Lecture 28 - Neuropathic Pain I

Question 1

How prevalent is neuropathic pain?

Answer 1

Around 20% of Australians suffer from it

In 5%, the pai has signficiant impact on ability to function and quality of life

Question 2

List some 2° physical consequences of chronic pain

Answer 2

• Deconditioning & postural changes
• Changes to:
  
  • Psyche
  • Sleep patterns
  • Behaviour
  • Appetite
  • Thought

Question 3

What is the definition of chronic pain?

Answer 3

Persists for more than 3 months

Question 4

Outline the three broad groups of chronic pain

Answer 4

1. Defined nociceptive basis
   
   • ​eg Chronic arthritis
2. Well-defined neuropathological basis
   
   • ​eg Post-herpetic neuralgia
   • Peripheral neuropathy
3. Idiopathic
   
   • ​Pathogenesis not well accepted
   • eg Chronic muskuloskeletal pain, esp. spinal pain
   • Some headaches

Question 5

List the classification groups of pain

Give examples of each

Answer 5

A. Nociceptive

1. Superficial somatic
   
   • ​Malignant ulcers
2. Deep somatic
   
   • ​Bone metastases
   • Liver capsule distension or inflammation
3. 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

Question 6

Outline the origin of stimulus for the various classifications of pain

Answer 6

A. Nociceptive

1. Superficial somatic
   
   • ​Skin
   • Subcutaneous tissue
   • eg mucosa of mouth
2. Deep somatic
   
   • ​Muscles
   • Bones
   • Joints
   • Organ capsules
   • Pleura
3. Visceral
   
   • ​Solid or hollow organs
   • Deep tumour masses

B. Neuropathic

• Damage to nocicpetive pathways

Question 7

Describe the sensation of the various classifications of pain

Answer 7

A. Nociceptive

• Superficial somatic
  
  • Hot, burning, stinging
• Deep somatic
  
  • Dull aching
• Visceral
  
  • Dull deep

B. Neuropathic

• ‘Pins and needles’
• Tingling & burning
• Allodynia
• Phantom pain

Question 8

List things that can initiate neuropathic pain

Answer 8

Trivial injury to the PNS or CNS:

• Infection
• Trauma
• Surgical intervention

Question 9

Describe the persistence of neuropathic pain

Answer 9

• Persists after the initial triggering stimulus has been removed
• Lasts indefinitely
• May escalate over time

Question 10

Describe the effect of analgesics in neuropathic pain

Answer 10

Poor response to conventional analgesics (<50%)

Question 11

List conditions which often lead to neuropathic pain

Answer 11

• Diabetes: **Diabetic neuropathy **(20-25%)
• Herpes zoster infection: Post-herpetic neuralgia (25-50%)
• Post-masectomy pain (20%)
• Cancer patients: neuropathic pain (33%)
  
  • +/- nociceptive pain

Question 12

List the various characteristics of neuropathic pain

Answer 12

1. Spontaneous pain
   
   • ​​Shooting, burning, electric shock-like
2. Hypersensitivity / hyperalgesia
   
   • ​​Increased pain derived from minimally painful stimuli
3. Allodynia
   
   • ​​Pain experienced due to usually innocuous stimuli
     
     • Tactile
     • Thermal

Question 13

What can we learn from studying pain in humans?

Answer 13

Mostly characterise pain states

Very few studies directly test mechanisms of pain (anatomical, biochemical, physiological)

Question 14

Outline the value of animal models in pain research

Answer 14

• 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

Question 15

Describe the tail flick test

Answer 15

• Application of heat stimulus to tail
• Time recorded until spontaneous ‘flick’ withdrawal
  
  • A spinal reflex

Question 16

Describe the animal model of neuropathic pain

Answer 16

• 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

Question 17

Describe the von Frey test

What is being tested?

Outline the process

Answer 17

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

Question 18

Describe how the effect of neuropathy surgery can be measured

Answer 18

Von Frey testing

• Unoperated side:
  
  • No tactile allodynia
  • No change in hindpaw tactile withdraw threshold
• Operated side:
  
  • Tactile allodynia:
  • Decreased threshold

Question 19

Describe the structure of voltage-gated Ca²⁺ channels

Answer 19

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

Question 20

Describe the diversity of α₁ subunits in voltage-gated Ca²⁺ channels

What is the implication of this?

Answer 20

• 10 different genes encoding α₁ subunits
  
  • L-type
    
    • Ca_v1.1-1.4
  • P/Q-type
    
    • Ca_v2.1
  • N-type
    
    • Ca_v2.2
  • R-type
    
    • Ca_v2.3
  • T-type
    
    • Ca_v3.1-3.3

​​

Different antagonists act on each of the subunit types

Question 21

What is the 1st line therapy for neuropathic pain?

Why?

Answer 21

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

Question 22

What do gabapentin and pregabalin act on?

Answer 22

α₂δ subunit ligand binding site

Question 23

What is the function of α₂δ?

Answer 23

• Accessory subunit of voltage-gated Ca channel
• Modifies channel functional properties
  
  • ↑ time to activation
  • Thus ↑ Ca²⁺ current

Question 24

What is the role of α₂δ in neuropathic pain?

Answer 24

Subunits are upregulated in the dorsal root ganglion and central terminals

​⇒ increased Ca²⁺ current

⇒ hyperexcited neuron

⇒ increased neurotransmitter release

⇒ increased nociception

Question 25

What is a hyperexcited neuron?

Answer 25

* Increased expression of α₂δ subunits * Increased time to inactivation of Ca_v channels * Increased Ca²⁺ current (influx) * More Ca²⁺ in synaptic terminals * Enhanced neurotransmitter release

Question 26

What are **Gabapentinoids**?

Answer 26

* 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

Question 27

Describe the features of pregabalin * Pharmacokinetics * Administration

Answer 27

* 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 * Twice daily administration

Question 28

How is pregabalin characterised? Why?

Answer 28

'Ca2+ channel **modulator**' Down-regulates Ca_v channel activity, but the channel remains in the open state

Question 29

Describe the MOA of pregabalin

Answer 29

1. Binds α₂δ binding site 2. ↓ Ca²⁺ influx through Ca_v channels into presynaptic neuron terminals 3. ↓ release of excitatory neurotransmitters * Glutamate * Noradrenaline * Substance P 4. ↓ excitation of post-synaptic neurons 5. Analgesia

Question 30

Where in the body do gabapentinoids act?

Answer 30

Action is largely confined to the CNS * Dorsal root ganglia * Dorsal horn This is because the N-type Ca_v are only really found in the CNS (not so much the PNS) (Gabapentinoids only act on N-type Ca_v channels)

Question 31

What does **Ziconotide** act on?

Answer 31

α₁ subunit of **N****-type **Ca_v channels (Ca_v2.2)

Question 32

What are conopeptides?

Answer 32

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

Question 33

Describe the features of **Ziconotide**

Answer 33

* ω-conotoxin * From *Conus magus* * Folded polypeptide * 3 disulphide bonds

Question 34

Describe the importance of **N-type Ca_v **in nociception

Answer 34

Predominantly control neurotransmitter release from Aδ/C fibres in dorsal horn * N-type Ca_v allows Ca²⁺ influx into presynaptic terminals * Triggers neurotransmitter release (eg glutamate) into synaptic cleft Thus, responsible for activation of nociception pathways in spinal cord

Question 35

Describe the **MOA** of Ziconotide

Answer 35

1. Binds α₁ subunit of N-type Ca_v 2. Blocks Ca²⁺ influx into presynaptic terminal of neuron 3. Blocks release of excitatory neurotransmitters 4. Secondary nociceptor neurons are not activated 5. Nociceptive signals are not transmitted to the brain 6. Analgesia

Question 36

Compare the efficacy of Ziconotide, Morphine and combination treatment of the two drugs

Answer 36

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)

Question 37

Describe the clinical use of Ziconotide

Answer 37

* 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

Question 38

Why is **Prialt (Ziconotide)** administered intrathecally?

Answer 38

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

Question 39

What are the **adverse effects** of Ziconotide?

Answer 39

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 Ca_v channels are found on cardiac cells and peripheral nerves (unlike gabapentin, which only binds channels in the CNS)

Question 40

What is **CVID**?

Answer 40

* Another ω-conotoxin, N-type Ca_v channel blocker * From *Conus catus* * Currently under investigation as a therapeutic * More selective than Ziconotide * Fewer AEs * Can be administered intravenously

Question 41

What is different about **N-type Ca_v **in neuropathic pain states?

Answer 41

* Upregulation of α₂δ subunits * ​Increased conductance of channels * Upregulation of N-type channel in general * ​Increased nociceptive transmission in spinal cord

Question 42

Where does ziconotide come from?

Answer 42

Conopeptide from *Conus magus*