PHAR: Neuropathic pain

Question 1

Definition of neuropathic pain.

• What two categories of neuropathic npain are there?

Answer 1

Pain initiated or caused by a primary lesion or disease of the somatosensory system.

• Peripheral neuropathic pain.
  
  • Pain initiated or caused by a primary lesion or disease in the peripheral somatosensory system.
• Central neuropathic pain.
  
  • Pain initiated or caused by a primary lesion or disease in the central somatosensory system.

Question 2

• What are the three different categories of pain?
  
  • Describe them.

Answer 2

• Nociceptive pain.
  
  • Early warning alarm system.
  • Withdrawal reflex.
  • High-threshold pain.
• Inflammatory.
  
  • Positive symptoms (pain).
  • Inflammatory cells: macrophages, mast cells, neutrophils, granulocytes.
  • Low-threshold pain.
• Pathological.
  
  • Nothing is wrong with the periphery, something is wrong with the system.
  • Feels as if it is in the periphery.
  • • and - symptoms (pain + numbness).

Question 3

• What are the two types of pathological pain?
• What differentiates them?
• Give an example of both.

Answer 3

1. Neuropathic pain.
2. Dysfunctional pain.

• Neuropathic pain = + and - symptoms.
  
  • Diabetic neuropathy.
    
    • Symptoms = dyesthesia (stabbing + burning pain) + paresthesia (tingling + numbness).
• Dysfunctional pain = only + symptoms.
  
  • Fibromyalgia.
    
    • Symptoms: whole body pain.
    • Treatment: pregabalin.

Note: COX inhibitors won’t work on pathological pain.

Question 4

Define allodynia.

• Give an example.

Answer 4

Central pain sensitization (increased response of neurons) following normally non-painful, often repetitive, stimulation.

• Patient compaining of blanket brushing their feet and causing pain.

Question 5

Give an example of:

Peripheral neuropathies under the following categories:

• Metabolic.
• Toxic.
• Post-infectious.

Post-traumatic (x5).

Others (x3).

Answer 5

• Metabolic: diabetic.
• Toxic: alcohol, chemotherapy, others.
• Postinfectious: PHN (postherpetic neuralgia), HIV, CMV.

Post-traumatic (x5).

• Sciatica.
• Postoperative.
• Neuroma or nerve entrapment.
• Phantom limb pain.
• CRPS (Complex Regional Pain Syndrome [RSD]).

Others (x3).

• Spinal cord injury.
• Post-stroke pain.
• MS.

NOTE: The longer the nerve, the further the damage spreads.

Question 6

• What is the mechanism of neuropathic pain?
• What is common to both peripheral and central neuropathic pain?

Answer 6

• Different mechanisms for different patients.
• Membrane hyperexcitability.
  
  • Ectopic discharge (discharge where discharge shouldn’t occur).
• Peripheral and central sensitisation occurs in the respective types of pain.

Question 7

Explain the mechanism of peripheral sensitisation.

Answer 7

• Sodium channel is most important channel in the periphery.
  
  • REVISION: Voltage-gated sodium channels play an important role in action potentials. If enough channels open when there is a change in the cell’s membrane potential, a small but significant number of Na⁺ ions will move into the cell down their electrochemical gradient, further depolarizing the cell.
• Damage nerves → nerves closed by or damaged nerve itself will overexpress Na channels → membrane becomes unstable (AP fired unnecessarily).

Question 8

Describe central sensitisation.

Answer 8

• Ca channels: central neurons hyperexcited.
• Hyperalgesia - increased Ca²⁺ influx → more pain than expected of injury.

Question 9

• Differentiate between hyperalgesia and allodynia.
• Describe the mismatch between stimulus and response process leading to allodynia.

Answer 9

• Hyperalgesia = exaggerated reaction to normally painful stimulus.
  
  • Allodynia = pain response to sensation that shouldn’t cause pain.
• Second order neurons are hyperactive → cross talk between nerve fibres → touch activates second order nerons → touch is painful.
  
  • Eg can’t wear a shirt without it hurting.

Question 10

• What are glia?
• What role do they play in central sensitisation?

Answer 10

• Non-neuronal cells.
  
  • Maintain homeostasis.
  • provide support and protection for neurons in the central and peripheral nervous systems.
  • “Skeleton” of the nervous system.
• Drives central sensitisation.
  
  • By chemokines and cytokines, which act as receptors on astrocytes.

Question 11

• Describe cortical reorganisation (use example from lecture).
• How is the example from the lecture treated?

Answer 11

• Severe neuropathic pain → not using arm -→ cortical representation shrinks down to nearly nothing.
  
  • Patient says arm feels like foreign body.
• Treat with rehabilitation program.

Question 12

• What are the 3 L’s of diagnosing neuropathic pain?
  
  • What sort of questions/inquiries are made?
• What are common characteristics described by the patient?
  
  • +/- signs and symptoms?
• What is the most common presentation?
• What are two validated tests for neuropathic pain?

Answer 12

• Listen to patient history.
  
  • ​Described as like ‘24/7 hitting the funny bone’ pain.
• Look for sensory deficit.
• Locate what could be a lesion.
• Burning, shock-like, pins and needles.
• NOTE: Lancinating (piercing or stabbing) pain most common in patients with neuropathic pain.

Most common presentation: Co-existence of positive and negative neurological signs.

Tests:

• DN4 diagnostic questionnaire.
  
  • Distinguishes nociceptive and neuropathic pain.
  • Completed by physician.
• painDETECT.
  
  • Completed by patient.

Question 13

What are the three most common comorbidities of neuropathic pain?

Answer 13

• Difficulty sleeping.
• Lack of energy.
• Drowsiness.

Question 14

• What is the most common pharmacological intervention prescribed for neuropathic pain.
  
  • Why does this present a problem?
• What four drugs SHOULD be being prescribed? (i.e. have establised efficacy).

Answer 14

• NSAIDS.
  
  • Have no effect on neuropathic pain.

SHOULD BE USED (top 2 = strong recommendation, second 2 = weak recommendation)

• Antidepressants and mood stabilisers.
• Anticonvulsants.
• Local anaesthetics.
• Opioids.
  
  • Rare to use.

Question 15

What are the three concepts for treatment of neuropathic pain?

Answer 15

• “Dampen down” peripheral sensitization in the damaged axon.
  
  • Sodium channel blockade.
• “Dampen down” central sensitization.
  
  • NMDA antagonists.
    
    • Less glutamate action.
    • Example = ketamine.
  • Calcium channel blockade.
• Enhancing descending inhibitory pathways.
  
  • Tricyclics.
  • SNRIs.
  • Tramadol.

Question 16

• Best documented analgesic for neuropathic pain?
  
  • Which one to use?
    
    • How is it given to patients?

Answer 16

• TCAs (tricyclic antidepressants).
  
  • Amitriptyline.
    
    • Start on low dose so there’s a higher chance of compliance.
    • Effects can be slow (4-6 weeks), needs to be given time.

Question 17

• What SNRIs are effective in the treatment of neuropathic pain?
• What SSRIs are effective in the treatment of neuropathic pain?

Answer 17

• Venlafaxine or duloxetine.
  
  • More data for duloxetine.
• None.
  
  • Noradrenergic effect necessary, hence use of SNRIs and TCAs.
    *

Question 18

• What are two anticonvulsants that have therapeutic effect against neuropathic pain?
  
  • Are they good as anticonvulsants?
• Not all anticonvulsants work. Give counterxamples.

Answer 18

• Pregabalin + gabapentin has strong evidence.
  
  • Not very good as anticonvulsants, but good for NP pain.
• Valproate - no evidence from RCTs.
• Carbamazepine - trigeminal neuralgia and facial neuropathic pain only.

Question 19

• What is the common mechanism of action of the two anticonvulsant drugs, pregabalin and gabapentin?
  *

Answer 19

• Binds to the α-2-δ subunit of the voltage-gated calcium channels.
• Normalises influx of Ca into pre-synaptic cell.
• Less excitatory neurotransmitter (glutamate) from pre-synaptic cell.
  
  • Reduction of central sensitisation.

Question 20

• Are opioids effective in treatment of neuropathic pain?
  
  • If effective, what line of therapy are they?
  • If effective, give examples of what could be used.

Answer 20

• Opioids are effective in neuropathic pain; however, not always necessary. Strong opioids have a risk of abuse, and there’s few long-term safety trials that have been conducted.
  
  • Second/third line therapy.
  • Tramadol = #1 (noradrenergic and serotoninergic effect).
  • Tapentadol (noradrenergic effect).
  • Buprenorphine.
  • Methadone.

Question 21

• Give an example of a pharmacological intervention for localised neuropathic pain.
  
  • How does it work?

Answer 21

• Lidocaine.
  
  • Blocks the voltage-gated Na^{<span>+</span>} channels in the neuronal cell membrane responsible for signal propagation.
  • Actional potential not transmitted.

Question 22

What class of drug has NO evidence of efficacy in cases of neuropathic pain? Explain.

Answer 22

• There is zero evidence for cannabinoids in NP pain.
• At high enough doses, it alters the mind of patient experiencing pain, so false evidence of pain reduction.

Question 23

Treatment guidlines.

Answer 23