Physiology and Pharmacology of Acute and Persistent Pain

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Physiology and Pharmacology of Acute and
Persistent Pain

• Martin Perkins
• AstraZeneca Research Development Montreal

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PAIN
An unpleasant sensory and emotional experience
associated with actual or potential tissue
damage, or described in terms of such damage
IASP, Subcommittee on Taxonomy, 1979
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Pain is an Unmet Medical Need

• 1 in 8 of you will experience poorly relieved
  persistent pain at some point in your life
• Only 50 of patients with post-operative pain are
  satisfied with the pain therapy received
• Chronic unrelieved pain produces a disease state
  with progressive physical social dysfunction
• Reduction in Quality of Life similar to
  depression
• Heavy Socio-economic burden.
• Poor choices of effective safe analgesic drugs
• The two main classes of analgesics (opiates and
  anti-inflammatorys) were discovered two centuries
  ago

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This Lecture

• The nociceptive pathways
• Physiological and Non-physiological pain
• Good and Bad pain
• Mechanisms underlying nociception
• Plasticity in nociceptive processing
• Existing therapeutic classes of analgesics
• advantages and disadvantages
• Summary and Future Directions

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Nociceptive pathways peripheral sensory nerves
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Termination Areas in Spinal Cord
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Ascending Pain Pathways

• Topographic representation maintained
• Sites for pain modulation are spinal cord and
  thalamus

Pons
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Mechanisms in Nociception
If it were only that simple..
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Physiological and Non-Physiological Pain
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Definitions

• Physiological Pain
• nociceptive pain activation of C and Ad fibres
• related to actual or potential tissue injury
• initiates protective reflexes or behaviour
• withdrawal from stimulus or guarding of
  affected area
• Non-physiological or pathological pain
• pain which continues beyond the point where it
  serves a physiological purpose
• Neuropathic pain
• pain associated with damage to the peripheral or
  central nervous system
• often/always pathological pain

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Definitions

• Hyperalgesia
• An increase in the perception of pain to a
  noxious stimulus
• Allodynia
• Pain caused by a stimulus which is not normally
  painful

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Peripheral Terminal Activation in Acute pain
Phase 1
First pain - sharp, pricking, localising Ad
fibres myelinated (12-30 m/s)

• Second pain - dull, burning, aching, not
  localised, diffuse
• C-fibres umyelinated slow conduction (0.5 - 2 m/s

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What kind of stimuli activate nociceptors in
acute pain?

• Ad fibre terminals respond to high threshold
  mechanical stimulation
• HTMs - High Threshold Mechanoreceptors
• essentially tissue-damaging stimuli
• C-fibre terminals respond to many noxious stimuli
• mechanical, heat (about 48oC), chemical
  (capsaicin), low pH
• called polymodal nociceptors

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Mechanisms of Acute and Persistent Pain

• Some of the Main Players

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Excitatory Neurotransmitters in Dorsal Horn of
Spinal Cord

• Excitatory Amino Acids (EAAs)
• glutamate, aspartate, (homocysteate)
• vast body of literature supporting major role in
  transmission in spinal cord
• primary afferent transmitters
• EAAs act on 4 main receptor types
• 3 ligand-gated ionotropic receptors
• kainate receptor
• AMPA receptor
• NMDA receptor
• 1 G-protein coupled receptor
• metabotropic glutamate receptor
• Bewildering number of receptor sub-types
• individual function not clear

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Neuropeptides in Dorsal Horn

• Tachykinins
• excitatory neuropeptides localised in nociceptive
  afferents
• Substance P, Neurokinin A,
• receptors NK1 and NK2
• ? transmitters or neuromodulators
• both central and peripheral role (Substance P)
• when released centrally - excitatory, contributes
  to central sensitisation wind-up
• when released peripherally - pro-inflammatory
  neurogenic inflammation
• Calcitonin Gene-Related Peptide (CGRP)
• localised in greater of nociceptive afferents
  than Sub P
• possibly two receptor sub-types
• excitatory centrally, powerful vasodilator
  peripherally,
• role unclear

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Opioid receptors

• 3 subtypes m, d, k
• About 60 homology between subtypes
• G protein-coupled receptors
• The Grandfather of all analgesics - Morphine -
  acts here
• Many synthetic opiates available

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Endogenous Opioid peptides

• Localised within several areas of CNS including
  dorsal horn of spinal cord
• not exclusive to nociceptive areas
• Relatively non-selective for opioid receptor
  sub-types
• Also produced by non-neuronal cells

Other opioid peptides e.g. nociceptin present in
CNS in pain pathways but significance to pain
transmission unclear
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Other transmitters/modulators

• Inhibitory transmitters
• Gamma Amino Butyric Acid (GABA) and Glycine
• released from interneurones in spinal cord and
  supra spinal
• inhibitory by reducing transmitter release
• glycine also has role as modulator of NMDA
  receptor
• 5-HydroxyTryptamine (5-HT)
• transmitter in inhibitory neurones from
  supra-spinal nucleus raphe medialis
• Noradrenaline
• inhibitory transmitter from supra-spinal locus
  coeruleus
• Inhibitory/excitatory
• Adenosine
• A1 receptor mediates analgesia
• A2 receptor activation is pro-nociceptive

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Peripheral Sensitisation

• Peripheral injury or inflammation initiates
  cascades of pro-inflammatory mediators released
  from many tissues
• These agents act on nociceptive nerve terminals -
  sensitisation
• decrease in threshold to stimulation
• increase in responsiveness to stimulation
• Sensory nerve terminals not only passive but
  contribute actively to the inflammatory process
• neurogenic inflammation
• release of neuropeptides, Sub P, CGRP
• vasodilation of blood vessels
• activate immunocompetent cells
• further release of pro-inflammatory, sensitising
  mediators

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Prostaglandins and Arachidonic cyclo-oxygenase
(COX)

• Two isoforms of COX
• Both produce prostaglandins (PGE2, PGF2a, PGI)
• COX-1 is constitutive, expressed in most tissues
• physiological and homeostatic role, cell
  signalling
• COX-2 is inducible following inflammation, trauma
  etc
• found in immunocompetent cells (e.g. leukocytes)
• pathophysiological role, initiates, maintains
  inflammation
• Prostaglandins (particularly PGE2) do not
  directly excite nociceptors but sensitise them to
  other stimuli

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Pro-inflammatory mediators and nociceptors
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Peripheral Sensitisation of Nociceptive Reflex to
Mechanical Stimulation

• A noxious mechanical stimulus is applied the foot
  of an anaesthetised rat
• The force that activates a nociceptive fibre is
  measured
• The noxious mechanical threshold
• Following a burn injury to the foot the threshold
  drops
• The nociceptors have become sensitised

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Central Sensitisation

• Sensitisation occurs at the level of the spinal
  cord and supra-spinally
• Persistent and/or powerful nociceptive activation
  elicits changes in the transmission of
  nociceptive information within the CNS
• Changes may last from hours to years
• In certain cases these changes can become
  pathological leading to unresolved persistent pain

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Central Sensitisation in Spinal Cord

• Neuronal recording from a nociceptive neurone in
  dorsal horn of spinal cord
• Noxious pinch to receptive field in foot
• Application of Mustard Oil to foot

• Both frequency and duration of response increases

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Central Sensitisation in Thalamus of Spinal Cord
in Rats
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Mechanisms of Central Sensitisation
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NMDA receptors contribute to spinal cord
sensitisation
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Neuropathic Pain Extreme case of Central
Sensitisation?

• Severe chronic pain not associated with any overt
  tissue damage
• Can occur after minor tissue damage, CNS
  disorders (stroke, MS), peripheral nerve damage
  (e.g. Herpes Zoster, diabetic neuropathy)
• Can last for years, poorly treated
• Characterised by severe mechanical and cold
  allodynia
• clothes can become unbearable, draughts
  excruciating pain
• Ab fibres now start to signal pain
• touch allodynia

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Sympathetic Nervous System and Pain

• Not normally directly involved in nociception
• Sympathetically Maintained Pain
• Complex Regional Pain Syndrome (CRPS)
• CRPS 1 Reflex Sympathetic Dystrophy
• CRPS 2 Causalgias
• Mechanism unclear but alpha-adrenergic receptors
  become expressed on nociceptive terminals
• Noradrenaline released from Sympathetic terminals
  now activate nociceptors
• This lead to further expression of adrenoceptors
  on nociceptors - another vicious circle

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Migraine chronic, episodic pain of
neurovascular origin

• Exact mechanism underlying migraine not clearly
  understood
• assumed to be strong genetic linkage
• Neurogenic inflammatory mechanisms a major
  component
• Major role for 5-Hydroxytryptamine (5-HT)
• principal current therapy is based on agonists at
  5-HT1D receptor sub-type
• so far 11 5-HT receptor sub-types and still
  counting
• Trigeminal neuronal system main pathway for
  initiation and pain perception

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Possible mechanism for Migraine
Abnormal neuronal discharge
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Current Therapies for Pain

• NSAIDs (Non-Steroidal Antiinflammatory Drugs,
  COX-1 COX-2)
• Opiates (mu agonists)
• Anticonvulsants (phenytoin), antidepressant
  (amitriptyline), antiarrhythmics (mexylitine)
• Sumatriptan, Zomig etc for migraine
• Gabapentin
• Tramadol (mu opioid plus your guess as good as
  mine)
• Combinations (opioids plus)

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Non Steroidal Anti-inflammatory Drugs (NSAIDs)

• Most widely used of all therapeutic agents
• Over 50 NSAIDs on the market
• Three main effects
• anti-inflammatory
• antipyretic
• analgesic
• Primary mechanism of action is inhibition of
  arachidonic cyclo-oxygenase (COX) and therefore
  reduction of prostaglandin levels
• most NSAIDs block both COX-1 and -2 e.g.
  naproxen, indomethacin, ibuprofen, aspirin etc
• Two recent selective COX-2 inhibitors - Vioxx and
  Celecoxib

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The Opiates

• Powerful analgesics all descended from Morphine
• All activate m receptors and varying degrees of d
  and k activation
• Pure agonist opiates
• morphine, codeine, oxymorphine, methadone,
  pethidine, fentanyl, sulfentanil, etc
• Partial/mixed agonists
• agonist on m, antagonist on d and/or k
• pentazocine, ketocyclazocine, buprenorphine etc
• Antagonists
• no analgesic activity by themselves
• e.g. naloxone, naltrexone

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Morphine acts in several sites to produce
analgesia
Morphine
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So, whats wrong with current therapy?

• Lack of efficacy
• in chronic pain 40 efficacy in Visual Analogue
  Scores typical
• Nothing works well in neuropathic pain
• Dose limiting adverse effects
• not only unpleasant but life-threatening as well
• NSAIDs
• gastric haemorrhage, renal/kidney toxicity
• Opiates
• respiratory depression, nausea vomiting,
  constipation, dependency, micturation
  difficulities.

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Summary and Conclusions

• Pain is complex, particularly chronic pain
• Transient pain is relatively well treated
• The sensation and perception of pain is not
  fixed or hardwired - its plastic
• Present therapies are old, inadequate and
  sometimes dangerous
• There is a real need for novel, powerful, safe
  analgesics in chronic pain