Multimorbidity, particularly among older adults, has become a defining challenge in contemporary clinical practice and is strongly associated with the rising prevalence of polypharmacy. While guideline-based, disease-specific treatment approaches remain central to modern therapeutics, their cumulative application in patients with multiple chronic conditions often leads to complex medication regimens that may not adequately reflect individual patient needs. This perspective explores the clinical, pharmacological, and systemic challenges associated with polypharmacy in multimorbidity and emphasizes the necessity of transitioning toward more integrated and patient-centered prescribing models. Current evidence highlights important limitations in the structure of clinical research and guideline development, as most randomized controlled trials focus on single diseases and frequently exclude patients with multimorbidity. This gap contributes to uncertainty in clinical decision-making and may result in therapeutic duplication, drug–drug interactions, and increased treatment burden. Consequently, polypharmacy should not be viewed solely as a pharmacological issue but rather as a broader clinical and systemic concern that impacts patient safety, healthcare utilization, and quality of life.
In response to these challenges, this perspective advocates for an integrated approach grounded in clinical pharmacology, incorporating pharmacokinetic and pharmacodynamic principles alongside patient-specific factors. Structured medication reviews, deprescribing strategies, and multidisciplinary collaboration—including the active involvement of clinical pharmacists—are highlighted as practical tools to optimize prescribing. Importantly, integrating patient preferences, functional status, and individual treatment goals is essential to ensure clinically meaningful and sustainable pharmacotherapy. From a patient care perspective, these strategies have the potential to reduce inappropriate prescribing, improve medication adherence, and minimize preventable adverse outcomes such as hospitalization and functional decline. Ultimately, embedding these principles into routine clinical workflows is critical for translating pharmacological knowledge into measurable improvements in patient-centered outcomes.