PAIN III: Neuropathic Flashcards
First pain is carried by
A-delta fibres
Second pain is carried by
C fibres
Neuropathic pain involves
Central sensitization
General characteristics of neuropathic pain
- Slow onset, long-lasting
- Hyperalgesia, Allodynia, Causalgia, Spontaneous Shooting Pain
- Sometimes involves sympathetic nervous system
- Often resistant to opioid analgesia
Why is neuropathic pain opioid resistant
downregulation of MORs
Neuropathic state and opioid-tolerant state have many similarities
Slow onset in Neuropathic pain
maybe months after initial injury
persists past healing
Alternate name for neuropathic pain
Disease of pain
Etiology of neuropathic pain–neuropathic pain induced by…
• Traumatic nerve, brain or spinal cord injury
• Amputation (Phantom Limb)
• Diabetic Neuropathy, Post Herpetic Neuropathy
(Shingles), HIV-AIDs or other infection, fibromyalgia
• Multiple Sclerosis
• Stroke (central pain)
How stroke can lead to neuropathic pain by
decreased blood supply in the pain pathway causing pain
Study of neuropathic pain–injury involve
damage to some but not all axons of a peripheral nerve
Central sensitzation
areas (of partial nerve injury) can become spontaneously active and drive further activity in higher centres
Pertubations at site of nerve injury leading to neuropathic pain
• Crushed axons degenerate and Schwann cells proliferate • Inflammatory mediators (interleukins, TNF-α, prostaglandins etc.) are released (exictes surviving sensory nerves and increase their excitability)
How inflammatory mediators at site of injury activate pain
crushed axons release inflam mediators –> these mediators directly excite surviving sensory nerves –> increased expression and function of Na channels decrease expression and function of K+ channels (increase excitability)
AND Promote de novo expression of CSF -1 (Colony stimulating factor 1)
Perturbations w/in the SC
- Activated primary afferents release glutamate, substance P, ATP and other mediators such as colony stimulating factor 1 (CSF-1)
- Increases activation of microglial cells (CNS macrophages)
- Microglia release further mediators (mainly BDNF)
Pertubations w/in SC (simple)
injury –> CSF-1 (etc.) release –> activate microglia –> BDNF release
Effects of Mediators from the microglia (released due to pertubations in the SC)
- Reduce inhibitory synaptic transmission (by GABAand glycine)
- Increase excitatory synaptic transmission (by glutamate on AMPARs and NMDARs)
- High concentrations of glutamate released during central sensitization favor the activation of NMDA receptors
Normal vs post-injury peripheral nerve
Normal: inhibitory neurons keep tactile info out of superficial lamina (where pain in signalling occurs)
Injured: loss of inhibit circuits –> tactile fibres leak into superficial lamina –> tactile stim will be interpreted as pain in brain –> allodynia
____ is responsible for initiation of central sensitization BUT ____ maintains it
microglia intitate; astrocyte proliferations maintains it
Why it’s hard to treat central sensitization
there are early and late mediators BUT doctors won’t see patients until it is well established with adtrocytic mediators
Would be easier to treat at start but you don’t have the pain then
Opioids in neuropathic pain
are poorly effective, other drugs only work in 30% of individuals
How The gabapentinoids (alpha 2 delta ligands) work
Structurally similar to GABA but do not affect actions of GABA, found to have high affinity for the α2δ-1 subunit of the voltage gated Ca2+ channel –> impair ability of Ca2+ channels to interact with the neurotransmitter release process –> decreased NT release (impairs exocytosis)
Examples of gabapentinoids
PREGABALIN (LYRICA) AND GABAPENTIN (NEURONTIN)
Therapeutics for neuropathic pain
- gabapentinoids
- antidepressants
- channel blockers
- NMDA antags
- canabinoids
ADs for neuropathic pain: types
AMITRPTYLINE (ELAVIL)–TCA
VENLAFAXINE (EFFEXOR)–SNRI
DULOXETINE–SNRI
AMITRPTYLINE (ELAVIL)–TCA function
- TCAs seem to work best
- Facilitates NA/5-HT descending inhibition of pain
- Anticholinergic side effects (constipation / dry mouth)
SNRIs–examples and uses
VENLAFAXINE (EFFEXOR) –works (not as good)
DULOXETINE–used for fibromyalgia and diabetic neuropathy
ADs dose needed and which type needed
- effective at lower doses than needed for depression
- need to work on NA and 5HT (SSRIs aren’t effective)
Carbamazepine –how it works
- Na+ channel blocker and GABA agonist introduced for trigeminal neuralgia in 1962
- May specifically target “pain” Na+ channel (Nav 1.7)
Trigeminal neuralgia
- stabbing facial pain lasts seconds-minutes ‘tic douloureux‘
- pattern of pain follows pattern of Vth cranial nerve (trigeminal nerve)
- usually maxillary/mandibular branch (not opthalmic branch)
- initiated by trivial stimulus, (e.g. shaving, chewing, talking)`
Issues with Carbamazepine (TEGRETOL)
- Potential for drug interactions as a result of its general depressant effect and ability to induce drug metabolizing enzyme, CYP 450 (reduces effectiveness of other drugs)
- Adverse effects drowsiness, headaches and migraines, impairment of motor co-ordination and/or upset stomach
omega- CONOTOXIN GVIA (ZIRCONOTIDE or PRIALT)
- N-type Ca2+ channel blocker
- administered intrathecally blocks glutamate/substance P release
- synthetic version of one of many toxins from conus magnus (cone snail)
Types of channel blockers
- Carbamazepine (TEGRETOL)
- omega-conotoxin gvia (or synthetically: zirconotide–trade name: prialt)
NMDA antags subtypes
Ketamine
Methadone
Ketamine–how does it work and CONS
• Dissociative anesthetic and NMDA receptor blocker
• DOWNSIDES: Psychomimetic effects (binds at phencyclidine site to cause hallucinations)
- can decrease hallucinations via co-admin with other drugs
Methadone–why better than other opioids
- Opioid, BUT also interacts weakly with NMDAR
* Interaction with NMDAR may explain its efficacy in neuropathic pain
What cannabinoid is used for neuropathic pain and why
Nabilone (synthetic cannabinoid)
Inhibits N-type Ca2+ channels in a similar fashion to opioids but act on cannabinoid CB1 receptors
Side effects of nabilone
Sedation, memory impairment, increased appetite, anti-emetic
What is better for pain THC or CBD
CBD–good analgesic that may attenuate psychomimetic effects of
THC
Sympathetically maintained pain–2 subtypes
Complex Regional Pain Syndrome I
Complex Regional Pain Syndrome II
Complex Regional Pain Syndrome I–definition
• pain disproportionate to injury,
• not associated with damage to major nerve
• vasomotor, sudomotor and trophic
perturbation
Complex Regional Pain Syndrome I aka…
reflex sympathetic dystrophy (old name)
Complex Regional Pain Syndrome II–definition
pain disproportionate to injury,
• IS associated with damage to major nerve
• vasomotor, sudomotor and trophic
perturbation
Etiology of Sympathetically maintained pain
Interaction of perivascular sympathetic nerves and sensory neurons in
the dorsal root ganglia and skin after injury
causes sensory nerves to express ectopic α adrenoceptors
Cause of sensory and sympathetic nerve interaction
Doesn’t occur normally
Perivascular sympth nerves sprout to interact with sensory neurons
How sympath spout in Sympathetically maintained pain
sympth nerves form basket-like structures around sensory nerves –> start to stimulate sensory nerves
Pain worsens w/ increased sympth activation
alpha-blockers for Sympathetically maintained pain
alpha blockers can stop sympathetically maintained pain BUT the amount needed to help would fatally decrease BP
–instead use it for diagnoses
central sensitization is seen outside of neuropathic pain example
sunburn + hot shower –> really hurts
The ____ channel is specially involved in the transfer of painful information
Sodium channel NaV1.7
Could be a potential target for therapies
Principal contributors to the spinal disinhibition that occurs after neuropathic injury and potential therapies that target this
alpha2- and alpha3-subunit containing GABA(A) receptors
benzodiazepine related drugs may restore lost inhibition
