Future options for combination therapy in the management of erectile dysfunction in older men

Drugs Aging. 2004;21(9):555-64. doi: 10.2165/00002512-200421090-00001.


The prevalence of erectile dysfunction (ED) has dramatically increased in parallel with the aging of the Western industrialised population. The estimated prevalence of ED worldwide in 1995 was 152 million men. As the population in industrial nations ages, an estimated 322 million men will be affected by ED by the year 2025. Oral drug therapy with the phosphodiesterase (PDE) type 5 inhibitor sildenafil fails in some patients with ED; however, several different classes of drugs demonstrate efficacy in treating ED, creating the potential for pharmacological combination therapy. Pharmaceutical products that lead to the activation of or an increase in cyclic nucleotides (cyclic adenosine monophosphate and cyclic guanosine monophosphate), with or without nitric oxide donors or nitrates, as well as alpha-adrenoceptor antagonists, have been used to treat ED. Sildenafil has been used in combination with alprostadil (prostaglandin E1) and administered via intraurethral or intracavernous route. Successful intercourse using this combination of agents varies from 47% to 100% following failed monotherapy. Various combination therapies for ED are being studied using PDE5 inhibitors, together with other agents, alpha-adrenoceptor antagonists, and testosterone replacement therapy for men with hypogonadism. The combination of centrally acting agents with PDE5 inhibitors, e.g. a regimen of apomorphine plus PDE5 inhibitor, is an attractive approach because the two therapies target different mechanisms. New PDE5 inhibitors such as vardenafil should be tried first as therapy for sildenafil nonresponders before exploring any combination therapy options. Preliminary observations of combination therapy have been encouraging and provide a scientific rationale for prospective, randomised clinical trials with adequate numbers of patients.

Publication types

  • Review

MeSH terms

  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Adrenergic alpha-Antagonists / therapeutic use
  • Aged*
  • Alprostadil / therapeutic use
  • Animals
  • Apomorphine / therapeutic use
  • Clinical Trials as Topic
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Dopamine Agonists / therapeutic use
  • Drug Therapy, Combination
  • Erectile Dysfunction / drug therapy*
  • Humans
  • Male
  • Phosphodiesterase Inhibitors / administration & dosage
  • Phosphodiesterase Inhibitors / therapeutic use*
  • Phosphoric Diester Hydrolases / physiology
  • Testosterone / therapeutic use


  • Adrenergic alpha-Antagonists
  • Dopamine Agonists
  • Phosphodiesterase Inhibitors
  • Testosterone
  • Phosphoric Diester Hydrolases
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • PDE5A protein, human
  • Alprostadil
  • Apomorphine