Treating erectile dysfunction in nonresponders to PDE5 inhibitors

Neil H. Baum, MD

Associate Clinical Professor of Urology

Department of Urology

Tulane Medical School

New Orleans, LA

Ann Ezzell, BA

Medical Student II

University of Tennessee College of Medicine

Memphis, TN

The three phosphodiesterase-5 inhibitors frequently used as first-line treatment for patients who have erectile dysfunction include sildenafil, vardenafil, and tadalafil. These agents demonstrate little difference in efficacy rates, and a patient who fails to respond to one likely will not respond to the others. Treatment failure has been attributed to various factors, including misuse of the medication, the drug?s side effects, and insufficient patient education. In an attempt to convert nonresponders to responders, physicians should address a patient?s specific issues and follow the treatment algorithm outlined in this article. If patients continue to fail therapy despite receiving appropriate counseling and maintaining optimal drug use, physicians may consider more invasive therapies.

Millions of American men suffer from erectile dysfunction (ED). Sildenafil (Viagra) was the first phosphodiesterase-5 (PDE5) inhibitor approved by the Food and Drug Administration to treat this condition, followed by vardenafil (Levitra) and tadalafil (Cialis). The efficacy rates of all three agents are similar, and about 80% of men state that these agents improve their ability to achieve and sustain erections; nearly 75% find themselves able to have intercourse successfully.¹

Treatment failure with a PDE5 inhibitor occurs when the patient is unable to achieve an erection sufficient for vaginal penetration or cannot sustain an erection long enough to complete intercourse. Identifying and addressing any relevant issues may correct some medication failures and should be attempted before initiating more invasive therapy.

TREATMENT FAILURE

Figure 1—Treatment algorithm for nonresponders to PDE5 inhibitor therapy. Click for a larger image.

Treatment with PDE5 inhibitors can fail for several reasons, including issues intrinsic to the medication, such as side effects; a breakdown in physician-patient communication, which can lead to misuse of the drug; and a patient?s personal issues, which may involve unrealistic expectations or fears concerning the drug.

Patients who remain unresponsive to PDE5 inhibitors despite measures taken to address these problems are considered true nonresponders when the following criteria are met:

• Four separate attempts at sexual intimacy fail to produce adequate erectile response despite sufficient sexual stimulation; and
• The patient is using the highest tolerated dose in accordance with the manufacturer?s guidelines regarding food and alcohol ingestion and concomitant use of other medications.²

Switching from one PDE5 inhibitor to another may be considered before proceeding to more invasive or costly treatments, but studies have found no difference in efficacy among the three PDE5 inhibitors currently available. In our clinical experience, only a few patients who were considered true PDE5 nonresponders achieved success after changing to a different PDE5 inhibitor.

Clinical matters

Clinical issues that result in treatment failure can include intolerance of the side effects of PDE5 inhibitors, inadequate dosing, and underlying health problems, such as diabetes or hypoandrogenism. PDE5 inhibitors should be titrated to the maximum tolerated dose before the patient is considered a true nonresponder. A 2006 report showed that 80% of patients achieved the best results when the highest recommended PDE5 dose was used.³

Side effects that can result in treatment failure include headaches, flushing, dyspepsia, nasal congestion, and abnormal vision.⁴ If the patient should decide that these side effects outweigh the benefits of taking the PDE5 inhibitor, he may discontinue the medication, which is considered treatment failure.

PDE5 inhibitors have lower efficacy rates (approximately 56%) for patients with diabetes mellitus. A diabetic or hypertensive patient is unlikely to have success following the first dose of a PDE5 inhibitor, particularly if the patient takes other medications that can impair his ability to produce or sustain an erection or he has not had intercourse for several months. PDE5 inhibitors also demonstrate reduced efficacy in men who have undergone radical prostatectomy; a study by Mueleman and Mulders determined that about 30% of such patients failed to respond to oral PDE5 inhibitors.⁵ This may result from injury during surgery to the neurovascular bundle that supplies blood to the corporal bodies of the penis. It is especially important to emphasize to diabetic patients and men who have had radical prostatectomy the need to attempt intimacy on at least four occasions before considering PDE5 treatment a failure.

Prior to classifying a patient as a true nonresponder, the physician should check the patient?s testosterone level to rule out hypoandrogenism as the etiology of sexual dysfunction. Patients with hypogonadism or hyperprolactinemia will need testosterone replacement therapy if their testosterone level is at the lower end of normal (<300 ng/dL).⁶ This can be administered through injection or gels (Andorgel, Testim). The gel?s transdermal delivery of testosterone allows patients to achieve a more physiologic level of testosterone and avoid the peaks and troughs common with injection therapy. Men receiving testosterone replacement therapy who continue to experience ED can have their treatment supplemented with PDE5 inhibitors.⁷

Patient issues

Patient issues must be addressed when assessing nonresponse to PDE5 inhibitors. These may include anxiety about intercourse after a prolonged period of abstinence or unreasonable expectations of the drug?s efficacy. Most patients who take PDE5 inhibitors report that the medication takes at least 1 hour to achieve maximum effect, although the onset of effectiveness can range from 15 to 60 minutes.⁸ In the event that the first dose is unsuccessful, the patient must be advised to remain persistent and attempt intercourse on at least four occasions after taking the maximum dose of the PDE5 inhibitor before aborting therapy. A study by McCullough and colleagues found that six to eight attempts were required to achieve an 80% success rate with sildenafil use.⁹

Some patients fear the drug?s side effects or have unaddressed psychological problems, such as guilt or religious concerns about engaging in sexual intimacy. These issues should be discussed with patients who appear to be nonresponders.

Physician-patient communication

Improving physician-patient communication and providing follow-up can prevent or resolve many of the issues that lead to treatment failure. After clinical and personal issues have been addressed with the nonresponder, it is important to ensure that the patient understands how to use the drug properly. Two different studies of sildenafil nonresponders showed that approximately 55% became responders following counseling on proper use of the medication.^10,11

Figure 2&#8212;Coloplast Titan&#8482; inflatable penile prosthesis. This inflatable prosthesis consists of two soft silicone or plastic tubes inserted in the penis, a small reservoir placed in the abdomen, and a small pump implanted in the scrotum.

Data show that a common cause of sildenafil failure is insufficient genital stimulation before attempting intercourse.¹² PDE5 inhibitors facilitate an erection but do not act as an aphrodisiac or initiate an erection.⁹ A 2005 study by Hatzichristou and associates noted that 2 of 100 sildenafil nonresponders were unaware that sexual stimulation was needed to achieve an erection.¹³ After being counseled on proper sildenafil use, one patient became a responder.

Hatzichristou and colleagues? study of nonresponders found that 56% were using the drug inappropriately; as previously mentioned, 2 patients failed to engage in genital stimulation prior to initiating intercourse, 45 patients were not taking the highest recommended dose of 100 mg, 22 patients failed to wait at least 30 minutes after taking the drug before attempting intercourse, and 32 patients consumed high-fat meals while using sildenafil.¹³ Taking PDE5 inhibitors after consuming a heavy or high-fat meal can result in treatment failure because fat inhibits absorption of the medication from the gastrointestinal tract. After counseling, 33% of patients who had been deemed treatment failures were converted to responders.

TRUE NONRESPONDERS

Proper treatment of PDE5 inhibitor nonresponders often allows these patients to engage in sexual intimacy successfully (Figure 1). When determining the best approach, physicians should consider ease of the treatment, its invasiveness, and cost.³ Useful treatments include chronic administration of a PDE5 inhibitor; combination therapy with more than one medication; and invasive measures, such as injection therapy, intraurethral prostaglandin, or surgery.

One study showed that increasing the dose of sildenafil to 200 mg helped 24.1% of nonresponders successfully engage in sexual intimacy, but side effects increased substantially and 31% of patients discontinued treatment.¹⁴ Although increasing the dosage of PDE5 inhibitors to suprapharmacologic levels may successfully treat ED in some nonresponders, the increased risk of adverse events indicates that nonre-sponders should not be treated with more than the recommended doses.

Chronic low-dose PDE5 inhibitor therapy

Daily administration of a low dose of a PDE5 inhibitor increases the concentration of cyclic guanine monophosphate, the compound responsible for smooth-muscle relaxation in the corporal bodies of the penis, which is needed for an erection. Adequate sexual stimulation should subsequently increase blood flow to the penis.

Hatzimouratidis and associates examined chronic administration of PDE5 inhibitors in a group of 54 true nonresponders.¹⁵ Patients took either 20 mg of tadalafil every other day or 20 mg of vardenafil daily for 2 weeks; 11.1% of men in the tadalafil group and 18.2% of men in the vardenafil group were converted to responders. Side effects with daily dosing did not increase compared with on-demand use of the drugs. Chronic administration of a PDE5 inhibitor has been found safe and may offer greater spontaneity for patients and their partners. One drawback of daily dosing is the cost, which may place it beyond the reach of many patients.

Combination therapies

Combination therapy uses drugs with different mechanisms of action to improve efficacy and has proven effective in treating PDE5 nonresponders. One noninvasive treatment involves administering oral sildenafil in combination with intraurethral prostaglandin E₁ (MUSE). The effectiveness of this combination therapy was confirmed in a study that administered 100 mg of sildenafil in conjunction with 1,000 mg of intraurethral prostaglandin E₁ to 65 patients who had undergone radical prostatectomy; 92% of patients were reported to be satisfied with their erectile response.¹⁶

Intracorporeal injection of a combination of vasoactive agents is another effective treatment for PDE5 nonresponders. One benefit of injection therapy is that even minimal genital stimulation can trigger an erection. Disadvantages include pain at the injection site, priapism (which occurs in less than 3% of patients) and the potential for subcutaneous hematomas.¹⁷ Its invasive nature also deters many patients from long-term use.

Erectile Dysfunction Statistics

• Worldwide, 1 in 10 men has erectile dysfunction (ED).
• 30 million men in the United States have ED.
• 50% of men with diabetes develop ED, frequently
• within 10 years of diagnosis.
• The likelihood of ED increases with age: men aged 40 and older have a 39% risk and men who are over age 65 have a 65% risk.
• Smokers have a higher likelihood of ED. Men who smoke more than 1 pack of cigarettes daily have a 50% higher chance of impotency than nonsmokers who are the same age.

Source: Minnesota Men?s Health Center.

Erectile dysfunction statistics. Available at:

www.mmhc-online.com.

A study by McMahon and colleagues found that intracavernosal injections consisting of prostaglandin E₁ and 100 mg of sildenafil allowed 31% of patients to engage in sexual intimacy; however 49% of patients receiving this combined therapy experienced adverse side effects.¹⁷ This same study showed that intracorporeal injection therapy consisting of a mixture of prostaglandin E₁, papaverine, and phentolamine mesylate (TriMix) was effective for many nonresponders.¹⁷

Surgical treatment

Surgery is a last resort for PDE5 nonresponders and is usually considered only after all other treatments have failed. The most common surgical treatment is insertion of a penile prosthesis, generally a semi-rigid rod or a three-piece inflatable prosthesis. Despite its invasive nature, penile prosthesis implantation is associated with low rates of infection and erosion.

The inflatable penile prosthesis consists of two soft silicone or plastic (Bioflex) tubes inserted in the penis, a small reservoir placed in the abdomen and a small pump implanted in the scrotum. To produce an erection, the patient squeezes the pump in the scrotum, forcing sterile liquid from the reservoir into the tubes. The tubes act as erectile tissue and expand to form an erection. When the erection is no longer desired, a valve can be released that allows the fluid to return to the reservoir. Inflatable prostheses are reportedly the most natural feeling penile implant and allow patients to control both rigidity and size (Figure 2).

Implanting an inflatable prosthesis requires a slightly more complicated surgical procedure than that used to implant a semi-rigid rod. Overall, malfunction rates of the inflatable penile prosthesis are relatively low, reportedly between 10% and 20% at 5 years.¹⁸ Because the inflatable prosthesis has more mechanical parts, there is increased risk that repairs or adjustments may be required in the event of mechanical failure.

CONCLUSION

ED is a common problem that affects millions of American men, but nearly all men who wish to achieve an erection sufficient for engaging in sexual intimacy can do so using current therapies. First-line therapy with PDE5 inhibitors is successful in most patients. Men who are initially deemed nonresponders can often become responders after addressing clinical or personal issues or being counseled on proper use of the medication. For many true nonresponders, chronic low-dose PDE5 inhibitor therapy or combination therapy using vasodilators such as prostaglandin or intracorporeal injections with prostaglandin mixtures have all proven effective. Should all medical treatments fail, surgical implantation of a penile prosthesis is possible.

PRACTICE POINTS

• All three PDE5 inhibitors on the market show similar efficacy; patients who fail treatment with one medication in this class likely will fail using the others.
• Reasons for therapeutic failure include misuse of the medication, intolerance of the drug's side effects, or the patient's personal issues.
• The physician should determine the reason for treatment failure, offer counseling, and initiate a repeat trial before considering invasive options.
• More invasive therapies, including injection therapy, intraurethral prostaglandin, and surgery, should only be considered for true nonresponders.

SELF-ASSESSMENT TEST

1. What is one step physicians can take to prevent PDE5 treatment failure in their patients?Advise the patient to seek psychological help before initiating PDE5 therapy.Inform patients that they need to wait at least 15 to 60 minutes after taking their PDE5 medication to engage in intercourse.Discourage patients from engaging in genital stimulation prior to intercourse.A and C.
2. When is a patient considered a true nonresponder to PDE5 inhibitor therapy?After the drug fails to produce an erection despite two attempts at intercourse.After four failed attempts at intercourse despite taking the maximum dose and following the manufacturer's recommendations.CAfter six failed attempts at intercourse despite consuming a high-fat meal to aide in absorption of the drug.After all three PDE5 inhibitors have been tried unsuccessfully.
3. Which treatment option is recommended for true nonresponders?Chronic administration of a low dose of a PDE5 inhibitor.Radical prostatectomy followed by placement of a penile implant.Combination therapy using several PDE5 inhibitors simultaneously.Switching to another PDE5 inhibitor.
4. What is one drawback of chronic administration of PDE5 inhibitors?It is cost-prohibitive.The medication's side effects are exacerbated.The lower dose requires more genital stimulation to produce an erection.It inhibits sexual spontaneity.
5. What is one advantage of injection therapy with intracorporeal vasoactive agents?One injection is sufficient treatment.No genital stimulation is required to produce an erection.Side effects are minimal.Only minimal genital stimulation is required to produce an erection.

(Answers at end of references list)

References

1. Sharlip I. New therapies for erectile dysfunction. Available at: www.medscape.com/viewarticle/459656. Accessed February 6, 2008.
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11. Jiann BP, Yu CC, Su CC, et al. Rechallenge prior sildenafil nonresponders. Int J Impot Res. 2004;16:64-68.
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13. Hatzichristou D, Moysidis K, Apostolidis A, et al. Sildenafil failures may be due to inadequate patient instructions and follow-up: a study on 100 non-responders. Eur Urol. 2005;47:518-522.
14. McMahon CG. High-dose sildenafil citrate as a salvage therapy for severe erectile dysfunction. Int J Impot Res. 2002;14:533-538.
15. Hatzimouratidis K, Moysidis K, Bekos TZ, et al. Treatment strategy for "non-responders" to tadalafil and vardenafil: a real-life study. Eur Urol. 2006;50:126-132.
16. 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.
17. McMahon CG, Samali R, Johnson H. Treatment of intracorpo-real injection nonresponse with sildenafil alone or in combination with triple agent intracorporeal injection therapy. J Urol. 1999;162:1992-1998.
18. Montague DK, Angermeier KW. Contemporary aspects of penile prosthesis implantation. Urol Int. 2003;70:141-146.

Answers: 1. B; 2. B; 3. A; 4. A; 5. D.