lecture 28: neuropathic pain and analgesia I Flashcards
1
Q
What is neuropathic pain and analgesia?
A
- 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
2
Q
What is chronic pain?
A
- ~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
3
Q
What is chronic persistent pain?
A
- 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
- defined nociceptive basis
4
Q
What is the classification of pain?
A
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
5
Q
What is neuropathic pain?
A
- 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%)
6
Q
What is the prevalence/invidence of neuropathic pain in different conditions?
A
- 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)
7
Q
What are neuropathic pain characteristics?
A
- 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)
8
Q
What is the value of animal models in pain research?
A
- 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
9
Q
Do animal models predict analgesic efficacy in humans?
A
- 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
10
Q
What is the tail flick test?
A
- 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
11
Q
What is the neuropathy model?
A
- 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
12
Q
What is the von Frey test?
A
- 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
13
Q
What are voltage-gated Ca2+ channels?
A
- 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
14
Q
What voltage-sensitive Ca2+ channels?
A
- 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
15
Q
What is the physiological function of the a2-delta protein?
A
- 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
16
Q
What hyperexcited neuron?
A
- 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
18
Q
What are physiochemical properties of pregabalin?
A
- pregabalin (S-(+)-3-isobutylGABA)
- amino acid
- readily crosses blood-brain barrier
- L-amino acid transporter
- gabapentin similar drug
- termed calcium channel modulator
19
Q
What is the mechanism of pregabalin?
A
- 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
21
Q
What are the conopeptide families?
A
- 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
22
Q
What is the fish-hunting cone snail?
A
- 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
23
Q
What are conus hunting methods?
A
- different conus species catch fish by different mechanisms
25
Q
What is the mechanism of action of ziconotide?
A
- 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
26
Q
What are tactile allodynia dose-response curves for ω-conotoxins and morphine?
A
- 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
28
Q
What are the effects of ziconotide on MAP in concious rabbits (i.v. vs i.t.)?
A
- intravenous bolus - lowers MAP significantly, rapid, ongoing
- intrathecal bolous - does not
31
Q
What are CNS side effects of Ziconotide?
A
- 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
