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GM6052 – directed study

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Instructions definitions of pain Types of pain Pain Transmission pathw

ay 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

Types of pain

Acute versus chronic Nociceptive versus neuropat

hic 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 painSudden onsetTemporary (disappears once stimulus is removed) can be somatic, visceral, referredAssociated anxietyPhysiological responses to acute pain include increased RR, HR, BP and reduction in gastric motility – sympathetic response)

Persistent – usually lasting more than six monthsCause unknown – may be due to neural stimulation or a decrease in endorphinsPhysiological responses are less obvious especially with adaptation.Psychological responses may include depression

See McCance and Heuther (2002) for more detail on this

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.

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.

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.

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).

See article by Kelly et al ( 2001) for interesting information on this aspect

Transduction TRAUMA•Mechanical

•Thermal

•chemical

Overall effect is increased nociceptor activation

nociceptor

MediatorsBradykininHistamineSerotoninAcetylcholinePotassium ions Prostaglandins (PGE2, PGI2)Substance P

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

Transduction - A delta fibres and C fibres

A-Delta fibres C- fibres

myelinated unmyelinated

fast ( first) pain -conduct at 5-35m/sec

Slow (second) pain – conduct at 0.5-2.0m/sec

Associated with Sharp, brief, prinking pain

Associated with dull,burning, aching, prolonged pain

Well localised More diffuse

Elicited by mechanical or thermal stimuli

Elicited mainly by 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

Transmission by primary A-delta and C-fibres

laminaIIIIII

IVV

A-Delta or C fibreGrey

matter of 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.

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.

Somatosensory cortex

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

Check out these web sites which demonstrate the homunculus and sensory perception.

http://www.cs.uta.fi/~jh/homunculus.html

http://faculty.washington.edu/chudler/flash/hom.html

Perception

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

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, β-endorphins and dynorphins) which act on the pre-synaptic terminals of nociceptor fibres to prevent the release of substance P / glutamate

To thalamus

Interneuron (releases endogenous opiates e.g.endorphins)

interneuron

opioid

opioid receptor

Primary neurone

Primary neuron (nociceptor)

Secondary neuron

Afferent

pathway

Pain transmission blocked by release of opiates

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 (μ) and kappa (κ) receptors)

Inhibit Neurotransmitter release by inhibiting voltage dependent calcium channels (delta (δ) 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

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

Periaqueductal grey matter

Medial lemniscus

Red nucleus

Corticospinal tract

Nucleus Raphe magnus

Medial lemniscus

Corticospinal tract

MIDBRAIN

MEDULLA

SPINAL CORD

Pain modulation – descending pathway

To thalamus

nociceptor

interneuron

Spinothalamic tract

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

Substantia gelatinosa in spinal cord

Large Abeta fibre impulses

Small Adelta / C fibres

Pain transmission

Closes pain gate

Opens pain gate

Actions and

responses

Central nervous system pain modulation may increase or decrease pain

Schematic diagram of gate control theory of pain mechanism

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 μ) 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.

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

ConstipationDecreases motility of gut

Euphoria Acts on receptors in reticular formation /

limbic system

agonist drug e.g. diamorphine mimics actionof endogenous opioid

receptor

endogenous opioid binds to receptor

produces reaction in cell

antagonist producesno reaction in cell

antagonists such as naloxonebind to receptorsand block actionof endogenous and exogenousopioids

Opioid agonist and antagonists

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)

A good website giving more detail on this is as follows: http://www.elfstrom.com/arthritis/nsaids/actions.html

Action of cyclo-oxygenase

COX – 1 enzyme

Constitutive Constitutive pathway pathway (stable conc)(stable conc)

phospholipid

Arachidonic acid

Prostaglandins associated with normal body functions

e.g. prostaglandin E2 (for kidney function), prostaglandin I2 (for stomach protection)

COX-2 enzyme

Induced Induced pathwaypathway

phospholipid

Arachidonic acid

Inflammatory prostaglandins

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)

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

Local anaesthetics

Epidurals – administered to epidural space

Spinal anaethesia Administered in intrathecal

(subarachnoid) space Refer to a text book to see

where these spaces are located in the meninges

Na+

Na+

nervous impulses depend on Na+ ions

entering axons of neurons via Na+

gates

local anaesthetics block Na+ gates so nervous impulse are not transmitted

nervous

impulse

axon of pain

neuronNa+ gates

Local Anaesthetics

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

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 Gatz’s

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

Web sites http://www.cs.uta.fi/~jh/homunculus.html http://faculty.washington.edu/chudler/flash/hom.html http://www.elfstrom.com/arthritis/nsaids/actions.html http://www.painresearch.utah.edu/crc/CRCpage/

definit.html

We hope that this has been a useful We hope that this has been a useful resource in preparing for the pain resource in preparing for the pain seminarseminar

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