Anatomy, Physiology, and Pharmacology of Pain
Core pathway
Nociception begins when noxious stimuli activate free nerve endings; A-delta fibers carry sharp, fast first pain and C fibers carry dull, slow second pain. Primary afferents synapse in the dorsal horn, where glutamate, substance P, and other transmitters modulate transmission. Ascending spinothalamic pathways convey sensory-discriminative information, while parallel pathways carry affective and motivational dimensions. Descending projections from the periaqueductal gray and rostral ventromedial medulla can inhibit or facilitate nociception. Peripheral sensitization lowers nociceptor thresholds after inflammation; central sensitization increases dorsal horn excitability and expands receptive fields. Distinguish nociceptive, neuropathic, and nociplastic pain because mechanism guides drug choice.
Pharmacologic targets
NSAIDs inhibit cyclooxygenase and reduce prostaglandins; they carry gastrointestinal, renal, and cardiovascular risks. Acetaminophen acts centrally but has hepatic ceilings. Opioids activate mu-opioid receptors, producing analgesia plus respiratory depression, constipation, tolerance, and dependence. Gabapentinoids bind alpha-2-delta subunits; SNRIs and TCAs enhance descending inhibition; local anesthetics block voltage-gated sodium channels. Adjuvants are not optional add-ons without rationale; match mechanism to pain type.
Traps and rule
Questions often confuse transduction, the conversion at the nociceptor, with transmission, the spinal relay, or ask whether tolerance means addiction. They are different. Do not assume all severe pain is opioid-responsive. Rule of thumb: burning, shooting pain with allodynia suggests neuropathic mechanisms, so a gabapentinoid or SNRI is a better first consideration than an NSAID alone. Worked example: postherpetic neuralgia in an older adult with chronic kidney disease - avoid NSAIDs; consider topical lidocaine or a renally adjusted gabapentinoid.