Expert: Dr Ian Jackson - please note UK based - 5/4/2008

Question
Hi,

Are any of these novel analgesics current used (or likely to be used) clinically in the UK ?

A) Inhibition of peripheral sensitisation

- TRPV1 antagonists (e.g. capsaicin)
- TRPM8 antagonists (e.g. menthol)
- ASIC antagonists / P2X antagonists
- Prostaglandin receptor antagonists
- Selective sodium channel antagonists (e.g. targeting sodium channels on C fibres - Nav1.7, 1.8, 1.9)

B) Inhibition of central sensitisation

- NK1 antagonists (e.g. saporin-substance P)
- NMDA antagonists (e.g. ketamine)
- Other glutamate receptor antagonsits (e.g. AMPA, mGluR)

3) Acting on descending pathways (e.g. PAG -> RVM -> Dorsal horn)

- 5-HT antagonists (e.g. 5-HT3 antagonist ondansetron)
- Centrally acting alpha-2 adrenoreceptor agonists
- CCK antagonists

I know it's not a very easy question to answer - but it would be really useful if you could give me some idea of which treatments are likely to be used clinically.

I've been having a lot of problems trying to work it out myself. Most of the papers I've read have a lot of bias (as all the scientists want to make out that their methods is best) and a lot of these complicated clinical studies are completely beyond me.

Thanks for your help.

Answer
I will give you info on anything I have heard of. many of these agents may well see use in chronic pain rather than acute pain and I have no experience in chronic pain management.

A) Inhibition of peripheral sensitisation

- TRPV1 antagonists (e.g. capsaicin) used in herpetic neuralgia but some interest in use for acute pain
- TRPM8 antagonists (e.g. menthol) not to my knowledge
- ASIC antagonists / P2X antagonists not a clue
- Prostaglandin receptor antagonists we use agents that act on the prostaglandin pathways NSAIDs with COX1 and COX2 activity and theorey that paracetamol works at a COX3 level. However none of these at receptor level - not aware of what is being acheived here but may offer something - difficulty is that this pathway has such a wide ranging effect that specific receptor activity might be too focussed.
- Selective sodium channel antagonists (e.g. targeting sodium channels on C fibres - Nav1.7, 1.8, 1.9) not a clue

B) Inhibition of central sensitisation

- NK1 antagonists (e.g. saporin-substance P) not aware of any agent available to us.
- NMDA antagonists (e.g. ketamine) used by anaesthetists, some interest that it may offer advantages in postop pain management but little evidence really of advantage so far. However lots of anecdotal evidence that people have been helped if introduced early.
- Other glutamate receptor antagonsits (e.g. AMPA, mGluR)

3) Acting on descending pathways (e.g. PAG -> RVM -> Dorsal horn)

- 5-HT antagonists (e.g. 5-HT3 antagonist ondansetron) bit of interest BUT main interest to anaesthetists is as an antiemetic.
- Centrally acting alpha-2 adrenoreceptor agonists - big interest here dexmedtomidine, clonidine etc being used extensively in various mixtures around the world.
- CCK antagonists no idea

There I have tried but this is well off base for me.
Dr Ian Jackson