Cox-2 inhibitors

Overview
Cyclooxygenase-2 (COX-2) inhibitors are a subclass of nonsteroidal anti-inflammatory drugs (NSAIDs) specifically designed to selectively block the COX-2 enzyme, which is primarily responsible for the synthesis of pro-inflammatory prostaglandins. This selectivity allows them to provide anti-inflammatory, analgesic, and antipyretic effects while reducing the risk of gastrointestinal (GI) irritation and ulceration associated with non-selective NSAIDs that also inhibit COX-1.

Mechanism of Action

• The COX-2 enzyme is induced at sites of inflammation in response to cytokines, growth factors, and other pro-inflammatory stimuli.

• COX-2 inhibitors selectively bind to the COX-2 isoenzyme, inhibiting its catalytic activity and thereby decreasing the formation of prostaglandins that mediate pain, fever, and inflammation.

• By sparing COX-1, which is involved in gastric mucosal protection, platelet aggregation, and renal blood flow regulation, these agents aim to minimize GI side effects.

Therapeutic Uses

• Symptomatic management of osteoarthritis and rheumatoid arthritis

• Relief of acute pain, including postoperative pain and musculoskeletal injuries

• Management of ankylosing spondylitis

• Dysmenorrhea treatment

• Off-label use in certain inflammatory conditions where reduced GI toxicity is desired

Commonly Used Agents (Generic and Brand Names)

• Celecoxib (Celebrex)

• Etoricoxib (Arcoxia)

• Parecoxib (Dynastat) – available as an injectable formulation for short-term pain relief

• Meloxicam (Mobic, Movalis) – preferential COX-2 inhibitor at lower doses

• Rofecoxib and valdecoxib – withdrawn from many markets due to cardiovascular safety concerns

Dosage and Administration

• Celecoxib: Typically 100–200 mg orally once or twice daily, depending on indication and patient response

• Etoricoxib: Usually 30–120 mg orally once daily, dose adjusted to lowest effective amount for shortest duration

• Meloxicam: 7.5–15 mg orally once daily

• Parecoxib: Administered via intravenous or intramuscular injection, commonly in postoperative settings

Contraindications

• Known hypersensitivity to COX-2 inhibitors or other NSAIDs

• History of asthma, urticaria, or allergic-type reactions after NSAID use

• Active peptic ulcer disease or gastrointestinal bleeding

• Established cardiovascular disease (e.g., recent myocardial infarction, stroke) where risk outweighs benefit

• Severe hepatic or renal impairment

Precautions

• Use the lowest effective dose for the shortest possible duration to minimize cardiovascular risk

• Monitor for signs of GI bleeding despite reduced risk compared to non-selective NSAIDs

• Assess renal function regularly, particularly in patients with pre-existing kidney disease or on diuretics

• Caution in elderly patients and those with fluid retention, hypertension, or heart failure

Adverse Effects

• Common: Dyspepsia, abdominal pain, headache, peripheral edema

• Less common: Hypertension, dizziness, upper respiratory tract infections

• Serious: Myocardial infarction, stroke, thromboembolic events, renal impairment, hypersensitivity reactions

Drug Interactions

• Anticoagulants (e.g., warfarin): Increased bleeding risk due to additive antiplatelet effects

• ACE inhibitors, ARBs, diuretics: Increased risk of renal dysfunction (“triple whammy” effect)

• Lithium: Reduced renal clearance, risk of lithium toxicity

• Methotrexate: Potential for elevated plasma concentrations and toxicity

• Other NSAIDs: Increased risk of GI and renal adverse events without additional therapeutic benefit

COX-2 Inhibitors vs Non-selective NSAIDs: Comparative Reference

Domain	COX-2 inhibitors (celecoxib, etoricoxib, parecoxib, meloxicam*)	Non-selective NSAIDs (ibuprofen, naproxen, diclofenac, indomethacin, ketorolac, etc.)
Enzyme selectivity	Preferentially inhibit inducible COX-2; relative sparing of COX-1 at usual anti-inflammatory doses.	Inhibit both COX-1 and COX-2 across the therapeutic range.
Analgesia/anti-inflammatory efficacy	Comparable pain and inflammation control for OA, RA, acute pain when used at equipotent doses.	Comparable efficacy at equipotent doses; larger legacy evidence base across diverse indications.
Gastrointestinal safety (ulcer/bleed)	Lower rates of endoscopic ulcers and clinically significant upper-GI events vs many non-selective NSAIDs; risk rises with higher dose, prolonged use, concurrent aspirin, corticosteroids, or anticoagulants.	Higher GI risk overall; naproxen and ibuprofen have relatively lower GI risk than indomethacin/ketorolac; risk markedly amplified with aspirin, age, prior ulcer, anticoagulants, corticosteroids.
Platelet function/bleeding time	Minimal effect on platelet thromboxane at usual doses; do not meaningfully impair surgical hemostasis; do not substitute for aspirin cardioprotection.	Reversibly inhibit platelet COX-1 (except aspirin, which irreversibly inhibits); may increase perioperative bleeding; ibuprofen can interfere with aspirin’s antiplatelet effect if dosed closely.
Cardiovascular (CV) risk	Class carries dose- and duration-related risk of MI and stroke; some COX-2s (rofecoxib, valdecoxib) were withdrawn for excess CV events; celecoxib requires lowest effective dose for shortest duration; etoricoxib associated with hypertension/edema.	All non-aspirin NSAIDs increase CV risk to varying degrees; naproxen has the most neutral CV profile among common options; diclofenac carries higher CV risk; risk rises with dose and chronicity.
Renal effects and fluid retention	Class risk of sodium/water retention, edema, hypertension, AKI, hyperkalemia; similar magnitude to non-selective NSAIDs at anti-inflammatory doses.	Same risks and mechanisms; caution in CKD, HF, cirrhosis, diuretic/ACEI/ARB use.
Lower-GI injury (small bowel/colon)	Reduced upper-GI injury does not eliminate lower-GI damage; enteropathy can still occur.	Lower-GI damage also occurs; risk can equal or exceed upper-GI injury with chronic use.
Interaction with low-dose aspirin	Celecoxib has minimal interference with aspirin antiplatelet effect; GI protection benefit is attenuated when aspirin is co-administered.	Ibuprofen can blunt aspirin’s platelet effect if taken first or in close sequence; co-administration increases GI risk.
Perioperative use	Parecoxib (IV/IM) valued for opioid-sparing post-op analgesia with limited platelet effects; still monitor renal and CV status.	Ketorolac and others effective but with higher bleeding risk; many surgeons restrict around high-bleed procedures.
Asthma and NSAID hypersensitivity	Can still provoke reactions in cross-intolerant patients; use only with prior tolerance.	Higher likelihood of reactions in aspirin-exacerbated respiratory disease; avoid if history suggests cross-intolerance.
Dosing convenience	Once-daily options common (etoricoxib 30–120 mg; meloxicam 7.5–15 mg; celecoxib once or twice daily); parecoxib parenteral for short-term use.	Dosing frequency varies; many require two to four daily doses for sustained anti-inflammatory effect.
GI protection strategy	In moderate–high GI risk, combine with PPI or consider alternatives; benefit vs non-selective + PPI depends on aspirin use and patient profile.	Non-selective + PPI is a standard risk-mitigation approach; naproxen + PPI often preferred when CV risk is a concern.
Oncology/chemoprevention notes	Celecoxib has labeled use for FAP in some regions but with strict CV risk warnings; not for general chemoprevention.	No routine chemoprevention role; risks outweigh benefits for general use.
Regulatory history	Market withdrawals: rofecoxib, valdecoxib due to CV safety; current agents carry boxed or prominent CV/GI warnings and dose limits.	Widespread availability with class boxed warnings for CV and GI risk; agent-specific differences in labeling.

*Meloxicam is preferential rather than highly selective; COX-1 inhibition increases with higher doses.

Practical prescribing notes

Patient selection
Choose COX-2 inhibitors for patients at elevated upper-GI risk who still need an NSAID and do not have high cardiovascular risk. In mixed risk, tailor by dominant risk: prefer naproxen + PPI when CV risk is paramount; consider celecoxib/etoricoxib + PPI when GI risk dominates and CV risk is acceptable.

Dosing principles
Use the lowest effective dose for the shortest necessary duration. Reassess blood pressure, edema, renal function, and hemoglobin periodically, particularly in older adults, those on diuretics/ACEI/ARB, or with CKD, HF, or cirrhosis.

Concomitant therapies
When low-dose aspirin is required, expect attenuation of the GI advantage of COX-2 inhibitors; maintain PPI gastroprotection. Separate ibuprofen from aspirin or choose alternatives to avoid antiplatelet interference.

Perioperative care
Parecoxib can be useful for multimodal analgesia where bleeding risk must be minimized, while observing standard renal and CV cautions. Avoid any NSAID in procedures with very high bleeding or renal hypoperfusion risk unless clearly indicated and monitored.

Key drug interactions
Anticoagulants and antiplatelets increase GI bleeding risk; ACEI/ARB/diuretic combinations raise AKI risk; lithium and methotrexate levels may rise due to reduced renal clearance; cytochrome interactions (celecoxib is a CYP2C9 substrate/inhibitor) can affect warfarin and certain sulfonylureas—monitor and adjust as needed.

Monitoring
Baseline and periodic blood pressure, renal function tests, and hemoglobin; assess for edema and dyspnea; review analgesic response after the first 3–7 days and at dose changes; in chronic users, schedule interval GI and CV risk reviews.

Formulary examples and dosing ranges (adults)

Celecoxib
Osteoarthritis 100 mg twice daily or 200 mg once daily
Rheumatoid arthritis 100–200 mg twice daily
Acute pain 400 mg once, then 200 mg if needed on day 1; 200 mg twice daily subsequently

Etoricoxib
30–60 mg once daily for osteoarthritis, up to 90 mg once daily for rheumatoid arthritis or ankylosing spondylitis; acute pain regimens up to 120 mg once daily short-term

Meloxicam
7.5–15 mg once daily (preferential COX-2 activity at 7.5 mg; selectivity diminishes at 15 mg)

Parecoxib
Initial 40 mg IV/IM, then 20–40 mg every 6–12 hours as needed for short-term post-operative pain; convert to oral celecoxib when appropriate

Safety checkpoints
Avoid in active GI bleeding, recent CABG, third-trimester pregnancy, uncontrolled heart failure, severe hepatic impairment, and severe renal impairment not on dialysis. In older adults and those with multiple comorbidities, consider non-NSAID options first when feasible (acetaminophen, topical NSAIDs, intra-articular therapy, non-pharmacologic measures).