What is pain?

Pain is a subjective experience; its intensity depends on how one

interprets what one is feeling. The intensity of pain is influenced by the
neural stimuli received from damaged tissue, the memory of previous
pain, the expected outcome, and psychological factors, predominantly
anxiety. Individuals perceive and respond to pain in different ways. It is
not easily described in words and even less easily measured. For instance,
your splitting headache is not necessarily the same as my pounding
headache. How can I possibly explain to you what I am feeling and how
much it hurts? This problem remains unsolved. Pain has survival value.
This unpleasant sensation and emotion helps prevent further injury. A
widely accepted definition of pain is a sensory and emotional experience
from actual or potential tissue damage, or described in terms of such
damage (to see various types of pain, see Table 5.1). In more practical
sense, pain is what the patient says hurts, and when the patient says it
hurts this is a most important concept to grasp. Pain is a combination of
what your patients feel, and their emotional response to it.
Table 5.1 Various types of pain
Type of pain
Description
Clinical
Somatic pain
Well localized, sharp, acute pain arising from
skin, muscles, joints. Visceral pain
Deep, diffuse, ill-localized arising
from an organ.
Pathological description
Neuropathic pain
Arises from injured nerves.
Nociceptive pain
Occurs where inflammation stimulates pain
receptors.
Why pain is harmful
Uncontrolled pain is harmful because it:
causes restlessness, which increases oxygen consumption; this in
turn, increases cardiac work, and can result in hypoxia;
contributes to postoperative nausea and vomiting;
increases the blood pressure, with the risk of precipitating cardiac
ischaemia;
decreases hepatic and renal blood flow, delaying the metabolism
and excretion of drugs, and promoting fluid retention;
prevents the patient from taking deep breaths and coughing,
especially following thoracic or upper abdominal operations. This
increases the risk of postoperative sputum retention and
pneumonia;
discourages patients from moving their legs slowing blood flow. The
venous stasis contributes to the formation of deep vein thrombi, and
pulmonary embolism;

increases the postoperative stress response, with greatly increased

cortisol secretion. This delays wound healing, and predisposes to
infection;
increases metabolic rate, protein breakdown, and the catabolic
effects of injury;
delays the return of normal bowel function;
impairs the bonding of a mother with her newborn child if the
mother is in pain after Caesarean section, and
demoralizes the patient, disrupts sleep, and causes distressing
anxiety and despair.

Uncontrolled pain can delay healing, and increase the risk of

infection.
The greatest physiological risk of untreated pain is to frail patients, those
with heart or lung disease, the very young and the very old, and those
undergoing major procedures such as aortic, abdominal, or major
orthopaedic surgery.
How we perceive pain
How we perceive pain involves two inputs: the injury that hurts
(noxious stimulus) and the anxiety or fear (affective feelings) that goes
with this. These interact in a complex way to form the sensation of pain.
If you stubbed your toe against a door, you would probably not feel
very anxious about it. You know the pain will soon go away, and there
should be no consequences. Your logical analysis involves experience,
knowledge, memory and foresight.
If you were to wake suddenly in the night with a terrible abdominal
pain you would rightly be alarmed, and your physiological and
psychological response quite different. The emotional responses to pain
can be harmful. Emotions may range through acceptance, apprehension,
fear or even terror. Fear of physical deformity is particularly evident in
patients who have been burnt, or who are undergoing disfiguring
operations such as mastectomy or amputation. The young tend to be
more fearful than older people. Sincere empathy, reassurance and skilled
nursing reduce destructive emotional responses substantially.
Emotional stress activates the sympathetic nervous system: blood
pressure rises, the heart beats faster and more forcibly and the brain
becomes hypervigilant about its surroundings and what is happening to
the body. If this stress remains unmodulated then enough cortisol is
secreted from the adrenal gland to jeopardize wound healing and
predispose to infection.
Pain physiology
Those organisms that can recognize that they have been injured and
then avoid further injury are far more likely to survive long enough to pass
on this ability to their offspring. One billion years of evolution have refined
this aptitude endlessly. We are the beneficiaries of eons of physiological
adaptations by these survivors, our ancestors, and we have inherited their

complex ways of recognizing and reacting to pain. The following

description is the barest outline of this process, but should give you a
feeling for its complexity, and how we can use this knowledge to modify
the response.
Sensory nerves to the spinal cord and brain carry pain sensations.
Here they are integrated and modified to produce a coordinated response
and remembered for later analysis. What part of me is hurting? Am I in
danger? How much does it hurt? Have I felt it before? and so on.
Meanwhile the subcortical areas of the central nervous system recruit
background responses such as an increase in blood pressure and heart
rate, the amount of sweating and the size of the pupils.
Nociceptors
Inflammation causes pain
Pain receptors in the tissues are called nociceptors. Under a
microscope nociceptors have no distinct structure, but appear as a woven
network of free bare nerve endings distributed everywhere through the
tissues; they are found in viscera, in periosteum, in connective tissue and
around blood vessels.
Inflammation is ultimately the original cause of all pain. Where there
is one, you will find the other; nevertheless, under some circumstances,
when the inflammation resolves, the pain persists. This neuropathic pain
can be unremitting and can eat away peoples lives. The sad thing is that
in most cases neuropathic pain is preventable if the original pain is
treated early and vigorously.
Inflammation is caused by thermal damage, mechanical trauma, or
chemical irritation. Surgery also damages tissue. The dead and damaged
cells release pain-producing (algogenic) chemicals including eicosanoids,
potassium ions, and bradykinins. The nerve endings also release
substance P. All these biochemicals cause vasodilation, and oedema at the
site of injury. Ischaemic injury does likewise, but adds hydrogen ions to the
inflammatory soup. Soaked in inflammatory mediators, the capillary beds
in the area leak protein-rich fluid (exudate) into the tissues. The exudate
carries more bradykinins and other algogenic chemicals such as
histamine, serotonin and noradrenaline into the area.
Macrophages and white cells flock to the site to mop up the
damaged cells, to deal with invading micro-organisms and start the repair
process. They send out distress messengers in the form of cytokines,
histamine, serotonin, bradykinin, purines and many others. All these
biochemicals further stimulate pain receptors.
Analgesics such as aspirin and the non-steroidal anti-inflammatory
drugs (NSAIDs) impair the synthesis of some inflammatory mediators,
Pain thresholds
What you feel depends on the type of sensory ending stimulated,
and its connections to the spinal cord and the brain. The stimulus, such as
a burn, a stab or a bite, must have enough strength (to exceed threshold
potential) to trigger a response; in contrast a signal of insufficient strength

is said to be subthreshold. A mosquito bite is subthreshold and passes

unnoticed, in contrast a dog bite certainly exceeds the threshold potential.
Nociceptors fire more easily, at a lower threshold, if they are
exposed to repeated high-intensity stimulation, or irritated by
inflammatory biochemicals. This process is called sensitization. If anyone
has slapped your sunburnt back you will recognize sensitization. Allodynia
is the name for the pain where a stimulus that does not normally cause
pain, begins to do so.
Substantia gelatinosa
Once a painful stimulus exceeds the threshold level, the impulse is
carried to the substantia gelatinosa (SG) in the dorsal horn of the spinal
cord. The substantia gelatinosa crudely analyses the intensity and quality
of the pain. Like a gatekeeper it acts to control which impulses are
important enough to pass and where to pass them. Are you wearing a
watch? Normally you are unaware of it, but once your conscious self (in
your cerebral cortex) interrogates your substantia gelatinosa it will direct
attention to the appropriate wrist, and allow a previously subthreshold
stimulus to pass back to your consciousness.
If you touch a hot stove you will immediately pull your hand away a
withdrawal reflex about 0.6 0.8 seconds before you consciously know
anything has happened, and hopefully before too much damage is done.
The substantia gelatinosa in the spinal card instantly recognized the
supra-maximal stimulus, and directed an impulse down your motor nerves
to get your hand out of the way of danger. This simple reflex response
avoids wasting about 1.8 to 2 seconds needed to pass messages back and
forth to obtain directions from your conscious self (to see an experiment in
neuronal transmission see Box 5.1).
Box 5.1 An experiment
Without having to actually burn yourself, you can demonstrate the
effects of the fast (A-delta fibres) and the slower (C fibres) neuronal
transmission. Take your Achilles tendon at the back of your heel between
your forefinger and thumb. Now, quickly squeeze it hard. You will feel two
pains; the first is sharp, well-localized and brief, and the second dull,
deep, diffuse, persistent, and uncomfortable.
Consider walking barefoot along a stony path. The substantia
gelatinosa, receiving impulses arising in the prefrontal region in the brain,
readjusts the threshold potential in the SG to tolerate jabs and pricks on
the sole of your foot. Now, if you stand on a thorn, the adjusted threshold
stimulus is exceeded and the withdrawal reflex pulls your foot out of the
way.
To some degree you can consciously override a response to pain,
such as when you make a grab to pull the plug out of a sink full of hot
water. Although the pain threshold is exceeded, you expected the pain,
and for that moment you can override the withdrawal reflex.
Peripheral nerves

First-order neurons carry sensation from skin, muscle, bone and the
organs to the spinal cord. If you have ever burnt your hand on a hot stove
you might, with dispassionate analysis, have noticed two sorts of pain.
First a fast onset pain that only last for a short time and pricks, stabs or
lances. Large myelinated A-delta nerve fibres carry this pain sensation.
Second, a slower onset pain is duller, and lasts longer. Small unmyelinated
C fibres carry this pain impulse. Both these first-order neurons carry
impulses from the periphery to the spinal cord.
Endorphins
All these responses to pain are regulated by local neurotransmitters,
which open and close neural gates in the substantia gelatinosa. Open
gates allow pain impulse to pass, and closed ones do not. Inhibitory
neurotransmitters close the gates and excitatory ones open them. One of
these inhibitory substances is a member of a group of naturally occurring
opioids called -endorphin. This acts on opioid -receptors near pain
synapses, hyperpolarizing the neuronal cell membrane so that it takes a
bigger stimulus to make them fire. Opioids, given with epidural or spinal
anaesthetics, mimic -endorphins and impede the passage of pain
impulses to the brain.
Ketamine1 blocks the effects of an excitatory neuropeptide,
glutamate, in the substantia gelatinosa. This slams the gate shut to stop
pain impulses reaching the central nervous system. Ketamine also
profoundly affects how the brain perceives pain.
Second-order neurons
Once through the gate, the pain impulses are relayed to secondorder neurons that splay out in the spinal cord to carry information to the
brain. Some impulses pass up to the thalamus in easily identifiable
contralateral spinothalamic tracts. Others enter the diffuse spinoreticular
tracts that connect with vital centres in the brainstems reticular
formation. These vital centres coordinate innate responses such as heart
rate, blood pressure, sweating, pupil size, respiratory rate and depth.
Thalamus
Astride the top of the midbrain sits the thalamus. It acts as the
bodys administrative headquarters coordinating the bodys automatic
functions such as temperature control, respiration, and blood pressure
maintenance. In the spinal cord the spinothalamic tracts lie laterally and
the paleospinothalamic tracts lie medially. The neospinothalamic tract
passes up the spinal cord to the posterior thalamus to carry and process
information about the location, duration and intensity of pain. The
paleothalamic tract sends its fibres to the medial thalamus and is
associated with the autonomic and emotional aspects of pain.
Third-order neurons
In the medial thalamus the quality of the pain touches
consciousness for the first time. Messages pass on through third-order
neurons to the prefrontal lobes (foresight and previous experience) and

the limbic lobe (emotion) where we analyse the memory and the
emotional implications of the pain. In other words I have felt this before, it
hurts its a burn.
Meanwhile messages from the lateral thalamus pass on to the
postcentral gyrus in the sensory cortex, where we integrate all the
messages to discover my left hand is burning. Now we know our hand is
burnt we can organize other appropriate and complex behavioural
responses such as finding water to cool it.
How pain is modified
We are genetically programmed to forget some types of acute pain.
This is fortunate, otherwise a woman would never go through childbirth for
the second time. Sometimes we need to cope with, or even ignore, pain.
In the brainstem the periaqueductal grey matter (PAG) monitors
emergencies. If roused it blocks pain impulses on their way to the brain.
This is why people injured in war, or on the sports field, often do not feel
pain until they are safe.
When the thalamus perceives the situation is an emergency it
induces the hypothalamus and pituitary gland to secrete -endorphin.
These endogenous opioids impede inward-bound pain impulses through
the PAG so that they are not passed on to consciousness.
Plasticity and wind-up
Plasticity
Once barraged by pain, stimuli sensory nerves recruit help from
their neighbours by producing neuropeptides including substance P,
neurokinin A, and calcitonin gene-related peptide (CGRP). These
substances also pass up the axon to the cell body, which then remodels its
connections in the substantia gelatinosa.
With repetitive painful stimuli nerves establish more peripheral pain
receptors, send out new dendrites to their neighbours, and increase the
number of receptors in the post-synaptic endplates in the substantia
gelatinosa. At the distal end of the nerve the overall effect is to increase
local sensitivity to inflammation, while at the proximal end in the
substantia gelatinosa the nerve radically improves its communication with
the central nervous system.
Now alerted to the problem, the neurons in the central nervous
system establish new connections, allow others to lapse, and then
increase their production of peptide neurotransmitters (glutamate,
aspartate, and substance P). All this ability to change, to remodel, nerve
connections and to adapt biochemical responses according to need is
termed plasticity.
Plasticity does not only occur with pain. Just studying this book will
actually remodel parts of your brain. Repetition reinforces the process;
hence the observation that practice makes perfect.
Unrelieved severe pain can evolve into permanent chronic pain.
How wind-up leads to chronic pain

Continuous severe pain changes the structure and function of

sensory nerves. If the neural circuits in the substantia gelatinosa are
barraged with pain impulses then calcium channels in the nerve
membranes become jammed open. Calcium ions flood into the nerve cells
and stimulate certain genes to act (express themselves). The genes
programme the microsomal protein factories to produce many more
neuropeptide transmitters, new receptors and cell membrane pumps. With
all this new equipment for detecting pain, the cell now responds massively
to stimuli that would previously have passed unnoticed.
With good pain relief we can prevent a catastrophe: unrelieved
severe pain can cause so much calcium to enter the nerve cells of the
dorsal horn that they die. Once this happens the neural gate mechanism
in the substantia gelatinosa is permanently jammed open. Pain becomes
entrenched so that even a minor stimulus now causes a massive
response. Unhappily this response continues long after the precipitating
injury has healed. An example of this phenomenon is the severe pain of
post-hepatic neuralgia following an attack of shingles.
Ketamine prevents chronic pain
We can predict that some injuries, such as pelvic fractures or
surgery like rib resection, will be so painful that wind-up is likely to occur.
In such cases ketamine is useful for preventing the onset of chronic pain
syndrome.
Ketamine blocks polysynaptic reflexes in the spinal cord and
functionally dissociates the thalamus so that it cannot pass on impulses
from limbic system (which recognizes pain) to the cortex (where the pain
impulses are consciously analysed). This means the pain never reaches a
conscious level.
Hatfield, Anthea. The Complete Recovery Room Book (pp. 83-84). OUP
Oxford. Kindle Edition.