PHYSIOLOGY OF PAIN PATHWAY AND ITS MODULATION. THE PHYSIOLOGICAL BASIS OF PAIN PATHWAY. ANAESTHETIC CONSIDERATION AND THE BASIS OF NERVE BLOCKS.

1. PHYSIOLOGYOFPAINPATHWAYS
ANDITSMODULATION
DR HASSAN

2. What is Pain???
•The International Association for
the Study of Pain (IASP) defines
pain as "an unpleasant sensory
and emotional experience
associated with actual or
potential tissue damage, or
described in terms of such
damage."

3. • Derived from Latin -“Poena” meaning
Penalty/punishment from God.
• JCAHO declared pain as fifth vital sign (1999).
• Net effect of a complex interaction of the
ascending and descending nervous systems
involving biochemical, physiologic,
psychological and neocortical processes.

4. Classification Of Pain:-
Basis Types of pain
Duration Acute
Chronic
Acute on chronic
Cause Cancer
Non cancer
Mechanism Nociceptive (physiological)
Neuropathic (pathological)

5. • Pain that is caused by noxious stimulation
due to injury, a disease process, or the
abnormal function of muscle or viscera.
• Two types of acute (nociceptive) pain
somatic and visceral.

6. CLASSIFICATION OF ACUTE PAIN
ACUTE PAIN
SOMATIC
(somasthetic)
VISCERAL (from viscera)
e.g. angina pectoris, peptic
ulcer, intestinal colic, renal
colic, etc
Superficial (from skin
& subcutaneous tissue)
e.g. superficial
cuts/burns, etc.
Deep (from muscles/ bones/
fascia/ periosteum) e.g.
fractures/arthritis/fibrositis,
rupture of muscle belly

7. CHRONIC PAIN:-
• Pain that extends 3 or 6 months beyond onset or
beyond the expected period of healing.
• It may be nociceptive, inflammatory,
neuropathic or functional in origin.
• A distinguishing feature is that psychological
mechanisms or environmental factors frequently
play a major role.

8. Acute pain Chronic pain
Onset & timing
Sudden, short duration
Resolves /disappears when
tissue heals
Insidious onset
Pain persists despite tissue
healing
Signal
Warning sign of actual or
potential tissue damage
Not a warning signal of
damage
False alarm
Severity
Correlates with amount of
damage
Severity not correlated with
damage
CNS
involvement
CNS intact- acute pain is a
symptoms
CNS may be dysfunctional-
chronic pain is a disease
Psychological
effects
Less, but unrelieved pain
 anxiety and
sleeplessness (improves
when pain is relieved)
Often associate with
depression, anger, fear,
social withdrawal etc.

9. Neuropathic Pain:-
• Definition:
• Pain that is caused by a lesion or disease of the
somatosensory system (PNS or CNS)
• Peripheral Nerves
• Traumatic brachial plexus injury
• Diabetes Mellitus
• Carpel tunnel syndrome
• Post herpetic neuralgia
• Central Nervous System
• Central post stroke pain
• Neuropathic associated with spinal cord injury

10. MECHANISM OF NEUROPATHIC PAIN
Nerve Damage/ Persistent Stimulation
Rewiring Of Pain Circuits Both Anatomically & Biochemically
Spontaneous Nerve
Stimulation
Autonomic neuronal
stimulation
Increased Discharge Of
Dorsal Horn Neurons
NEUROPATHIC PAIN
Results in
causing
Finally leading to

11. NOCICEPTIVE VS NEUROPATHIC PAIN
NOCICEPTIVE PAIN NEUROPATHIC PAIN
Well localized Not well localized
Sharp
Worse with movement
Burning
Shooting
Numbness
Pins and needles
Obvious tissue injury or
illness
Tissue injury may not be
obvious
Inflammation
Nerve injury
Changes in wiring
Abnormal firing
Loss modulation
Physiological pain * Pathological pain

12. REFERRED PAIN
• Pain that is perceived at the site different from
its point of origin but innervated by the same
spinal segment.
• Usually applies to pain that originates from the
viscera.
• Eg. The pain associated with MI commonly is
referred to the left arm, neck & chest.

13. •Convergence Theory:
•This type of referred pain
occurs because both visceral and
somatic afferents often converge
on the same interneurons in the
pain pathways.
so we “refer” the location of
visceral receptor activation to
the somatic source even though
in the case of visceral pain.
The perception is incorrect.
The convergence of
nociceptor input from the
viscera and the skin.
REFERRED PAIN

15. BREAKTHROUGH PAIN:-
• Pain is intermittent, transitory & an increase in pain
occurs at a greater intensity.
• Usually lasts from minutes to hours and can interfere
with functioning.
• Eg. Neuropathic pain
Lower back pain

16. What are the consequences
of not treating acute pain?

17. Adverse Effects Of Severe Acute Pain
System Adverse effects
Cardiovascular  Heart rate, BP
Risk of myocardial ischaemia
Psychological Anxiety
Insomnia
Economic Increased in-hospital complications
Prolonged length of stay in the hospital
Increased health care utilization and costs
Gastrointestinal ileus
Chronic pain Higher risk of developing chronic pain
e.g. post surgical pain syndrome
System Adverse effects
Psychological Anxiety
Insomnia
Economic Increased in-hospital complications
Prolonged length of stay in the hospital
Increased health care utilization and costs

18. Peripheral Receptor (Nociceptor)
• Nociceptors are free nerve endings that sense
heat, mechanical and chemical tissue damage.
• Characteristic of nociceptors -
• High threshold for activation
• Encode the intensity of stimulation by
increasing their discharge rates in a graded
fashion.
• These receptive endings are widely distributed
in-Skin,Dental pulp,Periosteum,Meninges.

19. •Types :-
• Mechano nociceptors (pinch and pinprick)
• Silent nociceptors (inflammation)
• Polymodal mechanoheat nociceptors:-
{Most prevalent and respond to excessive
pressure, extremes of temperature (> 42°C and
< 18°C), and alogens (pain-producing
substances)}.

20. Types of Fibers involved in Pain
C fibers
Small diameter, unmyelinated, slow
conduction velocity
Normally activated by noxious
stimuli
(responsible for secondary pain,
normally burning, aching pain)
Harrison’s Textbook of Medicine Vol 1, Part II, Chap 11
Aβ fibers
Large diameter,
myelinated, fast conduction
velocity
Mechanoreceptors
normally activated by non-
noxious mechanical stimuli
(touch)
Aδ fibers
Medium diameter,
myelinated, intermediate
conduction velocity
Normally activated by
noxious stimuli (transmit
sharp pain)
20

21. SOMATIC NOCICEPTORS:-
• Somatic nociceptors include those in skin and
deep tissues (muscle, tendon, fascia and bone)
whereas.
• Deep somatic nociceptors are less sensitive to
noxious stimuli than cutaneous nociceptors but
are easily sensitized by inflammation.
21

22. VISCERAL NOCICEPTORS:-
• visceral nociceptors include those in internal organs.
• Visceral organs are generally insensitive tissues that
mostly contain silent nociceptors.
• Most organs such as the intestine are innervated by
polymodal nociceptors that respond to smooth muscle
spasm, ischemia and inflammation.
• These receptors generally don’t respond to cutting
,burning or crushing that occurs during surgery.

23. •Noxious sensations can often be broken down
into two components(DOUBLE PAIN):-
•A fast (sharp) and a slow (burning) sensation.
• The fast phase is mediated by myelinated
fibers (A).
• The slow and delayed pain is mediated by
unmyelinated fibers (C-fibers).
• This distinction has been used to explain the
phenomenon of double-pain.

24. • Afferent activity from these neurons enters the
spinal cord between T1 and L2.
• Fibers from the esophagus, larynx, and trachea
travel with the vagus nerve to enter the nucleus
solitarius in the brain stem.
• Fibers from the bladder, prostate, rectum,
cervix and urethra, and genitalia are
transmitted into the spinal cord via
parasympathetic nerves at the level of the S2–
S4 nerve roots.

25. • FAST PAIN
• Felt about 0.1 sec after a pain
stimulus is applied.
• It is described as sharp pain,
pricking pain, acute & electric
pain.
• Fast sharp pain is not felt in
most deeper tissues of the
body.
• SLOW PAIN
• Usually begins after 1 sec or
more and may range from
seconds to minutes.
• Described as slow, burning,
aching, throbbing, nauseous
pain and chronic pain.
• Associated with tissue
destruction.

26. • Glutamate - Central
• Substance P - Central
• Brandykinin - Peripheral
• Prostaglandins – Peripheral
• Aspartate
Pain
Initiators
• Serotonin
• Endorphins
• Enkephalins
• Dynorphin
• GABA
• Glycine
Pain
Inhibitors
NEUROTRANSMITTERS

27. THREENEURONS
DUAL
ASCENDINGPATHWAY

28. First Order Neuron:-
• Pseudounipolar cell (dorsal root ganglion) ,
divides into central and peripheral branch.
• Impulses are transmitted by Aδ fibre or C fibres.
• Cell bodies located in dorsal root ganglia.
• These impulses are transmitted through the
axons to spinal cord.
• axons of first order neurons may synapse with
interneurons, sympathetic neurons and ventral
motor neurons.

29. SECOND ORDER NEURONS
• Second order neurons consist of -
• Nociceptor specific primarily in LAMINA I
• Wide Dynamic Range(WDR) neurons
primarily in LAMINA V
• Nociceptive specific neurons serve only noxious
stimuli, but WDR neurons also receive non
noxious afferent input from Aβ, A∂ and C fibers.
• Cell body in the Spinal Cord or medulla
oblongata.

30. • Spinal cord grey matter was divided by
REXED into ten lamina.
• The first six lamina, which make up the
dorsal horn, receive all afferent neural
activity, and represent the principal site of
modulation of pain by ascending and
descending neural pathways.

31. • Lamina II also called the SUBSTANSIA
GELATINOSA ,contains many interneurons
It is believed to be a major site of action for
opioids.
• Lamina V contains WDR neurons ,responds
to both noxious and non noxious sensory
input and receives both visceral and somatic
pain afferents. Thus responsible for referred
pain.

33. • THIRD ORDER NEURON:-
• located in the thalamus and send
fibers to somatosensory areas 1
and 2 in the postcentral gyrus of
the parietal cortex and the
superior wall of the sylvian
fissure respectively.
• Perception and discrete
localization of pain take place in
this cortical areas.

34. SPINOTHALAMIC TRACT
• The axons of most second order neurons cross
the midline close to their level of origin to the
contralateral side before they form the
spinothalamic tract
• They send their fibres to the thalamus ,the
reticular formation, the nucleus raphe Magnus
and the peri aqueductal grey matter.
• The tract can be divided into a lateral and
medial tract.

35. • The lateral spinothalamic tract projects
mainly to the ventralposterolateral nucleus
of the thalamus and carries discriminative
aspects of the pain such as location ,intensity
and duration and Thermal sensation.
• The medial spinothalamic tract projects to
the medial thalamus and
is responsible for mediating
the autonomic and unpleasant
emotional perception of the
pain, Touch and Pressure.

36. • Although most neurons from the lateral
thalamic nuclei project to the primary
somatosensory cortex .
• Those from the intralaminar and medial
nuclei project to the anterior cingulate gyrus
and mediate the suffering and emotional
components of pain.

37. ALTERNATE PAIN PATHWAYS
• Pain fibres ascend diffusely ipsilaterally and
contralaterally, hence some patients continue
to receive pain following ablation of the
contralateral spinothalamic tract.
• The spinoreticular tract is thought to mediate
arousal and autonomic responses to pain.
• The spinomesencephalic tract may be
important inactivating anti-nociceptive
because it has some projection to the
periaqueductal grey matter.

38. • The spinohypothalamic and spinotelencephalic
tract activates the hypothalamus and evoke
emotional behavior.
• The spinocervical tract ascends uncrossed to
the lateral cervical nucleus which relays the
fibres to the contralateral thalamus. This tract
is likely a major alternative pathway for pain.

39. MECHANISMS OF PAIN
• Pain sensation involves a series of complex
interactions between peripheral nerves & CNS.
• Pain sensation is modulated by excitatory and
inhibitory NTs released in response to stimuli.
• Sensation of pain is composed of :--
-Transduction;-Transmission;
-Modulation;-Perception

41. •MODULATION OF PAIN

42. • Modulation of pain occurs
• - peripherally at the nociceptors ,
- spinal cord
-supraspinal structure.
• This modulation can either inhibits or facilitates
pain.
• The major site of modulation is dorsal horn of
spinal cord.

43. PERIPHERAL MODULATION
• Nociceptors and their neurons display
sensitization following repeated stimulation.
• It occurs by two mechanisms:
• PRIMARY HYPERALGESIA (exaggerated
response to pain at site of injury)
SECONDARY HYPERALGESIA (response to
pain outside the site of injury)

44. PRIMARY HYPERALGESIA
• Sensitization of nociceptors commonly occurs
with injury and following application of heat.
• Primary hyperalgesia is mediated by the
releaseof alogens from damaged tissues:-
1) Bradykinin- macrophages
2) Histamine- platelets and mast cells
3) Serotonin
4) Prostaglandin

45. Innocuous/Noxious
stimulus
Reduced Transduction Threshold
primary sensory neuron central neuron
Peripheral Sensitization
Primary hyperalgesia
Primary heat allodynia
Inflammation

46. Prostaglandins:-
• Prostaglandins are produced following tissue damage
by the action of phospholipase A2 on phospholipids
released from cell membranes to form arachidonic
acid.
• The cyclooxygenase (COX) pathway then converts
the latter into endoperoxides, which in turn are
transformed into prostacyclin and prostaglandin E2
(PGE2).
• PGE2 directly activates free nerve endings, whereas
prostacyclin potentiates the edema from bradykinin.

47. • Pharmacological agents such as acetylsalicylic
acid (ASA, or aspirin), acetaminophen, and
nonsteroidal antiinflammatory drugs
(NSAIDs) produce analgesia by inhibition of
COX.
• Analgesic effect of corticosteroids
• likely the result of inhibition of prostaglandin
production through blockade of phospholipase
A2 activation.

49. SECONDARY HYPERALGESIA
(Neurogenic inflammation)
• It is manifested by the “triple response’’ of a red
flush at the site of injury(flare), local tissue edema,
and sensitization to noxious stimuli.
• Secondary hyperalgesia is primarily due to release
of substance P (and probably CGRP) from
collateral axons of the primary afferent neuron.

50. Substance P
• Substance P is an peptide that is synthesized and
released by first order neurons both peripherally
and in the dorsal horn.
• It degranulates histamine and 5-HT, vasodilates
blood vessels, causes tissue edema, and induces
the formation of leukotrienes.
• The compound capsaicin, degranulates and
depletes substance P. When applied topically,
capsaicin diminishes neurogenic inflammation
and appears to be useful for some patients with
postherpetic neuralgia.

51. Tissue injury causes
release of chemicals.
They sensitize or
activate receptors.
Neurons release
substance P, which
stimulates mast cells
and blood vessels.
Histamine released
from mast cells and
bradykinin released
from blood vessels add
to pain stimulus.

52. What are the Modulators
Of peripheral Sensitisation?

54. Noxious
stimulus
Increased Pain Responsiveness
primary sensory neuron central neuron
Central Sensitization
Secondary hyperalgesia
Tactile allodynia
Irritants
Tissue damage
Inflammation

55. CENTRAL MODULATION
FACILITATION
• Three mechanisms are responsible for central
sensitization in the spinal cord:-
(1) Wind up and sensitization of second order
neurons. WDR neurons increase their frequency of
discharge with same repeated stimuli and exhibit
prolonged discharge even after afferent C fiber input
has stopped.

56. (2) Receptor Field Expansion Dorsal horn
neurons increase their receptive fields
such that adjacent neurons become
responsive to stimuli to which they were
previously unresponsive .
(3) Hyperexcitability of flexion reflexes

57. • Neurochemical Mediators Of Central
Sensitization:-
• Substance P
• Vasoactive Intestinal Peptide (VIP)
• Cholecystokinin (CCK)
• Angiotensin
• L-glutamate
• L-aspartate

58. •Mechanism Of Action:-
•These substances trigger changes in
membrane excitability by interacting with G
protein–coupled membrane receptors on
neurons, activating intracellular second
messengers, which in turn phosphorylate
substrate proteins.
•A common pathway is an increase in
intracellular calcium concentration.

59. • Glutamate and aspartate receptors play an
important role in wind up via activation of
NMDA and non NMDA receptor mechanism.
• These amino acids are believed to be largely
responsible for the induction and
maintenance of central sensitization.

60. • The spreading flare of pain, allodynia, and hyperalgesia is
explained by activated NMDA receptors in the dorsal horn which
increases calcium conductance, leading to activation of protein
kinases and to activation of the enzyme nitric oxide synthase,
leading to nitric oxide synthesis. These actions also depend on
activation of secondary messenger systems

61. • Both prostaglandins and nitric oxide
facilitate the release of excitatory amino
acids in the spinal cord.
• Thus, COX inhibitors such as ASA and
NSAIDs also appear to have important
analgesic actions in the spinal cord.

62. •What are the Modulators
Of Central Sensitisation?

64. INHIBITION
• SEGMENTAL INHIBITION
• Activation of large afferent fibers inhibits
WDR neuron and spinothalamic tract activity.
• Moreover, activation of noxious stimuli in
noncontiguous parts of the body inhibits WDR
neurons at other levels; ie, pain in one part of
the body inhibits pain in other parts.
• These two observations support a gate theory
for pain processing in the spinal cord.

65. Gate Theory of Pain
• Melzack & Wall (1965).
• The gate = spinal cord interneurons that
release opioids.
• The synaptic junctions between the peripheral
nociceptor fiber and the dorsal horn cells in
the spinal cord are the sites of considerable
plasticity.
• A “GATE” can stop pain signals arriving at
the spinal cord from being passed to the brain.

66. The Gate-Control Theory ofPain
Figure 10-12a

67. The Gate-Control Theory of Pain
Figure 10-12b

68. The Gate-Control Theory of Pain
Figure 10-12c
ACUPUNCTURE
ANDTENS

69. • The introduction of the gate control theory in
1965 [Melzack &Wall 1965] has acted as a
catalyst for the global proliferation of the
different techniques for pain alleviation based
on afferent stimulation, such as
transcutaneous electric nerve stimulation
[TENS] and ACUPUNTURE.

70. Mechanisms Of Action Of TENS
• Afferent activity set up by TENS inhibits
nociceptive transmission in the spinal cord
through pre as well as post synaptic inhibitory
mechanisms. Not only the spinal cord but also
the thalamic regions may be involved.
• TENS stimulation may activate mechanisms at
both spinal segment and supraspinal centres.

71. Mechanism Of Action Of ACUPUNTURE
• Acupuncture is a mode of peripheral stimulation
based on the activation of peripheral receptors,
sensory nerve fibers or both.
• While a needle can mechanically stimulate nerve
fibers of many types, the pain relieving effect of
acupuncture has been attributed to the
activation of Aδ and possibly C fibers.

72. SUPRA SPINAL INHIBITION
• Several supraspinal structures send fibers down
the spinal cord to inhibit pain in the dorsal horn.
• Important site of origin for these pathways include
the periaqueductal grey, reticular formation and
nucleus raphe Magnus(NRM)
• Stimulation of the periaqueductal gray area in
midbrain produces widespread analgesia in
humans. Axons from these tracts act
presynaptically on primary afferent neurons and
postsynaptically on second-order neurons (or
interneurons).

73. • These pathways mediate their
antinociceptive action via α2-adrenergic,
serotonergic, and opiate (μ,∂ and k)
receptor mechanisms.
• The role of monoamines in pain inhibition
explains the analgesic action of
antidepressants that block reuptake of
catecholamines and serotonins.

74. COGNITIVE MODULATION
• Cognitive modulation of pain involves the
patients ability to relate a painful experience
to another event.
• Example if a patient in pain concentrate on
separate and unrelated images it is possible to
decrease the effects of painful sensation.

75. PSYCOLOGICAL MODULATION
• Relaxation – systematic relaxation of the
large muscle groups.
• Hypnosis – effective analgesic, state of
inner absorption and focused attention.
Reduces pain by distraction, altered pain
perception, increased pain threshold.

76. NON-PHARMACOLOGICAL MODULATION
• Massage reduces pain, including release of muscle
tension, improved circulation, increased joint
mobility, and decreased anxiety.
• Physical modalities
• Cold for acute injuries in first 48 hours, to
decrease bleeding or hematoma formation,
edema, and chronic back pain.
• Heat works well for relief of muscle aches and
abdominal cramping.

77. Neurostimulation
Neurostimulation uses a small implanted
system to send precisely controlled mild
electrical impulses to the nervous system
–Typically the dorsal horn in the Spinal
Cord
The patient feels the Neurostimulation as a
pleasant tingling sensation, also known as
“paraesthesias”
Neurostimulation is divided into subcategories
based upon the type of nerve that is being
stimulated.
Spinal cord stimulation (SCS) involves
stimulation of the dorsal column of the
spinal cord,
Peripheral nerve stimulation (PNS)
involves stimulation of a specific nerve
branch.
SCS is the most effective technique for
chronic pain management.
SCS
PNS

78. Intracerebral Stimulation
• Method of Deep Brain Stimulation.
• Used for intractable cancer pain , intractable
neuropathic pain .
• for nociceptive pain electrodes are implanted into the
periaqueductal and periventricular gray areas.
• For neuropathic pain the electrodes are placed into
specific sensory thalamic nuclei.

79. THANK YOU
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