GM6052 directed study

Welcome To Pain Materials

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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

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
Sudden onset Temporary (disappears once stimulus is removed) can be somatic, visceral, referred Associated anxiety Physiological responses to acute pain include increased RR, HR, BP and reduction in gastric motility sympathetic response)

Chronic pain
Persistent usually lasting more than six months Cause unknown may be due to neural stimulation or a decrease in endorphins Physiological 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

Mediators
Bradykinin Histamine Serotonin Acetylcholine Potassium 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 Slow (second) pain at 5-35m/sec conduct at 0.5-2.0m/sec Associated with Sharp, brief, prinking pain Well localised Associated with dull,burning, aching, prolonged pain 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 A-delta fibres synapse in lamina I, II and V C-fibres in lamina I and II

Evidence to suggest that:

Transmission by primary A-delta and Cfibres

Grey matter of Dorsal horn IV II I A-Delta or C III fibre

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/homuncul us.html http://faculty.washington.edu/chu dler/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, -endorphins and dynorphins) which act on the pre-synaptic terminals of nociceptor fibres to prevent the release of substance P / glutamate

interneuron

Pain transmission blocked by release of opiates

opioid

opioid receptor

Primary neurone

To thalamus

Interneuron (releases endogenous opiates e.g.endorphins)

Secondary neuron

Primary neuron (nociceptor)

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

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

MIDBRAIN
Periaqueductal grey matter Medial lemniscus Red nucleus Corticospinal tract

MEDULLA Medial lemniscus Corticospinal tract

Nucleus Raphe magnus

To thalamus SPINAL CORD

interneuron

Spinothalamic tract

nociceptor

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

Large Abeta fibre impulses Central nervous system pain modulation may increase or decrease pain Closes pain gate Pain transmission Actions and responses

Substantia gelatinosa in spinal cord

Opens pain gate

Small Adelta / C fibres

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.

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

Effect on oculomotor nucleus mediated by parasympathetic nervous system

Pupillary constriction

Nausea

Acts on chemoreceptor trigger zone in medulla

Decreases motility of gut

Constipation Euphoria

Acts on receptors in reticular formation / limbic system

Opioid agonist and antagonists

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

antagonists such as naloxone bind to m receptors and block action of endogenous and exogenous opioids

produces reaction in cell

antagonist produces no reaction in cell

NSAIDS

All nociceptors can be sensitised by prostaglandins. i.e. prostaglandins greatly enhance the receptor response to noxious stimuli NSAIDs act by suppressing cyclooxygenase, an enzyme involved in synthesis of prostaglandins This blocks inflammatory process (antiinflammatory) 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 cyclooxygenase
Constitutive pathway (stable conc) phospholipid

Induced pathway
phospholipid

Arachidonic acid
COX 1 enzyme
Prostaglandins associated with normal body functions e.g. prostaglandin E2 (for kidney function), prostaglandin I2 (for stomach protection)

Arachidonic acid
COX-2 enzyme 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):4655/.

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

Local Anaesthetics
nervous impulses depend on Na+ ions entering axons of neurons via Na+ gates local anaesthetics block Na+ gates so nervous impulse are not transmitted

Na
+

Na+

nervou s impuls e

axon of pain neuron

Na+ gates

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 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 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/def init.html

Web sites

END OF SESSION
We hope that this has been a useful resource in preparing for the pain seminar