All four major classes of analgesic medications (opioids, paracetamol, antidepressants, α2δ-antagonists) act within the central nervous system to affect descending pain modulating pathways. Specifically, they act on circuits within the dorsal horn of the spinal cord to reduce pain transmission and modulate pain signaling. The sites of action for these drug classes include opioid receptors, areas involved in serotonergic and noradrenergic signaling, and calcium channels. By acting at these various targets within central pain processing pathways, analgesic medications are able to reduce the perception of pain.

1. Where do analgesic medications work?
Peter Kamerman
PainSA, Pretoria, South Africa, 2013

4. • All four drug classes act within the CNS
• All four drug classes affect descending
pain modulating pathways

5. Major pain modulating pathways
Adapted from: McMahon & Koltzenburg: Wall and Melzack’s Textbook of Pain 5e, © Elsevier 2006

6. Bee & Dickenson, Future Neurol 2: 661-671, 2007

7. Dorsal horn circuits
Adapted from: McMahon & Koltzenburg: Wall and Melzack’s Textbook of Pain 5e, © Elsevier 2006

8. Opioid analgesics

9. Sites of mu opioid receptors
Adapted from: McMahon & Koltzenburg: Wall and Melzack’s Textbook of Pain 5e, © Elsevier 2006

10. Effect of opioids on dorsal horn circuits
Adapted from: McMahon & Koltzenburg: Wall and Melzack’s Textbook of Pain 5e, © Elsevier 2006

11. Non-opioid analgesics
Paracetamol

12. Sites of action of paracetamol
Adapted from: McMahon & Koltzenburg: Wall and Melzack’s Textbook of Pain 5e, © Elsevier 2006

13. Effects of paracetamol on dorsal horn circuits
Adapted from: Mallet et al., Pain 139: 190-200, 2008

14. Effects of paracetamol on dorsal horn circuits
Adapted from: Andersson et al., Nat Commun 2: 551, DOI 10.1038/ncomms1559, 2011

15. Antidepressants
Serotonin and noradrenaline reuptake inhibitors (SNRI)
Tricyclic antidepressants (TCA)

16. Sites of action of antidepressants
Adapted from: McMahon & Koltzenburg: Wall and Melzack’s Textbook of Pain 5e, © Elsevier 2006

17. Adapted from: McMahon & Koltzenburg: Wall and Melzack’s Textbook of Pain 5e, © Elsevier 2006
Effects of antidepressants on dorsal horn circuits

18. α2
δ-antagonists
Gabapentin
Pregabalin

19. Sites of action of α2
δ-antagonists
Adapted from: McMahon & Koltzenburg: Wall and Melzack’s Textbook of Pain 5e, © Elsevier 2006

20. α2
δ-antagonist
↓GABA release
LC neurone
Action potential
GABAergic terminal
Calcium channel block
Adapted from: Tanabe et al., J Neurosci Res 86: 3258-3264, 2008
Effects of α2
δ-antagonists on dorsal horn circuits
SUPRASPINAL MECHANISMS

21. Effects of α2
δ-antagonists on dorsal horn circuits
SPINAL MECHANISMS (STATE-DEPENDENT)

22. Effects of α2
δ-antagonists on dorsal horn circuits
Bee & Dickenson, Pain 140: 209-223, 2008
SPINAL MECHANISMS (STATE-DEPENDENT)

23. Conclusion