Pain Patho-physiology

Pain is
– subjective
– protective
– and it is modified by developmental, behavioural, personality
and cultural factors
Can be associated with crying, sweating, increased heart rate, B.P,
behavioral changes etc
-an unpleasant or emotional experience originating in real or
potential damaged tissue or is described in terms of such damage-
(IASP)

Type of Pain
Nociceptive (Acute/Chronic)
-results –tissue injury
Neuropathic pain
-caused by nerve irritation
Inflammatory Pain
 Functional/Psychogenic:
-anxiety, mental agony, depression, and other emotional problems
can cause pain -- or make existing pain worse.
Chronic pain: is persistent or intermittent -lasting at least 6 months

Chronic pain produces significant behavioural and

psychological changes
The main changes are:
- depression/sense of hopelessness
- an attempt to keep pain - related behaviour to a minimum
- sleeping disorders
- preoccupation with the pain-results anxiety/irritation
--Mood swing
 Pathophysiology
Nociceptor – receptor preferentially sensitive to a noxious stimulus
or to a stimulus that will become noxious if prolonged.

has a detection threshold potential which must be exceeded before

an impulse travels from the peripheral - to CNS.
Receptors
Pain receptors: -nociceptive- sensitive to noxious stimuli that can
elicit tissue damage and activate nociceptors

Nociceptors are free nerve endings

Free nerve endings are distributed everywhere

-both somatic and visceral tissues
-except brain tissue and lung parenchyma
 Nociceptive Pain
Tissue
 Clinically, pain can be labeled
Injury Neuron
“nociceptive”
 if it is inferred that the pain is Neuron
due to ongoing activation of the
nociceptive system by tissue Nociceptor
injury. Pain Allodynia

 Tissue injury activates primary afferent neurons called nociceptors,

which are small diameter afferent neurons
 A-delta and C-fibers
Hyperalgesia
 Nociceptors
Recently, it was found that nerve endings contain transient receptor potential
(TRP) channels that sense and detect damage.
TRP channels, similar to voltage-gated K+ channels, having 6
transmembrane domains

SP

TRP channel
 Nociceptors

Nociceptors are found in

 skin , muscle, joints
 and some visceral tissues
 A-delta and C-fibers

specific to one type of stimulus, such as

- mechanical
- or thermal
but most are polymodal (respond to many stimuli)
the number and size of the receptive fields served by each fiber
may be small or large
 Contd....
nociceptors free nerve endings has capacity to
distinguish between noxious and innocuous stimuli
when exposed to
 mechanical
 thermal
 chemical (toxic substance) stimuli

tissue damage occurs

-subs are released by the damaged
-facilitates the movement of pain impulse to the
spinal cord
 Pain processing
Fast pain Slow pain
– acute – chronic
– pricking type – dull, aching , throbbing type
– well localized – poorly localised
– short duration – long duration

– Thin myelinated nerve fibres – Unmyelinated nerve fibres -c

are involved (A delta) fibres
– Their receptive area is large.
 Pain terminology
 Hyperalgesia: Increased pain from a stimulus

 Allodynia : a stimulus that does not normally provoke pain

 Paraesthesia: abnormal sensation, whether spontaneous or

evoked

 Anaesthesia: loss of sensation

 Neuralgia: pain in the distribution of a nerve or nerves

 Analgesia :absence

 Neuropathic Pain : caused by a lesion or disease of the NS

Nociceptive pain: arises from actual or threatened damage to non-neural
tissue

Visceral pain :arising from visceral organs-heart, lungs, kidneys

Different types of stimuli

Chemical stimuli: Exogenous /Endogenous

Thermal
Mechanical
Somatic Pain: Both A- delta & C fibers, discretely localizable
Visceral pain: C fibers only, poorly localized.

Silent nociceptors: subtype of C-fibers (recruited - inflammation)

 Mediators/ Chemicals/Substances released

Chemical/mediators released from the affected tissue are:

 PGs
 Bradykinin
 5-HT
 substance P
 Histamine
 PAF and NGF
 CGRP

Sub- P and CGRP, released by injury., which excites nociceptor

  Physiological Pain: a protective mechanism to causes avoidance,
pain stops once the stimulus is removed

 Pathological Pain: Results from tissue /nerve injury, inflammation

occurs in the area

 Neuropathic pain: occurs as a result of injury to or dysfunction of the

NS itself, peripheral or central NS

- Alcoholism, Amputation, Back, Leg, and Hip problems, Chemotherapy,

- DM, Facial nerve, HIV infection or AIDS Multiple sclerosis
 Contd........
 Deaferentation pain/anesthesia dolorosa: -sensory deficit

-malfunctioning sensation of pain is left intact

Phantom pain- pain localizei into non-existing organ (tissue)

Geniculate and Trigeminal Neuralgia: a rare type of nerve pain

that happens when a branch of the facial nerve - nervus intermedius

-or trigeminal nerve becomes damaged or compressed

-Carbamazepine is the drug of choice for nerve pain

 Contd........
Hemiagnosia: loss of ability to identify the source of pain on one side

- produces anxiety, moaning, agitation and distress but no attempt to

withdrawal from or push aside the offending stimulus

-associated with stroke that produces paralysis and hypersensitivity to

painful stimu

Phantom limb pain: - individual feels in amputated limb

Silent MI: Chest pain -a late and inconstant marker of episodes of

transient MI in vasospastic angina and in stable angina
Pain Pathway
The Ist order- neuron originates in the periphery and projects to
the spinal cord.
2nd- order neuron ascends the spinal cord.
3rd -order neuron projects into the brain.
 Nerve pathways carrying pain signals to the brain
 First synapse is present in the dorsal horn of the spinal cord
 Second order neuron travels through the lateral spinothalamic tracts

The brain first perceives the sensation of pain

The thalamus, sensitive cortex :

perceiving
describing of pain
localising

Parts of thalamus, brainstem and reticular formation:

- identify dull longer-lasting, and diffuse pain
The reticular formation and limbic system: - control the emotional and affective
response to pain
 Because the cortex, thalamus and brainstem are interconnected with the
hypothalamus and ANS, the perception of pain is associated with an
autonomic response

 afferent fibre enters the spinal cord

 synapses in laminae ii,iii
 substantia gelatinosa

 Acute pain : glutamate

 Chronic pain: substance P/CGRP

 Pain inhibitory neurotransmitters: NA*, enkephalin, GABA

 Tracts of the Spinal Cord
Tracts that serve to join brain to the spinal cord
 Ascending
 Descending Brain
Pain
x

PAG
X
C fibre
lateral
spinothalamic
substantia tract
gelatinosa
thalam thalamus
ocortic
al
tracts

lateral
spinothalamic
tract

C fibre
 The process of nociception: four phases.
Transduction,
 transmission,
perception,
and modulation.

Ist-order neurons synapse with neurons in dorsal horn of the spinal

cord
STT is most prominent nociceptive pathway-transmission of 2nd-order
neurons terminates in thalamus.

Modulation-undergo either inhibition or enhancement, at the dorsal

horn -spinal cord or in the brain.

-Perception-a noxious stimulus/pain-3rd-order neurons transmit

information from the thalamus to higher cortical.
The role of the spinal cord in pain processing

• Most afferent pain fibers terminate in the dorsal horn of the spinal
segment that they enter.

A-  fibers, some large A-delta fibers and small C- fibers

terminate in the laminae of dorsal horn and in the substantia
gelatinosa

Laminae than transmit specific information to 2nd afferent neuron

-2nd afferent neurons : transmit the impulse from SG and laminae

through the ventral and lateral horn,
From there the impulse is carried through the STT to the brain.

1. the neospinothalamic tract - it carries information to the mid

brain, thalamus and post central gyrus (A delta fibers)

2. the paleospinothalamic tract - it carries information to the

reticular formation, pons, limbic system, and mid brain
- the multisynaptic paleospinothalamic and
archispinothalamic tracts conduct slow pain (via C fibers)
Descending Tracts
 descending tracts involving opioid peptides as neurotransmitter
were discovered
 modify (inhibit) pain impulse transmission at the first synapse at
the SG

first tract was discovered in 1981 by Fields and Basbaum

– it involves enkephalin secreting neurons in the reticular
formation
– starting from the PAG of the midbrain
– ending in the NRM of the medulla
– Raphe magnus/LC
– from their ending in the SG of the dorsal horn
 descending inhibitory tract
substantia

gelatinosa

dorsal horn

c fibre input
substantia gelatinosa cell

in SG-enkephalin secreting neuron - presynaptic inhibition of the pain

impulse by transmission by blocking sub- P release
Presynaptic inhibition

Enkephalin
cannabinoids

substance P
Presynaptic inhibition enkephalin
substance P

blocking of
pain impulse

SP pain impulse
X

Glutamate
 pain perception depends on
activity of the

Ascending pain impulse

transmitting tracts

Descending pain modulator

–inhibitory tracts
C fibre
Descending pain modulatory system
– stimulus produced analgesia (Reynolds)
– stimulation of certain areas in the brain stem was known
to decrease the neuronal transmission along the
spinothalamic tract

– discovery of morphine receptors

– they were known to be present in the brain stem areas

– discovery of endogenous opioid peptides

-eg. endorphines, enkephalins, dynorphin
 Descending Pain-inhibitory System

Cortex receives descending fibres from the cortex that can influence
transmission :
Four
 Cortical & diencephalic systems.
 Mesencephalic periaqueductal grey matter - rich in enkephalins and
opiate receptors.
 Parts of rostroventral medulla- the nucleus raphe magnus
 The spinal and medullary dorsal horn.
These axons are prominently seratonergic terminating on cells in the laminae I,II & V
and selectively inhibit nociceptive neurons and interneurons.
Descending anlagesic system
 Modulation of pain
 changing or inhibiting pain impulses in the descending tract
(brain  spinal cord).

 descending fibers -endogenous opioids or endorphins- inhibiting

the transmission of noxious stimuli.

 also release NA and serotonin-

 cancer /Neuropathic Pain: responds to antidepressants which

increase the NA/ 5-HT availability
 Endogenous Opioid Peptides
 In 1970-73, endogenous opioid system and opiate binding sites in
the brain through the use of radioligand-binding assays

 In 1975, an endogenous opiate-like factor called enkephalin was

found and shortly after this two more classes of endogenous
opiate peptides

-dynophorins and the endorphins.

 opioid peptides
 endorphin
-Earliest to discover, present in pituitary
enkaphalins - met & leu
-widely distributed
dynorphin
Endomorphine 1 & 2
Pronociceptins

There are four main opioid receptors:

-mu, kappa, delta, recently discovered ORL1 receptor
The μ-receptor
The mu-receptor opens up the ion channel allowing K+ ions to flow out -
hyperpolarization of the membrane potential.

Respiratory depression -side effect of opioid analgesic drugs may cause of death
in all overdose cases.

The κ-receptor
Implicated in depression , stress, reward

K-receptor is associated with analgesia/sedation but with none of the undesired

side effects- Levorphanol, Nalbuphine (k-agonist while – mu –antagonist)

current research -promise in the development of a safer analgesic.

When and agonist or ligand binds to the k -receptor -results directly in the
closing of the Ca2+ ion channels in the terminal of the neuron

The delta receptor is a G-protein linked receptor.

 The ORL-1 receptor
 ORL-1 receptor or the “orphan” receptor was very recently
discovered.

 Natural opioid peptide that is a ligand for this receptor is- nociceptin
which is also called orphanin.

 ORL-1 receptor is associated with many diff biological effects such

as memory processes, CVS function, and renal function.

 It is thought to have effects on DA levels and is associated with NT

release during anxiety/stress
 MORPHINE

 Morphine is the golden standard among opioid

analgesics
 isolated in 1806
 Morphine has strong binding affinity for the mu and
delta and some weak affinity for the kappa receptor

 Codeine, Oxycodone and methadone are analogs of

codeine

Fentanyl- 1000 times stronger than morphine.

Side effects of morphine include a depression of cough due to respiratory depression,

nausea caused by increased vestibular sensitivity, and decreased gastric motility and some
constipation
 Heroin
 Heroin -white crystalline form –DAM-
hydrochloride.
 administered through i.v inj. but can
also be administered orally or
vaporized.
-binds most strongly to the mu-R and is
also active in the form of morphine

produces euphoric effects, however, it is thought that these effects are

greater to morphine and more addicting because of extremely rapid effect

 fast action- due to lipid-soluble because of its acetyl groups -immediately

cross BBB

Methadone is often used to treat heroin addiction

 Opioid Antagonists
 Naloxone is an example of a opioid antagonist, administered I.V

 can rapidly produce the withdrawal symptoms associated with

opioid addiction.

 Naltrexone , is more potent than Naloxone and is used in the

treatment of alcohol addiction

The future of Opioid Analgesics seems to be linked to the study of

the k- Receptor.

K- receptor induces analgesia without the dangerous and unwanted

side effects that the mu and delta
 Pain Pain Inhibitors
Initiators

Serotonin / NA
 Sub P/CGRP/ Endorphins/ Enkephalins/
 Glutamate - Central Dynorphin
 Brandykinin - Peripheral
X
 Prostaglandins - Peripheral

Neurochemicals-Pain
 Pain Processes
Transduction:
– Can be blocked by local anesthetics by injection either at the site of
injury/incision or intravenously
– Can be decreased by use of NSAIDs which decrease the -PGs
Transmission:
– Can be prevented by opioids/ Las by inj along peripheral nerves, at
nerve plexus, or in the epidural or subarachnoid spaces
Modulation:
– Can be augmented by inj of LAs or α2-agonists; gabapentin may also
effect modulation
Perception:
– Altered by use of GAs or systemic inj. of opioids and/or α2-agonists
 Noxious Stimulus
LAs, NSAIDs
Transduction
LAs

Transmission

Opiods, α2-agonists

Modulation
General Anaest, Opiods,
α2-agonists
Perception
Pharmacologic approach
Customized Multimodal Therapy.
 Local Anaesthetics, NSAIDs, Opioids – alone or in
combination.
 Phenothiazine tranquilizers, BZDs, tranquilizers & α2
agonists.

Opoids: meperidine—preferred in urinary and biliary colic, less

resp. depression newborns

Morphine/pentazocine

OxyContin/ alfentanil

fentanyl, carfentanil, etorphine and methadone.

 Non Pharmacological

Stimulation of touch fibres for pain relief:

– TENS (transcutaneous electrical nerve stimulation)
– Acupuncture
– Massage

Release of natural opioids

– Hypnosis
– Natural childbirth techniques
Local Anaesthetics
Used in perioperative and postoperative pain.
Application
 minor surgery/ Infiltration of surgical site
 Direct nerve blocks
 Regional Infiltration
 Intra-articular infiltration
 Epidurals

Mainly used – Lidocaine & Bupivacaine, benzocaine etc

NSAIDs

Inhibition of prostaglandin synthesis

 NSAIDs vary in their ability to inhibit COX 1 & 2

 Cox-1: Asprin, Diclofenac, Indomethacin, etc

 COX 2 inhibition -will provide enhanced analgesia , free from

ulcer

 Eg. Celecoxib, Rofecoxib, Meloxicam,

Continue…….
 reduce pain associated with inflammation
 include aspirin and salicylates
 are useful in the management of
 headache (nonmigraine)
 muscle aches and pain,
 Dysmenorrhea
 joint pain of osteoarthritis/ gout
Thank You….