Anatomy and Physiology
of Pain
“Pain is a more terrible lord of
mankind than even death itself.”
Albert Schweitzer
Pain definitions:
(The International Association
for the Study of Pain (IASP)
 An unpleasant sensory and
emotional experience associated
with actual or potential tissue
damage
 May not be directly proportional to
amount of tissue injury
 This definition recognizes that
pain is a perception and not a
sensation!!
Pain definitions:
(hierarchical model of pain)
 Pain is whatever the experiencing person
says it is
Pain definitions - implication of
both the IASP and the hierarchical
model of pain
 As a perception, pain may or may not correlate
with an identifiable source of injury
 The activity in the body’s “nociceptive”
system,
 which senses noxious stimuli and
 generates a physiological and behavioral
response,
 can be initiated by injury and sustained by
neuroplastic changes even after healing
 activity in this system can occur in the absence
of any discrete injury but in association with
a recognizable disease
Pain definitions - implication
of both the IASP and the
hierarchical model of pain
 In some cases, pain can
develop and be unrelated to
any identifiable physical
process
 In all cases, the reality that
pain is a perception
indicates the potential for:
 profound influence of
psychological and emotional
factors, cognitions
 and varied external events
Pain definitions - implication of both
the IASP and the hierarchical model of
pain - concept of pain as perception
 It is almost always best to believe
that the patient is experiencing
what is being reported.
 Because there is no objective
indicator for pain, experts agree that
the best clinical approach in most
circumstances is to assume that the
patient is reporting a true
experience, even in the absence of a
clear explanation.
 Importantly, accepting a patient’s
complaint of pain as valid does not
require clinical identification of a
physical cause, or demand the
initiation of a specific treatment.
Pain definitions - implication of both
the IASP and the hierarchical model of
pain - concept of pain as perception
 Almost always, it is a sound
foundation for assessment and an
important beginning in developing
an effective physician-patient
dialogue.
 The risk that rare cases of
malingering or factitious disorder may
lead the credulous physician to initial
error is more than balanced by the
benefits associated with a stance of
compassionate acceptance and
concern.
Types of Pain
 1.Acute - a protective mechanism
that alerts the individual to a
condition or experience that is
immediately harmful to the body;
 Onset - usually sudden
 2.Chronic - is persistent or
intermittent
 usually defined as lasting at least 6
months
Types of Pain
Responses to acute pain
 diaphoresis
 pallor or flushing
 increased heart rate
 elevated blood pressure
  blood flow to the viscera, kidney and skin
  gastric acid secretion
  gastric motility
 nausea occasionally occurs
 increased respiratory rate
 dilated pupils
  blood sugar
 fear
 general sense of unpleasantness
 anxiety
Types of Pain - response to chronic
pain
 Psychological response
 Intermittent pain produces a physiologic response
similar to acute pain
 Persistent pain allows for adaptation (functions of
the body are normal but the pain is not reliefed)
Chronic pain produces significant
behavioural and psychological changes:
 depression
 an attempt to keep pain - related behaviour to a
minimum
 sleeping disorders
 preoccupation with the pain
 tendency to deny pain
Pain threshold and pain tolerance
 The pain threshold - the point at which a stimulus is
perceived as pain.
 It does not vary significantly among healthy people or
in the same person over time
Perceptual dominance - intense pain at one location may
cause an increase in the pain threshold in another
location
The pain tolerance - duration of time or the intensity of
pain that an individual will endured before initiation overt
pain responses.
It is influenced by:
- persons cultural prescriptions
- expectations
- role behaviours
- physical and mental health
Pain threshold and pain tolerance
Pain tolerance is generally decreased:
 with repeated exposure to pain
 by fatigue, anger, boredom, apprehension
 sleep deprivation
Tolerance to pain may be increased:
 by alcohol consumption
 medication, hypnosis
 warmth, distracting activities
 strong beliefs or faith
Pain tolerance varies greatly
 among people
 in the same person over time
 a decrease in pain tolerance is also evident in the elderly
 women appear to be more tolerant to pain than men
Age and perception of pain
Children and the elderly may experience or express
pain differently than adults:
 Infants in the first 1 to 2 days of life are less
sensitive to pain (or they simply lack the ability to
verbalise the pain experience)
 A full behavioural response to pain is apparent
at 3 to 12 month of life
 Older children, between the ages of 15 and 18
years, tend to have a lower pain threshold than
do adults
 Pain threshold tends to increase with ageing
 this change is probably caused by peripheral
neuropathies
 and changes in the thickness of the skin
Clasification of Pain by pathophysiology
1. Nociceptive pain (stimuli from somatic
and visceral structures)
2. Neuropathic pain (stimuli abnormally
processed by the nervous system)
3. Psychogenic pain is pain for which there
is unknown physical cause but
processing of sensitive information in CNS
is dysturbed
4. mixed pain
5. idiopathic pain
Nociceptive Pain and its Mechanisms
 Clinically, pain can be labeled “nociceptive” if it
is inferred that the pain is due to ongoing
activation of the nociceptive system by tissue
injury.
 Although neuroplastic changes (such as
those underlying tissue sensitization) are
clearly involved, nociceptive pain is
presumed to occur as a result of the
normal activation of the sensory system by
noxious stimuli, a process that involves 4 basic
processes




Transduction
Transmission
Perception of pain
Modulation of pain
Nociceptive Pain and its Mechanisms
 Tissue injury activates primary
afferent neurons called nociceptors,
which are small diameter afferent
neurons (with A-delta and C-fibers)
 Nociceptors respond to noxious stimuli
 Nociceptors are found in
 skin
 muscle
 joints
 and some visceral tissues.
Nociceptive Pain and its Mechanisms
Nociceptive primary afferent neurons are
varied:
 Most are “silent” - active only when
suprathreshold stimuli impinge
 Some are specific to one type of
stimulus, such as
 mechanical
 or thermal
 but most are polymodal
 The number and size of the receptive
fields served by each fiber may be
small or large, respectively
Nociceptive Pain and its Mechanisms
 nociceptors free nerve endings has
capacity to distinguish between noxious
and innocuous stimuli when exposed to
 mechanical (incision or tumor growth)
 thermal (burn)
 chemical (toxic substance) stimuli
 tissue damage occurs
 substances are released by the damaged
tissue which facilitates the movement of
pain impulse to the spinal cord
Substances released
 The substances released from the traumatized
tissue are:
 prostaglandins
 bradykinin
 serotonin
 substance P
 Histamine
 Protons
 NGF
The role of this substances provide opportunities for the
development of new analgesic drugs
So, for instance
 Non-steroidal anti-inflammatories, such
as ibuprofen, are effective in
minimizing pain because they
minimize the effects of these substances
released, especially prostaglandins
 Corticosteroids, such as
dexamethasone used for cancer pain,
also interferes with the production of
prostaglandins
1. Transduction
 sufficient amounts of noxious stimulation
cause the cell membrane of the neuron
(nervous system cell) to become permeable
to sodium ions, allowing the ions to rush
into the cell and creating a temporary
positive charge
 then potassium transfers back into the
cell, thus changing the charge back to a
negative one
 with this depolarization and repolarization,
the noxious stimuli is converted to an
impulse
 this impulse takes just milliseconds to occur
 Some analgesics relieve pain
primarily by decreasing the sodium
and potassium transfers at the
neuron level, thereby slowing or
stopping pain transmission
 Examples—local anesthetics,
anticonvulsants used for neuropathic
pain, migraines
2.Transmission
 Once depolarization
occurs,
 transmission of
information
proceeds proximally
along the axon to the
spinal cord and then
on to higher centers.
2.Transmission
 Transmission across
the first central
synapse may be
influenced by activity
in the primary
afferent itself and
modulatory neural
pathways
 that originate
segmentally or
supraspinally
 further modulation
results from processes
initated by glial cells.
2.Transmission
 Impulse  spinal cord  brain stem
 thalamus  central structures of
brain  pain is processed
 Neurotransmitters are needed to
continue the pain impulse from the
spinal cord to the brain
3. Perception of Pain
 the end result of the neural activity of pain
transmission
 it is believed pain perception occurs in the
cortical structures
 behavioral strategies and therapy can be
applied to reduce pain
 brain can accommodate a limited number of
signals —
 distraction, imagery, relaxation signals may get
through the gate, leaving limited signals (such as
pain) to be transmitted to the higher structures
4.Modulation of Pain
 The neurochemistry of these
processes involves an extraordinary
array of compounds, including
 endorphins,
 neurokinins,
 prostaglandins,
 biogenic amines,
 GABA,
 neurotensin,
 cannabinoids,
 purines,
 and many others.
4.Modulation of Pain
 The endorphinergic pain modulatory pathways are
characterized by multiple endogenous ligands and different
types of opioid receptors: mu, delta, and kappa.
 Endorphins are present in the periphery,
 on nerve endings,
 immune-related cells
 and other tissues,
 Endorphins are widely distributed in the central nervous
system (CNS).
 They are involved in many neuroregulatory processes
apart from pain control, including
 the stress response
 and motor control systems.
 Opioid drugs mimic the action of endogenous opioid ligands.
Most of the drugs used for pain are full mu receptor
agonists.
4.Modulation of Pain
 Other pain modulating systems, such as those that use
 monoamines (serotonin, norepinephrine and dopamine),
 histamine,
 acetylcholine,
 cannabinoids,
 growth factors
 and other compounds,
 are targets for nontraditional analgesics, such as specific
 antidepressants and
 anticonvulsants.
It is likely that entirely novel analgesic compounds will become
commercially available in the future as drug development
programs target these systems.
4.Modulation of Pain
 changing or inhibiting pain impulses in the
descending tract (brain spinal cord)
 descending fibers also release substances
such as norepinephrine and serotonin
(referred to as endogenous opioids or
endorphins) which have the capability of
inhibiting the transmission of noxious
stimuli
 cancer pain responds to antidepressants
which interfere with the reuptake of
serotonin and norepinephrine which
increases their availability to inhibit noxious
stimuli
Clinical Characteristics of
Nociceptive Pain
acute (short-lived, remitting)
persistent (long-lived, chronic),
primarily involve injury to somatic
or visceral tissues.
“somatic pain”- pain related to ongoing activation of
nociceptors that innervate somatic structures, such
as
 bone,
 joint,
 muscle
 and connective tissues,
 this pain is recognized by identification of a lesion
 characterisitics typically include a well localized site
and an experience described as aching, squeezing,
stabbing, or throbbing.





Clinical Characteristics of
Nociceptive Pain
 Arthritis and metastatic bone pain are examples of
somatic pain.
 Pain arising from stimulation of afferent receptors
 in the viscera is referred to as visceral pain.
 Visceral pain caused by
 obstruction of hollow viscus is poorly localized and
is often described as cramping and gnawing, with a
daily pattern of varying intensity.
 when organ capsules or other structures such as
myocardium, are involved, however, the pain usually is
well localized and described as sharp, stabbing or
throbbing,
 descriptors similar to those associated with somatic
pain.
Clinical Characteristics of
Nociceptive Pain


Nociceptive pain may involve acute or chronic
inflammation.
The physiology of inflammation is complex.
 an immune component
 retrograde release of substances from C polymodal
nociceptors - “neurogenic inflammation” - involves
the release from nerve endings of compounds such as







substance P,
serotonin,
histamine,
acetylcholine,
and bradykinin.
these substances activate and sensitize other nociceptors.
Prostaglandins produced by injured tissues also may
enhance the nociceptive response to inflammation by
lowering the threshold to noxious stimulation.
Neuropathic Pain and its
Mechanisms
 abnormal processing of the impulses either
 by the peripheral
 or central nervous system
 may be caused by
 injury (amputation and subsequent phantom limb
pain)
 scar tissue from surgery (back surgery high risk)
 nerve entrapment (carpal tunnel)
 damaged nerves (diabetic neuropathy)
 unclear why depolarization and
transmission of pain impulse are
 spontaneous
 and repetitive
Neuropathic Pain and its
Mechanisms
 It occurs as a result of injury to or dysfunction
of the nervous system itself, peripheral or
central
 Deaferentation pain - form of neuropathic pain:
a term implying that sensory deficit in the
painful area is a prominent feature (anesthesia
dolorosa)
 Phantom pain- pain localised into non-existing
organ (tissue)
 Long-lasting pain after short-lasting pain stimulus
Clinical Manifestation of Pain
Acute Pain
 Somatic
 Visceral
 Reffered pain
 Somatic pain is superficial coming from the skin or close to
the surface of the body.
 Visceral pain refers to pain in internal organs, the abdomen,
or chest.
 Referred pain is pain that is present in an area removed or
distant from its point of origin.
 The area of referred pain is supplied by the nerves from the
same spinal segment as the actual site of pain.
Different types of chronic somatic pain
I. Nervous system intact
1. nociceptive pain
2. nociceptive - neurogenic pain
(nerve trunk pain)
II. Permanent functional and/or
morphological abnormalities of the
nervous system (preganglionic, spinal supraspinal)
1. neurogenic pain
2. neuropathic pain
3. deafferentation pain
The most common chronic pain
1. Persistent low back pain
result of poor muscle tone,
inactivity,
muscle strain,
sudden vigorous exercise
2. Chronic pain associated with cancer
The most common chronic pain
3. Neuralgias
 Causalgia -
- results from damages of peripheral nerves
severe burning pain appearing 1 to 2 weeks after
the nerve injury associated with discoloration
and changes in the texture of the skin
in the affected area.
 Reflex sympathetic dystrophies - occur after peripheral
nerve injury and is characterised by continuous
severe burning pain. Vasomotor changes are
present (vasodilatation vasoconstriction 
cool cyanotic and edematous extremities).
The most common chronic pain
4. Myofascial pain syndromes - second most
common cause of chronic pain.
 include: myositis, fibrositis, myalgia, muscle
strain, injury to the muscle and fascia
 The pain is a result of muscle spasm, tenderness
and stiffness
The most common chronic pain
5. Hemiagnosia
 a loss of ability to identify the source of pain on one side
(the affected side) of the body.
 Application of painful stimuli to the affected side thus produces
anxiety, moaning, agitation and distress but no
attempt to withdrawal from or push aside the offending
stimulus.
 Emotional and autonomic responses to the pain my be
intensified.
● Hemiagnosia is associated with stroke that produces
paralysis and hypersensitivity to painful stimuli in the
affected side
6. Phantom limb pain - is pain that an individual feels in
amputated limb
Pathophysiology of muscle pain (MP)
 MP - a part of somatic deep pain,
 it is common in rheumathology and sports medicine
 is rather diffuse and difficult to locate
 MP is not a prominent feature of the serious progressive diseases
 affecting muscle, e.g. the muscular dystrophies, denervation,
 or metabolic myopathies, but it is a feature of
rhabdomyolysis

 Muscles are relatively insensitive to pain when elicited by needle
prick or knife cut, but overlying fascia is very sensitive to pain.
Events, processes which may lead to muscular pain are:
 metabolic events:
 metabolic depletion ( ATP  muscular contracture)
 accumulation of unwanted metabolities (K+, bradykinin)
Pathophysiology of visceral pain
Visceral pain:
Types - angina pectoris, myocardial infarction, acute
pancreatitis, cephalic pain, prostatic pain,
nephrlolytiatic pain
 Receptors: unmyelinated C – fibres
 For human pathophysiology the kinds of stimuli apt to
induce pain in the viscera are important.
It is well-known that the stimuli likely to induce cutaneous
pain are not algogenic in the viscera. This explains why in
the past the viscera were considered to be insensitive
to pain
Adequate stimuli of inducing visceral pain:
•
1. abnormal distention and contraction of the hollow
viscera muscle walls
2. rapid stretching of the capsule of such solid visceral
organs as are the liver, spleen, pancreas...
3. abrupt anoxemia of visceral muscles
4. formation and accumulation of pain - producing
substances
5. direct action of chemical stimuli (oesophagus,
stomach)
6. traction or compression of ligaments and vessels
7. inflammatory processes
8. necrosis of some structures (myocardium, pancreas)
Characteristic feature of true visceral pain
a) it is dull, deep, not well defined, and differently
described by the patients
b) sometimes it is difficult to locate this type of pain
because it tends to irradiate
c) it is often accompanied by a sense of malaise
d) it induces strong autonomic reflex phenomena
(much more pronounced than in pain of somatic origin)
- diffuse sweating, vasomotor responses, changes of
arterial pressure and heart rate, and an intense psychic
alarm reaction -"angor animi" - in angina pectoris)
 There are many visceral sensation that are unpleasant
but below the level of pain, e.g. feeling of disagreeable
fullness or acidity of the stomach or undefined and
unpleasant thoracic or abdominal sensation.
 These visceral sensation may precede the onset of visceral
pain
Refered visceral pain (transferred pain)
 Refered pain = when an algogenic process affecting a visceral
recurs frequently or becomes more intense and prolonged, the
location becomes more exact and the painfull sensation is
progressively felt in more superficial structures
 Refered pain may be accompanied by allodynia and
cutaneous and muscular hyperalgesia
Mechanisms involved in refered pain creation:
 convergence of impulses from viscera and from the skin
in the CNS:
 Sensory impulses from the viscera create an irritable
focus in the segment at which they enter the spinal
cord.
 Afferent impulses from the skin entering the same
segment are thereby facilitated, giving rise to true
cutaneous pain.
 senzitization of neurons in dorsal horn
Refered visceral pain (transferred pain)
 Painful visceral afferent impulses activate anterior horn
motor cells to produce rigidity of the muscle
(visceromotor reflexes)
 A similar activation of anterolateral autonomic cells induces
pyloerection, vasoconstriction, and other sympathetic
phenomena
 These mechanisms, which in modern terms can be defined
as positive sympathetic and motor feedback loops, are
fundamental in refered pain
 It is clear that painful stimulation of visceral structures
evokes a visceromuscular reflex, so that some muscles
contract and become a new source of pain
Refered visceral pain (transferred pain)
 It has been observed that the local anesthetic block of the
sympathetic ganglia led to the disappearance, or at least to a
marked decrease, of refered pain, allodynia, hyperalgesia.
 In some conditions, reffered somatic pain is long-lasting,
increases progressively, and is accompanied by dystrophy
of somatic structures.
Possible mechanisms:
onset of self-maintaining vicious circle impulses:
peripheral tissue  afferent fibers

central nervous system
peripheral tissue  somatic and sympathetic efferent fibres
 Intricate conditions - in some types of pain,
e.g. chest pain, is difficult to distinguish the
true cause of pain because such kind of pain
may be related to cervical osteoarthrosis,
esophageal hernia, or cholecystitis.
 It is difficult to ascertain whether these
intricate conditions are due to a simple
addition of impulses from different sources in
the CNS or to somatovisceral and viscerosomatic
reflex mechanisms.
 It has been demonstrated that the mnemonic process is
facilitated if the experience to be retained is repeated many
times or is accompanied by pleasant or unpleasant emotions.
 Pain is, at least in part, a learned experience - e.g. during the
first renal colic, true parietal pain followed visceral pain after a
variable interval.
 In subsequent episodes of renal colic pain, parietal pain
developed promptly and was not preceded by true visceral
pain.
 This is probably due to the activation of mnemonic traces.
Silent myocardial ischemia (SMI)
 Chest pain is only a late and inconstant marker of episodes of
transient MI in vasospastic angina (30 %), in stable angina (50 %)
1.
Mechanisms of SMI
a) Lack of the pain is, in part, related to the duration and
severity of MI.
1. Episodes shorter than 3 min, and those accompanied by
a modest impairment of left ventricle ( in enddiastolic pressure inferior to 6 mm Hg) are always
painless.
2. Longer and more severe episodes are acccompanied by
chest pain in some instances but not in others.
b) Pacients with predominantly SMI appear to have a
generalized defective perception of pain (threshold and
tolerance).
Mechanism:  level of circulating -endorphin (?)
Disturbances in pain perception and nociception
Most of the disturbances are congenital
a) Congenital analgesia - nociceptive stimuli are not
processed and/or integrated at a
level of brain.
Patient does not feel a pain
b) Congenital sensoric neuropathy - nociceptive stimuli are
not transmitted by peripheral
nerves or by spinal afferent
tracts.
Acquired disturbances in pain perception and nociception
 They may occur at syringomyely,
 disturbances of parietal lobe of brain,
 in patients suffering from neuropathy
(e.g. chronic diabetes mellitus)