Antidepressants for pain: TCAs and SNRIs

Tricyclics and SNRIs are first-line for neuropathic pain, and duloxetine also covers chemotherapy-induced neuropathy and chronic low back pain. The exam tests their limits: anticholinergic burden in older adults and duloxetine's renal and hepatic restrictions.

1. First-line for neuropathic pain. The 2025 NeuPSIG update gives strong recommendations and first-line status to SNRIs such as duloxetine, tricyclic antidepressants, pregabalin and gabapentin; TCAs had the lowest NNT of the first-line classes (4.6). Lidocaine 5% plasters are second line, a weak recommendation ¹.
2. Part of AAN's four classes for diabetic neuropathy. AAN 2022 recommends TCAs, SNRIs, gabapentinoids or sodium-channel blockers; TCAs had the largest effect size (SMD 0.95), tempered by low confidence, and SNRIs 0.47 ².
3. Duloxetine is the CIPN drug. ASCO concludes duloxetine is the only agent with adequate evidence for established painful chemotherapy-induced neuropathy, though benefit is modest; no agent is recommended for prevention ³.
4. Duloxetine also treats chronic low back pain. The ACP lists duloxetine, with tramadol, as a second-line drug after NSAIDs for chronic low back pain, which is useful when depression coexists ⁴.
5. Respect organ limits. Avoid duloxetine when GFR is below 30 mL/min and in chronic liver disease or cirrhosis; the label offers no reduced-dose option for severe renal impairment ⁵.
6. TCAs in older adults. Beers lists strongly anticholinergic antidepressants such as amitriptyline and nortriptyline to avoid because they are highly anticholinergic, sedating and cause orthostatic hypotension, and flags antidepressants in patients with falls or fractures ⁶.

In an older adult with glaucoma, falls or cognitive impairment, amitriptyline is a poor choice ⁶; for localized neuropathic pain a lidocaine 5% plaster (second line) avoids systemic anticholinergic effects ¹.

• NeuPSIG 2025 first-line: SNRIs, TCAs, pregabalin and gabapentin (strong recommendations); NNT 7.4 for SNRIs, 4.6 for TCAs ¹.
• ASCO discourages acetyl-L-carnitine for CIPN prevention because it may worsen neuropathy ³.
• ACP chronic low back pain drug order: NSAIDs first, then tramadol or duloxetine, opioids last ⁴.
• Duloxetine renal cut-off: avoid below a GFR of 30 mL/min ⁵.
• AAN advises switching to a different effective class when one fails, rather than adding an opioid ².
• AAN also recommends assessing patients with painful diabetic neuropathy for mood and sleep disorders ².
• Beers flags antidepressants as a group in patients with a history of falls or fractures ⁶.

• Treating a TCA as harmless in a frail older adult because the dose is low ⁶.
• Reducing the duloxetine dose instead of avoiding it in severe renal impairment ⁵.
• Choosing gabapentin for established CIPN over the one ASCO-recommended drug ³.
• Adding a benzodiazepine or muscle relaxant for a patient with depression and back pain when duloxetine can address both ⁴.