Antidepressant Paired With Tramadol or Ibuprofen Eased Diabetic Nerve Pain at Lower Doses in Rats

TL;DR: In diabetic rats, giving the antidepressant nortriptyline together with tramadol or ibuprofen eased pain behavior at much lower doses than each drug alone. The combinations worked better together than their separate effects would predict, but this was a short lab pain test in rats.

Source: Frontiers in Pharmacology (2026) | Pérez-Hernández et al.

Nerve pain from diabetes, often burning or stabbing in the feet, is notoriously hard to treat. Ordinary painkillers barely touch it, and the drugs that do help often cause drowsiness, dizziness or other side effects at the doses needed.

One way around that is combining drugs that fight pain in different ways, so each can be used at a lower dose. Researchers at the University of Colima in Mexico tested two such pairs in rats.

Three Familiar Drugs, Two Pairings

All three drugs are already used in people:

• Nortriptyline: An older antidepressant used for nerve pain.
• Tramadol: A mild opioid that also boosts serotonin and noradrenaline.
• Ibuprofen: A common anti-inflammatory painkiller.

The team made male rats diabetic with a chemical that destroys insulin-making cells, then waited at least 3 weeks for high blood sugar to take hold. To test pain, they injected a weak formalin solution into a hind paw and counted paw flinches over an hour. Diabetic rats flinch more, a sign of heightened pain sensitivity.

Each drug was first tested alone at four doses, with 6 rats per dose. Then the researchers combined nortriptyline with tramadol or ibuprofen in fixed ratios.

Lower Doses Did the Same Job

Alone, nortriptyline was the most potent, with half its maximum effect at 3 mg/kg. Tramadol needed 5.2 mg/kg and ibuprofen 41.6 mg/kg.

Together, the doses dropped sharply. With tramadol, the nortriptyline dose fell about 10-fold and the tramadol dose about 4-fold for similar relief. With ibuprofen, nortriptyline fell about 10-fold and ibuprofen about 4-fold.

The team then checked whether that was simply the two effects adding up or something more. Based on each drug alone, the tramadol pair should have needed about 4.1 mg/kg to reach half effect. It needed only 0.97 mg/kg. The ibuprofen pair should have needed 22.3 mg/kg but needed 15.6. Both are what pharmacologists call synergy, with the tramadol pairing much stronger.

Both Pairs Beat a Single Gabapentin Dose

The team also gave one group gabapentin, a first-line nerve pain drug, as a comparison.

The tramadol pair reached 96% relief and the ibuprofen pair 81%. Gabapentin at 50 mg/kg reached 35%. The tramadol pair's top relief wasn't better than tramadol or nortriptyline alone, though. The gain was in needing less of each drug.

A Short Paw Test Isn't Long-Term Nerve Pain

• Rats only: Doses and effects may not translate to people.
• Male rats only.
• Short-term test: One-hour formalin response, not weeks of everyday pain.
• Side effects not measured: Lower doses may mean fewer side effects, but this wasn't tested.
• Small groups: 6 rats per dose.
• Uneven comparison: Gabapentin given at one dose only.
• Mechanism unclear: How the pairs work together wasn't studied.

Lower-Dose Combinations Are Worth Testing in People

This doesn't mean anyone should combine these medicines on their own. Tramadol plus an antidepressant like nortriptyline can raise the risk of serotonin syndrome and seizures, so any combination needs a doctor's oversight. The open question is whether low-dose pairings can ease diabetic nerve pain in people with fewer side effects than higher doses of one drug.