Gene silencing therapies have succeeded in controlling expression levels of a desired gene in animal models. By infusing short-interfering RNAs (siRNA), these molecules target particular messenger RNA (mRNA) in the cells through sequence-specific binding, suppressing the translation for the target protein. These therapies hold great promise for treating numerous disorders of the central nervous system (CNS) including novel approaches to chronic pain management. While novel siRNA targets are being discovered rapidly, difficulties in siRNA delivery such as anatomical accessibility of the target tissue, slow diffusion and non-specific uptake make achieving a precise degree of protein downregulation nearly impossible. We propose to design optimal infusions integrating medical imaging with systems engineering principles. A novel pain management therapy is designed to suppress the expression of pain-transducing NMDA receptors in the subject's spinal cord. The coupling of biotransport equations with intracellular siRNA kinetics enables the design of siRNA gene silencing therapies. The accurate prediction of dose-response and the computation of optimal infusions are expected to accelerate clinical implementations of gene silencing therapies.