Beyond Analgesia: Therapeutic Repurposing of COX-2 Inhibitors—Clinical Evidence, Safety Trade-offs, and Translational Gaps

Abstract Selective cyclooxygenase-2 (COX-2) inhibitors were developed to provide analgesic and anti-inflammatory efficacy while reducing gastrointestinal injury associated with non-selective non-steroidal anti-inflammatory drugs. Subsequent clinical experience showed that isoform selectivity does not ensure overall safety, while experimental research revealed biological effects extending beyond conventional inflammatory indications. This review examines the class through a translational lens: how unexpected observations generate repurposing hypotheses, what evidence supports these hypotheses, and why promising signals often fail to become clinical practice. Established evidence is considered alongside research on colorectal adenoma prevention, oncology, neuropsychiatric disorders, ion-channel modulation, and formulation-enabled repositioning. Particular attention is given to celecoxib because it has the largest body of repurposing research, while recognizing that findings for one molecule cannot automatically be generalized to all coxibs. The evidence indicates that COX-2/PGE2 biology provides a plausible rationale for selected applications, but mechanistic plausibility and preclinical activity are not equivalent to patient benefit. Psychiatric studies illustrate this distinction: a 2026 meta-analysis reported a possible adjunctive signal in major depressive disorder but rated efficacy evidence as very uncertain because of small samples, heterogeneity, and risk of bias. Oncology research faces similar challenges, compounded by cardiovascular and renal risks. COX-2-independent effects reported for celecoxib further complicate attribution of activity and raise questions about clinically achievable exposure. We propose a practical framework for evaluating repurposing claims using mechanism, exposure, comparative controls, clinical evidence, safety, and regulatory status. The central conclusion is that the most informative story of coxibs is not a catalogue of possible new indications, but a case study in the distance between molecular discovery and therapeutic validation. Keywords cyclooxygenase-2; coxibs; celecoxib; serendipity; drug repurposing; off-target pharmacology; clinical translation; benefit–risk