Combination Therapy for Non-neurogenic Male Lower Urinary Tract Symptoms: 1 + 1 Does Not Equal 2

Abstract

A clinically significant drug response rarely achieves adequate disease control, resulting in the need for combination pharmacotherapy. Virtually every prevalent chronic condition including hypertension, coronary artery disease, hyperlipidemia, chronic obstructive pulmonary disease, rheumatoid arthritis, and diabetes are commonly treated with combination drug regimens. Non-neurogenic male lower urinary tract symptoms (NNMLUTS) should be no exception. a-Blockers, 5a-reductase inhibitors (5-ARIs), antimuscarinics (anti-Ms), and phosphodiesterase (PDE) inhibitors are effective monotherapies for subsets of NNMLUTS. These monotherapies rarely ‘‘cure’’ LUTS. Therefore, combining these agents is the next obvious step in pharmacologic management of NNMLUTS. Fullhase et al. [1] examined the medical evidence supporting combination medical treatment of NNMLUTS. The authors are to be congratulated for their comprehensive and scholarly systematic review. Unfortunately, there are at least three fundamental limitations of the medical literature for NNMLUTS combination therapy. First, there is a paucity of randomized, double-blind, placebo-controlled trials for themajority of the combinations. Second, there are no cost-effectiveness studies to assess whether observed benefits justify the added cost. Third, the definition of NNMLUTS is unclear. The differential diagnosis of NNMLUTS includes a multitude of non-neurogenic factors that contribute to lower urinary tract symptoms (LUTS). For several of the a-blocker/5-ARI studies identified in the review, NNMLUTS includes clinical benign prostatic hyperplasia (BPH). For other a-blocker/5-ARI studies, NNMLUTS includes clinical BPH and large prostates. For most a-blocker/anti-M studies, NNMLUTS includes clinical BPH refractory to a-blockers. For the a-blocker/PDE studies, NNMLUTS includes BPH and erectile dysfunction. Every combination examined by Fullhase et al. defines a unique cohort of men with NNMLUTS. I have been an active participant in the evolving story of medical therapy since 1983, when I characterized the human prostatic a1 adrenoceptors. I will use this editorial as an opportunity to express my perspective about the role of combination medical therapy for BPH (NNMLUTS) based onmy interpretation of themedical evidence with, at times, deviation from the conclusions of Fullhase et al. [1]. I will limit my comments to the a-blocker plus 5-ARI and a-blocker plus anti-M combinations because the medical evidence for all other combinations is deficient. I will also limit my analysis to LUTS and disease progression due to space limitations.