The SNRI that showed up for pain as well
(3S)-N-methyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propan-1-amine · C18H19NOS · MW 297.41 g/mol · CAS 116539-59-4 · Cymbalta · ChEMBL CHEMBL1175
Duloxetine (Cymbalta). A serotonin–norepinephrine reuptake inhibitor that is more balanced at therapeutic doses than venlafaxine #048 (which is SERT-first, NET only as the dose climbs). That dual occupancy is why it has pain indications — diabetic neuropathy, fibromyalgia, chronic musculoskeletal pain — as well as MDD and GAD. Hepatotoxicity is the label scar; discontinuation is the practical one.
Duloxetine inhibits SERT and NET at concentrations you actually reach — SERT Ki sub-nM to low-nM, NET Ki low-nM, DAT far weaker. The descending inhibitory pain pathways (spinal NE/5-HT) are the mechanistic excuse for the pain labels; the mood labels are the same SERT/NET occupancy in limbic circuits. It is not a µ-opioid, not a gabapentinoid, and not 'non-addictive Tylenol.'
Versus venlafaxine: you do not have to climb into hypertension-dose territory to get NET. Versus SSRIs: more noradrenergic adverse effects (sweating, urinary hesitation, blood pressure). CYP1A2 (major) plus CYP2D6; smoking (1A2 induction) can lower levels. The hepatic warning is not boilerplate — duloxetine has a clearer hepatotoxicity signal than most SSRIs.
Sub-nanomolar class occupancy. Serotonergic adverse effects and the MAOI hard stop still apply.
The difference from low-dose venlafaxine. Sweating, urinary retention, noradrenergic analgesia.
Much weaker. Not bupropion, not a street stimulant.
Diabetic peripheral neuropathy, fibromyalgia, chronic musculoskeletal pain — descending monoamine inhibition, modest effect sizes, real GI/liver tradeoffs.
Fluvoxamine (1A2) or strong 2D6 inhibitors raise exposure. Smoking may lower it.
Hepatotoxicity including liver failure reports. Avoid in substantial alcohol use or chronic liver disease — that is on the label.
Tmax ~6 h (enteric-coated); t½ ~12 h. Highly protein-bound. Do not crush capsules (acid-labile). Taper: discontinuation is venlafaxine-adjacent, not fluoxetine-smooth.
Urinary hesitation, sweating, nausea, sexual dysfunction, and a discontinuation syndrome that people underestimate. Serotonin syndrome with MAOIs/linezolid/triptans/tramadol is the hard toxicology line — same rule as #048 and the SSRIs.
PDB 5I6X is SERT with paroxetine — no duloxetine co-crystal here, same
honest surrogate the venlafaxine page uses. Dual SERT/NET occupancy is two related NSS S1 sites paying
similar desolvation costs. The thiophene/naphthyl hydrophobic surface is the enthalpic hook; the
secondary amine is the salt bridge. FlexAIDΔS would flag a ligand that can satisfy two related pockets
without a large extra ΔS_conf penalty — a compact SNRI.
Serotonin syndrome is the acute killer combination. Hepatotoxicity is the chronic one. Discontinuation is the everyday one.
| Target | Affinity | Rel. | Action |
|---|---|---|---|
|
SERT
serotonin transporter
|
Ki ≈ 0.8 nM
ChEMBL / literature
|
Inhibitor | |
|
NET
norepinephrine transporter
|
Ki ≈ 7 nM
balanced at Rx doses
|
Inhibitor | |
|
DAT
dopamine transporter
|
Ki ~240 nM
not clinical driver
|
Weak | |
|
5-HT receptors
direct agonism
|
no
reuptake only
|
None |