The Treatment of Erectile Dysfunction
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By Stephen M.Auerbach, MD
California Professional Research, Newport Beach, CA
Reprinted from PCRI Insights August 2005, vol. 8, no. 3

Editor’s Note: For men diagnosed with prostate cancer, erectile dysfunction (ED) has been a major problem because a high percentage of men treated with radical prostatectomies, radiation therapy, and cryosurgery have traditionally become impotent as a result. Indeed, many men have chosen their treatment (or non-treatment) based on the probability of this side effect.

ERECTILE DYSFUNCTION (ED) IS THE INABILITY TO ACHIEVE AND MAINTAIN AN ERECTION SUITABLE FOR SEXUAL RELATIONS. It is not widely known, but ED, or impotence, affects over 30 million men and their partners. Most men can tell their best friend they have been diagnosed with a cancer or had a heart attack, but are afraid to ever mention anything about ED. As a result, ED is very personal and traditionally has been a closet or taboo subject to most people. However, beginning with the release of Viagra®, ED is now discussed more openly by everyone. There is no longer the same stigma of having it. Help is available.

ED can easily be diagnosed and treated in most men. The first step is made when the victim realizes he is having a problem. The quicker a man admits there is a problem, the earlier he can be diagnosed and treated so that his chances of getting back to normal are improved.

Prior to Viagra®, Levitra®, and Cialis®, finding a doctor to treat ED was a very difficult process for most men. Patients did not know where to seek help. Physicians were not aware of the disease process, nor did they feel comfortable talking about this subject. Most doctors thought that ED was not a real disease like diabetes or hypertension. Moreover, most doctors do not like talking about emotional subjects and believe that they don’t have the time to get bogged down on an emotional topic.

Normal Erectile Function
An erection occurs by blood flowing into and being trapped in the penis. When a man has a sexual thought or is physically touched, messages are sent to the penis where there is release of nitric oxide that causes a chemical reaction. This reaction results in smooth muscle relaxation and increased blood flow into the penis. As the smooth muscle relaxes, the blood is trapped in the penis. With increased blood accumulation, the penis becomes rigid.1

Development of ED
Man is one of the few species of animals that has sex not only for procreation, but also for sexual pleasure. In previous eras, ED was not a problem, because most men died before they aged enough to develop ED. With longer and expected fuller lives, ED has become an issue with advancing age.

There are numerous causes of ED as well as prostate cancer, and usually it develops gradually. Men notice that they have a more difficult time achieving and maintaining rigidity. Also, they find that more stimulation may be required to achieve and maintain the erection. Men may notice that they have fewer and less rigid erections upon awakening from sleep in the middle of the night or morning.

ED is Associated with Other Illnesses
ED is associated with a number of medical problems and conditions. Men with heart disease, diabetes, elevated cholesterol, hypertension, and depression have a higher incidence of ED than the normal population. ED is more common with advancing age. Also, men requiring surgical treatment of prostate cancer are more likely to develop ED than the normal population does.1,2,3

Many men who have been diagnosed with prostate cancer choose their treatment because of the potential development of ED with surgery or radiation therapy. Men are much more open to nerve-sparing robotic prostatectomy, open surgery, and new radiation techniques now that there is hope of fewer side effects.

Even with the best treatment, complications can occur. There can be problems with ejaculation and impotence. Even though the medical therapies can give a man a good erection, there are occasional problems of difficulty reaching orgasm and in some cases experiencing burning or pain with ejaculation.

I urge patients who have been diagnosed with prostate cancer to choose the best treatment for the cancer instead of worrying about their erections. Men do not die from improperly treated ED, but they can die from prostate cancer. Moreover, although almost every man can regain his potency with one of the available erectile treatments, we cannot reach the same success with every prostate cancer treatment. Therefore, I always educate my patients of the risks and benefits of each treatment, so that they choose the best treatment for their prostate cancer.

Male Aging Issues Affecting Sexual Function
There are a number of aging issues that affect ED:

  • A man can have a natural decrease in sex drive as he ages due to decreased testosterone levels. With each advancing year, a man’s testosterone level can drop.
  • Usually erectile difficulties start slowly. A man will have more difficulty achieving and then maintaining an erection after insertion.
  • A man can still ejaculate with a semi-rigid or flaccid penis.
  • Achieving ejaculation may take longer as a man starts to have erectile difficulties; conversely ejaculation may occur more quickly. In the latter case, as a man sees his erection fading, he may ejaculate sooner. In fact, some men will develop premature ejaculation.
  • The sensation of ejaculation may be less intense as a man ages.
  • The volume of ejaculation may decrease with advancing age due to decreased prostatic secretions or retrograde ejaculation. As the prostate grows bigger, the bladder neck muscle does not contract as efficiently and is unable to propel the ejaculate out the urethra. Either all or part of the ejaculate seeps into the bladder and is expelled from the body when the man voids.4

Partner Involvement
Communication between the couple is important. Men try to hide their ED from their wives. Frequently, men will avoid any physical contact that could lead to sexual activity, go to bed earlier or get involved in a TV program. Even though the couple is together, there can be a loss of intimacy. By the same token, a male’s sexual function can be directly related to his partner’s interest in having relations.5,16 Among the issues involved are:

  • A woman’s sexual drive decreases following menopause. They may have a drop in estrogen affecting vaginal lubrication and testosterone that can negatively impact sexual drive.
  • A change in body appearance with increased weight gain can dramatically affect a woman’s desire to have sex.
  • Urinary incontinence can decrease a woman’s sexual desire. They can have stress incontinence associated with exertion or urge incontinence where they can not get to the bathroom quickly enough.

Diagnosis of ED
A history of difficulty achieving or maintaining an erection is the cornerstone of the diagnosis. However, serum and free testosterone blood levels should be evaluated, and a serum PSA blood test to evaluate for prostate cancer though not essential for the diagnosis of ED is always part of my work-up.

Treatment Options for ED
PDE-5 inhibitors: When Viagra® was released in 1998, it was the first effective oral medication to show efficacy in the treatment of ED. Subsequently, Levitra® and Cialis® were approved by the FDA. All three of these medications work in a similar fashion by blocking the breakdown of the enzyme, cyclic GMP, which is responsible for the smooth muscle relaxation and trapping blood in the penile tissue when a man is sexually stimulated.1,6,7

There is tremendous competition by the manufacturers of these three medications to achieve market share and sales. We have found all three of these medical compounds are effective and very safe in the majority of patients. Patients always ask, “Which medicine is best for me?” My response is, “ Whichever medication works the best for you, fits your lifestyle the best, and has the fewest side effects on you.” Even though, they are similar in action, they are very different.

Similarities and Differences of the PDE-5 Inhibitors
All three medicines work in a similar fashion and have certain precautions and side effects. Basic common similarities include:

  • They require sexual stimulation.
  • They should be tried multiple times before calling them a failure (I tell my patients to try each medication 5-10 times before giving up on it).
  • PDE-5 medicines cannot be taken with any nitrate.8,9,10 Nitroglycerin is used to treat chest pain and must not be taken in combination with Viagra®, Levitra®, or Cialis®. There is no negotiation about the use of PDE-5 and nitrates. In a rare patient, they can cause a significant drop in blood pressure, up to 30 mmHg or more. If someone has chest pain after taking one of these PDE-5 inhibitors, the treating physician should be told so that he knows to give you an alternative medicine to nitroglycerin.
  • Alpha-Blockers used for the treatment of Benign Prostatic Hypertrophy (BPH) must be used cautiously in combination with Viagra, Levitra®, or Cialis®.8,9,10 The combined use of these medications is generally safe, but can cause a drop in blood pressure resulting in light headedness or dizziness in a rare patient. Unfortunately, we do not know which patient will have the drop in blood pressure. The vast majority of men tolerate alpha blockers and PDE-5 medications without any side effects.11,15 Therefore, the following precautions should be taken:
    • Viagra®: The alpha-blocker can be taken simultaneously with a 25 mg dose. When taking the 50 mg or 100 mg dose, there should be a four hour separation between Viagra® and the alpha-blocker.8
    • Levitra® and Cialis®: The alphablocker or Levitra® should be started at the lowest prescribing dose for both drugs and raised to the most efficacious dose slowly to ensure tolerability.9,10,11 I tell my patients to take Levitra® or Cialis® four hours after the alpha-blocker.

Absorption and Half-Life of PDE-5 Medications
The manufacturers of all three medications have data that show that in some patients there is efficacy as early as 14-16 minutes after taking the medication. In some studies, up to 50% of patients show efficacy by 30 minutes.12 However, the number one reason these medications fail is that the patient tries to have sexual relations too quickly before the medication has been absorbed.15 After one or two failures, most men just quit trying. Each man should find out what is the best time for him after taking the medication, and use that as a guide as to when to begin sexual relations. We regard the following manufacturer recommendations to be good guidelines:

  • Viagra® (sildenafil citrate): Approximately a 4-5 hour half-life allowing for sexual activity for up to six hours or longer. Viagra® should be taken about one hour before use if on an empty stomach (up to two hours after a fatty meal or with alcohol).12,13
  • Levitra® (vardenfil HCL): Approximately a 4-5 hour half-life allowing for sexual activity up to six hours or longer. It may be taken with a low fat meal and alcohol one hour before expected relations. With a high fat meal, a man should take it two hours before sexual relations.9,12
  • Cialis® (tadalafil): It has a 17.5 hour half-life with double blind studies showing activity up to 36 hours.10,12 A man can take Cialis® earlier in the day or on a Friday evening and choose to have sexual relations at the most natural or convenient time. This time freedom is attractive to both men and women because sex appears to be more natural and not dictated by the clock.15

Common Side-Effects
The following side effects are listed in the package inserts of the three medications. These are not from head to head trials. As can be seen, all three medications have a similar side-effect profile.9,10,13

Common Side Effects

Recent Reports of Visual Problems in Men Taking PDE-5 Inhibitors
There is a medical condition called Non-Arteritic Anterior Ischemic Nueropathy that I will refer to as NAION. This is a rare condition where disruption of the blood supply to the optic nerve causes damage to the nerve. The injury can cause decreased visual acuity and in some cases, blindness. The exact cause of NAION is unknown, however, but known risk factors include:

  1. Age (> 50 years old)
  2. High blood pressure
  3. Diabetes
  4. Hyperlipidemia
  5. Coronary Artery Disease
  6. Smoking
  7. An abnormal optic disc on eye exam

The natural annual incidence of this condition is between 2-10 cases per year, per 100,000 people over 50 years of age in the United States.14 There are no reported cases in the clinical trials with Cialis®, and none to my knowledge with Viagra® and Levitra®. Since the release of these medications, patients have been diagnosed with NAION. The PDE-5 medications have been used in more than 30 million men worldwide. The percentage of NAION cases associated with patients using the PDE-5 medications is less than that of the general population. In other words, the PDE-5 medications have not been shown to cause NAION. However, if any patient taking a PDE-5 medication develops sudden loss of vision or visual difficulties, he should stop taking the PDE-5 and seek immediate medical attention, preferably by an ophthalmologist.

Patient Choice
One of the best things with multiple medications is that a couple and the physician can choose the medication that works the best and has the fewest side effects. I have patients who have chosen one medication over the other because of efficacy or side effect profile. Moreover, patients have chosen all three for one reason or another. To repeat, the best medication for a given patient is whichever medicine works the best for him and/or best fits his lifestyle.

New Medications on the Horizon
1. NEXMED Medication. This Prostaglandin-E cream is applied to the urethral opening and glans penis. Initial studies show that this medication works effectively in many patients.17 The advantage is that it works locally on the penis and increases blood flow to the penis.

2. Palatin Medication. This compound is inhaled and works centrally to stimulate messages down the spinal cord that helps to increase blood flow to the penis, initiating the erectile process. This medicine works rapidly.18

3. Dong-A Medication. This is a PDE-5 Inhibitor that has a 12-hour half-life. It is in early clinical trials.19

4. VIVUS Medication. This is a PDE-5 inhibitor that may work faster than the present available medicines. It is is in early clinical development.20

5. Dapoxetine® by Ortho McNeil, a division of Johnson & Johnson, is before the FDA and is awaiting approval for the treatment of “Premature Ejaculation.”

6. Potential gene therapy is being considered for clinical trials.

Vacuum Erection Devices
As shown in Figure 1, a cylinder is placed over the penis, using a lubricant to create a seal. Vacuum pressure provided by a pump draws blood into the penis. A rubber band traps the blood in the penis. These devices can be helpful also, in maintaining penile length after prostate cancer surgery. Many men have found these devices to be successful, while others find them cumbersome to use.

Vacuum Erection Device
Vacuum Erection Device
Figure 1. Vacuum Erection Devices. These are among the most widely used devices to enable erections for men with erectile dysfunction problems. Photos provided by Augusta Medical Systems, LLC.

MUSE (Medical Urethral System for Erection)
This is Prostaglandin-E medicine that is applied into the urethra. The man then rubs the penis causing the medicine to dissolve and be absorbed into the glans and erectile bodies of the penis. The erection occurs usually within 10-15 minutes if this medicine is going to work for the patient. MUSE has had less success than the oral medications for most men.15

Penile Injection Therapy
The thought of a penile injection has to be the most foreign thought for any man, but it is probably one of the most effective treatments available. There is a small plastic device that automatically performs the injection on the side of the penis. It feels like a pinch on the shaft of the penis. There are a number of medications that can be directly applied into the erectile chambers.

The advantage of this treatment is that it gives a very natural and firm erection. In fact, I have a number of patients who prefer this treatment over the oral medications because of its dependability and quick onset of action. Most of my patients report that the erection occurs within 3-5 minutes after an automatic injector device is used.15 The medicine can be titrated to give an erection that will last about 45 minutes. However, a side effect can be a prolonged erection that will last four hours or more.

Inflatable Penile Prosthesis
A penile implant is a great option for a couple facing ED. However, most men will never consider this treatment option unless all other treatment options fail. The thought of a penile implant seems unnatural to most men, and they just cannot picture themselves getting this type of a surgery. In fact, the manufacturer reports that approximately 90% of men and their partners proceeding with this treatment are extremely satisfied.

Most men prefer the inflatable penile implant as it gives the most natural erection. The erection is immediate and simulates a natural erection. (See Figure 2.) The procedure, which is covered by most insurance companies and Medicare, is performed as an outpatient and is about as invasive as a hernia operation. Thus, most men can return to work within four to seven days of surgery and are able to have sexual relations within six to eight weeks.15 Over the past 30 years, more than 300,000 men have had penile protheses implanted. And the present inflatable implants have much greater success than earlier models, with fewer leaks and mechanical malfunctions. Today, in fact, the implant manufacturers give a lifetime warranty.

Penile Prosthesis Figure 2. Implanted completely within the body, penile prostheses produce an erection-like state that enables the man to have normal sexual intercourse. Neither the operation to implant a prosthesis nor the device itself will interfere with sensation, orgasm or ejaculation. Illustration provided by American
Urologic Association.

Immediate Action Advised
Whenever a man develops erectile difficulties, he should seek help right away. Prior to the availability of PDE-5 medications, men would wait up to five years before seeking help. People did not talk about ED and were not aware of available treatments. And when they learned of the treatments, they were not too excited with their options of urethral penile inserts with MUSE, penile injections, and penile implants.

Delaying ED treatment for more than a few months is inadvisable. A minor problem may grow into a more significant one. When men experience failures, sexually, they get very nervous whenever they engage in sexual relations. This can result in more failure and subsequent avoidance of sexual activity. When a man is not getting regular erections, he can develop scarring of the erectile tissue with fibrosis of the delicate smooth muscle that creates an erection. This scarring can result in penile retraction or shrinkage.15

Ask your doctor for help. Try all three of the present available medications. If they are not effective, ask your physician for a referral to an urologist who is knowledgeable in the treatment of ED. Even if the oral medications fail, a man can achieve a successful result with alternative treatments. As previously mentioned, there are excellent treatment options that are effective in almost 100% of ED problems arising from prostate cancer treatments.

What Treatment Plan is the Best for a Couple with ED?
Having the partner involved in the treatment plan is a good idea. Communication between the couple is important and begins when both understand that there is a medical solution or solutions for an ED problem. Most patients will start with an oral medication. As previously described, each medicine has specific advantages for some patients. I urge patients to try all three medicines to see which one bests fits their lifestyle. Side-effect profile, quality of erection, and duration of activity are key determining factors.15

If the couple is not successful with oral medications, then they should consider the use of injection therapy or even an implant. Couples can return to a normal sex life. In fact, I have many patients who say their sex life is better following treatment. They are certain of their sexual performance, and this increases their confidence so they can return to a closer, more intimate relationship. The fundamental goal of ED treatment is purely and simply to help the couple get back to a normal sex life.

A normal sex life is more than an erection or the sexual act. Returning to a normal sex life gives a man confidence and a feeling of youthfulness. For the partner, there is a return of intimacy and closeness. I find that most men feel a sense of ease and self-assuredness that was lacking when suffering with ED. When treatment is complete, most couples state, “I only wish we would have fixed our problem sooner.” 

References
1. Goldstein, I., Lue, T.F., Padma-Nathan, H., Rosen, R.C., Steers, W.D., and Wicker, P.A.: Oral Sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group, N. England Journal of Medicine, 338: 1397, 1998.

2. Feldman, H.A., Goldstein, I., Hatzichristou, D.G., Krane, R.J., and McKinlay, J.B., Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J. Urology, 151: 54, 1994.

3. Gacci, M., Bartoletti, R., Figlioli, S., Sarti, E., Eisner, B. , Boddi,V. et al: Urinary symptoms, quality of life and sexual function in patients with benign prostatic hypertrophy before and after prostatectomy: a prospective study. BJU Int, 91: 196, 2003.

4. Hellstrom, Wayne J.G., Urology Times, June 2005, Vol. 33 No. 7, Premature Ejaculation: Out of the Dark Ages and Into the 21st Century

5. Berman, J.R., Berman, L, and Goldstein, I., Female Sexual dysfunction: incidence, pathophysiology, evaluation, and treatment options. Urology 54: 385, 1999.

6. Brock, G, McMahon, C.G., Chen, K.K., Costigan, T., Shen, W., Watkins, V. et al: Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses, J Urology, 168: 1332, 2002.

7. Stark, S., Sachse, R., Liedl, T., Hensen, J., Rhode, G., Wensing G., et al: Vardenafil increases penile rigidity and tumescence in men with erectile dysfunction after a single oral dose. Eur Urol, 40: 181, 2001

8. United States Package Insert (UPSI) for Sildenafil, Food and Drug Administration, 2005.

9. UPSI for Vardenafil, Food and Drug Administration, 2005.

10. UPSI for Tadalafil, Food and Drug Administration, 2005.

11. Auerbach, S.M., Gittleman, M., Mazzu, A., Cihon, F., Sundaresan, P., White, W., Simultaneous administration of vardenafil and tamsulosin do not induce clinically significant hypotension in patients with benign prostatic hypertrophy, Urology 64: Number 5 November 2004.

12. 12 Educational slide decks provided by Pfizer, Eli Lilly, and GSK 2005.

13. UPSI for Sildenafil, Food and Drug Administration, 2005.

14. Cialis® Speaker Bureau Update Information letter June 6, 2005.

15. Clinical experience of Stephen M. Auerbach, MD.

16. Laumann EO, Nicolosi A, Glasser DB, Paik A, Gingell C, Moreira E, Wang T., Sexual problems among women and men aged 40-80 y.o.: Prevalence and correlates identified in the Global Study of Sexual Attitudes and Behaviors, Int. Journal Impotence Research 2005; 17:39-57.

17. Information at NexMed Advisory Board, June 2004.

18. Information from Palatin Investigator Meeting, July 2005.

19. Information from Dong-A Investigator Meeting, May 2005.

20. Information from VIVUS investigator Meeting, March 26, 2004.

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