Erectile Dysfunction: Meeting the Expectations of Men and Women

Erectile dysfunction (ED) is the most common form of male sexual dysfunction. Various medications with different mechanisms of action and non-pharmacological measures (including psychotherapy, reflexology, etc.) are used to treat it. The most effective are phosphodiesterase (PDE) inhibitors, which are now considered first-line drugs for the treatment of ED. PDE inhibitors differ in their onset and duration of action, other pharmacokinetic properties, safety, and tolerability.

Recent studies show that not all drugs used to treat ED meet the expectations of patients—men and their sexual partners—with regard to important aspects of sexual intercourse, such as spontaneity, satisfaction of both partners, and the desired onset and duration of action.

A. Burri and colleagues conducted an online survey of 1,124 men with ED and 410 healthy men aged 30–75 years. A specially designed questionnaire based on the International Index of Erectile Function was used to assess participants’ erectile function. According to the responses of all participants, the criterion for a good drug effect was the ability to maintain an erection until the partner reached orgasm, acknowledging that providing pleasure to the partner is the most important aspect of a fulfilling sexual life. Other sexual expectations of the study participants were also assessed:

• 38.1% of male survey participants indicated that the optimal time from taking the drug to the start of sexual intercourse (penetration) should be approximately 15 minutes;
• 95.9% of men stated that the drug should remain effective for up to 4 hours;
• 71% of men believed that a duration of action longer than 12 hours would be too long.

These three characteristics of drug action are considered the most important in the treatment of ED. Other aspects of efficacy and advantages, such as spontaneity of sexual intercourse and partner satisfaction, are also crucial when selecting the optimal treatment for a specific patient, as they help achieve maximum satisfaction and ensure appropriate drug use.

Sexuality and Quality of Life

Sexuality is one of the most important components of a person’s life and relationships with others, regardless of sexual orientation or age. Recent surveys conducted in Australia have shown that an active sex life is very important to the quality of life of nearly 50% of men aged 75–95 years.

Studies by various authors show that sexual function noticeably deteriorates in many older men. This begins, on average, in the fifth decade of life, and sexual dysfunction worsens with age. With aging, not only does erectile function decline, but other components of male sexuality, such as libido, arousal, ejaculation, and the ability to achieve orgasm, also deteriorate. However, ED has the greatest disruptive effect on partners’ sexual relationships.

Erectile dysfunction and premature ejaculation (PE) are the most common male sexual dysfunctions. A survey of 108,477 men aged 45 years and older, conducted between 2006 and 2010, showed that:

• 39.31% of study participants did not have ED;
• 25.14% had mild (occasional) ED;
• 18.79% had moderate ED (almost always);
• 16.77% had complete ED (always).

Erectile dysfunction also frequently occurs in younger men. According to the latest research, one in four men with erectile dysfunction is younger than 45 years.

Sexual disorders such as ED negatively affect not only a man’s self-esteem, quality of life, and emotional state, but also his sexuality, jeopardizing the quality and stability of relationships with a partner or family. These negative aspects are further exacerbated by the prevailing “impotence stigma” in society.

Nowadays, the range of measures available for treating ED is extensive. The introduction of new drugs—phosphodiesterase-5 inhibitors (PDE5Is)—has made ED treatment significantly more effective in clinical practice. Treatment with PDE5Is has fundamentally improved ED treatment outcomes, positively affecting patients’ self-esteem, self-confidence, quality of life, partner satisfaction, and harmony in relationships.

All modern international and national ED treatment guidelines classify PDE5Is as first-line drugs. Studies show that PDE5Is enable complete sexual intercourse in 60–70% of patients.

Meta-analyses of prospective randomized controlled clinical trials and double-blind studies show that successful ED treatment significantly improves patients’ quality of life, sexual satisfaction, self-esteem, and self-confidence while reducing depression. However, not all men with ED benefit from PDE5I treatment; some patients discontinue PDE5I use because the treatment does not satisfy them or their partners. Reasons for discontinuation vary: the drug may be too expensive or insufficiently effective, or it may fail to meet expectations in terms of partner satisfaction, naturalness of erection, onset or duration of action, safety, and tolerability. Overall, up to 50% of patients discontinue PDE5I use for various reasons within 2 years. Therefore, it is crucial to determine what contributes to such common dissatisfaction with ED treatment, including PDE5Is.

Review of the Study

The average age of men in the study by A. Burri was 46 years: 73% of men had a history of ED, while 47% had never been treated for ED. In the majority of patients (38.46%), ED was mild, while 1.11% had severe ED. The average duration of erectile dysfunction was 49 months. The most common comorbid sexual disorders were PE (22.6%) and decreased libido (18.2%). One in five patients (19.6%) had high blood pressure, while dyslipidemia (17.3%) and diabetes (11.5%) were less common. Among psychosocial disorders, these men most commonly experienced anxiety (16.9%) and depression (12.3%). In sexually healthy men, all of these comorbid conditions were significantly less frequent.

The Importance of Sex and Erection

All men surveyed (both healthy men and those with ED) stated that the most important aspect of sexual intercourse was maintaining an erection until the partner reached orgasm, while the least important was achieving multiple erection episodes after taking a single dose of medication. Men who had never been treated for ED considered all aspects of sexual intercourse less important compared with healthy men and other groups of men with ED. The older the man, the less important it was for him to achieve multiple erection episodes, while maintaining a sufficient erection until the partner reached orgasm (i.e., satisfying the partner) was more important. The sexual priorities of younger men were arranged in the opposite order.

Quality of Sexual Life

The survey showed that the most important components of a fulfilling sexual life for men were: a) the ability to satisfy the partner, b) to experience pleasure, and c) to involve the partner in the process of satisfaction. Less important to men were: a) the possibility of having unplanned sexual intercourse and b) engaging in sex whenever desired.

All aspects related to erectile function were more important to healthy men compared with men with ED, while they were less important to men who had never been treated for ED. For younger men, the possibility of engaging in sex spontaneously and “whenever desired” appeared to be more important.

Ideal Onset of Action

The majority (38.1%) of men surveyed indicated that the ideal onset of action of the drug should be approximately 15 minutes after administration, 27.6% indicated between 15 and 30 minutes, and 34.4% indicated 30–60 minutes. None of the survey participants indicated that an adequate or desirable onset of action would be >60 minutes. According to all men with ED, regardless of the severity of ED, the onset of action of an erection-enhancing drug should be approximately 15 minutes. The reasons for this view varied but were of similar importance: the most important was the ability to engage in sex spontaneously and respond immediately to the partner’s desires, while the least important was avoiding the need to spend a lot of time on preparations.

Ideal Duration of Action

The absolute majority of men with ED (95.91%) stated that the ideal duration of action of the drug should be up to 4 hours, while 47.69% preferred 6–12 hours. Approximately 71% of the men surveyed believed that a duration of action >12 hours would be too long. The assessment of an ideal or excessive duration of action was essentially independent of the severity of ED.

The study showed that for men who had never been treated for ED, sexuality and erectile function were less important compared with those currently or previously treated with ED medications or healthy men. A significant proportion of men with ED prematurely discontinue treatment because it does not meet their expectations: due to insufficient hardness and naturalness of the erection, lack of confidence in the treatment, or an onset and duration of action that differ from what they desire.

To select the optimal ED treatment, it is necessary to understand the individual expectations and desires of patients, as well as which aspect (or aspects) of ED causes them the greatest discomfort. Research shows that for men with ED, as well as for healthy men, the most important aspects are:

• spontaneity of sexual intercourse;
• sudden erection;
• the ability to maintain a sufficient erection until both partners experience orgasm.

Less important for all men is the ability to have multiple sexual acts after a single dose of medication. Therefore, the most important expectation of ED treatment is the ability for both partners to participate in sexual intercourse and for both to be satisfied. When this expectation is met, other aspects of sexual intercourse become important.

Therefore, the most important requirements of modern ED treatment are a rapid onset of action and a reasonable, desired duration of action.

Treatment for erectile dysfunction (ED) that meets these criteria most closely mimics the naturalness and spontaneity of sexual intercourse. Interestingly, according to this survey, sex was less important to men with ED than to their healthy peers, and even less important to men who had never been treated for ED compared with those currently or previously treated. Sexual fulfillment and erection characteristics (penile hardness and the ability to satisfy and please a partner) were less important to men with ED, especially those who had never been treated, compared with healthy men. These differences in evaluation may be partially influenced by the psychoemotional depressive state that is more common in men with ED. Studies show that men with ED undergo psychological and spiritual changes over time: behaviors, expectations, ideas, and values change.

Avanafil Restores Naturalness to Sex

Recent studies show that one of the newest PDE5 inhibitors, avanafil, best meets the expectations of men with ED and their partners. It is characterized by rapid absorption and high receptor selectivity. Avanafil is recommended to be taken approximately 15 minutes before sexual activity.

Avanafil has weaker effects on PDE-1 receptors than sildenafil and on PDE-11 receptors than tadalafil. Avanafil reliably ensured a successful attempt at sexual intercourse within 15 minutes after administration more often than placebo.

In a phase 4 randomized, double-blind, placebo-controlled trial conducted by W. Hellstrom et al., patients aged 18 years or older with ED lasting 6 months or longer and meeting the following criteria participated:

• mild or moderate ED (>50% of attempts at sexual intercourse were unsuccessful due to insufficient duration of erection);
• attempted sexual intercourse at least 4 times per month;
• did not use other erection-enhancing drugs during the study period.

Their erectile function, according to the standardized IIEF scale, was scored between 5 and 25. The study participants (n = 440) were randomly divided into 3 groups: one group received placebo (n = 145), the second group (n = 147) received 100 mg of avanafil, and the third group (n = 148) received 200 mg of avanafil before sexual activity. Metabolic condition (diabetic or non-diabetic) and ED severity according to IIEF (mild ED: 17–25; moderate ED: 11–16; severe ED: 10 or less) were taken into account during randomization.

For 8 weeks, participants, when they and their partners experienced sexual desire, took a dose of the assigned medication and engaged in sexual activity. A condition was that they did not take more than 1 dose of the medication within 24 hours. Food and alcohol consumption was not restricted. Participants were advised to engage in sexual activity approximately 15 minutes after taking the medication. Participants had to answer two questions:

• Were you able to insert the penis into your partner’s vagina?
• Was the duration of the erection sufficient to successfully complete sexual intercourse?

The sexual function of the study participants was evaluated at the beginning of the study and at all subsequent visits based on the patient’s diary and IIEF. The primary endpoint was a successful attempt at sexual intercourse approximately 15 minutes after taking the medication, with sufficient penile erection for vaginal penetration.

Results

The study showed that both doses of avanafil were significantly more effective than placebo. In the groups of patients taking avanafil (100 or 200 mg), a significantly higher proportion of patients successfully completed at least one sexual intercourse approximately 15 minutes after taking the medication compared with the placebo group. The advantage of avanafil doses of 100 and 200 mg in terms of the proportion of successful sexual acts, compared with placebo, was evident 12 and 10 minutes after the doses were taken, respectively. Avanafil (100 and 200 mg doses) significantly outperformed placebo in other effects:

• over 8 weeks, it increased the proportion of successful attempts at sexual intercourse with sufficient erection, regardless of the start time of the attempt;
• it increased successful attempts at vaginal penetration, regardless of the start time of the attempt;
• it significantly improved erectile function according to the standardized IIEF scale 4 weeks after the start of the study and at the end of the study;
• patients taking avanafil (100 or 200 mg) transitioned from the moderate to the mild category in terms of erectile function during the study period, while no such shift was observed in the placebo group.

Over the 8 weeks of the study, 48.7% of all attempts at sexual intercourse in the groups of patients taking 200 mg of avanafil ended successfully, compared with 27.7% in the placebo group (difference 21.0%). The proportion of successful attempts within 15 minutes of taking the dose in these patient groups was 28.2% and 13.8%, respectively (difference 14.4%). Most men for whom avanafil was effective experienced significant efficacy of the drug within the first 15 minutes after administration.

Compared with placebo, a significantly higher frequency of one or more successful attempts within 15 minutes was observed in groups of patients who took 100 or 200 mg of avanafil: 40.4% vs. 57.6% and 59.7%, respectively.

The longest duration of penile rigidity (60% or greater) when taking avanafil (50, 100, or 200 mg) was recorded 20–40 minutes after drug intake, while with sildenafil (50 mg), it was recorded 60–80 or 100–120 minutes after sildenafil intake.

When evaluating primary and secondary outcomes, no significant differences were found between the groups of patients taking 100 or 200 mg of avanafil.

Differences in Phosphodiesterase Inhibitor Molecules

Phosphodiesterase-5 inhibitors differ in their activity, safety, and tolerability profiles, as well as in the onset of action, which depends on the drug’s pharmacokinetic properties. PDE5 inhibitors differ in plasma elimination half-life and duration of action, with vardenafil and sildenafil lasting 8–12 hours and tadalafil lasting 24–36 hours. Three phase 2 studies showed that the effect of avanafil lasts for more than 6 hours, with the frequency of successful sexual acts after taking avanafil ranging from 59% to 83%.

Table 1. Assessment of Treatment Effectiveness After ~15 Minutes of Use

Treatment	According to Treatment Effect	Adequate Duration of Effect	Prolonged Effect	Excessively Prolonged Effect
CTG	15.44	38.59	43.96	2.01
PTG	21.55	36.36	40.74	1.35
NG	24.76	31.38	42.53	1.32

Assessment by men currently undergoing treatment (CTG; n = 298), men previously treated (PTG; n = 297), and men not treated for ED (NG; n = 529).

Table 2. Duration of the Effect Assessed by Patients as “Too Long”

Duration	Patients (%)
<4 hours	4.18%
4–6 hours	21.8%
6–12 hours	49.38%
>12 hours	71%

In the USA, 4 PDE5Is are registered. When taken, they are absorbed on average within 2 hours. The maximum plasma concentration of avanafil is reached 30–45 minutes after administration.

The results of this study are essentially consistent with data from three previous studies on the effectiveness of avanafil in improving erectile function. When evaluating only patients attempting sexual intercourse within 15 minutes after taking avanafil, avanafil was significantly superior to placebo: the frequency of successful attempts to engage in sexual intercourse within 15 minutes in the group of patients taking avanafil was 64–71% vs. 27% in the placebo group. According to another study, the frequency of successful attempts in the avanafil 100 mg group was 62%, in the avanafil 200 mg group 36%, vs. 26% in the placebo group (Table 3). In the group of patients after prostatectomy, the frequency of successful attempts was 36.4% (in the 100 and 200 mg groups) vs. 4.5% in the placebo group. Patients in all groups were not restricted in their food and alcohol consumption.

Table 3. Pharmacokinetic Parameters of Phosphodiesterase-5 Inhibitors

Adverse Effects

Patients in all three groups most commonly experienced the following adverse effects, although they were rare:

• headache – 3.7%;
• upper respiratory tract infection – 3.2%;
• nasal congestion – 1.6%.

The frequency of adverse effects of avanafil was similar to that of other PDE5 inhibitors, but back pain and visual side effects were less common when taking avanafil.

Conclusions

• Compared with placebo, avanafil significantly increased successful attempts to initiate and complete sexual intercourse with insufficient erection within 15 minutes of administration.
• This advantage of avanafil over placebo was evident as early as 10 minutes after avanafil administration.
• With avanafil, an erection sufficient for sexual intercourse is achieved on average within 15 minutes of administration, making avanafil a suitable “on-demand” treatment for ED.

Source: Pharmacy and Time