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To Pain
Materials

Content
Instructions
definitions of pain
Types of pain
Pain Transmission pathway
Analgesic drugs
Exit

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What is pain?
Many definitions..
pain is whatever the
experiencing person says it is,
existing when he says it does
(McCaffery, 1980)
Pain is an unpleasant sensory
or emotional experience
associated with actual or
potential tissue damage
(International Association for the
study of pain 1986)
Complex warning sign. Difficult to
measure as peoples perception
of pain varies

Perception of Pain?
Perception of pain is
dependent upon:
Cellular damage
Receptor stimulation
Ascending neural pathways
Sensory cortex arousal
Conscious awareness of
stimulation of pain

2
Types of pain
Acute versus chronic
Nociceptive versus
neuropathic
Somatic versus visceral
Referred versus non referred
pain
Somatogenic versus
psychogenic
Causes of pain (e.g. cancer,
trauma etc)

Acute v chronic

Acute pain Chronic pain


Sudden onset Persistent
Temporary usually lasting more
(disappears once than six months
stimulus is Cause unknown
removed) may be due to
can be somatic, neural stimulation
visceral, referred or a decrease in
Associated anxiety
endorphins
Physiological
Physiological
responses to acute responses are less
pain include obvious especially
increased RR, HR, with adaptation.
BP and reduction in Psychological

gastric motility responses may


sympathetic include depression
response)
See McCance and Heuther (2002) for
more detail on this

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Nociceptive v
neuropathic
Nociceptive pains result
from activation of nociceptors
(Pain receptors)
Neuropathic pains result
from direct injury to nerves in
the peripheral nervous
system

Somatic v Visceral
Somatic pain
Superficial: stimulation of receptors
in skin
Deep: stimulation of receptors in
muscles, joints and tendons

Visceral pain
Stimulation of receptors in internal
organs, abdomen and skeleton
Often poorly localised as fewer
receptors located in viscera
Visceral pain can be referred.

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Referred pain
Pain experienced at a point
distant to its point of origin
Area of referred pain is supplied
by same spinal segment as
actual site of pain
Brain misinterprets signals as
coming from somatic regions
Knowledge of different types of
referred pain is important in
clinical diagnosis because in
many visceral ailments the only
clinical signs is referred pain.
Good section on referred pain
can be found in Guyton and Hall
(2006)

Somatogenic versus
psychogenic
Somatogenic pain is a pain
originating from an actual
physical cause e.g. trauma,
ischaemia etc

Psychogenic pain is pain for


which there is no physical
cause. It is not however
imaginary pain and can be as
intense as somatic pain.

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Pain pathway
There are four processes in
the pain pathway
1. transduction
Noxious stimuli translated into electrical
activity at sensory nerve endings
2. Transmission
Propagation of impulses along
spinothalamic pathway.
3. Modulation
Transmission is modified
4. Perception
Affective / motivational aspect

Each of these processes present a


potential target for analgesic therapy

Transduction -
receptors
Pain is detected by
nociceptors (noci = harmful)
Free nerve endings of
sensory neurones
Found in all tissues and
organs (except brain)
Can be classified as either:
Unimodal respond to only
one type of stimulus
Polymodal respond to more
than one type of stimuli.

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Transduction -
Receptor activation
When cellular damage occurs,
tissues release chemicals that
stimulate nociceptors
Bradykinin Histamine
Serotonin Acetylcholine
Potassium ions
Prostaglandins (PGE2, PGI2)
Substance P

The activity and sensitivity of


nociceptors is profoundly altered
by such mediators (enhances
receptor response to noxious
stimuli).

TRAUMA
Transduction Mechanical
Thermal
chemical

Overall effect is
increased nociceptor
activation

Mediators
Bradykinin Histamine
Serotonin Acetylcholine
Potassium ions

Prostaglandins (PGE2,

PGI2)
Substance P

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Types of stimuli
Receptors respond to injury
Thermal excessive heat or cold
Mechanical tearing, crushing,
stretching etc
Chemical
Inflammatory mediators
Lactic acid
ischemia

Transduction - A delta
fibres and C fibres
Nociceptors respond to noxious
stimuli and covert energy at the
site of the stimulus into neural
impulses
Nociceptors are terminal endings
of primary afferent fibres. These
can be classed into two main
types
myelinated A-delta fibres
or
non-myelinated C fibres
When the threshold level of the
stimulus is reached, then
depolarisation occurs along
these fibres in the form of action
potentials

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Transduction - A delta
fibres and C fibres
A-Delta fibres C- fibres

myelinated unmyelinated

fast ( first) pain - Slow (second) pain


conduct at 5-35m/sec conduct at 0.5-2.0m/sec

Associated with Sharp, Associated with


brief, prinking pain dull,burning, aching,
prolonged pain
Well localised More diffuse

Elicited by mechanical Elicited mainly by


or thermal stimuli chemical stimuli or
persisting mechanical
or thermal stimuli

Transmission
A-delta and C ( primary) fibres
enter the spinal cord via the
dorsal root
They synapse with secondary
neurones in the grey matter of
the dorsal horn
Marginal zone ( lamina I)
Substantia gelatinosa ( lamina II)
Lamina V
Evidence to suggest that:
A-delta fibres synapse in lamina I, II
and V
C-fibres in lamina I and II

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Transmission by
primary A-delta and C-
fibres
I A-Delta or C
II
III fibre
Grey IV
matter of V
Dorsal
horn

Secondary neuron

Pain Transmission
Pathway
Both A delta and C nociceptor fibres
synapse in the dorsal horn of the
spinal cord
Evidence suggests that
neurotransmitters released at this point
include substance P, glutamate,
calcitonin gene-related peptide
(CGRP).
Secondary neurones cross the cord
and ascend through the antero-lateral
spinothalamic tract to the thalamus
where they synapse with tertiary
neurones
These tertiary neurones ascend from
the thalamus to somatosensory cortex.

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Pain Transmission
Pathway
Some neurones ascend directly
to the thalamus allowing rapid
analysis
The spinothalamic tract also
sends collaterals to reticular
formation, hypothalamus and
other limbic structures
(associated more with C-fibres
and slow pain)
This more indirect pathway
mediates arousal and emotional
reactions to pain. It is also
responsible for somatic and
autonomic motor reflexes.

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Somatosensory cortex
Somatosensory cortex is
involved in the localisation
and identification of pain.

Perception
Transduction, transmission,
modulation interact to create
subjective emotional
experience of pain.

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Modulation of Pain
Evidence that pain is inhibited by
select neural pathways
In dorsal horn
Interneurones in the substantia
gelatinosa can regulate the
conduction of ascending afferent
input
Such interneurons can exert an
inhibitory effect on synapses
between primary and secondary
neurones
These neurones release opioid
peptides (enkephalin, -endorphins
and dynorphins) which act on the
pre-synaptic terminals of nociceptor
fibres to prevent the release of
substance P / glutamate

interneuron

opioid
Pain
transmission opioid
blocked by receptor
release of
opiates

Primary
neurone

Interneuron
(releases
To thalamus endogenous
opiates
e.g.endorphins)

Secondary
Primary neuron
neuron
(nociceptor)

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Modulation of Pain
Action of opioids
Pre-synaptic terminals of neurones
involved in pain transmission are
opioid receptors
When these receptors are activated
by opioid peptides or other agonists
the release of Neurotransmitters
(Sub P, glutamate etc) is
decreased.
Achieved in two ways:
Inhibit Neurotransmitter release by
activation of potassium channels on
pre-synaptic terminal (mu () and kappa
() receptors)
Inhibit Neurotransmitter release by
inhibiting voltage dependent calcium
channels (delta () receptors)

Modulation of Pain

Interneurons in the
Substantia gelatinosa cells
respond to the activity of :
Descending pathways
Endogenous analgesic
pathway. Norepinephrine,
serotonin and opioids are
involved in brainstem inhibitory
pathways that modulate pain
in the spinal cord.
Afferent fibres entering the
cord (gate control theory)
Touch receptors v pain
receptors

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Modulation of Pain
descending pathways

The periaqueductal grey matter


(PAG) in the midbrain has a role
in analgesia and is rich is opioid
receptors
PAG receives impulses from
many brain regions inc.
hypothalamus, cortex and
thalamus. Stimuli include stress,
exercise, acupuncture.
Main neuronal pathway activated
by PAG stimulation extends first
to nucleus raphe magnus (NRM)
in the medulla and then to dorsal
horn interneurones. Enkephalins
are released at these synapses
and inhibit nociceptor NT release

Pain modulation descending pathway

Periaqueductal grey
MIDBRAIN matter
Medial lemniscus
Red nucleus
Corticospinal tract

MEDULLA Nucleus Raphe


magnus
Medial lemniscus
Corticospinal tract

To thalamus interneuron

SPINAL CORD

Spinothalamic nociceptor
tract

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Gate control theory
Stimulation of large touch sensory
fibres ( type A beta fibres) can depress
transmission of pain signals from the
same body area.
Thought that A beta fibres stimulate
endorphin releasing inteneurons in
dorsal horn
Thus pain pathway gate is closed by
touch.
Research into this theory continues
May be basis of tens and acupuncture
along with psychogenic excitation of
central analgesia system

Schematic diagram of gate


control theory of pain
mechanism
Central nervous system
pain modulation may increase
Large or decrease pain
Abeta fibre
impulses
Closes pain
gate

Substantia Pain Actions


gelatinosa transmission and
in spinal
responses
cord

Opens
pain
gate
Small Adelta
/ C fibres

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Analgesic drugs
As mentioned previously the
aim of analgesic drugs is to
inhibit the processes of pain
transmission. Drug types
considered in this
presentation include opioids,
NSAIDS, paracetamol, local
anaesthetics, amitriptyline
and anticonvulsants.
Can you identify where each
group act on the pain
pathway?

Opioid drugs
The term opioid is used to describe a
group of drugs that are opium- like
Act on opioid receptors (mainly ) as
agonists
Opioids excite neurones in
periacqueductal grey matter and thus
activate the descending analgesia
pathway.
Also act directly on pre-synaptic
terminal of nociceptor neurons in
dorsal horn and inhibit pain impulse
transmission
Bind to other receptors affecting
chemoreceptor trigger zone,
respiratory centre and bowel.

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Side effects of Opiates
Respiratory Depression
Opioids bind to receptors which cause
reduced sensitivity of central
chemoreceptors in medulla to pCO2
Bradycardia / Hypotension
Depresses cardiovascular centre in
medulla
Pupillary constriction
Effect on oculomotor nucleus mediated by
parasympathetic nervous system
Nausea
Acts on chemoreceptor trigger zone in
medulla
Constipation
Decreases motility of gut
Euphoria
Acts on receptors in reticular formation /
limbic system

Opioid agonist and antagonists

agonist drug
endogenous e.g.
opioid diamorphine
binds to mimics
receptor action
of
receptor endogenou
s opioid

produces reaction
antagonists in cell
such
as naloxone
bind to
receptors
and block
action
of
endogenous
and
exogenous
opioids

antagonist produces
no reaction in cell

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NSAIDS
All nociceptors can be sensitised
by prostaglandins. i.e.
prostaglandins greatly enhance
the receptor response to noxious
stimuli
NSAIDs act by suppressing
cyclo-oxygenase, an enzyme
involved in synthesis of
prostaglandins
This blocks inflammatory process
(anti- inflammatory) and reduces
sensitivity of nociceptors
(analgesic)

Action of cyclo-
oxygenase
Constitutive
pathway Induced
(stable conc) pathway

phospholipid phospholipid

Arachidonic acid Arachidonic acid


COX 1 COX-2
enzyme enzyme

Prostaglandins Inflammatory
associated with prostaglandins
normal body
functions
e.g. prostaglandin E2
(for kidney function),
prostaglandin I2 (for
stomach protection)

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NSAIDS: mode of
action
NSAIDS block both COX-1
and COX-2
This accounts for most of the
side effects of NSAIDS
Different types of NSAIDS
have different specificities for
COX-1 and COX-2
This contributes to
differences in side effects
between the NSAIDS.

Side effects of
NSAIDs
Linked to inhibition of
prostaglandins
Gastric problems prostaglandins
have a role in protecting gastric
mucosa and also regulate blood
flow to gastric mucosa ( inhibition of
COX-1)
Renal failure prostaglandins
influence renal blood flow (inhibition
of prostaglandin reduces glomerular
filtration as well as causing sodium
retention)
Aspirin anti-coagulant as inhibits
platelet aggregation (inhibition of
COX-1)

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Paracetamol
Mechanism not certain may be
weak inhibitor of the synthesis of
prostaglandins or act on
descending analgesic pathway.
Read this article to find out more
you can access it online!!!
Graham,GG and Scott, KF
(2005). Mechanism of action of
paracetamol American Journal of
Therapeutics Jan-Feb;12(1):46-
55/.

Anaesthetics
Local : block
neurotransmission by
blocking sodium transport

General: affect ion channels


to prevent impulse
transmission

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Local anaesthetics
Epidurals administered to
epidural space

Spinal anaethesia
Administered in intrathecal
(subarachnoid) space

Local Anaesthetics

nervous impulses local anaesthetics


depend on Na+ ions block Na+ gates so
entering axons of nervous impulse are
neurons via Na+ not transmitted
gates

Na Na+
+
nervou
s
impuls
e

axon of
pain Na+ gates
neuron

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Side Effects of Local
Anaesthetics

Epidurals / spinal
anaethesias
Sympathetic block -
hypotension
Urine retention
Motor block

Amitriptyline
Acts to Increase levels of
norepinephrine and serotonin
Norepinephrine and
Serotonin act on endogenous
descending analgesic
pathway
Reduces / blocks impulses
along pain pathway
Useful in neuropathic pain

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Anti-convulsants
Mechanism of action unclear
Decreases electrical activity
along pain pathway
Useful in some types of
neuropathic pain

References
Gilman S and Newman SW (2002) Manter and
Gatzs Essentials of clinical neuroanatomy and
neurophysiology (10th Ed). FA Davis.
Graham,GG and Scott, KF (2005). Mechanism of
action of paracetamol American Journal of
Therapeutics Jan-Feb;12(1):pp46-55.
Guyton,A.C. and Hall,J.E. (2006) Textbook of
Medical Physiology. Philadelphia, Elsevier
Kelly, D.J. (2001) Preemptive analgesia I:
physiological pathways and pharmacological
modalities. Canadian Journal of Anaesthesia. Vol
48:10, pp1000-1010
McCance,K.L. and Heuther,S.E. (2002).
Pathophysiology: The Biological basis for Disease in
Adult and Children. St.Louis, Mosby.
Rang et al (2003) Pharmacology. Edinburgh.
Churchill Livingstone

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