Alternatives to Oral Therapies for Erectile Dysfunction


Kenneth Brummel-Smith, MD


Pages 26 - 32

Erectile dysfunction (ED) is defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance. Although ED is not a normal change of age, it is very common. While not a life-threatening problem, it nevertheless is a source of significant stress to many men. Regardless of the man’s age, it is likely to have a significant effect on self-esteem and quality of life. While there are some normal changes in sexual function with healthy aging, these changes are not so severe that enjoyment of sexual activity must be abandoned. Unlike younger men, psychological causes for ED are less frequent (but must still be considered), and organic causes are much more likely. With the advent of the phosphodiesterase type 5 (PDE5) inhibitors, treatment, after an initial evaluation for reversible causes, will be successful in 65-70% of patients.1 Of those who initially respond to PDE5 inhibitors, only about 30% will be using them 6-12 months later.1 Hence, a fairly large percentage of men with ED may wish to consider other alternative treatments.

Sexual health is related to overall health and function. Older men need to understand that while impairment of erectile function is common with aging, it is not inevitable and is often a sign of underlying medical conditions that may have been inadequately addressed. Erectile dysfunction can have a profound effect on emotional well-being and interpersonal relationships with the patient’s partner. A thorough evaluation is critical to successful management. It is recommended that questions about satisfaction with one’s sexual life and ED should be included in the routine assessment of functional status of all elderly men.

Erectile dysfunction affects 20-30 million men in the United States. From 52-70% of men over age 60 have one or more episodes of ED per month.2 The prevalence increases with advancing age3 (Figure). In those who have a sudden onset of ED, psychogenic or adverse drug events are the most likely causes. But, the more common scenario in older men is the gradual onset of ED, in which vascular or neurogenic causes are more common.

Vascular diseases, which are frequent causes of ED, include atherosclerotic cardiovascular disease, hypertension, and diabetes. Men presenting with ED have been shown to have a high risk of subsequent development of cardiovascular conditions (eg, angina, myocardial infarction, transient ischemic attack, stroke).4 A comprehensive assessment of cardiovascular risk should be part of the general evaluation. Neurological conditions such as stroke, neuropathies, Parkinson’s disease, and Alzheimer’s disease are also common causes. In addition, substance abuse (especially alcohol and cocaine), obesity, cigarette smoking, depression, chronic renal disease, trauma or spinal cord injuries, and radical pelvic surgery can all cause or worsen ED. Perhaps surprisingly, hypogonadism, or low serum testosterone, is an uncommon cause of ED. Of course, medications are always a concern (Table I).

Normal erections are a complex event. They require psychosexual stimulation, and usually some physical stimulation as well. The arterial and venous supply of the penis must be functioning well. Nervous innervations must function normally. The man must have adequate hormonal function. And finally, the erectile tissues of the penis must function normally. It is not difficult to see how a multiplicity of factors may be involved in the etiology of ED in a particular patient.

Sexual functioning does change with age, even in normal circumstances. Older men have a prolonged latency period (the time required to develop a full erection). Erections are generally less turgid and ejaculations are less forceful. There is also a decrease in volume of the ejaculate and penile sensitivity. Whether decreased serum testosterone is a normal change of age or simply a very common finding is controversial. These changes are not usually bothersome enough to make men unsatisfied with their sexual performance, and some have even suggested that they may even be an advantage to older men. For instance, because vaginal secretions are diminished in older women, a less turgid erection may make heterosexual intercourse more pleasurable for both partners.

In most cases, the primary care physician can completely evaluate and treat ED (Table II). A thorough general, functional, and sexual history should be obtained. In addition to questions about onset and duration of problems, the history should clarify whether there are problems with adequacy of erections, decrease in libido, or problems with orgasm. The time course in which ED has developed and whether sleep-associated erections occur should be assessed. The patient’s relationship with a sexual partner and his or her responses to the patient’s problem are important. Social stressors, substance or alcohol use, and history of depression or other affective disorders are important lines of inquiry. The general medical history should focus on known risk factors—medications, diabetes, hypertension, peripheral arterial disease, neurologic conditions, hyperlipidemia, and smoking. Any attempted home remedies or other treatments are also important to consider.

A focused physical exam is required. Erectile dysfunction may be the presenting symptom of a number of chronic conditions. Vital signs, a thorough assessment of the vascular system including all palpable pulses and capillary filling, and a cardiac exam should be completed. A neurologic exam should follow, including testing for penile sensation and peripheral sensation (looking for signs of peripheral neuropathy). Cremasteric, superficial anal, and bulbocavernosus reflexes generally do not need to be assessed. Evaluation of the genitalia, including the size of testes, hair pattern, and observation of any penile abnormalities, is important.

Screening laboratory tests that are necessary include a urinalysis, complete blood count, chemistry panel, thyroid-stimulating hormone, and lipids testing. Many authorities recommend a morning sample serum free testosterone, and some recommend a prostate-specific antigen test, though these are somewhat controversial in the routine assessment of ED.5 Some recommend the use of the Sexual Health Inventory for Men, a five-item screening questionnaire.6 Many men will have some abnormalities when conducting a large number of tests, but the abnormal lab values may not account for the patient’s problem. In the past, other tests such as nocturnal penile tumescence and a diagnostic trial of intracavernosal injection were recommended, but these are not necessary in the initial assessment of ED.7

Finally, the patient should be encouraged to bring in all medications: prescribed, over-the-counter (OTC), and home or herbal remedies.

Before embarking on any long-term therapy, an attempt should be made to eliminate reversible causes (Table III). Control of comorbidities has been shown to increase the response rate to PDE5 inhibitors to 82%.8 Any medication with the potential for affecting erections should be discontinued, weaned, or substituted, if possible. Alcohol intake should be limited, and the patient should stop smoking. If psychological causes are found in the evaluation, referral for therapy is paramount. Couples therapy may be beneficial. Treatment of depression is complicated because tricylic, monoamine oxidase inhibitor, and selective serotonin reuptake inhibitor antidepressants can affect erectile function and libido. Increased exercise is beneficial for enhancing cardiovascular function and blood flow, as well as having positive effects of physical conditioning, affect and mood, and to support changes in diet and smoking behavior.9 Some patients who achieve an erection but do not maintain it sufficiently to have intercourse may wish to try constriction bands, which are placed on the penis after the erection occurs. A meta-analysis of an old-fashioned treatment, yohimbine, showed it superior to placebo in the treatment of ED (odds ratio [OR], 3.9; 95% confidence interval [CI], 2.2-6.7). Most patients required one tablet (5.4 mg) 3-4 times daily.10 Side effects were few, and the cost is only about $24 per month. Most OTC drugs advertised for ED have no evidence to support their use or effectiveness.

However, if the above measures fail or the patient desires treatment, then usually a PDE5 inhibitor is the next step. These agents do not cause spontaneous erections but require sexual stimulation to induce an erection. Approximately 30-35% of patients do not respond to PDE5 inhibitors.11 In addition, after one year, only about 30% of patients are still using the drug.1 These medications are expensive, costing $10-$12 per pill. One must also be very careful about purchasing them online, where black market imitations have been found. Finally, there are many patients in whom PDE5 inhibitors are absolutely or possibly contraindicated (Table IV). The only absolute contraindication is the concomitant use of nitrates because hypotension can cause adverse cardiovascular events, including death. Relative contraindications include the use of alpha blockers (with their hypotensive side effects), amiodarone, and sotalol, patients with coronary ischemia in whom nitrates may be necessary, poorly controlled congestive heart failure or chronic hypotension, and patients with retinal disease or those on complex antihypertensive programs or complex cardiovascular drug regimens.12ALTERNATIVE THERAPIES FOR ERECTILE DYSFUNCTION
Fortunately, there are a number of other treatment approaches for the patient who cannot take or fails treatment with PDE5 inhibitors. In order of complexity and risk, these include vacuum erection devices, intraurethral alprostadil, intracavernosal injections, and surgical approaches, such as prostheses or vascular reconstruction. In addition, combining PDE5 inhibitors with one of the above treatments may also help some men.

Vacuum Erection Devices
Vacuum erection devices have a success rate of 66-83%. They are associated with moderate patient satisfaction, are noninvasive (no surgery, injections, or medications are used), and, when used properly, have no serious side effects. Medicare and some insurance plans cover them. It is important that a high-quality device be used that has a pressure limiter. Many devices sold on the Internet do not have this protection. Patients can purchase them on their own, but a prescription is usually required for insurance coverage. A penile constriction ring is placed on the base of the penis after an erection is achieved using the pump. Pumps can be manual or electric.

Complications, which can occur, include bruising, pain, and numbness of the penis and pulling on the scrotum. Some men experience discomfort if the penis becomes cold during pumping. The process does require some manual dexterity and can be cumbersome or difficult to use for some men; however, skill increases with repeated use. Some couples are inhibited by the lack of spontaneity. Some also notice less glans sensitivity, and some may have difficulty with ejaculations, primarily due to the constriction ring. The increased mobility of the penis requires getting used to. Finally, if not covered by insurance, the cost of $150-$450 may be prohibitive for some men; however, over time, it is the least-expensive treatment of all types. A money-back warranty is important. Video instructions should accompany the devices to illustrate their use.

Intraurethral Alprostadil
Intraurethral alprostadil offers another alternative for men with ED. Using a small instillation device, a 3-mm pellet of alprostadil is placed in the distal urethra. This approach alleviates the need for intracavernosal injections using the same medication. Alprostadil is a prostaglandin E inhibitor, which works by causing relaxation of the penile sinusoidal systems and maintaining blood flow into the penis. Erections are achieved in 40-60% of men using intraurethral alprostadil (OR, 7.22; 95% CI, 5.68-9.18).13,14

It is recommended to urinate first to lubricate the urethra. An erection usually occurs in 10-15 minutes and lasts 30-60 minutes. The instillation requires practice and should be first done in a physician’s office in order to titrate the proper dosage and ensure that the rare complication of priapism does not develop. Dosage strengths are 125 g, 250 g, 500 g, and 1000 g. The lowest dose that causes an erection is advised. Some men find a constriction device to be helpful if the erection does not last long enough. Intraurethral alprostadil may also be used to engorge the glans and improve the ability to penetrate in men with a penile prosthesis.

Problems with intraurethral alprostadil include transient penile or urethral burning, which affects about one-third of men using it. Penile pain or burning is the most common reason cited for discontinuing use. It has been reported that this side effect often decreases after a few doses. Manual dexterity and practice are needed to use it effectively. Serious side effects are rare but can include hypotension, syncope, or allergic reactions.15 Intraurethral alprostadil should not be used if penile fibrosis is present. It is expensive, costing about $20 per pellet. Insurance may cover all or some portion of the cost.

Intracavernosal Injection
Intracavernosal injection of either alprostadil alone (in premixed syringes), or a combination of alprostadil, papaverine, and phentolamine (trimix) is highly effective in producing erections, even in the absence of sexual stimulation.16 Monotherapy with alprostadil is widely available, but bimix or trimix requires compounding by a pharmacist, so they may have limited availability in some areas. Approximately 66-83% of men achieve an erection sufficient to have intercourse. Like intraurethral alprostadil, it has no effect on glans sensitivity or ejaculation. The lowest optimum dose should be used, which requires titrating up initial injections from 2.5 gm to a maximum of 10 g. The initial dose titration should be performed in a physician’s office under supervision. The injection is made in the dorsolateral shaft of the penis, into the corpus cavernosum, avoiding the superficial veins.

However, because of the requirement of injections, some men may be hesitant to use this method. The drop-out rate has been reported from 28% to over 60%. Complications include bruising, pain at the ejection site (OR, 7.39; 85% CI, 5.40-10.12), and priapism in 4% of users.14 Like intraurethral alprostadil, it should not be used if penile fibrosis is present, and mixtures with papaverine and phentolamine can cause fibrosis or angulation when used repeatedly. It is also contraindicated in patients on anticoagulants. It requires training and follow-up, so many primary care physicians prefer to refer such patients to a urologist. All patients should be informed of the emergency steps to follow if priapism occurs.15 The cost of the medication may be covered by insurance, but it is expensive (about $25 per dose).

Combined Therapy
Combined therapy (a PDE5 inhibitor + intraurethral or intracavernosal alprostadil) could be considered in men who fail on one method. Nehra et al17 reported the results of a study of 28 patients (mean age, 59 yr) using sildenafil 100 mg and intraurethral alprostadil 500 g. Over 30 months, 100% reported satisfactory erections with an average of 3.6 intercourse episodes per month.17 Mydlo et al18 reported similar results, with 60 of 65 patients expressing satisfaction with the combination of sildenafil and intraurethral alprostadil. When intracavernosal trimix and sildenafil were used together in men who failed either drug alone, 48% responded; however, 33% reported adverse events (including 20% incidence of dizziness).19 Some drug resources, such as Epocrates, suggest avoiding this combination.

A penile prosthesis is often the best treatment for men who do not respond or cannot use any form of medication.11 Approximately 20,000-30,000 penile prostheses are implanted in American men annually. New prostheses have good long-term reliability and high satisfaction rates in both partners, from 69-85%.20 There are two types: malleable and inflatable. Inflatable prostheses provide a more normal flaccid state and erection, but they are associated with higher rates of failure, pump displacement, or auto-inflation. The five-year failure rate is approximately 6-16%.21 They do offer more spontaneity than most medication approaches and allow for prolonged erections. The main concerns are infection (persons with diabetes are at particularly high risk), device failure, the possible impact on penile or glans sensitivity from the surgery, and the high cost ($8000-$15,000). Additionally, there is limited experience of the devices over 8-10 years, and it is possible that subsequent devices will be necessary if the device fails due to it reaching its normal “lifespan.” Newer models have antibiotic coatings and have significantly reduced the risk of infection (from approximately 2% over 1 year to 1%).21 A noninflatable, malleable prosthesis is sometimes preferred by men due to its lower cost and low chance of device failure. It is always semi-rigid, so it may be the cause of embarrassment in some men. Penile arterial reconstructive surgery is controversial and the Erectile Dysfunction Guideline Panel of the American Urological Association did not recommend it at this time for older men.16SUMMARY
Erectile dysfunction is not a normal change of age, and it is likely to have a significant effect on self-esteem and quality of life. It usually has an organic basis in older men, although psychosocial issues must still be considered. It may be the presenting symptom of a significant medical condition, such as diabetes, cardiovascular disease, or a neurologic condition. A thorough evaluation is required before starting treatment.

Generally, if an organic cause is suspected, treatment may begin with yohimbine or a PDE5 inhibitor. If patients do not respond, or these drugs are contraindicated, alternative therapies should be offered. A step-wise approach is useful, beginning with the least-invasive approach. Penile constriction rings and/or a vacuum pump are often the first step. Intraurethral alprostadil is the next step. Intracavernosal injection therapy may work when the intraurethral approach does not. For men who do not respond to these measures, referral to a urologist for possible penile prosthesis is recommended.

The author reports no relevant financial relationships.Dr. Brummel-Smith is Charlotte Edwards Maguire Professor and Chair, Department of Geriatrics, Florida State University College of Medicine, Tallahassee.References
1. Fagelman E, Fagelman A, Shabsigh R. Efficacy, safety, and use of sildenafil in urologic practice. Urology 2001;57:1141-1144.

2. Lue TF. Erectile dysfunction. N Engl J Med 2000;342:1802-1813.

3. McKinlay JB. The worldwide prevalence and epidemiology of erectile dysfunction. Int J Impot Res 2000;12(Suppl 4):S6-S11.

4. Thompson IM, Tangen CM, Goodman PJ, et al. Erectile dysfunction and subsequent cardiovascular disease. JAMA 2005;294:2996-3002.

5. Earle CM, Stuckey BG. Biochemical screening in the assessment of erectile dysfunction: What tests decide future therapy? Urology 2003;62:727-731.

6. Rosen RC, Cappelleri JC, Smith MD, et al. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res 1999;11(6)2:319-326.

7. Miller TA. Diagnostic evaluation of erectile dysfunction. Am Fam Physician 2000;61:95-104, 109-110.

8. McCullough AR, Barada JH, Fawzy A, et al. Achieving treatment optimization with sildenafil citrate (Viagra) in patients with erectile dysfunction. Urology 2002;60(2 Suppl 2);28-38.

9. Singh MA. Exercise to prevent and treat functional disability. Clin Geriatr Med 2002;18:431-462, vi-vii.

10. Ernst E, Pittler MH. Yohimbine for erectile dysfunction: A systematic review and meta-analysis of randomized clinical trials. J Urol 1998;159:433-436.

11. McMahon CN, Smith CJ, Shabsigh R. Treating erectile dysfunction when PDE5 inhibitors fail. BMJ 2006;332:589-592.

12. Cheitlin MD, Hutter AM Jr, Brindis RG, et al. ACC/AHA Expert Consensus Document. Use of sildenafil in patients with cardiovascular disease. American College of Cardiology/American Heart Association. J Am Coll Cardiol 1999;33(1):273-282. [Erratum in: J Am Coll Cardiol 1999;34(6):1850.]

13. Padma-Nathan H, Hellstrom WJ, Kaiser FE, et al. Treatment of men with erectile dysfunction with transurethral alprostadil. Medicated Urethral System for Erection (MUSE) Study Group. N Engl J Med 1997;336:1-7.

14. Urciuoli R, Cantisani TA, Carlini IM, et al. Prostaglandin E1 for treatment of erectile dysfunction. Cochrane Database Syst Rev 2004;(2):CD001784.

15. Linet OI, Prince FG. Efficacy and safety of intracavernosal alprostadil in men with erectile dysfunction. The Alprostadil Study Group. N Engl J Med 1996;334:873-877.

16. Montague DK, Jarow JP, Broderick GA, et al; Erectile Dysfunction Guideline Update Panel. Chapter 1: The management of erectile dysfunction: An AUA update. J Urol 2005;174:230-239.

17. Nehra A, Blute ML, Barrett DM, Moreland RB. Rationale for combination therapy of intraurethral prostaglandin E (1) and sildenafil in the salvage of erectile dysfunction patients
desiring noninvasive therapy. Int J Impot Res 2002;14(Suppl 1):S38-S42.

18. Mydlo JH, Volpe MA, Macchia RJ. Initial results utilizing combination therapy for patients with a suboptimal response to either alprostadil or sildenafil monotherapy. Eur Urol 2000;38:30-34.

19. McMahon CG, Samali R, Johnson H. Treatment of intracorporeal injection nonresponse with sildenafil alone or in combination with triple agent intracorporeal injection therapy. J Urol 1999;162:1992-1998.

20. Carson CC. Penile prostheses: Are they still relevant? BJU Int 2003;91:176-177.

21. Wolter CE, Hellstrom WJ. The hydrophilic-coated inflatable penile prosthesis: 1-year experience. J Sex Med 2004;1:221-224.