Pathophysiology

---

Pain pathway

• Nociceptors detect a chemical, mechanical, or thermal noxious stimulus → conversion of stimulus to an electric signal (action potential) → C fibers and Aδ fibers carry afferent input to the dorsal horn of the spinal cord → secondary nociceptive neurons in the spinothalamic tract carry afferent input to the thalamus in the CNS → pain perception and a response sent along efferent pathways, which results in pain modulation and/or a reaction
• Neurotransmitters
  • Excitatory (Promoting Pain Transmission):
    • Glutamate
    • Substance P
    • CGRP (Calcitonin Gene-Related Peptide)
    • Aspartate
  • Inhibitory (Reducing Pain Transmission - Modulation):
    • Serotonin (5-HT)
    • Norepinephrine
    • GABA
    • Endogenous Opioids

Analgesics

---

Drug	Mechanism of action
Tricyclic antidepressants (eg, amitriptyline, nortriptyline) SNRIs (eg, duloxetine)	↓ Reuptake of serotonin & norepinephrine Inhibition of pain signals
Anticonvulsants (eg, gabapentin, pregabalin)	• Decreased depolarization of neurons in the CNS
Opioids	• Activation of central opioid receptors
Capsaicin (topical)	Loss of membrane potential in nociceptive fibers
Lidocaine (topical)	• Decreased depolarization of neurons in peripheral nerves

Non-opioid analgesics

Topical analgesics

• Capsaicin is an irritant found in the chili pepper family. It causes excessive activation of TRPV1 (a transmembrane cation channel), causing a buildup of intracellular calcium that results in long-lasting dysfunction of nociceptive nerve fibers (defunctionalization). In addition, capsaicin causes release and subsequent depletion of substance P, a polypeptide neurotransmitter involved in transmission of pain signals. On initial application, topical capsaicin causes burning, stinging, and erythema, but persistent exposure leads to a moderate reduction in pain over time.

Adjuvant analgesics

Anticonvulsants

Anticonvulsants are useful adjuncts in the management of neuropathic pain. They typically will not be helpful for acute pain, rather are more commonly used for chronic neuropathic pain.

• Gabapentin
• Pregabalin
• Carbamazepine

Muscle relaxants

Consider muscle relaxants in patients with pain associated with muscle spasticity.

• Cyclobenzaprine
• Methocarbamol
• Baclofen

Antidepressants

Tricyclic antidepressants and SNRIs can be helpful for chronic pain syndromes and neuropathic pain.

• Tricyclic antidepressants
  • Amitriptyline
  • Doxepin
  • Clomipramine
• SNRIs
  • Duloxetine
  • Venlafaxine