In a 67-year-old hypertensive woman with grade 2 bilateral knee osteoarthritis who was switched from aceclofenac to etoricoxib 90 mg twice daily and started pregabalin, she now has mild-to-moderate swelling of the more painful leg. What is the likely cause and how should it be managed?

Etoricoxib-Induced Peripheral Edema in a Hypertensive Patient

The leg swelling is almost certainly caused by etoricoxib, which causes fluid retention and peripheral edema through COX-2 inhibition of renal prostaglandins, and you should immediately discontinue the etoricoxib and switch to a safer alternative given her controlled hypertension and age. 1

Mechanism of Etoricoxib-Induced Edema

• COX-2 inhibitors like etoricoxib cause peripheral edema and weight gain through salt retention, resulting from the loss of natriuretic prostaglandins such as PGE2, which are essential for normal renal sodium excretion. 1

• Etoricoxib 90 mg twice daily represents double the maximum approved dose for osteoarthritis (the approved dose is 60 mg once daily), which substantially increases the risk of fluid retention, hypertension, and cardiovascular complications. 2, 3

• In the EDGE trial involving 7,111 osteoarthritis patients, etoricoxib 90 mg once daily (still lower than your patient's current dose) caused significantly more hypertension-related adverse events compared to diclofenac (2.3% vs 0.7%, p < 0.001), with peripheral edema being a common manifestation. 2

Critical Safety Concerns in This Patient

• Your patient is at particularly high risk because she is elderly (67 years), has controlled hypertension, and is receiving twice the recommended dose of etoricoxib. 1

• The American Heart Association explicitly warns that etoricoxib should not be considered a first choice for pain relief in patients with or at risk for cardiovascular disease, which includes all hypertensive patients. 1

• COX-2 inhibitors destabilize blood pressure control in hypertensive patients, with increases in pressure often accompanied by peripheral edema and weight gain. 1

Immediate Management Steps

Step 1: Discontinue etoricoxib immediately 4

• Physicians report discontinuing COX-2 inhibitors 58-82% of the time when edema or destabilized blood pressure occurs. 4
• The edema will typically resolve within days to weeks after discontinuation. 1

Step 2: Monitor blood pressure and assess for hypertension destabilization 1

• Check her blood pressure now and monitor closely over the next 1-2 weeks, as etoricoxib may have elevated it even if she appears "controlled." 2
• Assess for other signs of fluid retention including weight gain and dyspnea. 1

Step 3: Rule out deep vein thrombosis

• Given unilateral leg swelling that is more pronounced in the previously more painful leg, perform a clinical assessment for DVT (calf tenderness, warmth, Homan's sign) and consider D-dimer or ultrasound if clinically indicated, as COX-2 inhibitors increase thrombotic risk. 1

Recommended Alternative Pain Management Strategy

For this 67-year-old hypertensive woman with grade 2 bilateral knee osteoarthritis:

First-line: Topical diclofenac gel 4g four times daily 5, 6

• The American Geriatrics Society strongly recommends topical NSAIDs over oral NSAIDs for patients ≥65 years due to substantially lower cardiovascular, gastrointestinal, and renal risks. 5
• Topical diclofenac provides equivalent pain relief to oral NSAIDs (effect size 0.91 vs placebo) with minimal systemic absorption and no fluid retention. 5, 6

Second-line: Acetaminophen up to 3000 mg/day 5, 6

• The American College of Rheumatology recommends acetaminophen as first-line oral therapy before any NSAID, with comparable efficacy to ibuprofen for knee pain and safe long-term use in elderly patients. 5, 6
• Use 3000 mg maximum daily dose in elderly patients rather than 4000 mg to minimize hepatotoxicity risk. 6

For neuropathic pain component: Continue pregabalin 7

• Pregabalin is appropriate for neuropathic pain and does not cause peripheral edema through fluid retention mechanisms. 7
• However, pregabalin can cause peripheral edema in 6-16% of patients through increased vascular permeability (not salt retention), so monitor whether edema resolves after stopping etoricoxib. 7

Third-line: Intra-articular corticosteroid injection 6

• Consider for acute flares or if topical NSAIDs plus acetaminophen provide inadequate relief. 6
• Particularly effective for short-term pain relief in knee osteoarthritis. 6

Essential non-pharmacologic interventions: 6

• Joint-specific strengthening exercises and general aerobic conditioning (effect sizes 0.57-1.0 for pain reduction). 6
• Weight reduction if overweight, which significantly decreases knee osteoarthritis symptoms. 6

Critical Prescribing Error to Avoid

• Never prescribe etoricoxib 90 mg twice daily for osteoarthritis—the approved dose is 60 mg once daily, and even 90 mg once daily (used in clinical trials) caused excessive hypertension-related adverse events. 2, 3

• The dose you prescribed (180 mg/day) is three times the approved dose and substantially increases cardiovascular, renal, and fluid retention risks in an already vulnerable elderly hypertensive patient. 2, 3

Monitoring After Medication Change

• Recheck blood pressure in 1 week and 2 weeks after stopping etoricoxib. 1
• Assess edema resolution at 1 week—if not improving, consider alternative causes (venous insufficiency, heart failure, DVT). 4
• If switching to topical diclofenac, reassess pain control in 1-2 weeks and adjust strategy if inadequate. 5