What medications, such as Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), beta-blockers, or antibiotics, can cause painful oral ulcers and severe throat pain in a patient without genital ulcers or fever?

Medications That Cause Painful Oral Ulcers and Severe Throat Pain

NSAIDs are the most common medication class causing isolated oral ulcers without systemic symptoms, with specific agents like diclofenac, flurbiprofen, indomethacin, naproxen, and piroxicam being frequent culprits. 1, 2, 3

High-Risk Medication Classes

NSAIDs (Most Common Cause)

• Oxicam derivatives (meloxicam, piroxicam) carry the highest risk for severe oral ulceration 1
• Acetic acid derivatives (diclofenac) are strongly associated with oral ulcers 1, 2
• Propionic acid derivatives (ibuprofen, naproxen, flurbiprofen) can cause oral ulcers, though ibuprofen at low doses carries lower risk 1, 2
• Indomethacin is frequently implicated in drug-induced oral ulceration 2
• These ulcers typically appear as solitary lesions after several weeks of treatment and resist conventional therapy until the drug is discontinued 2, 4

Cardiovascular Medications

• ACE inhibitors (captopril, enalapril) commonly cause isolated oral ulcers 2
• Angiotensin-2 receptor antagonists (losartan) can induce oral ulceration 2
• Anti-anginal agents (nicorandil) are associated with oral ulcers 2

Rheumatologic Disease-Modifying Agents

• Methotrexate causes oral ulceration as a known side effect 2
• Azathioprine can induce oral ulcers 2
• Penicillamine is associated with oral ulceration 2
• Gold compounds and tiopronin can cause oral ulcers 2

Psychiatric Medications

• Tricyclic antidepressants (nortriptyline) can cause painful oral ulcers 5
• SSRIs (fluoxetine) are implicated in oral ulceration 2
• Lithium can cause oral ulcers 2

Antibiotics and Antivirals

• Foscarnet (antiviral for AIDS) causes oral ulceration 2
• Zalcitabine (antiretroviral) is associated with oral ulcers 2

Clinical Recognition Pattern

Look for these diagnostic clues suggesting drug-induced etiology:

• Oral ulceration preceded by burning mouth sensation, metallic taste, dysgeusia, or ageusia 2, 4
• Solitary ulcers appearing after several weeks of starting a new medication 2, 4
• Ulcers that resist topical corticosteroids and conventional treatments 2
• Rapid healing (within 2-4 weeks) after drug discontinuation 2, 5
• Absence of fever, genital ulcers, or systemic symptoms distinguishes this from Behçet's disease or infectious causes 4

Critical Drug Interactions Increasing Risk

NSAIDs combined with the following medications dramatically increase ulceration and bleeding risk:

• Corticosteroids increase gastrointestinal ulceration risk 1, 6
• Anticoagulants (warfarin) compound bleeding risk from ulcers 1, 6
• Antiplatelet agents (aspirin, clopidogrel) increase ulcer bleeding 1, 6
• SSRIs/SNRIs increase bleeding risk when combined with NSAIDs 6

Management Algorithm

Step 1: Identify and Discontinue Culprit Medication

• Review all medications started within 2-8 weeks before ulcer onset 2, 4
• Discontinue the most likely offending agent (prioritize NSAIDs, ACE inhibitors, or recently started medications) 2, 3
• Do not wait for biopsy results if clinical suspicion is high and the medication is non-essential 2, 3

Step 2: Initiate Symptomatic Treatment

• Apply clobetasol gel 0.05% to localized ulcers twice daily 1, 7
• Use dexamethasone mouth rinse 0.1 mg/ml for multiple or widespread ulcers 1, 7
• Prescribe viscous lidocaine 2% before meals for pain control 1, 7
• Consider topical NSAIDs (amlexanox 5% paste) for moderate pain, but avoid if systemic NSAID was the culprit 1

Step 3: Monitor for Resolution

• Expect complete healing within 2-4 weeks after drug discontinuation 2, 5
• If ulcers persist beyond 2 weeks despite drug cessation, perform biopsy to rule out malignancy or other causes 7, 4

Common Pitfalls to Avoid

• Do not assume aphthous stomatitis in patients on chronic medications without considering drug-induced etiology 2, 4
• Do not continue the offending medication while attempting topical treatments—drug-induced ulcers will not heal until the drug is stopped 2, 3
• Do not overlook polypharmacy—patients on multiple NSAIDs or combining NSAIDs with other ulcerogenic drugs face exponentially higher risk 1
• Avoid prescribing NSAIDs for pain management in patients with active oral ulcers, as this perpetuates the problem 1, 6

Special Consideration: NSAID Rechallenge

If NSAID therapy is essential:

• Switch to a different chemical class of NSAID (e.g., from oxicam to propionic acid derivative) 1
• Use the lowest effective dose for the shortest duration 1, 6
• Consider COX-2 selective inhibitors as alternatives, though they still carry some mucosal risk 1
• Add proton pump inhibitor co-therapy if gastrointestinal protection is needed 1