lecture 28: neuropathic pain and analgesia I

Question 1

What is neuropathic pain and analgesia?

Answer 1

• chronic persistent pain (esp. neuropathic)
• value of preclinical testing in animal models
• Ca2+ channel modulators
  
  • pregabalin (and gabapentin)
• N-type Ca2+ channel antagonists
  
  • w-conotoxin peptides, e.g. zicontide
• cannabinoid CB1 and CB2 receptor agonists
• microglial activation in neuropathic pain
• synergy with opioid and other analgesics

Question 2

What is chronic pain?

Answer 2

• ~20% of australians suffer chronic pain
• in 5% (~1 million people) the pain has significant impact on function and quality of life
• complex medical condition - may lead to secondary physical consequences with major impact
  
  • deconditioning and postural changes
  • changes to psyche, sleep patterns, appetite, behaviours and thoughts
  • social and psychological environments contribute to perception of pain

Question 3

What is chronic persistent pain?

Answer 3

• more than 3 months
• 3 broad groups
  
  • defined nociceptive basis
    
    • e.g. chronic arthritis
  • well-defined neuropathological basis
    
    • e.g. post-herpetic neuralgia; peripheral neuropathy
    • phantom limb pain (less well defined)
  • idiopathic
    
    • pathogensis not well accepted
    • chronic musculoskeletal pain, esp. spinal pain; chronic abdominal pain; some forms of headaches

Question 4

What is the classification of pain?

Answer 4

stimulus origin, examples, description, sudomotor/vasomotor effects

• nociceptive- superficial somatic
  
  • skin, subcutaneous tissue; mucosa of mouth, etc
  • malignant ulcers
  • hot, burning, stinging
  • no
• nociceptive - deep somatic
  
  • bones, muscles, joints; organs, capsules, pleura
  • bone metastases; liver capsule distension or inflammation
  • dull aching
  • may occur
• nociceptive - visceral
  
  • solid or hollow organs; deep tumour masses
  • deep abdominal or chest masses; intestinal, biliary-colic
  • dull deep
  • nausea, vomiting, sweating, BP/HR changes
• neuropathic
  
  • damage to nociceptive pathways
  • tumour-related: spinal cord compression, brachial plexus; non-tumour-related: post-herpes neuralgia, phantom pain
  • pins and needles, tingling, burning, shooting; allodynia; phantom pain
  • sudomotor/vasomotor instability: warmth, sweating, pallor, cold, cyanosis

Question 5

What is neuropathic pain?

Answer 5

• pain generated and perpetuated by nervous system (pain conducting system)
• may be initiated by trivial injury to central or peripheral nervous system - surgical interventions; infection; trauma
• pain becomes independent of initial triggering injury i.e. beyond tissue healing
• lasts indefinitely and may escalate over time
• response to conventional analgesics poor (less than 50%)

Question 6

What is the prevalence/invidence of neuropathic pain in different conditions?

Answer 6

• 20-25% of diabetics experience painful diabetic neuropathy
• 25-50% of patients older than 50 with herpes zoster develop post-herpatic neuralgia (3 months after healing of rash)
• 20% of women develop post-mastectomy pain
• 33% of cancer patients ahve neuropathic pain (alone or with nociceptive pain)

Question 7

What are neuropathic pain characteristics?

Answer 7

• spontaneous pain
  
  • shooting, burning or electric shock-like
  • numbness, pins and needles
• hypersensitivity/hyperalgesia
  
  • increased pain arising from minimally painful stimulus
• allodynia
  
  • pain in response to a normally innocuous stimulus
  • tactile (light touch)
  • thermal (hot or cold)

Question 8

What is the value of animal models in pain research?

Answer 8

• research papers published in Pain *
  
  • 2/3 in human patients or healthy volunteers
  • 1/3 in laboratory animals (rats and mice)
• most human studies characterised pain stats
  
  • very few directly test anatomical, biochemical or physiological mechanisms of pain
• animal models offer fine characterisation of neurochemistry and anatomy
• standardisation of genetic and environmental backgrounds
• samples (e.g. mRNA) from pain-relevant tissues usually only obtained from animals
• allow controlled investigation of chronic pain conditions:
  
  • peripheral neuropathic pain caused by partial denervation (mix of intact and injuryed fibred)
  • can’t do in humans
• advantage of exploration of basic physiological mechanisms of pain

Question 9

Do animal models predict analgesic efficacy in humans?

Answer 9

• a molecule or pain-related phenomenon has never been found in humans that did not have a rodent counterpart
• but, failed “translation” cases where efficacy in animals is not found in man (e.g. MK-869, neurokinin-1 antagonist)
• successful “forward” translation is the snail conopoeptide, ziconotide
  
  • neuroactive after intracranial injection in mice
  • high affinity binding to N-type Ca2+ channels
  • strong analgesic effects (i.t.) in many animal models
  • in clinical use for severe chronic pain → successful “rational” analgesic drug development

Question 10

What is the tail flick test?

Answer 10

• latency for tail flick in response to focused heat stimulus (thermal analgesia)
  
  • focused heat stimulus applied to tail
  • time recorded for spontaneous ‘flick’ withdrawal
    
    • auomated timer
    • based on reflected red detection
• simple spinal reflex

Question 11

What is the neuropathy model?

Answer 11

• as described by Kim and Chung (1992)
• surgery:
  
  • tight ligation of spinal nerves L5 and L6 on Left
• neuropathic signs apparent within days:
  
  • tactile allodynia
  • thermal allodynia
• signs persist at least 5 weeks

Question 12

What is the von Frey test?

Answer 12

• assessment of tactile allodynia
  
  • measures plantar withdrawal thresholds to light touch
  • graded force applied to plantar surface
  • von Frey hairs (calibrated nylon filaments) applied sequentially
• neuropathy surgery outcome
  
  • tactile allodynia - von frey hair testing

Question 13

What are voltage-gated Ca2+ channels?

Answer 13

• composed of 4 subunits
  
  • alpha1 subunit - 4 homologous domains, each with 6 transmembrane segments → the pore-forming subunit
  • beta subunit - intracellular
  • gamma subunit - 4 transmembrane segments
  • delta subunit - 1 transmembrane segment attached to extracellular alpha2 subunit via disulfide bond

Question 14

What voltage-sensitive Ca2+ channels?

Answer 14

• 10 different genes encoding alpha-1 subunits identified
• type - family - therapeutically-used modulators
• L-type
  
  • Cav1.1-1.4
  • verapamil, dilitazem, nifedipine (DHPs)
• P/Q type
  
  • Cav2.1
• N-type
  
  • Cav2.2
  • ziconotide
• R-type
  
  • Cav2.3
• T-type
  
  • Cav3.1-3.3
  • mibefradil (withdrawn), ethosuximide
• ancillary subunits
  
  • alpha2delta - gabapentin, pregabalin
  • Beta
  • gamma

Question 15

What is the physiological function of the a2-delta protein?

Answer 15

• accessory subunit of voltage-gated Ca2+ channels
• modifies channel functional properties when present (increase time to inactivation, thus increase Ca2+ current)
• subunits up-regulated in dorsal root ganglion and central terminals in neuropathic pain

Question 16

What hyperexcited neuron?

Answer 16

• a presynaptic hyperexcited neuron (tends to happen in neuropathic pain that’s had damage in the nerve pathway)
• a2-delta subunits are upregulated allowing the N-type calcium channel to stay open for long allowing lots more Ca2+ into the cell
• ca2+ entry is essential for the release of transmitter
• more calcium more excitatory neurotransmitter released

Question 17

What are gabapentinoids?

Answer 17

• antiepilepsy drugs shown in clinical trials to be effective in management of neuropathic pain
  
  • gabapentin and pregabalin
• designed to mimic neurotransmitter GABA, but
  
  • do not interact with GABA-A or GABA-B receptor
  • are not metabolised to GABA
  • do not block GABA reuptake or metabolism

Question 18

What are physiochemical properties of pregabalin?

Answer 18

• pregabalin (S-(+)-3-isobutylGABA)
• amino acid
• readily crosses blood-brain barrier
  
  • L-amino acid transporter
• gabapentin similar drug
• termed calcium channel modulator

Question 19

What is the mechanism of pregabalin?

Answer 19

• pregabalin binds to the a2-delta subunit of voltage-gated Ca2+ channels and decreases ca2+ influx at presynaptic terminals in hyperexcited neurons
• termed ‘modulator’ as binding decreases time channel remains in open state
• subsequent to a2-delta binding, pregabalin decreases release of excitatory neurotransmitters
  
  • e.g. glutamate, substance P, noradrenaline → decreases stimulation of post-synaptic receptors
  • analgesia (in neuropathic pain) due to suppression of ectopic discharges in hyperexcited neurons
    
    • nociceptive dorsal root ganglia and dorsal horn neurons

Question 20

What is pregabalin in neuropathic pain?

Answer 20

• non-saturable absorption; bioavailability 90%; fast onset of action; twice daily administration
• also improves disturbed sleep and anxiety
• well tolerated, few adverse effects of drug interactions
  
  • no liver metabolism → safe in druf combination
  • most common side effects are somnolence, dizziness, ataxia and weight gain
• pregabalin (and gabapentin) considered 1st line therapy for neuropathic pain due to consistent efficacy, safety and minimal potential for drug-drug interactions
• strong rationale for combining drugs with different modes of action, but little clinical evidence to date
  
  • gabapentin + morphine combination more effective at lower doses of each drug (than if each used as a single agent)
• efficacy in painful diabetic neuropathy, post-herpetic neuralgia, multiple sclerosis pain, cancer pain, phantom limb pain and spinal cord injury

Question 21

What are the conopeptide families?

Answer 21

• 700 conus species identified (100-200 peptides each)
• conus magus
• conus imperialis
• conus geographus
• conantokins → NMDA receptors
• w-conotoxins → Ca2+ channels
• µ-conotoxins → Na+ channels
• k-conotoxins → K+ channels

Question 22

What is the fish-hunting cone snail?

Answer 22

• venom is synthesised in a long tubular duct from which it is squeezed by muscular bulb and injected into prey through a hollow radular tooth
• these disposable teeth are like barbed needles, and thus are difficult for prey to dislodge

Question 23

What are conus hunting methods?

Answer 23

• different conus species catch fish by different mechanisms

Question 24

What are ω-conotoxins?

Answer 24

• highly selective blockers of N-type Ca2+ channels
• folded polypeptides
  
  • 3 disulphide links
  • 22-29 amino acids, MW ~2700
• ziconotide
  
  • conus magus
• n-type Ca2+ channels upregulated in dorsal horn after peripheral tissue inflammation or nerve damage → especially important role in nociceptive processing in pathological conditions

Question 25

What is the mechanism of action of ziconotide?

Answer 25

• release of neurotransmitters from adelta/fibres in superficial dorsal horn predominantly (not exclusively) controlled by N-type Ca2+ channels
  
  • these allow Ca2+ to enter presynaptic terminals when membrane depolarised, thereby triggering release of neurotransmitters (e.g. glutamate) into synaptic cleft
• ziconotide binds to N-type channels disrupting ca2+ influx into presynaptic terminals and release of neurotransmitters → i.t. ziconotide effectively inhibits pain transmission in spinal cord

Question 26

What are tactile allodynia dose-response curves for ω-conotoxins and morphine?

Answer 26

• given directly as a bolus injection into spinal cord
• omega- CTX GVIA is from conus geographus - most potent but with most side effects
• ziconotide ed50 of 0.3

Question 27

What is clinical use of ziconotide?

Answer 27

• prialt - approved in USA and europe for neuropathic and severe pain
  
  • when intolerant/refractory to other treatments
• administration via intrathecal catheter
  
  • major cardiovascular side effects if i.v.
    
    • bradcardia, orthostatic hypotension
  • supraspinal side effects if dose too high
• continuous i.t. infusion, analgesic efficacy for months; no evidence of tolerance (or addiction)

Question 28

What are the effects of ziconotide on MAP in concious rabbits (i.v. vs i.t.)?

Answer 28

• intravenous bolus - lowers MAP significantly, rapid, ongoing
• intrathecal bolous - does not

Question 29

What are the autonomic and cardiovascular effects of ω-CTXs in animals?

Answer 29

• peripheral administration
  
  • potent hypotensive agents due to sympatholytic action
  • affect sympathetic and vagal components of the baroreflex
  • postural hypotensive effects
• intrathecal administration
  
  • no effect on MAP and HR
  • no effect on sympathetic - or vagally-mediated reflexes
  • no postural hypotension

Question 30

What is clinical use of ziconotide?

Answer 30

• at least 10 times more potent than i.t. morphine
• analgesic efficacy in
  
  • cancer and AIDS patients with severe pain refractory to other systemic ot i.t. analgesics
  • neuropathic pain
• additive analgesic effects observed when i.t. ziconotide combined with i.t. morphine
  
  • confirming animal studies

Question 31

What are CNS side effects of Ziconotide?

Answer 31

• low doses of i.t. ziconotide → low occurrence of CNS side-effects
• high doses of i.t. ziconotide → high occurrence of CNS side-effects
  
  • dizziness, abnormal gait/ataxia, confusion, memory impairment, somnolence

Question 32

What are future directions?

Answer 32

• current research is investigating other ω-conotoxins such as CVID from conus catus
  
  • more selective for N-type Ca2+ channels than ziconotide with fewer adverse effects
  • evidence that i.v. administration is possible with minimal side effects
• novel ω-conotoxins in early development, such as CVIE and CVIF, may have improved efficacy and wider therapeutic window than ziconotide
• potential role of T-type Ca2+ channels in neuropathic pain