Can duloxetine (Cymbalta) and naproxen (Nonsteroidal Anti-Inflammatory Drug (NSAID)) be used together?

Can Duloxetine and Naproxen Be Used Together?

Yes, duloxetine and naproxen can be used together, and this combination is explicitly supported by clinical guidelines for managing chronic pain conditions, particularly osteoarthritis and chronic low back pain. However, you must counsel patients about an increased risk of gastrointestinal bleeding and monitor accordingly.

Guideline-Supported Combination Therapy

The 2022 CDC Clinical Practice Guideline explicitly recommends that systemic NSAIDs (like naproxen) or duloxetine can be used together for patients with osteoarthritis pain in multiple joints or when topical NSAIDs provide incomplete pain control 1. This represents a standard treatment approach, not an off-label or cautionary combination.

• For chronic low back pain, both NSAIDs and duloxetine are recommended options when nonpharmacologic approaches have been insufficient 1
• The 2012 American College of Rheumatology guidelines conditionally recommend duloxetine as an alternative when patients have inadequate response to NSAIDs alone 1

Critical Safety Consideration: Bleeding Risk

The primary concern with this combination is an increased risk of gastrointestinal bleeding, which requires specific management:

Magnitude of Risk

• Duloxetine alone increases bleeding-related adverse events compared to placebo 2
• Concomitant NSAID use increases bleeding risk regardless of whether patients take duloxetine or placebo 2
• The combination of any serotonin reuptake inhibitor (including SNRIs like duloxetine) with NSAIDs increases GI bleeding risk synergistically, with odds ratios ranging from 3.17 to 10.9 across studies 3
• Importantly, clinical trial data showed that duloxetine plus NSAIDs had higher bleeding rates than duloxetine alone, but this same pattern occurred with placebo plus NSAIDs versus placebo alone, suggesting the NSAID is the primary driver 2

Risk Mitigation Strategy

Add a proton pump inhibitor (PPI) when prescribing this combination, particularly for patients with additional risk factors 1:

• Patients over age 65 1
• History of peptic ulcer disease or GI bleeding 1
• Concomitant use of anticoagulants or antiplatelet agents (including low-dose aspirin) 1
• Concomitant corticosteroid use 1

The American College of Rheumatology strongly recommends using NSAIDs with PPIs in patients with GI risk factors 1.

Practical Prescribing Algorithm

For patients requiring both medications:

1. Assess GI bleeding risk factors (age >65, prior ulcer/bleeding, anticoagulants, aspirin, corticosteroids) 1

2. If ANY risk factors present: Prescribe a PPI concurrently with the NSAID 1

3. Use the lowest effective NSAID dose for the shortest duration needed, as risks increase with higher doses and longer use 1

4. For patients age ≥75 years: Strongly consider topical NSAIDs instead of oral naproxen if feasible for the pain location 1

5. Counsel patients to avoid OTC NSAIDs (ibuprofen, additional naproxen) and report any signs of GI bleeding (black stools, coffee-ground emesis, abdominal pain) 4

Additional Safety Monitoring

Beyond bleeding risk, monitor for:

• Blood pressure changes: Both increases and orthostatic hypotension can occur with duloxetine 4
• Renal function: NSAIDs should be used cautiously in patients with renal disease, heart failure, or cirrhosis 1
• Fall risk: Duloxetine may cause dizziness, and NSAIDs increase fall risk in elderly patients 1, 4

Drug Interaction Considerations

No significant pharmacokinetic interaction exists between duloxetine and naproxen 5. The FDA label for duloxetine specifically lists NSAIDs among medications that may interact but focuses on the pharmacodynamic bleeding risk rather than altered drug levels 4.

Common Pitfall to Avoid

Do not withhold this effective combination solely due to bleeding concerns in patients without risk factors. The clinical trial data showed that while bleeding events were more common with the combination, serious adverse events remained rare 2. The key is appropriate patient selection and PPI co-prescription when indicated, not blanket avoidance of a guideline-supported treatment approach.

For patients at very high bleeding risk (recent GI bleed within past year), if you must use an NSAID, strongly consider a COX-2 selective inhibitor plus PPI instead of naproxen 1.