Pain Pharmacology

## Pain Pathways

Pain processing involves four steps: transduction (nociceptor activation), transmission (A-delta and C fibers to dorsal horn), modulation (descending pathways from PAG and RVM), and perception (cortical processing). Nociceptive pain results from tissue damage activating peripheral nociceptors. Neuropathic pain arises from nervous system damage causing aberrant signaling.

## NSAIDs and Acetaminophen

NSAIDs inhibit cyclooxygenase (COX) enzymes, reducing prostaglandin synthesis:

- **Non-selective** (ibuprofen, naproxen) -- block COX-1 and COX-2; anti-inflammatory, analgesic, antipyretic; GI and renal risks
- **COX-2 selective** (celecoxib) -- reduced GI toxicity but cardiovascular risk (increased thrombotic events)
- **Acetaminophen** -- weak peripheral COX inhibition; central mechanism possibly involving cannabinoid and serotonergic pathways; no anti-inflammatory effect; hepatotoxic in overdose (NAC is the antidote)

## Opioid Analgesics

Mu receptor agonists (morphine, oxycodone, fentanyl, hydromorphone) activate descending inhibitory pathways and reduce dorsal horn transmission. They are effective for severe acute and cancer pain. See the dedicated opioid receptor pharmacology guide for details on receptor subtypes and dependence.

## Adjuvant Analgesics for Neuropathic Pain

Neuropathic pain responds poorly to NSAIDs and partially to opioids. First-line adjuvants include:

- **Gabapentinoids** (gabapentin, pregabalin) -- alpha-2-delta ligands that reduce excitatory neurotransmitter release at dorsal horn synapses
- **TCAs** (amitriptyline, nortriptyline) -- block NE and 5-HT reuptake in descending inhibitory pathways
- **SNRIs** (duloxetine, venlafaxine) -- enhance descending monoaminergic pain inhibition; duloxetine is FDA-approved for diabetic neuropathy and fibromyalgia
- **Topical agents** -- lidocaine patches (sodium channel block), capsaicin (TRPV1 desensitization)

## Emerging Targets

- **CGRP monoclonal antibodies** (erenumab, fremanezumab) -- preventive migraine therapy
- **Nav1.7 blockers** -- sodium channel subtype in nociceptors; loss-of-function mutations cause congenital insensitivity to pain
- **TRPV1 antagonists** -- targeting peripheral heat-sensitive nociceptors
- **Anti-NGF antibodies** (tanezumab) -- reduce nociceptor sensitization in osteoarthritis

## Key Takeaways

- Nociceptive pain is treated stepwise: acetaminophen/NSAIDs, then opioids for severe pain
- Neuropathic pain requires adjuvant analgesics (gabapentinoids, TCAs, SNRIs) rather than NSAIDs alone
- Descending monoaminergic pathways from the brainstem are key targets for SNRIs and TCAs
- CGRP-targeted therapies have transformed migraine prevention