It has been estimated that globally, the number of patients with ED will exceed 300 million by 2025.4 Despite recognition that ED is a common medical illness and not only psychogenic in origin--as historically described--patients and physicians alike often have difficulty communicating on this topic. In an international survey of more than 27,000 men and women, only 9% of respondents reported that their physician had inquired about their sexual health in the last three years.5
Pharmacists--a trusted source of objective medical information--are responsible for counseling and routinely dispensing medications for ED. This affords many opportunities to improve outcomes as well as provide valuable education on optimization of treatments--especially when a suboptimal response is experienced with phosphodiesterase type 5 (PDE-5) inhibitors. ED is an important patient care topic, as patients may associate sexual health with vitality and overall well-being. Furthermore, there are several treatment options, making this an amenable medical condition potentially responsive to both pharmacotherapy and nonpharmacologic measures.
Etiology of Erectile Dysfunction
A complex sequence of biochemical steps results in an erection during sexual stimulation.6 The principal mediator is nitric oxide (NO), which activates guanylyl cyclase, thereby increasing concentrations of cyclic guanosine monophosphate. The resulting relaxation of smooth muscle allows for engorgement of the penis to provide rigidity for intercourse.
ED has multiple etiologies including vascular, neurologic, and endocrine disorders. This highlights the importance of a proper physical exam and a thorough patient history. Many patients have specific modifiable vascular risk factors that can impact erectile function. Patients with vascular risk factors including hypertension, coronary artery disease (CAD), high cholesterol, and diabetes are at increased risk for ED compared to patients without these conditions.7,8 Smoking appears to further increase the risk of ED in patients with vascular risk factors, likely due to direct effects on endothelial function.9 Health care providers should routinely remind current smokers with ED of the beneficial effects of smoking cessation from both a cardiovascular and sexual health perspective. In regard to diabetes, poor glycemic control and duration of disease further increases risk, which highlights the need for prevention and vigilance in this patient population.10
Obese patients are also at risk for ED, possibly due to increases in oxidative stress that may render NO inactive.11 In obese men, lifestyle changes including moderate weight loss and increased exercise can have a significant impact on retaining and improving erectile function. Additionally, ED is often the first sign of underlying, undiagnosed cardiovascular disease.11
It is important that pharmacists recognize medication classes associated with ED and sexual dysfunction. For example, incidence of selective serotonin reuptake inhibitor (SSRI)–induced sexual dysfunction is estimated at 30% to 50%.12 In this situation, as well as in beta-blocker–induced ED, drug holidays to avoid sexual side effects should not be routinely recommended. Whenever possible, conversion to another agent within the same therapeutic class with a lower incidence of sexual side effects should be recommended. PDE-5 inhibitors may be appropriate and have been studied to improve specific causes of drug-induced sexual dysfunction.13,14 Other medications commonly associated with ED include antihypertensive agents such as calcium channel blockers, beta-blockers, and thiazide diuretics as well as miscellaneous agents including methotrexate, interferon-alpha, and 5-alpha reductase inhibitors.15
Phosphodiesterase Inhibitors
When potentially reversible causes of ED have been ruled out, PDE-5 inhibitors are considered first-line therapy unless otherwise contraindicated by patient-specific comorbidities or concomitant administration with certain medications.16 Three agents are currently available: sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis). Current guidelines for the management of ED do not favor one agent over another for initial treatment of ED. Post-hoc analysis of phosphodiesterase inhibitor– naïve men did not identify specific patient characteristics predicting patient preference for either sildenafil or tadalafil.17 Specific differences between the three available agents are largely based on pharmacokinetics and onset of action (Table 1).18-20
Patients with CAD who are considered for PDE-5 inhibitor therapy should undergo cardiovascular risk stratification.21,22 Patients determined to be at low risk may receive medication for ED and may cautiously resume sexual activity. Higher-risk patients, including those with unstable angina; untreated, poorly controlled, accelerated, or malignant hypertension; a recent (within two weeks) myocardial infarction (MI); or aortic stenosis should be advised to abstain from sexual activity until stabilization has occurred.22 Due to possible precipitous decreases in blood pressure, PDE-5 inhibitors should not be used in men taking nitrates.
An additional contraindication to PDE-5 inhibitor use is prior diagnosis of nonarteritic ischemic optic neuropathy (NAION), a rare ophthalmologic disorder. Temporal association between PDE-5 inhibitor use and diagnosis of NAION has been documented; however, a cause-effect relationship has yet to be fully established.23 Patients with this ophthalmologic disorder often share similar vascular risk factors including hypertension and smoking--further confounding this relationship. A case control study examining this issue found no increased risk of this condition except in patients with a history of MI.24 Overall, the risk of this condition is low, but patients with a history of NAION should not take PDE-5 inhibitors.
Other rare side effects reported with tadalafil and sildenafil include sudden loss of hearing; however, a cause-effect relationship has yet to be fully established.19,25 More commonly reported side effects include changes in blue-green vision with sildenafil and a higher reported incidence of back pain with tadalafil.18,19
While PDE-5 inhibitors have revolutionized the management of ED, the remainder of this review will focus on alternative treatment options and potential treatment strategies in the setting of failed PDE-5 inhibitor therapy or contraindications.
Alternative Therapies
Approximately one in three men who suffer from ED will have inadequate response, contraindications, or side effects to PDE-5 inhibitors.15 The American Urological Association (AUA) states that for patients who fail an adequate trial of a PDE-5 inhibitor, a trial of another such agent may be appropriate. However, no studies have shown benefit for one PDE-5 inhibitor over another.16 Alternative therapies include intracavernosal injections, intraurethral therapy, vacuum devices, and penile prostheses (Table 2). Although more invasive than oral medications, these options are effective for many patients.
Injectable Therapies: One injectable medication used as a second-line therapy in the treatment of ED is alprostadil. This naturally occurring form of prostaglandin E1 acts to increase cyclic adenosine monophosphate (cAMP), which in turn relaxes smooth muscle, leading to an erection.26 Phentolamine (an alpha-adrenergic blocker) and papaverine (a nonspecific phosphodiesterase inhibitor) both act as vasodilators and may be used in combination with alprostadil if the patient has an inadequate response to alprostadil alone. Alprostadil is the most effective monotherapy followed by papaverine; phentolamine is used only in combination as augmentation. It may be preferable to use all three medications in combination, as efficacy increases from approximately 80% to 92% with use of the combination (tri-mix), and side effects may decrease since lower doses of each agent are used.15,27 When side effects do occur, they may include penile ache (5%) and, in rare cases, penile fibrosis or priapism.15 Hypotension is also rare.26
Although intracavernosal injection provides local, rapid response, the invasiveness and requirement for injection may deter patients or decrease compliance.28 As previously noted, injection therapies are considered second-line treatment and are typically offered to patients who have failed or cannot tolerate therapy with PDE-5 inhibitors. Contraindications to intracavernosal injection therapy include anatomical deformation of the penis, leukemia, myeloma, sickle cell disease, predisposition to priapism, or hypersensitivity to the agents.26 Precautions to their use include bleeding disorders or concomitant use of anticoagulants.26 When this therapy is initiated, the first dose should be administered under the supervision of a health care provider to allow teaching of administration technique and titration of dose required to obtain adequate erection.
Intraurethral Suppository: Alprostadil may also be administered via urethral suppository. A medicated pellet more commonly called MUSE (medicated urethral system for erection) is inserted by the patient into the distal urethra prior to intercourse. This formulation often provides local, rapid response although efficacy (~67%) may be less than intracavernosal injection.29 Despite using the same active medication to achieve an erection, it has been shown that patients who fail intracavernosal injection therapy may have success with use of intraurethral alprostadil.29 Engel and McVary reported in a retrospective review that 58% of men who described intracavernosal injection as "not effective" were able to achieve an erection with use of intraurethral alprostadil in the clinic setting.29 It is recommended that intraurethral suppository be offered to patients who have failed PDE-5 inhibitors.15 It may be an especially useful second-line option for patients who are deterred by intracavernosal injections due to needle aversion or pain from injection. Side effects are similar to those of intracavernosal injection and include local pain (32%) and, in rare cases, persistent penile pain or priapism.30 Intraurethral administration may also lead to urethral bleeding (5%) and increased risk of urinary tract infection (0.2%).27
Vacuum Constriction Devices: Other second-line therapies include vacuum constriction devices (VCDs), which use negative pressure to draw blood into the penis. A band is placed at the base of the penis to maintain the erection for no longer than 30 minutes. Efficacy of VCDs is unclear due to the lack of high-quality studies, but it has been estimated at 35% to 90%.15,27 Low patient acceptability again limits the use of these devices, but they may be appropriate and effective, especially when it is necessary to avoid drug therapy and provide a noninvasive mode of administration. Use of anticoagulants or presence of a bleeding disorder are considered contraindications to use of VCDs.27
Penile Prostheses: Penile prostheses are considered third-line treatment options due to the need for surgical implantation of the devices. There are two main types--malleable, also known as semirigid, and inflatable devices. Despite their invasiveness, prostheses may be preferred by patients over vacuum devices. Recent analysis of patient satisfaction and device reliability have yielded very positive results.15,31 Essentially all patients with proper device function can achieve an erection. Failure of the device most often results from infection or mechanical failure. The five-year rate of mechanical failure is estimated to be 6% to 16% depending on the type of device used.16 Infection can also lead to prosthesis failure, but with appropriate surgical techniques and antibiotic practices these rates are only 2% to 3% (slightly higher in diabetics).27 Device manufacturers have also attempted to decrease rates of infection by use of antibacterial-impregnated prostheses or hydrophilic coatings.16,27 If infection does occur, the prosthesis must be removed and infection treated appropriately. Reimplantation is an option after a period of several months, but is more technically challenging. Due to the replacement of penile erectile tissue during implantation, PDE-5 inhibitors, intracavernosal injection, and MUSE are not considered options after implantation and subsequent removal of a prosthesis. In these patients, the only viable option remains reimplantation. However, a vast majority of patients have previously failed most other therapies upon arrival to this stage.
Other Alternative Therapies: Despite being advertised as an herbal alternative for the treatment of ED, yohimbine is not recommended by the AUA, as safety and efficacy in humans have yet to be determined. This herbal medication, believed to increase libido in rats, has alpha2-adrenergic inhibition leading to increased blood pressure, heart rate, and motor activity in humans.16 Yohimbine may also cause irritability and tremor.16
Use of trazodone for treatment of ED is not recommended by the AUA. It has been hypothesized that this antidepressant, via antagonism of alpha2-adrenergic receptors, would possibly relax penile smooth muscle and dilate penile arteries, leading to an erection. Results from clinical trials have been conflicting and, therefore, its use cannot be recommended.16
It is estimated that approximately 12% of patients with ED have hypogonadism, and in some cases this may be a reversible cause of ED through treatment with administration of exogenous testosterone.32 If symptoms persist beyond three months of testosterone therapy, dysfunction is most commonly due to or complicated by the adverse effects of the patient's comorbid conditions, including impaired penile vasculature.32 Dual treatment with testosterone and a PDE-5 inhibitor may be indicated. As AUA guidelines state, administration of exogenous testosterone in someone with normal serum testosterone values is not recommended.16
Subgroup Analysis: Status Post Radical Prostatectomy
As practitioners attempt to individualize treatment of ED, unique situations arise. A common scenario includes treatment of ED post radical retropubic prostatectomy (RRP), as with the 50-year-old man presented in the case study. Prostate cancer is the fourth most common cancer in adults, and it is estimated that approximately 40% of patients with localized disease will undergo radical prostatectomy.33 Urinary incontinence and ED are the most common complications from this procedure, with the latter attributed mainly to damage to nerves regulating erections.33 Advances in surgical techniques, including nerve-sparing procedures, may reduce ED and subsequently improve response to PDE-5 inhibitors.
Therapy with PDE-5 inhibitors may be warranted not only to treat but also to prevent ED in patients who have undergone RRP. Bannowsky et al conducted a randomized, placebo-controlled trial (N = 43) comparing sildenafil 25 mg nightly on recovery of erectile function after nerve-sparing radical prostatectomy (NSRP).34 Their findings suggest that sildenafil may enhance recovery of erectile function by supporting cavernosal oxygenation and preventing subsequent fibrosis. One year postsurgery, 47% of patients randomized to sildenafil were able to achieve and maintain an erection sufficient for vaginal intercourse, compared to 28% of controls. When "on-demand" sildenafil 50 to 100 mg as needed was allowed, potency increased to 86% versus 66%, respectively (P <.001).34
Based on these findings, Bannowsky et al have proposed a new therapeutic concept, termed the Kiel concept, for optimum reestablishment of erectile function and satisfying sexual function after NSRP, which is based on the significant benefit observed in patients taking sildenafil 25 mg nightly.34 They suggest that patients with no confirmed erections at one year postsurgery should undergo a trial of intracavernosal injection therapy, and if no spontaneous erections occur at two years, more invasive therapy may be required.34 Future studies are needed to further investigate the theories behind the Kiel concept, as it remains controversial; however, this study conveys the possible importance of early therapy to support cavernosal oxygenation after RRP. It also emphasizes the importance of following up with patients for symptoms of ED and utilization of alternative therapies to treat this clinical problem.
Conclusion
In summary, pharmacists should be readily available to counsel patients on the differences not only between PDE-5 inhibitors but between second-line therapies as well. Because failure of one PDE-5 inhibitor does not necessarily preclude effectiveness of another agent, pharmacists should determine if the medication has benefited the patient. In the setting of failed PDE-5 inhibitors, several alternative therapies exist, and patients may be considered for second-line treatment options. Patient specific factors, as well as convenience and patient adherence, should be considered prior to initiating therapy with any agent.
The authors wish to acknowledge Douglas Geraets, PharmD, BCPS, for his assistance with editing and revisions.
REFERENCES
1. NIH Consensus Development Panel on Impotence. NIH Consensus Conference. Impotence. JAMA.1993;270:83-90.
2. Grover SA, Lowensteyn I, Kaouache M, et al. The prevalence of erectile dysfunction in the primary care setting: importance of risk factors for diabetes and vascular disease. Arch Intern Med.2006;166:213-219.
3. Walsh PC, Retik AB, Vaugh ED, et al. Campbell's Urology. 8th ed. Philadelphia, PA: WB Saunders; 2002.
4. Ayta IA, McKinlay JB, Krane RJ. The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int. 1999;84:50-56.
5. Moreira ED Jr, Brock G, Glasser DB, et al. Help-seeking behaviour for sexual problems: the global study of sexual attitudes and behaviors. Int J Clin Pract. 2005;59:6-16.
6. Lue TF. Erectile dysfunction. N Eng J Med. 2000;342:1802-1811.
7. Feldman HA, Johannes CB, Derby CA, et al. Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts male aging study. Prev Med. 2000;30:328-338.
8. Fung MM, Bettencourt R, Barrett-Connor E. Heart disease risk factors predict erectile dysfunction 25 years later: the Rancho Bernardo Study. J Am Coll Cardiol. 2004;43:1405-1411.
9. McVary KT, Carrier S, Wessells H. Smoking and erectile dysfunction: evidence based analysis. J Urol. 2001;166:1624-1632.
10. Brown JS, Wessels H, Chancellor MB, et al. Urologic complications of diabetes. Diabetes Care. 2005;28:177-185.
11. Esposito K, Giugliano F, Di Palo C, et al. Effect of lifestyle changes on erectile dysfunction in obese men: a randomized controlled trial. JAMA. 2004;291:2978-2984.
12. Balon R. SSRI-associated sexual dysfunction. Am J Psychiatry. 2006;163:1504-1509.
13. Nurnberg HG, Gelenberg A, Hargreave TB, et al. Efficacy of sildenafil citrate for the treatment of erectile dysfunction in men taking serotonin reuptake inhibitors. Am J Psychiatry. 2001;158:1926-1928.
14. Segraves RT, Lee J, Stevenson R, et al. Tadalafil for treatment of erectile dysfunction in men on antidepressants. J Clin Psychopharmacol. 2007;27:62-66.
15. McVary KT. Erectile dysfunction. N Engl J Med. 2007;357:2472-2481.
16. Montague DK, Jarow JP, Broderick GA, et al. Chapter 1: the management of erectile dysfunction: an AUA update. J Urol.2005;174:230-239.
17. Eardley I, Montorsi F, Jackson G, et al. Factors associated with preference for sildenafil citrate and tadalafil for treating erectile dysfunction in men naïve to phosphodiesterase 5 inhibitor therapy: post hoc analysis of data from a multicentre, randomized, open-label, crossover study. BJU Int. 2007;100:122-129.
18. Viagra (sildenafil) package insert. New York, NY: Pfizer; October 2007.
19. Cialis (tadalafil) package insert. Indianapolis, IN: Eli Lilly; February 2008.
20. Levitra (vardenafil) package insert. West Haven, CT: Bayer Pharmaceuticals; October 2007.
21. Jackson G, Rosen RC, Kloner RA, Kostis JB. The second Princeton consensus on sexual dysfunction and cardiac risk: new guidelines for sexual medicine. J Sex Med. 2006;3:28-36.
22. Kostis JB, Jackson G, Rosen R, et al. Sexual dysfunction and cardiac risk (the Second Princeton Consensus Conference). Am J Cardiol. 2005;96:313-321.
23. Pomeranz HD, Bhavsar AR. Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (viagra): a report of seven new cases. J Neuroophthalmol. 2005;25:9-13.
24. McGwin G Jr, Vaphiades MS, Hall TA, Owsley C. Non-arteritic anterior ischaemic optic neuropathy and the treatment of erectile dysfunction. Br J Ophthalmol. 2006;90:154-157.
25. Mukherjee B, Shivakumar T. A case of sensorineural deafness following ingestion of sildenafil. J Laryngol Otol. 2007;121:395-397.
26. Alprostadil injection package insert. Irvine, CA: Sicor Pharmaceuticals; June 2005.
27. Hatzimouratidis K, Hatzichristou DG. A comparative review of the options for treatment of erectile dysfunction: which treatment for which patient? Drugs. 2005;65:1621-1650.
28. Shah PJ, Dinsmore W, Oakes RA, Hackett G. Injection therapy for the treatment of erectile dysfunction: a comparison between alprostadil and combination of vasoactive intestinal polypeptide and phentolamine mesilate. Curr Med Res Opin. 2007;23:2577-2583.
29. Engel JD, McVary KT. Transurethral alprostadil as therapy for patients who withdrew from or failed prior intracavernous injection therapy. Urology. 1998;51:687-692.
30. MUSE (alprostadil urethral suppository) package insert. Mountain View, CA: Vivus, Inc; August 2003.
31. Carson CC, Mulcahy JJ, Govier FE. Efficacy, safety and patient satisfaction outcomes of the AMS 700CX inflatable penile prosthesis: results of a long-term multicenter study. AMS 700CX Study Group. J Urol. 2000;164:376-380.
32. Shabsigh R, Rajfer J, Aversa A, et al. The evolving role of testosterone in the treatment of erectile dysfunction. Int J Clin Pract. 2006;60:1087-1092.
33. Mettlin CJ, Murphy GP, McDonald CJ, Menck HR. The National Cancer Data Base Report on increased use of brachytherapy for the treatment of patients with prostate carcinoma in the U.S. Cancer. 1999;86:1877-1882.
34. Bannowsky A, Schulze H, van der Horst C, et al. Recovery of erectile function after nerve-sparing radical prostatectomy: improvement with nightly low-dose sildenafil. BJU Int. 2008;101:1279-1283.
