Withdrawal effects following treatment discontinuation: A blind spot in evidence-based medicine.

Abstract

Treatment withdrawal effects are transient increases in clinical risk following treatment discontinuation that exceed the loss of treatment effect alone. They have been described across multiple therapeutic classes spanning diverse disease areas yet remain under-recognized and insufficiently addressed in both research and clinical practice. Because treatment interruption and non-adherence are common in routine care, failure to account for these effects can distort clinical decision-making and the generation and interpretation of research evidence. Withdrawal effects arise from treatment-induced biological adaptations that persist after cessation, creating a transient period of heightened vulnerability. Despite their clinical relevance, they are not consistently anticipated or explicitly incorporated into research design, analysis, or guideline development. This perspective argues that treatment discontinuation represents a distinct and clinically meaningful phase of exposure and outlines implications across the evidence continuum and clinical practice, alongside approaches to better identify and interpret withdrawal-related risks.