Combination therapy for erectile dysfunction: where we are and what's in the future.

Penile erection occurs in response to visual, olfactory, imaginative, and tactile stimuli initiated within the brain and/or on the periphery. Responses to these stimuli are mediated by efferent autonomic outflow originating in the sacral spinal cord and transmitted by the cavernosal and penile nerves. A number of neurotransmitters can play an integral role in corpus cavernosum smooth muscle relaxation, in part regulating penile erection through increased smooth muscle synthesis of the secondary messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). In addition to direct-acting agents, there are indirect-acting smooth muscle-relaxing agents. Phosphodiesterase (PDE) inhibitors such as sildenafil act indirectly and require sexual stimulation and endogenous nitric oxide production to activate the cGMP pathway effectively. In contrast, agents such as prostaglandin E(1) (PGE(1)) act directly on the trabecular smooth muscle, binding to specific e-prostanoid receptors and increasing cAMP synthesis. For this reason the direct-acting agents do not require sexual stimulation for efficacy. Combination pharmacotherapy has been used experimentally to treat erectile dysfunction for 25 years, using combinations of cAMP synthesis augmentors, smooth muscle relaxants and PDE inhibitors, and alpha-blockers administered via intracavernosal injection. The present era of oral pharmacotherapy treatment has resulted in significant awareness in the field of sexual dysfunction; however, a single agent may not be ideal to sustain penile rigidity, especially if comorbidities and severity of erectile dysfunction are accounted for. The rationale for and recent reports on combination therapy are presented in this review.