Lecture 27 - Novel Analgesics I

Question 1

Difference between modulators and blockers

Answer 1

Modulators don’t block channel, but instead modulate amount of ion that can travel through

Question 2

Proportion of Australians that suffer from chronic pain at one point in their lives

Answer 2

~20%

Question 3

How might chronic pain lead to secondary conditions?
1)
2)

Answer 3

1) Deconditioning, postural changes

2) Changes to psyche, sleep, appetite, behaviour, thoughts

Question 4

Definition of chronic, persistent pain

Answer 4

Present for over three months

Question 5

Three broad groups of chronic pain

Answer 5

1) Defined nocicieptive basis (EG: arthritis)
2) Well-defined neurologic basis (EG: post-herpetic neuralgia, phantom limb pain)
3) Idiopathic (EG: chronic musculoskeletal pain, some types of headaches)

Question 6

Neuropathic pain
1)
2)
3)
4)

Answer 6

1) Generated, perpetuated by nervous system
2) Might be initiated by trivial injury to CNS or PNS
3) Pain persists independently of initial injury.
4) Response to conventional analgesics is poor (under 50%)

Question 7

What does post-herpetic neuralgia occur after?

Answer 7

Shingles

Question 8

Characteristics of neuropathic pain
1)
2)
3)

Answer 8

1) Spontaneous pain (shooting, burning, electric shock, pins and needles)
2) Hypersensitivity/hyperalgaesia
3) Allodynia

Question 9

Value of animal models in pain research
1)
2)
3)
4)
5)

Answer 9

1) Human studies can’t directly test anatomical, biochemical, physiological pain responses
2) Animal models offer good neurochemical, biochemical pain models.
3) Can standardise genetic, environmental backgrounds
4) Can denervate, experiment on animals
5) A molecule or pain-related phenomenon has never been found in humans that didn’t have a rodent analogue

Question 10

Example of a successful forward translation of a drug from animal models to humans

Answer 10

Ziconotide
From snail conopeptide
Binds N-type ca2+ channels

Question 11

Chung neuropathy model
1)
2)
3)

Answer 11

1) Surgical tight ligation of spinal nerves L5 and L6 on left side. Right side is not operated on,
2) L5/L6 lead to sciatic nerve.
3) Neuralgia, allodynia appear within days

Question 12

Von Frey test

Answer 12

Use Von Frey filaments to test allodynic response.

Poke feet with filaments calibrated to bend at a specific grams of force.

Question 13

What does von Frey test test?

Answer 13

Assessment of tactile allodynia of plantar skin.

Question 14

Composition of voltage-gated Ca2+ channels 
1)
2)
3)
4)

Answer 14

Four subunits:

1) Alpha1 - 4 homologous domains, each 6-pass transmembrane. Forms pore.
2) Beta - Intracellular
3) Gamma - Transmembrane segments
4) Delta - Transmembrane segment attached to alpha2 via disulphide bond.

Question 15

Number of genes encoding alpha1 subunits of voltage-gated Ca2+ channels

Answer 15

Ten

Question 16

Type of voltage-gated Ca2+ channel that ziconotide affects

Answer 16

N-type

Question 17

Which part of voltage-gated Ca2+ channel do gabapentin and pregabalin affect?

Answer 17

Alpha2/delta subunit

Question 18

Where are L-type voltage-gated Ca2+ channels found?

Answer 18

Mostly in cardiac, smooth muscle

Question 19

Where are N-type voltage-gated Ca2+ channel found?

Answer 19

In pre-synaptic neurons

Question 20

Function of alpha2/delta subunit
1)
2)

Answer 20

1) Accessory subunit of voltage-gated Ca2+ channel

2) When present, increases amount of time until channel inactivation, leading to greater Ca2+ influx

Question 21

What is upregulated in dorsal root ganglia and central terminals in neuropathic pain?

Answer 21

Alpha2/delta subunits of voltage-gated Ca2+ channels

Question 22

Gabapentinoids
1)
2)
3)

Answer 22

1) Anti-epilepsy drugs
2) Also effective in management of neuropathic pain
3) Designed to mimic GABA, but don’t interact with GABA-A or -B receptors, aren’t metabolised to GABA and don’t block GABA reuptake or metabolism.

Question 23

Pregabalin
1)
2)
3)
4)
5)
6)

Answer 23

1) A gabapentinoid
2) An amino acid
3) Readily crosses blood-brain barrier
4) A voltage-gated Ca2+ channel modulator
5) Binds alpha2/delta subunit with high affinity in CNS.
6) Not metabolised in the liver

Question 24

Pregabalin mechanism of action
1)
2)
3)
4)

Answer 24

1) Binds alpha2/delta subunit on voltage-gated Ca2+ channels.
2) This reduces Ca2+ influx to presynaptic neurons.
3) This decreases amount of excitatory neurotransmitters released.
4) Analgesia from reducing ectopic discharges of hyperexcited neurons.

Question 25

Pregabalin bioavailability

Answer 25

90%

Question 26

Why is pregabalins metabolism good?

Answer 26

Not metabolised in the liver.
Used in cancer patients, who are often on other medications. It isn’t metabolised in the liver, so doesn’t exacerbate liver damage

Question 27

Most common side-effects of pregabalin 
1)
2)
3)
4)

Answer 27

1) Somnolence
2) Dizziness
3) Ataxia
4) Weight gain

Question 28

How well-tolerated are pregabalin and gabapentin?

Answer 28

Very well-tolerated

Question 29

Useful combination therapy for analgesia

Answer 29

Morphine+gabapentin

Question 30

What do conantotoxins target?

Answer 30

NMDA receptors

Question 31

What do omega-conotoxins target?

Answer 31

Voltage-gated Ca2+ channels

Question 32

What do mu-conotoxins target?

Answer 32

Voltage-gated Na+ channels

Question 33

What do kappa-conotoxins target?

Answer 33

Voltage-gated K+ channels

Question 34

What is ziconotide derived from?

Answer 34

Omega-conotoxins

Question 35

What are upregulated in dorsal horn after peripheral inflammation or nerve damage?

Answer 35

N-type Ca2+ channels

Question 36

What does ziconotide target?

Answer 36

N-type Ca2+ channels

Question 37

Ziconotide mechanism of action
1)
2)

Answer 37

1) Adelta/C fibre neurotransmitter release primarily controlled by N-type Ca2+ channel action
2) Ziconotide binds N-type channels, disrupts Ca2+ influx to presynaptic neurons in dorsal horn

Question 38

How is ziconotide administered?

Answer 38

Intrathecal injection (to spinal cord)

Question 39

Why does ziconotide have to be administered intrathecally?

Answer 39

Major cardiovascular side effects if delivered intravenously.
Bradycardia (slow heart rate), drop in blood pressure, orthostatic hypertension

Question 40

Addiction potential of ziconotide

Answer 40

Extremely low

Question 41

Ziconotide efficacy compared to morphine

Answer 41

At least ten times as potent as morphine

Question 42

Ziconotide side effects
1)
2)

Answer 42

1) CNS side effects when delivered intrathecally (dizziness, abnormal gait, ataxia, confusion, memory impairment, somnolence)
2) Cardiovascular side effects if administered intravenously (bradycardia, hypotension)