mechanism of action of analgesics (2012)

Where do analgesic medications work?

Peter Kamerman

PainSA, Pretoria, South Africa, 2013

• All four drug classes act within the CNS

• All four drug classes affect descending pain modulating pathways

Major pain modulating pathways

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

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

Dorsal horn circuits

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

Opioid analgesics

Sites of mu opioid receptors

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

Effect of opioids on dorsal horn circuits

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

Non-opioid analgesicsParacetamol

Sites of action of paracetamol

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

Effects of paracetamol on dorsal horn circuits

Adapted from: Mallet et al., Pain 139: 190-200, 2008

Effects of paracetamol on dorsal horn circuits

Adapted from: Andersson et al., Nat Commun 2: 551, DOI 10.1038/ncomms1559, 2011

AntidepressantsSerotonin and noradrenaline reuptake inhibitors (SNRI)

Tricyclic antidepressants (TCA)

Sites of action of antidepressants

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

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

Effects of antidepressants on dorsal horn circuits

α2δ-antagonistsGabapentin Pregabalin

Sites of action of α2δ-antagonists

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

α2δ-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 α2δ-antagonists on dorsal horn circuitsSUPRASPINAL MECHANISMS

Effects of α2δ-antagonists on dorsal horn circuitsSPINAL MECHANISMS (STATE-DEPENDENT)

Effects of α2δ-antagonists on dorsal horn circuits

Bee & Dickenson, Pain 140: 209-223, 2008

SPINAL MECHANISMS (STATE-DEPENDENT)

Conclusion