbs with other limbs, cramping pain in specific (nonexistent)
muscle groups, and so on? This must occur in the brain,
in which neurosignatures are produced by neuromatrixes that
are triggered by the output of hyperactive cells.
When all sensory systems are intact, inputs modulate the
continuous neuromatrix output to produce the wide variety
of experiences we feel. We may feel position, warmth,
and several kinds of pain and pressure all at once. It is a
single unitary feeling, just as an orchestra produces a single
unitary
sound at any moment even though the sound
comprises
violins, cellos, horns, and so forth. Similarly, at a
particular moment in time we feel complex qualities from

all of the body. In addition, our experience of the body

includes visual images, affect, and knowledge of the self
(versus not-self), as well as the meaning of body parts in
terms of social norms and values. It is hard to conceive of all
of these bits and pieces coming together to produce a unitary
body-self, but we can visualize a neuromatrix that impresses
a characteristic signature on all the inputs that converge on
it and thereby produces the never-ending stream of feeling
from the body.
The experience of the body-self involves multiple
dimensions
sensory, affective, evaluative, postural, and many
others. The sensory dimensions are subserved, in part at least,
by portions of the neuromatrix that lie in the sensory projection
areas of the brain; the affective dimensions, Melzack
assumed, are subserved by areas in the brainstem and limbic
system. Each major psychological dimension (or quality) of
experience, Melzack12,13,15 proposed, is subserved by a particular
portion of the neuromatrix that contributes a distinct portion
of the total neurosignature. To use a musical analogy once
again, it is like the strings, tympani, woodwinds, and brasses of
a symphony orchestra that each make up a part of the whole;
each instrument makes its unique contribution yet is an integral
part of a single symphony that varies continually from
beginning to end.
The neuromatrix resembles Hebb's cell assembly by being
a widespread network of cells that subserves a particular psychological
function. However, Hebb16 conceived of the cell
assembly as a network developed by gradual sensory learning,
whereas Melzack proposed that the structure of the neuromatrix
is predominantly determined by genetic factors, although
its eventual synaptic architecture is influenced by sensory
inputs. This emphasis on the genetic contribution to the brain
does not diminish the importance of sensory inputs. The
neuromatrix
is a psychologically meaningful unit, developed
by both heredity and learning, that represents an entire unified
entity.12,13,15

Action Patterns: The Action-Neuromatrix

The output of the body neuromatrix, Melzack12,13,15 proposed,
is directed at two systems: (1) the neuromatrix that produces
awareness of the output and (2) a neuromatrix involved in
overt action patterns. In this discussion, it is important to keep
in mind that just as there is a steady stream of awareness, there
is also a steady output of behavior (including movements
during
sleep).
Behavior occurs only after the input has been at least partially
synthesized and recognized. For example, when we respond to
the experience of pain or itch, it is evident that the experience
has been synthesized by the body-self neuromatrix (or relevant
neuromodules) sufficiently for the neuromatrix
to have
imparted the neurosignature patterns that underlie the quality
of experience, affect, and meaning. Apart from a few reflexes
(e.g., withdrawal of a limb and eye blink), behavior
occurs only
after inputs have been analyzed and synthesized sufficiently to
produce meaningful experience. When we reach for an apple,

the visual input has clearly been synthesized by a neuromatrix

so that it has three-dimensional shape, color, and meaning as
an edible, desirable object, all of which are produced
by the
brain and are not in the object out there. When we respond
to pain (by withdrawal or even by telephoning
for an ambulance),
we respond to an experience that has sensory qualities,
affect, and meaning as a dangerous (or potentially dangerous)
event to the body.
Melzack12,13,15 proposed that after inputs from the body
undergo transformation in the body-neuromatrix, the appropriate
action patterns are activated concurrently (or nearly
so) with the neuromatrix for experience. Thus, in the actionneuromatrix,
cyclical processing and synthesis produce
activation of several possible patterns and their successive
elimination until one particular pattern emerges as the most
appropriate for the circumstances at the moment. In this way,
input and output are synthesized simultaneously, in parallel,
not in series. This permits a smooth, continuous stream of
action patterns.
The command, which originates in the brain, to perform
a pattern such as running activates the neuromodule, which
then produces firing in sequences of neurons that send precise
messages through ventral horn neuron pools to appropriate
sets of muscles. At the same time, the output patterns from
the body-neuromatrix that engage the neuromodules for particular
actions are also projected to the sentient neural hub
and produce experience. In this way, the brain commands may
produce the experience of movement of phantom limbs even
though the patient has no limbs to move and no proprioceptive
feedback. Indeed, reports by paraplegic patients of terrible
fatigue resulting from persistent bicycling movements 17
and the painful fatigue in a tightly clenched phantom fist in
arm amputees18 indicate that feelings of effort and fatigue are
produced by the signature of a neuromodule rather than by
particular
input patterns from muscles and joints.
The phenomenon of phantom limbs has allowed researchers
to examine some fundamental assumptions in psychology.
Among these assumptions are that sensations are produced
only by stimuli and perceptions in the absence of stimuli
are psychologically abnormal. Yet phantom limbs, as well
as phantom
seeing,19 indicate that this notion is wrong. The
brain does more than detect and analyze inputs; it generates
perceptual
experience even when no external inputs occur.
Another entrenched assumption is that perception of one's
body results from sensory inputs that leave a memory in the
brain; the total of these signals becomes the body image.
However, the existence of phantoms in people born without a
limb or who lost a limb at an early age suggests that the neural
networks for perceiving the body and its parts are built into
the brain.12,13,20,21 The absence of inputs does not stop the networks
from generating messages about missing body parts;
the networks continue to produce such messages throughout
life. In short, phantom limbs are a mystery only if we assume

that the body sends sensory messages to a passively receiving

brain. Phantoms become comprehensible once we recognize
that the brain generates the experience of the body. Sensory
inputs merely modulate that experience; they do not directly
cause it.

Pain and Neuroplasticity

The specificity concept of the nervous system for had no place

for plasticity, in which neuronal and synaptic functions are
capable of being molded or shaped so that they influence
subsequent perceptual experiences. Plasticity related to pain
represents persistent functional changes, or somatic memories,
22,23 produced in the nervous system by injuries or other
pathologic events. The recognition that such changes can occur
is essential to understanding the chronic pain syndromes, such
as low back pain and phantom limb pain, that persist and often
destroy the lives of the people who suffer them.

Denervation Hypersensitivity
and Neuronal Hyperactivity
Sensory disturbances associated with nerve injury have been
closely linked to alterations in central nervous system (CNS)
function. Markus, Pomerantz and Krushelnyky 24 demonstrated
that the development of hypersensitivity in a rat's hind
paw following sciatic nerve section occurs concurrently with
the expansion of the saphenous nerve's somatotopic projection
in the spinal cord. Nerve injury may also lead to the
development of increased neuronal activity at various levels
of the somatosensory system (see review by Coderre et al25).
In addition to spontaneous activity generated from the neuroma,
peripheral neurectomy also leads to increased spontaneous
activity in the dorsal root ganglion and the spinal cord.
Furthermore, after dorsal rhizotomy, increases in spontaneous
neural activity occur in the dorsal horn, the spinal trigeminal
nucleus, and the thalamus.
Clinical neurosurgery studies reveal a similar relationship
between denervation and CNS hyperactivity. Neurons in the
somatosensory thalamus of patients with neuropathic pain
display high spontaneous firing rates, abnormal bursting activity,
and evoked responses to stimulation of body areas that
normally do not activate these neurons.26,27 The site of abnormality
in thalamic function appears to be somatotopically
related to the painful region. In patients with complete spinal
cord transection and dysesthesias referred below the level
of the break, neuronal hyperactivity was observed in thalamic
regions that had lost their normal sensory input, but not in
regions with apparently normal afferent input.26 Furthermore,
in patients with neuropathic pain, electrical stimulation of
subthalamic, thalamic, and capsular regions may evoke pain, 28
and in some instances it may even reproduce
the patient's
pain.2931
Direct electrical stimulation of spontaneously hyperactive
cells evokes pain in some but not all patients with pain; this
finding
raises the possibility that in certain patients the observed
changes in neuronal activity may contribute to the perception
of pain.26 Studies of patients undergoing electrical brain stimulation
during brain surgery reveal that pain is rarely elicited
by test stimuli unless the patient suffers from a chronic pain
problem. However, brain stimulation can elicit pain responses

in patients with chronic pain that does not involve extensive

nerve injury or deafferentation. Lenz et al30 described the case
of a woman with unstable angina who, during electrical stimulation
of the thalamus, reported heart pain like what I took
nitroglycerin for except that it starts and stops suddenly.
The possibility that the patient's angina was the result of
myocardial strain, and not the activation of a somatosensory
pain memory, was ruled out by demonstrating that electrocardiograms,
blood pressure, and cardiac enzymes remained
unchanged over the course of stimulation.
It is possible that receptive field expansions and spontaneous
activity generated in the CNS following peripheral nerve
injury are, in part, mediated by alterations in normal inhibitory
processes in the dorsal horn. Within 4 days of a peripheral
nerve section, one notes a reduction in the dorsal root potential
and, therefore, in the presynaptic inhibition it represents. 32
Nerve section also induces a reduction in the inhibitory effect
of A-fiber stimulation on activity in dorsal horn neurons. 33
Furthermore, nerve injury affects descending inhibitory
controls
from brainstem nuclei. In the intact nervous system,
stimulation of the locus ceruleus34 or the nucleus raphe magnus35
produces inhibition of dorsal horn neurons. Following dorsal
rhizotomy, however, stimulation of these areas produces excitation,
rather than inhibition, in half the cells studied. 36
Advances in our understanding of the mechanisms that
underlie pathologic pain have important implications for the
treatment of both acute and chronic pain. Because it has been
established that intense noxious stimulation produces sensitization
of CNS neurons, it is possible to direct treatments
not only at the site of peripheral tissue damage, but also at
the site of central changes (see review by Coderre and Katz 37).
Furthermore, it may be possible in some instances to prevent
the development of central sensitization, which contributes to
pathologic pain states. The evidence that acute postoperative
pain intensity and the amount of pain medication patients
require after surgery are reduced by preoperative administration
of variety of agents administered by the epidural 3840 or
systemic route4143 suggests that the surgically induced afferent
injury barrage arriving within the CNS, and the central sensitization
it induces, can be prevented or at least obtunded significantly
(see review by Katz44). The reduction in acute pain
intensity associated with preoperative epidural anesthesia may
even translate into reduced pain45 and pain disability46 weeks
after patients have left the hospital and returned home.
The finding that amputees are more likely to develop phantom
limb pain if they had pain in the limb before amputation 23
raises the possibility that the development of longer-term
neuropathic
pain also can be prevented by reducing the
potential
for central sensitization at the time of amputation
(see Katz and Melzack47). Whether chronic postoperative problems
such as painful scars, postthoracotomy chest wall pain,
and phantom limb and stump pain can be reduced by blocking
perioperative nociceptive inputs awaits additional wellcontrolled
clinical trials (see Katz and Seltzer48). Furthermore,
research is required to determine whether multiple-treatment
approaches (involving local and epidural anesthesia, as well as

pretreatment with opiates and anti-inflammatory drugs) that

produce effective blockade of afferent input may also prevent
or relieve other forms of severe chronic pain such as postherpetic
neuralgia49 and complete regional pain syndrome. It is
hoped that a combination of new pharmacologic developments,
careful clinical trials, and an increased understanding
of the contribution and mechanisms of noxious stimulus
induced neuroplasticity will lead to improved clinical treatment
and prevention of pathologic pain.

Pain and Psychopathology

Pains that do not conform to present day anatomic and

neurophysiologic
knowledge are often attributed to psychological
dysfunction.
There are many pains whose cause is not known. If a
diligent
search has been made in the periphery and no
cause is found, we have seen that clinicians act as though
there was only one alternative. They blame faulty thinking,
which for many classically thinking doctors is the same
thing as saying
that there is no cause and even no disease.
They ignore a century's work on disorders of the spinal
cord and brainstem
and target the mind. . . . These are the
doctors
who repeat again and again to a Second World War
amputee in pain that there is nothing wrong with him and
that it is all in his head.50, p. 107
This view of the role of psychological generation in pain
persists to this day notwithstanding evidence to the contrary.
Psychopathology has been proposed to underlie phantom
limb pain,18 dyspareunia,51 orofacial pain,52 and a host of
others including pelvic pain, abdominal pain, chest pain, and
headache.53 However, the complexity of the pain transmission
circuitry described in the previous sections means that many
pains that defy our current understanding will ultimately be
explained without having to resort to a psychopathologic
etiology. Pain that is nonanatomic in distribution, spread
of pain to noninjured territory, pain that is said to be out of
proportion to the degree of injury, and pain in the absence of
injury have all, at one time or another, been used as evidence
to support the idea that psychological disturbance underlies
the pain. Yet each of these features of supposed psychopathology
can now be explained by neurophysiologic mechanisms
that involve an interplay between peripheral and central neural
activity.3,52
Data linking the immune system and the CNS have provided
an explanation for another heretofore medically unexplained
pain problem. Mirror-image pain, or allochiria, has
puzzled clinicians and basic scientists ever since it was first
documented in the late 1800s.54 Injury to one side of the body
is experienced as pain at the site of injury as well as at the
contralateral, mirror-image point.55,56 Animal studies show
that induction of sciatic inflammatory neuritis by perisciatic
microinjection of immune system activators results in both
ipsilateral hyperalgesia and hyperalgesia at the mirror-image
point on the opposite side in the territory of the contralateral
healthy sciatic nerve.57 Moreover, both ipsilateral hyperalgesia

and contralateral hyperalgesia are prevented or reversed by

intrathecal injection of a variety of proinflammatory cytokine
antagonists.58
Mirror-image pain is likely not a unitary phenomenon, and
other nonimmune mechanisms may also be involved. 59 For
example, human60 and animal61 evidence points to a potential
combination of central and peripheral contributions to
mirrorimage pain because nerve injury to one side of the body
has been shown to result in a 50% reduction in the innervation
of the territory of the same nerve on the opposite side of the
body in uninjured skin.61 Although documented contralateral
neurite loss can occur in the absence of contralateral pain or
hyperalgesia, pain intensity at the site of the injury correlates
significantly with the extent of contralateral neurite loss.60
This finding raises the intriguing possibility that the intensity
of pain at the site of an injury may be facilitated by contralateral
neurite loss induced by the ipsilateral injury,61 a situation
that most clinicians would never have imagined possible.
Taken together, these novel mechanisms that explain some
of the most puzzling pain symptoms must keep us mindful
that emotional distress and psychological disturbance in our
patients are not at the root of the pain. Attributing pain to
a psychological disturbance is damaging to the patient and
provider alike; it poisons the patient-provider relationship by
introducing an element of mutual distrust and implicit (and
at times, explicit) blame. It is devastating to the patient, who
feels at fault, disbelieved, and alone.

Conclusion: The Multiple

Determinants of Pain

The neuromatrix theory of pain proposes that the neurosignature

for pain experience is determined by the synaptic architecture
of the neuromatrix, which is produced by genetic and
sensory influences. The neurosignature pattern is also modulated
by sensory inputs and by cognitive events, such as psychological
stress.62 Furthermore, stressors, physical as well as
psychological, act on stress regulation systems, which may produce
lesions of muscle, bone, and nerve tissue and thereby contribute
to the neurosignature patterns that give rise to chronic
pain. In short, the neuromatrix, as a result of homeostasis regulation
patterns that have failed, may produce the destructive
conditions that give rise to many of the chronic pains that so
far have been resistant to treatments developed primarily to
manage pains that are triggered by sensory inputs. The stress
regulation system, with its complex, delicately balanced interactions,
is an integral part of the multiple contributions that
give rise to chronic pain.
The neuromatrix theory guides us away from the Cartesian
concept of pain as a sensation produced by injury or other
tissue disease and toward the concept of pain as a multidimensional
experience produced by multiple influences. These
influences range from the existing synaptic architecture of the
neuromatrix to influences from within the body and from
other areas in the brain. Genetic influences on synaptic architecture
may determineor predispose tothe development
of chronic pain syndromes. Figure 1.3 summarizes the factors
that contribute to the output pattern from the neuromatrix
that produce the sensory, affective, and cognitive dimensions
of pain experience and the resultant behavior.

Multiple inputs act on the neuromatrix programs and

contribute
to the output neurosignature. They include the
following: (1) sensory inputs (cutaneous, visceral, and other
somatic receptors); (2) visual and other sensory inputs
that influence the cognitive interpretation of the situation;
(3) phasic and tonic cognitive and emotional inputs from other
areas of the brain; (4) intrinsic neural inhibitory modulation
inherent in all brain function; and (5) the activity
of the body's
stress regulation systems, including cytokines as well as the
endocrine, autonomic, immune, and opioid systems.
We have
traveled a long way from the psychophysical
concept
that seeks
a simple one-to-one relationship
between injury and pain.
We now have a theoretical framework in which a genetically
determined
template for the body-self is modulated by the
powerful stress system and the cognitive functions
of the
brain, in addition to the traditional
sensory inputs.

References

Full references for this chapter can be found on www.expertconsult.com.