Lecture 28 - Neuropathic Pain I Flashcards
How prevalent is neuropathic pain?
Around 20% of Australians suffer from it
In 5%, the pai has signficiant impact on ability to function and quality of life
List some 2° physical consequences of chronic pain
- Deconditioning & postural changes
- Changes to:
- Psyche
- Sleep patterns
- Behaviour
- Appetite
- Thought
What is the definition of chronic pain?
Persists for more than 3 months
Outline the three broad groups of chronic pain
-
Defined nociceptive basis
- eg Chronic arthritis
-
Well-defined neuropathological basis
- eg Post-herpetic neuralgia
- Peripheral neuropathy
-
Idiopathic
- Pathogenesis not well accepted
- eg Chronic muskuloskeletal pain, esp. spinal pain
- Some headaches
List the classification groups of pain
Give examples of each
A. Nociceptive
-
Superficial somatic
- Malignant ulcers
-
Deep somatic
- Bone metastases
- Liver capsule distension or inflammation
-
Visceral
- Deep abdominal/chest masses
B. Neuropathic
- Trivial injury to the CNS or PNS
- Tumour related:
- Spinal cord compression
- Non-tumour related:
- Post-herpetic neuralgia
- Phantom pain
Outline the origin of stimulus for the various classifications of pain
A. Nociceptive
- Superficial somatic
- Skin
- Subcutaneous tissue
- eg mucosa of mouth
- Deep somatic
- Muscles
- Bones
- Joints
- Organ capsules
- Pleura
- Visceral
- Solid or hollow organs
- Deep tumour masses
B. Neuropathic
- Damage to nocicpetive pathways
Describe the sensation of the various classifications of pain
A. Nociceptive
- Superficial somatic
- Hot, burning, stinging
- Deep somatic
- Dull aching
- Visceral
- Dull deep
B. Neuropathic
- ‘Pins and needles’
- Tingling & burning
- Allodynia
- Phantom pain
List things that can initiate neuropathic pain
Trivial injury to the PNS or CNS:
- Infection
- Trauma
- Surgical intervention
Describe the persistence of neuropathic pain
- Persists after the initial triggering stimulus has been removed
- Lasts indefinitely
- May escalate over time
Describe the effect of analgesics in neuropathic pain
Poor response to conventional analgesics (<50%)
List conditions which often lead to neuropathic pain
- Diabetes: **Diabetic neuropathy **(20-25%)
- Herpes zoster infection: Post-herpetic neuralgia (25-50%)
- Post-masectomy pain (20%)
-
Cancer patients: neuropathic pain (33%)
- +/- nociceptive pain
List the various characteristics of neuropathic pain
-
Spontaneous pain
- Shooting, burning, electric shock-like
-
Hypersensitivity / hyperalgesia
- Increased pain derived from minimally painful stimuli
-
Allodynia
- Pain experienced due to usually innocuous stimuli
- Tactile
- Thermal
- Pain experienced due to usually innocuous stimuli
What can we learn from studying pain in humans?
Mostly characterise pain states
Very few studies directly test mechanisms of pain (anatomical, biochemical, physiological)
Outline the value of animal models in pain research
- Animal models were used in 1/3rd of articles in Pain
- Allow investigation of:
- Neurochemistry and anatomy
- Samples from pain relevant tissues
- eg mRNA
- Pain conditions
- Genetic and environmental conditions
- Physiological mechanisms
- Comparative value
- Molecule / pain related phenomenon in man always found in rodents
- Failures:
- However, there are notable cases where antagonists/drugs developed in murine models have failed to translate into humans (ie not worked in humans)
- Successes
- Ziconitide
- First found to be efficacious in mice
Describe the tail flick test
- Application of heat stimulus to tail
- Time recorded until spontaneous ‘flick’ withdrawal
- A spinal reflex
Describe the animal model of neuropathic pain
- Tight ligation of spinal nerves L5 and L6 on LHS
- Supply Sciatic nerve
- However, sciatic nerve is not completely ligated, the rat can still ambulate as normal.
- Neuropathic signs within days:
- Themal & tactile allodynia
- Persists for at least five weeks
Describe the von Frey test
What is being tested?
Outline the process
Assesses tactile allodynia by measuring plantar withdrawal thresholds in respond to light touch
Process:
- Graded force applied to plantar surface
- Von Frey hairs applied sequentially
- Calibrated nylon filaments
Describe how the effect of neuropathy surgery can be measured
Von Frey testing
- Unoperated side:
- No tactile allodynia
- No change in hindpaw tactile withdraw threshold
- Operated side:
- Tactile allodynia:
- Decreased threshold
Describe the structure of voltage-gated Ca2+ channels
Four subunits:
-
α1
- Four homologous units
- Transmembrane
- Forms the pore
- 10 different genes encoding this subunit have been identfied
-
β
- Intracellular
- Alpha helices
-
γ
- Four transmembrane segments
- Alpha helices
-
δ
- One transmembrane segment
- Attaches to extracellular α2 with a disulphide bond
-
α2
- Binds δ extracellularly with disulfide bond
- Contains α2δ ligand binding site
- Binding site for pregabalin
Describe the diversity of α1 subunits in voltage-gated Ca2+ channels
What is the implication of this?
- 10 different genes encoding α1 subunits
- L-type
- Cav1.1-1.4
- P/Q-type
- Cav2.1
-
N-type
- Cav2.2
- R-type
- Cav2.3
- T-type
- Cav3.1-3.3
- L-type
Different antagonists act on each of the subunit types
What is the 1st line therapy for neuropathic pain?
Why?
Pregabalin (& gabapentin)
- Both Gabapentinoids
Why:
- Consistent efficacy
- Few AEs
- No drug-drug interactions
- Safe
Efficacy demonstrated in:
- Diabetic neuropathy
- Post-herptic neuralgia
- MS pain
- Cancer pain
- Phantom limb pain
- Spinal cord injury
What do gabapentin and pregabalin act on?
α2δ subunit ligand binding site
What is the function of α2δ?
- Accessory subunit of voltage-gated Ca channel
- Modifies channel functional properties
- ↑ time to activation
- Thus ↑ Ca2+ current
What is the role of α2δ in neuropathic pain?
Subunits are upregulated in the dorsal root ganglion and central terminals
⇒ increased Ca2+ current
⇒ hyperexcited neuron
⇒ increased neurotransmitter release
⇒ increased nociception
What is a hyperexcited neuron?
- Increased expression of α2δ subunits
- Increased time to inactivation of Cav channels
- Increased Ca2+ current (influx)
- More Ca2+ in synaptic terminals
- Enhanced neurotransmitter release
What are Gabapentinoids?
- Anti-epileptic drugs
- Shown to be effective in management of neuropathic pain
- Examples
- Gabapentin
- Pregabalin
- MOA:
- Bind with high affinity to α2δ ligand binding site
- Designed to mimic GABA
- However:
- Don’t interact with GABA-A/B receptors
- Not metabolised into GABA
- Don’t block GABA reuptake of metabolism
- However:
Describe the features of pregabalin
- Pharmacokinetics
- Administration
- Amino acid
- Readily crosses the BBB
- Non-saturable absorption
- 90% bioavailability
- Fast onset of action
- Well tolerated
- Few AEs
- Somnolence
- Ataxia
- Weight gain
- Dizziness
- Few drug interactions
- No liver metabolism
- Few AEs
- Twice daily administration
How is pregabalin characterised?
Why?
‘Ca2+ channel modulator’
Down-regulates Cav channel activity, but the channel remains in the open state
Describe the MOA of pregabalin
- Binds α2δ binding site
- ↓ Ca2+ influx through Cav channels into presynaptic neuron terminals
- ↓ release of excitatory neurotransmitters
- Glutamate
- Noradrenaline
- Substance P
- ↓ excitation of post-synaptic neurons
- Analgesia
Where in the body do gabapentinoids act?
Action is largely confined to the CNS
- Dorsal root ganglia
- Dorsal horn
This is because the N-type Cav are only really found in the CNS (not so much the PNS)
(Gabapentinoids only act on N-type Ca<span>v</span> channels)
What does Ziconotide act on?
α1 subunit of N**-type **Cav channels (Cav2.2)
What are conopeptides?
Peptides derived from various species of snails of genus Conus
Function in snail:
- Venom synthesised by snail
- Venom injected into prey by proboscis
Examples:
- Conantokins: NMDA receptor blockers
- ω-conotoxins: N-type Ca2+ channels blockers
- μ-conotoxins: Na+ channels blockers
- κ-conotoxins: K+ channels blockers
Describe the features of Ziconotide
- ω-conotoxin
- From Conus magus
- Folded polypeptide
- 3 disulphide bonds
Describe the importance of **N-type Cav **in nociception
Predominantly control neurotransmitter release from Aδ/C fibres in dorsal horn
- N-type Cav allows Ca2+ influx into presynaptic terminals
- Triggers neurotransmitter release (eg glutamate) into synaptic cleft
Thus, responsible for activation of nociception pathways in spinal cord
Describe the MOA of Ziconotide
- Binds α1 subunit of N-type Cav
- Blocks Ca2+influx into presynaptic terminal of neuron
- Blocks release of excitatory neurotransmitters
- Secondary nociceptor neurons are not activated
- Nociceptive signals are not transmitted to the brain
- Analgesia
Compare the efficacy of Ziconotide, Morphine and combination treatment of the two drugs
From most to least efficacious:
- Combination treatment
- Ziconotide
- Morphine
Measured by Van Frey testing
Ziconotide is >10 times as potent as Morphine
(Additive analgesic effects observed when combined with morphine)
Describe the clinical use of Ziconotide
- Licensed as Prialt
- Licensed for neuropathic and severe pain
- Administered via intrathecal catheter
- Under arachnoid membrane of the CNS
- Mini-pump under the skin provides continuous dose
- Major side effects if intravenous
- Efficacy:
- Analgesic efficacy for months
- No evidence of tolerance or addiction
- Use:
- Individuals with conditions with associated refractory pain
- AIDS
- Cancer
- Neuropathic pain
- Individuals with conditions with associated refractory pain
Why is Prialt (Ziconotide) administered intrathecally?
Intravenous injection results in major cardiovascular AEs:
- Bradycardia
- Orthostatic hypotension
- Massive drop in MAP
Peripheral administration:
- Hypotension
- Affects vagal and sympathic components of the baroreflex
This is not seen with intrathecal catheter administration
What are the adverse effects of Ziconotide?
Only seen with high dose intrathecal administration (as well as i.v. and peripheral administration)
CNS side effects:
- Dizziness
- Nausea
- Ataxia
- Confusion
- Memory impairment
- Somnolence
When the dose is high, the drug gets into the brain.
-
Cardiovascular side effects:
- Bradycardia
- Orthostatic hypotension
This is because N-type Cav channels are found on cardiac cells and peripheral nerves (unlike gabapentin, which only binds channels in the CNS)
What is CVID?
- Another ω-conotoxin, N-type Cav channel blocker
- From Conus catus
- Currently under investigation as a therapeutic
- More selective than Ziconotide
- Fewer AEs
- Can be administered intravenously
What is different about **N-type Cav **in neuropathic pain states?
- Upregulation of α2δ subunits
- Increased conductance of channels
- Upregulation of N-type channel in general
- Increased nociceptive transmission in spinal cord
Where does ziconotide come from?
Conopeptide from Conus magus
