Pain Types: (1) Nociceptive: Pain 2/2 ongoing high-threshold noxious stimulus (injury, trauma, surgery). (2) Inflammatory: Physiologic or pathologic pain 2/2 inflammation (release of “inflammatory soup” following nerve injury). (3) Neuropathic: Pathological pain 2/2 lesion in PNS/CNS; pain often present despite absence of continued stimulus (spontaneous pain). Quality may be burning, gnawing, aching (C-fibers, spontaneous), vs. shooting, lancinating (A fibers upon touch). Includes trigeminal neuralgia, postherpetic neuralgia, neuropathy, trauma, neuromas, root irritation, SC injury, thalamic pain syndrome. See detailed syndromes below. (4) Dysfunctional: Maladaptive/pathological pain; no known CNS/PNS lesion. Related to abnormal processing (i.e., depression, somatization, fibromyalgia). Pain can be primary as well as amplified by or manifestation of psychiatric disease (i.e., depression) (J Clin Inv 2010;120(11):3742-3744).

Abnormal sensory responses: Hyperalgesia (↑ pain sensation to noxious stimulus), dysesthesias (unpleasant paresthesia), allodynia (pain elicited by nonnoxious stimulus, e.g., wind, light touch, clothing). Spontaneous pain—stimulus independent. Sensitization: A-Peripheral: Tissue injury → release of inflam. mediators & influx of inflam. cells → posttranslational modifications of nociceptor receptors & channels → lower activation threshold & increased pain responses. B-Central: 1-Nonnociceptive afferents (Aβ) become able to mediate pain → invasion of superficial dorsal horn: explains allodynia. 2-Posttranslational modifications of AMPA & NMDA receptors → enhance Ca influx → activates kinases → plasticity in different areas of CNS → prolonged response (up to hrs) to brief stimulations: explains hyperalgesia. 3-Peripheral nerve injury → activation of CNS microglia & astrocytes → CNS inflam. → hypersensitivity. 4-Death of inhibitory interneurons in SC → cross-talk from nonnociceptive inputs via (Aβ) → activate central pain tracts in response to nonnoxious stim. (touch) → allodynia (Cell 2009;139:267-284) (Nat Neur 2014;17(2):183-191) (Nat Med 2010;16(11):1267-1276). Central sensitization major determinant in chronic pain.

Pain perception: Variable threshold to activate pain fibers. Lowered by inflam. → hyperalgesia, allodynia. Increased by other mechanisms: Placebo, acupuncture, distraction, positive mood → lower pain perception.

Endogenous Modulation of Nociception: 1-Activation of nonnociceptive afferents → inhibit pain transmission via inhibitory interneurons in dorsal horn → raise pain threshold (gate control theory). 2-Descending NT systems: Opioid, serotonergic, adrenergic systems → inhibit nociceptive transmission but become facilitatory as part of central sensitization.

Acetaminophen: Counsel re: Toxicity (<3.25 g/day, <2 g/day if liver disease).

NSAIDS: If one NSAID fails, try another class (ibuprofen 200-800 mg tid; naproxen 25-500 mg bid, celecoxib 100-200 mg bid, diclofenac 50-75 mg bid, ketorolac 10 mg PO qid × 5d or 30-60 mg IV/IM q6h, indomethacin 25-50 mg tid, nabumetone 1,000-1500 mg qd, meloxicam 7.5-15 mg qd). SE: GI bleeding (consider PPI if high risk), renal dysfunction w/prolonged use.

Tricyclic antidepressants (TCAs): Nortriptyline, amitriptyline. Avoid in elderly, pts w/risk of delirium, pts w/heart disease. Effect expected in 7-14 days. SE: Anticholinesterase effects—dry mouth, urinary retention, constipation, orthostatic hypotension, sedation, glaucoma, arrhythmias, conduction disorders. Major risk: Cardiac tox, risk of death w/OD. Consider EKG (QRS/QT) if > 40 yo. Uptitrate q4-7d to minimize SE. Nortriptyline better tolerated 2/2 secondary amine structure; less SE than amitriptyline (↑ antichol SE) (tertiary amine).

Selective serotonin & norepinephrine reuptake inhibitors (SSNRI): Duloxetine, venlafaxine. Common SEs: Nausea (˜20%-30%), drowsiness (10%-20%), loss of appetite (8%). Venlafaxine may cause HA (30%), HTN (3%-10%), constipation (8%-15%). Less sexual SEs than TCAs. Minimize venlafaxine SE by slow uptitration (75 mg q4d).

Carbamazepine: Generally well tolerated. Blocks Na channels. SE: Stevens-Johnson’s (test for HLA-B*1502 for at-risk population—Asian descent), dizziness (44%), nausea (29%), vomiting (18%), bone marrow suppression, hypoNa (4%-21%), pruritus (8%), ataxia (15%), hepatic dysfunction, interaction w/other rx.

Oxcarbazepine: Similar to carbamazepine but better tolerated.

Valproic acid: Avoid in young females 2/2 teratogenicity, weight gain (4%-9%), hair loss (6%-24%). SE: hyperammonemia, tremor (9%-57%), sedation (17%-30%), nausea (22%-48%), other GI toxicity, bone marrow suppression (dose dependent) (1%-27%).

Gabapentin: Generally well tolerated. Acts on voltage-gated Ca channels → reduces release of glut & subs P. SE: Somnolence (4%-21%), dizziness (10%-28%), ataxia (3%-12%), suicidal ideations. Minimize SE by slow uptitration (100 mg q3d). Renal dosing if AKI/CKD. Potential for abuse at high doses. To d/c, slow taper.

Pregabalin: Similar to gabapentin; negligible hepatic metabolism (use in liver patients). SE: Sedation (10%-35%), dizziness (9%-40%), dry mouth (2%-11%), peripheral edema (5%-12%), blurry vision or diplopia (3%-10%), suicidal ideations.

Topiramate: SE: Memory problems (3%-12%), word finding difficulty, confusion (3%-11%), sedation (6%-29%), dizziness (4%-25%), nephrolithiasis (1%-3%), GI upset, weight loss (4%-21%), hyperammonemia (26%).

Lidocaine patch: 5%, apply 12 h/day. Useful for postherpetic neuralgia & myofascial pain especially in elderly (no systemic SE). 5% ointment alternative.