Optimizing Outcomes of Oral Therapy for Patients with Erectile Dysfunction

TREATING ERECTILE DYSFUNCTION Optimizing Outcomes of Oral Therapy for Patients With Erectile Dysfunction James H. Barada, MD, FACS Center for Male Sexual Health, Department of Surgery, Division of Urology, Albany Medical College, Albany, NY The evaluation and treatment of erectile dysfunction (ED) differs from that of many medical conditions. An intimate dialogue between the patient and physician must be established for accurate assessment of ED severity and successful therapy. Patient and partner education on the nuances of oral phosphodiesterase inhibitor therapy is important to maximize treatment success with this currently first-line therapy. Realistic expectations for the erectile response and patience are necessary to resume satisfactory sexual functioning. Relationship issues or partner resistance can contribute to a suboptimal erectile response to therapy, in which case the patient may benefit from sexual therapy referral. [Rev Urol. 2003;5(suppl 7):S28-S34] © 2003 MedReviews, LLC Key words: Erectile dysfunction • Phosphodiesterase-5 inhibitors • Outcomes • Sexual therapy he evaluation and treatment of erectile dysfunction (ED) differs from that of most other medical conditions. The National Institutes of Health Consensus Conference on Impotence in 1992 established the current disease definition: “the persistent inability to achieve or maintain an erection of sufficient rigidity and duration to engage in pleasurable sexual intercourse."1 This definition, however, is open to both patient and clinician interpretation. “Persistent" can T S28 VOL. 5 SUPPL. 7 2003 REVIEWS IN UROLOGY Optimizing Outcomes of ED Therapy ↓ Rigidity ↓ Duration ↑ Frustration ↑ Anxiety ↓ Intercourse attempts ↑ Conscious effort ↑ Psychological barriers Figure 1. The erection/dysfunction cycle: For the man, focusing consciously on achieving and sustaining an erection is counterproductive, as it increases adrenergic discharge that results in further diminution of corporal smooth muscle relaxation. The additional dysfunction that results leads to more anxiety, and so on, creating a vicious cycle. ↑ Adrenergic discharge ↓ Endothelial relaxation be one or many times, over a variable time interval, with one or more partners. “Pleasurable intercourse” implies the active participation of a partner, who may have his or her own resistance to intimacy. This definition thus recognizes that ED is a couple-based disease.2 The quality of erectile function is also open to the patient’s interpretation of “sufficient” erectile rigidity and duration. Despite the development of standardized questionnaires and extensive invasive and noninvasive testing algorithms, ED is primarily a self-assessed condition. Symptomatic treatment is elective and, like normal sexual activity, intermittent. Clinical assessment of the therapeutic intervention is not done with a measurable laboratory value or physical finding but is derived from patient reporting and indirectly from partner perception. Successful ED management requires an ongoing physician-patient dialogue for accurate diagnosis, treatment, and outcome assessment. In the course of ED evaluation, therapy selection, and outcome assessment, the patient and physician enter into an intimate communicative relationship in which there is some element of bias. Physician bias arises from the desire to achieve an excellent response without side effects, and patient bias may occur in the additive unconscious need to please the physician. This may lead to treatment outcome inaccuracies, with an over-reporting of efficacy sions, when the need to perform is heightened. In addition, secondary sexual dysfunction in the form of acquired ejaculatory dysfunction (delayed ejaculation/anorgasmia or premature ejaculation) may arise. Although time of progression from mild to moderate to severe ED is variable, many men will adapt to their condition and offer excuses for avoiding sexual activity, which results in a progression to a more generalized lack of sexual interest. The female partner may downplay the importance of sexual intercourse, although her own needs for sexual intimacy may not be met. Concomitant female sexual dysfunction may also be present—for example, vaginal dryness commonly seen in postmenopausal or diabetic women. This may be misinterpreted as a sign of decreased arousal. In addition, further discomfort associated with continued sexual encounters may reduce her interest in continuing or resuming sexual activity. It is not uncommon for both Successful ED management requires an ongoing physician-patient dialogue for accurate diagnosis, treatment, and outcome assessment. and an under-reporting of treatment side effects. Psychological Factors in ED Most ED occurs over time, and a decrease in the perceived quality of erection or sexual performance results in the establishment of psychosexual protective barriers by both partners. For the man, an increased conscious focus on erection enhancement is counterproductive, as it increases adrenergic discharge that results in further diminution of corporal smooth muscle relaxation (Figure 1). The resulting failure leads to further anxiety and a reduction of sexual attempts to “special” occa- partners to suffer in silence, and frustration over a lack of sexual intimacy may arise in other areas of their relationship. Even couples who are “open” to each other about sexual matters may bring other conflicts in their relationship into the bedroom. PDE-5 Inhibitor Therapy for ED The final common pathway of an erection is corporal smooth muscle relaxation. The etiologies of ED are diverse and, in many cases, multifactorial. There is always a psychological component that may accelerate or magnify the physical response. With the advent of phosphodiesterase-5 (PDE-5) inhibitor therapy, the treat- VOL. 5 SUPPL. 7 2003 REVIEWS IN UROLOGY S29 Optimizing Outcomes of ED Therapy continued Table 1 Ideal Attributes of Oral ED Therapy • Dosed on demand; short onset of action • Site-specific action with no primary libido effect • Few systemic side effects Optimizing Results of Sildenafil Therapy • Non-cumulative effect • Efficient and predictable across a wide range of ED etiologies and severities ED, erectile dysfunction. ment algorithm has been shortened in that the pharmacologic mechanism of action is on the cellular level. With sufficient inhibition of the PDE-5 enzyme, the signal for smooth muscle relaxation, mediated by the release and diffusion of nitric oxide from nerve terminals, is amplified such that for each “unit” of sexual stimulation, a corresponding increase in smooth muscle relaxation occurs. An erection is the mechanical (physical) result of a neurovascular event, and it varies in absolute rigidity and duration depending on the specifics of the individual sexual encounter. The application of oral PDE-5 inhibitor therapy is a discrete event that takes place away from the direct supervision of the physician. Because sexual activity is by nature intermittent, the use of an on-demand therapy may increase the time necessary for patient comfort to develop, as it does not involve a short-interval repetitive pattern of use. This places a premium on patient understanding of the mechanism of action, the drug-specific pharmacokinetics, and the importance of communication with the partner for establishing a modified (drugenhanced) sexual script. Patients are enthused by the prospect of oral therapy for ED. However, there is a perception of “fixing” ED that is beyond the capabilities of any current or potential S30 VOL. 5 SUPPL. 7 2003 ficient stimulation. Combining fantasy with physical stimulation, including partner stimulation, enhances the erectile response, as it does in men without ED. future therapy. The goal of therapy is to restore erectile capacity so that it is sufficient for predictable sexual intercourse. The quality of the sexual experience, however, is primarily dependant on the quality of the sexual relationship beyond intercourse. Patient education is helpful for understanding the normal erectile response, the pathophysiology of ED, and the mechanism of PDE-5 inhibitor therapy. It is important to differentiate between a “normal” or “functional” erection and the patient’s recollection of a temporally distant “best” erection as the goal of therapy. The introduction of sildenafil represented a paradigm shift in the evaluation and treatment of ED. This medication fulfills many of the ideals of oral pharmacologic therapy for ED (Table 1).3 The medication is used on demand, with a site-specific action. The outcomes of improvement in erectile rigidity, erectile duration, orgasm, and patient satisfaction, as measured by the validated International Index of Erectile Function, are significantly improved over baseline and compared with placebo. There is no primary libido effect or aphrodisiac quality, although sexual activity may increase following successful therapy. Initial frequency of sildenafil use is high but over time approaches the mean for age-adjusted sexual activity in men without ED.4 An erection is the mechanical (physical) result of a neurovascular event, and it varies in absolute rigidity and duration depending on the specifics of the individual sexual encounter. The erection following PDE-5 inhibitor therapy requires an interval between dosing and response and sexual stimulation for initiation. The time required for absorption, transport, and binding to the corporal endothelial PDE-5 receptor site is determined by the pharmacokinetics of the drug; however, it is also patient- and encounter-specific. Maximal peak serum levels need not be achieved in many instances, because the erectile event threshold may be lowered and endothelial relaxation achieved sooner with suf- REVIEWS IN UROLOGY Sildenafil therapy has demonstrated effectiveness across all ages, ED etiologies, and ED severities. The availability of an effective therapy prompted an immediate shift in the setting of ED care—from the specialist using extensive and detailed diagnostic evaluations and invasive therapy to the primary provider using a goal-oriented approach with minimal diagnostic testing. The most important outcome of therapy is the resumption of successful sexual intercourse. In prospective, randomized, placebo-controlled trials in Optimizing Outcomes of ED Therapy Table 2 Factors Associated With a Poor Erectile Response to Sildenafil Table 3 Patient Instructions to Maximize the Erectile Response to Sildenafil • Take sildenafil on an empty stomach. • Avoid taking with a high-fat meal. Physical factors • Avoid alcohol and smoking when taking sildenafil. • Lack of stimulation* • Wait 45 minutes to 1 hour after ingestion before sexual stimulation. • Lack of signal transmission • Be relaxed and rested. • Inadequate arterial inflow • Maximize sexual stimulation, arousal, and fantasy thoughts. • Endothelial noncompliance • Don’t give up after 1 or 2 attempts. • High-grade CVOD Medication factors • Dosage* • Dosing interval* • Duration of therapy* • Adverse events* Psychological/relationship factors • Anxiety/fear* • Negative thinking* • Female sexual dysfunction* • Relationship discord* CVOD, cavernous veno-occlusive dysfunction. *Potentially correctable with education, sexual therapy, or combination therapy. variable patient populations, the rate of successful intercourse has been 65% to 78%.5-8 McCullough and associates,9 in a retrospective pooled analysis of placebo-controlled trials of sildenafil, showed that the probability of successful intercourse following a single dose was 55%, gradually increasing in cumulative probability to 85% by the eighth attempt. A plateau was seen after 8 attempts, and almost one third of patients who eventually succeeded required more than 3 treatment encounters. The cumulative effect of repeated dosing was more pronounced in men classified as having severe ED. Just as ED is variably progressive, so is treatment: multiple sildenafil encounters may be required for the patient to become comfortable with the nuances of therapy and the return to intimacy, which can result in an increasing response of endothelial smooth muscle to PDE-5 inhibition. The clinical use of sildenafil has evolved over time. Initially, some physicians were uncomfortable with the topic and adopted a “pen and pad” approach, initiating therapy only in patients who specifically requested treatment, with little attention to education and therapeutic instruction. The perception of the topic’s complexity and time demands made it intimidating. As with other newly developed therapies, physician comfort increased with experience, and many physicians now report that a proactive approach is an efficient technique for initiating discussion of sexual issues.10 Early identification of ED, while it is classified as mild in severity, increases the probability of success with sildenafil.11 As with any therapy, the success rates seen in rigidly controlled phase 3 studies in a specific, motivated patient population may not translate to comparable clinical utility in a broader, general clinical practice. Barada12 and McCullough and associates13 reported on cases referred to as “sildenafil failures.” In both studies, more than half of the patients had been exposed to less than the maximum dose (100 mg) or made fewer than 4 sexual attempts. In addition, a general lack of follow-up for efficacy determination, dose adjustment, and discussion of partner issues was identified. These patients were given new instruction and adjusted doses and encouraged to make multiple attempts while addressing partner issues. At follow-up, 56% and 54% of these patients were responders, with resumption of sexual intercourse. Thus, initial treatment failure may not reflect true pharmacologic failure. When a patient fails to respond to his initial exposure to sildenafil, it is important to ascertain correct usage, expectations, and partner issues as contributory factors and to address these issues before moving on to more invasive therapy. Multiple factors contribute to a poor response to sildenafil therapy. It is important to identify and address those factors that are correctable with education and therapy optimization and those that represent end-stage pharmacologic non-response and require a different treatment modality (Table 2). Based on the package insert and the salvage data discussed above, a set of fairly rigid rules evolved to maximize patient response to sildenafil therapy (Table 3).14,15 It must be noted that, in most patients, an acceptable response to sildenafil is seen, as long as it is taken as prescribed. Patients should be encouraged to find what works for them, allowing flexibility in the timing of VOL. 5 SUPPL. 7 2003 REVIEWS IN UROLOGY S31 Optimizing Outcomes of ED Therapy continued dosing and food consumption. Adherence to the outlined suggestions early in the treatment course rapidly produces a sufficient response under ideal conditions, after which time the patient can introduce some flexibility in dosing and food intake. Patients who are initial poor responders or have a variable response should pay particular attention to maximizing the peak serum levels of drug. For example, patients who complain of unreliability of the medication are often taking it on a full stomach; this decreases absorption of the drug and can delay and reduce the magnitude of peak serum levels, especially when a high-fat meal has been eaten. The product insert recommends an interval of 45 minutes mal sexual function despite the presence of a pharmacologic agent. The half-life of sildenafil citrate is approximately 4 hours, and some patients report sustained secondary erections beyond this therapeutic window. Predicting Outcomes of ED Therapy As a general rule, it is easy to predict a lesser response to oral therapy based on a multitude of factors, including patient age, ED severity, comorbidities, duration of sexual inactivity, concomitant medications, and partner interest in and support of resuming sexual intimacy. However, there is no cumulative assessment that universally predicts non-response to an appropriate trial of sildenafil, particularly in a motivated couple. A significant number of women initiate the discussion about ED and direct their partner to obtain appropriate evaluation and therapy. to 1 hour between sildenafil ingestion and the maximal penile response to stimulation; however, some patients report an adequate response in as little as 15 to 20 minutes, particularly when the drug is taken on an empty stomach.16 Older patients and those with delayed gastric emptying (such as diabetic patients) may need a prolonged interval before an effect is achieved. A survey of male sexual habits indicates that the time interval between the respondent’s first thought that he might have intercourse and the beginning of intercourse is approximately 1 hour and does not vary significantly between men with and without ED (59.8 minutes vs 55.8 minutes, respectively) (data on file, Pfizer Inc, New York). This approximates the median time needed for maximal peak serum sildenafil levels to occur, as seen in pharmacokinetic studies, and thus parallels nor- S32 VOL. 5 SUPPL. 7 2003 Therefore, aside from those with a direct contraindication to PDE-5 inhibitor therapy, all patients with ED should be considered candidates for an optimized trial of sildenafil therapy. The clinician should refrain from projecting a dire picture of nonresponse, emphasize empathy and optimism, and stress attention to detail. One may be pleasantly surprised by a treatment success in a patient for whom failure seemed likely on first consideration. Again, this highlights that one patient may be pleased with what another would consider a “minimal” response; nevertheless, the response is adequate for the patient at hand and may result in long-term treatment satisfaction. Alternatively, a failure to respond puts to rest the question of utility of available oral pharmacotherapy; the patient may then be more open to a discussion of highly REVIEWS IN UROLOGY successful, albeit more invasive, vasoactive or surgical therapies. The Role of the Partner in Optimizing Results of ED Therapy Although most physicians interested in treating ED support the concept of involving the partner in the diagnosis, therapy selection, instruction, and outcome assessment, in reality this does not often occur. Time constraints inherent in the increasingly common dual-income household, as well as the perception of ED as the “man’s problem,” make initial or subsequent couple evaluation less likely. The clinician may consider that a partner’s support is implied in the man’s attention to his ED. In addition, a gap may exist between the man’s interpretation of “support” and that which may be attained by actual partner interview. A significant number of women initiate the discussion about ED and direct their partner to obtain appropriate evaluation and therapy.17 Fortunately, many partners are cooperative with the treatment process, which in part accounts for the high success rates of medical and surgical interventions. This benefit extends beyond the controlled clinical trials, which require patient and partner informed consent, and may account for much of the success of many ED patients who see their physicians unaccompanied for evaluation and subsequent pharmacotherapy.18 Mass media articles and direct-toconsumer advertising may provide a significant amount of pertinent information to reinforce this trend. The physician has an opportunity to inquire about and assess the quality of the sexual relationship indirectly and, in many cases, an interview of the patient or couple would yield no additional information. The physician may encourage the attendance of the partner for the benefit of both; Optimizing Outcomes of ED Therapy however, this must be done gently, so as not to assign blame to an individual or the relationship. One must also be cognizant of some men’s desire to attain therapy for an extramarital relationship or the situation of a single man entering into a relationship, which may preclude partner involvement. Newly implemented Health Insurance Portability and Accountability Act guidelines clearly define the need for direct permission to be obtained from a patient before contact is initiated with an identified partner or before health information is given on a partner’s request, by the physician or his proxy.19 The absence of a partner at evaluation and therapy discussion does not predict a significantly lower response rate to PDE-5 inhibitor therapy. Directly or indirectly, the patient assumes responsibility for some degree of partner education. It is valuable to provide supporting educational materials that are relevant, informative, and non-judgmental. Multiple media formats (handouts, audio, video, and electronic) and additional sources for information, such as reputable Web sites, allow for depth and breadth of patient and partner information that can be useful for current and future reference and support. Follow-up for Therapy Assessment The initial evaluation and therapy selection should stress the importance of treatment assessment and follow-up. ED therapy is tailored to the specific needs of the individual couple, and follow-up reinforces the desire of the treating physician to ensure an optimal outcome. The timing of the initial follow-up visit should allow sufficient opportunity for an adequate trial of therapy but not be so distant that a patient feels frustrated if the response to therapy is suboptimal. Hopefully, educational materials provided to the patient are sufficient to ward off a significant number of patient queries, but the patient should feel that his condition is of sufficient concern to the physician to allow telephone or internet interaction if significant questions or concerns arise. The initial follow-up visit should include a brief therapy review, assessment of the erectile response, and inquiry about treatment side effects. A step-by-step description of the most recent sexual encounter (dose, timing, partner interaction, and response) is useful in determining treatment compliance. Most side effects are mild or moderate, primarily nonspecific PDE inhibitor headache, flushing, or dyspepsia. In my experience, the frequency and magnitude of reported side effects is inversely proportional to the erectile response. Fortunately, the patient can be reassured that side effects tend to moderate or disappear over time and can be treated symptomatically. Many patients choose to continue therapy if a sufficient erectile response is achieved, as evidenced by the low discontinuation rate for treatmentemergent side effects seen in the pivotal trials (active treatment, 2.8%; placebo, 2.5%).20 Treatment response can be assessed globally by patient recall or quantitatively by the validated International Index of Erectile Function or the Erectile Dysfunction Inventory of Treatment Satisfaction questionnaire.21,22 A discussion of overall satisfaction and the partner’s acceptance of and satisfaction with the therapy can identify a mismatch of Main Points • Erectile dysfunction (ED), like sexual satisfaction, is assessed subjectively and affected by multiple physical, psychological, and partner-related factors, all of which should be addressed as early as possible to avoid an ongoing cycle of dysfunction and frustration in both the patient and his partner. • Just as ED evolves over time, so does the effectiveness of phosphodiesterase-5 (PDE-5) inhibitor therapy; patients should be informed of the importance of having patience, following the physician’s instructions for dosing, and making multiple attempts in order to give therapy the greatest chance for success. • There are sometimes obvious comorbidities or other factors that make PDE-5 inhibitor therapy more likely to fail; however, only a true contraindication to the drug is reason to dismiss this treatment option, as various other influences make it impossible to predict in whom it will actually fail. • Follow-up of PDE-5 inhibitor therapy is crucial, and failures should be assessed for their origin: many stem from factors that are easily remedied with patient education, whereas some point to the need for further evaluation and consideration of more invasive treatments. • The patient’s partner plays an important role in the successful treatment of ED, and discussions including the partner can be beneficial to all, as long as the physician is careful not to violate confidentialities and promotes a nonjudgmental and open atmosphere. VOL. 5 SUPPL. 7 2003 REVIEWS IN UROLOGY S33 Optimizing Outcomes of ED Therapy continued therapy or relationship expectations. If such a mismatch is present, additional counseling or referral for sexual therapy can be suggested. The combination of pharmacotherapy and sexual therapy yields significant improvement in overall satisfaction, particularly if additional psychological and relationship issues are identified and addressed.23 Continued patientphysician dialogue prompts early identification of initial treatment difficulties. Specific interventions may increase overall success or guide the patient to a discussion of alternative therapies. It is important to recognize the expected frustration associated with multiple failed attempts, and the physician should continue to be empathic and supportive in guiding the patient to an effective therapeutic outcome. Conclusions VOL. 5 SUPPL. 7 2003 References 1. 2. 3. 4. The introduction of oral PDE-5 inhibitors has significantly improved patient acceptance of effective therapy for ED. There has been a significant shift from a specialist model of detailed diagnostic evaluation followed by invasive therapies to a primary care–guided, patient goal–oriented model utilizing a PDE-5 inhibitor as first-line therapy. More patients are being offered oral therapy which, although easier to prescribe, does not reduce the need for adequate patient education in proper use of the medication, discussion of realistic expectations and sufficient trial time, and timely assessment of outcomes. Initial S34 or follow-up assessment of the partner’s perception of therapy is important to identify couples who may benefit from additional sexual therapy. A properly prepared and executed treatment plan allows the physician to confidently categorize the patient as a true responder or nonresponder to PDE-5 inhibitor therapy. 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