Treating Erectile Dysfunction and Central Neurological Diseases with Oral Phosphodiesterase Type 5 Inhibitors. Review of the Literature

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REVIEW Treating Erectile Dysfunction and Central Neurological Diseases with Oral Phosphodiesterase Type 5 Inhibitors. Review of the Literature jsm_2615

970..985

Giuseppe Lombardi, MD, Federico Nelli, MD, Maria Celso, MD, Marco Mencarini, MD, and Giulio Del Popolo, MD Neuro-urology Department, University of Florence, Florence, Italy DOI: 10.1111/j.1743-6109.2011.02615.x

ABSTRACT

Introduction. Erectile dysfunction (ED) is reported in a high percentage of patients with central neurological disorders (CND). Aim. An up-to-date review on oral phosphodiesterase 5 inhibitors (PDE5): sildenafil, tadalafil, and vardenafil for individuals with CND and ED. Main Outcome Measures. Various questionnaires on ED, such as the International Index of Erectile Function composed of 15 questions. Methods. Internationally published clinical studies evaluating the efficacy and safety of PDE5 on subjects with CND and ED were selected. Results. Overall, 28 articles on PDE5 used to treat patients with CND and ED were included. With each of the three PDE5 compared to placebo or erectile baseline, literature reported significant statistical improvement (P < 0.01; P < 0.05) only in patients with spinal cord injury (SCI). PDE5 efficacy was documented for SCI patients up to 10 years. The most frequent predicable factor for PDE5 success was the presence of upper motoneuron lesion. Each of the three clinical sildenafil studies documented statistically significant improvement on erectile function in Parkinson’s patients (P < 0.01; P < 0.05). Two studies reported discordant results about sildenafil’s effectiveness on multiple sclerosis (MS) patients; one on tadalafil showed significant statistical efficacy on erection versus baseline (P < 0.01; P < 0.05). The only spina bifida article determined that sildenafil remarkably improved erectile function. Overall, drawbacks were mostly slight-moderate, except in subjects with multiple system atrophy where sildenafil caused severe hypotension. Conclusions. PDE5 represent first line ED therapy only for SCI patients, though treatment results through meta-analysis were not possible. Encouraging results are reported for Parkinson’s and MS patients. PDE5 use for other CND patients is limited for various reasons, such as ED and concomitant libido impairment caused by depression and/or sexual endocrinology dysfunctions, and because PDE5 may cause a worsening of neurological illness. Medical centers staffed by health professionals able to counsel patients on the possible use of PDE5 are needed. Lombardi G, Nelli F, Celso M, Mencarini M, and Del Popolo G. Treating erectile dysfunction and central neurological diseases with oral phosphodiesterase type 5 inhibitors. Review of the literature. J Sex Med 2012;9:970–985. Key Words. Erectile Dysfunction; PDE5 Inhibitors; Central Neurogenic Diseases; Spinal Cord Injury; Multiple Sclerosis; Parkinson’s Disease

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© 2012 International Society for Sexual Medicine

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Treating Neurogenic ED with PDE5 Introduction

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eurogenic erectile dysfunction may be defined as the inability to obtain and maintain a penile erection due to neurological impairment, which may have its origin in the central nervous system (spinal and/or sopraspinal network) or in the peripheral neural pathways. There are three different segments in the spinal cord correlated to erectile function: the sympathetic (level T10-L2) responsible for psychogenic erection, parasympathetic (level S2-S4) fundamental for reflexogenic erection, and somatic (S2-S4) situated in the Onuf’s nucleus where the nerves originate and which innervate the ischiocavernous and bulbocavernous muscles needed for penile sensation and the rigid phase of erection [1]. In the last decade, positron emission tomography scanners and functional magnetic resonance imaging have been used to evaluate the modification of brain activity during sexual excitement and penile erection [2–5]. Literature reports that sustained erection is correlated to increased activity in the secondary somatosensory and temporal cortex, in the inferior frontal gyrus, the insula, the anterior cingulatem, and the medial nucleo of the amygdala [6]. Erection is also accompanied by elevated activity in the hypothalamus, mainly in the paraventricular nucleo and the medial preoptic area [1–6]. Central nervous diseases (CND), linked to erectile dysfunction (ED), may be due not only to the singular damage of a specific central area (such as the temporal lobe, substantia nigra) involved in erectile function, but also because this injury may lead to a communication block between different central structures and/or afferent and efferent pathways [1,6,7]. These structures and healthy sexuality are also influenced by steroid hormones, neurochemical regulations, neurotransmitters, the monoamin system, opioids, gamma-aminobutyric acid (GABA), and neuroendocrine hormones (oxytocin, prolactin, gonadotropon realizing hormone) [1,6,7]. Furthermore, the incidence and severity of ED in CND depends upon pharmacological treatments for their neurological illness (such as for epilepsy) and the frequent use of antidepressants in the CND population [7–9]. Moreover, concomitant risk factors for ED, such as diabetes mellitus, hypertension, smoking, dyslipidemia, and coronary heart disease, are also considerations [10–13]. Though the prevalence range of ED for each CND reported in the literature is wide, a minimum of approximately 40% of subjects with CND has ED. A high prevalence of ED is reported in about 80% of spinal cord injury (SCI)

patients while the prevalence varies from 50% to 75% for multiple sclerosis (MS) patients [14–16]. A recent article by Bener et al. demonstrates that 48.3% of post-stroke patients have some degree of ED [10]. A similar prevalence of around 50% is documented in a sample of epileptic subjects, and in sufferers of Parkinson’s disease (PD) [11,17,18]. Actually, for about 40% of patients affected by multiple system atrophy (MSA), ED presents as the first symptom of the neurological disease [12,19]. At presentation, urogenital symptoms are common in patients with probable MSA. The predominance of ED in early MSA could be of diagnostic and therapeutic value to specialists dealing with lower urinary tract and sexual dysfunction [12]. Currently, three oral agents approved for use by the U.S. Food and Drug Administration can treat ED. These are sildenafil citrate (Viagra, Pfizer, New York, NY, USA), vardenafil hydrochloride (Levitra, Bayer Pharmaceutical Company, Leverkusen, Germany), and tadalafil (Cialis, Eli Lilly Pharmaceutical Company, Indianapolis, IN, USA). The aim of this review is to evaluate the impact of phosphodiesterase type 5 inhibitors (PDE5) on all categories of CND sufferers with ED. At this time, the wider literature lacks any similar reviews that deal with ED incidents in patients with CND and the PDE5 treatment of ED. As a result, this review may be useful for all professional operators in contact with these neurological populations, especially health care professionals when making their clinical decisions to prescribe opportune diagnostic investigation or therapies for ED including PDE5. Materials and Methods

Data Sources All authors searched MEDLINE through OVID and PubMed, using the search phrase of each CND combined with “ED,” “sexual dysfunction,” and “sexual disorders” with “PDE5s” (i.e., spinal cord injury erectile dysfunction and PDE5), and each PDE5 combined with each CND category. The last search was conducted in June 2011. We hand-searched the reference list of all returned articles and included studies and any relevant review articles. Study Selection For the purposes of this study, the authors aimed to include all clinical studies reporting efficacy/ safety on treatments of at least 4 weeks with PDE5 J Sex Med 2012;9:970–985

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in human patients with CND suffering from ED. Studies not published as full-text articles, single case reports, articles reporting the outcome of a single dose of PDE5 on erectile function, or exclusively reporting the draw-backs of a single dose of the PDE5 were excluded. Moreover, opinion articles, and studies reporting the effect of PDE5 on subjects with peripheral neuropathy or surgical disruption of the genital autonomic nerve supply, were not included in our study. No language restrictions were imposed. Hard copies of all articles were obtained and read in full. All full articles were read by two independent reviewers (LG, NF), and data from the articles were extracted according to pre-defined criteria. Data collected from each study included the study design, participants, interventions/exposures, outcome measures, and results.

Table 1

Quality Assessment The two independent reviewers (LG, NF) conducted a further clinical study selection to evaluate the reliability of these studies. Discrepancies were resolved through discussion and, if needed, by seeking the opinion of a third reviewer (DG). Efficacy Assessment on Erectile Function Various outcome measures for evaluating the efficacy on erectile function were used. These may be divided into three broad categories: general assessment of global efficacy, patient-recorded event log of sexual activity, and more specific assessments of erectile function. The most commonly used General Efficacy Question (GEQ) were numbers 1 and 2 (GEQ1 and GEQ2) (see Table 1). For the patient-recorded event log of sexual activity, subjects answered a series of questions after each

Reports the main outcome measures for evaluating erectile function

Outcome measures for evaluating the efficacy of oral phosphodiesterase type 5 inhibitors for erectile dysfunction Global efficacy questions (GEQ): Yes/No responses Has treatment improved your erections? (GEQ1) Did the treatment improve your ability to engage in sexual activity? (GEQ2) Sexual Encounter Profile (SEP): a 5-item questionnaire which is completed after each sexual intercourse attempt and contains the following questions: Yes/No responses Were you able to achieve at least some erection (some enlargement of the penis)? (SEP1); Were you able to insert your penis into your partner’s vagina? (SEP2); Did your erection last long enough for you to have successful intercourse? (SEP3); Were you satisfied with the hardness of your erection? (SEP4); Were you satisfied overall with this sexual experience? (SEP5) Percentage of successful intercourse attempts: Number of successful attempts divided by the number of total attempts. Percentage of successful stimulation: Number of successful stimulations divided by the number of total attempts. Duration of erection (minutes) International Index of Erectile Function composed of 15 questions (IIEF15) Erectile function: (Questions 1–5, 15 or Questions 3, 4) 1) How often were you able to get an erection during sexual activity? 2) When you had erections with sexual stimulation, how often were your erections hard enough for penetration? 3) When you attempted sexual intercourse, how often were you able to penetrate (enter) your partner? 4) During sexual intercourse, how often were you able to maintain your erection after you had penetrated (entered) your partner? 5) During sexual intercourse, how difficult was it to maintain your erection to completion of intercourse? 15) How do you rate your confidence that you can get and keep your erection? Sexual satisfaction (Questions 6–8) 6) How many times have you attempted sexual intercourse? 7) When you attempted sexual intercourse how often was it satisfactory for you? 8) How much have you enjoyed sexual intercourse? Orgasmic function (Questions 9 and 10) 9) When you had sexual stimulation or intercourse how often did you ejaculate? 10) When you had sexual stimulation or intercourse how often did you have the feeling of orgasm or climax (with or without ejaculation)? Sexual Desire (Questions 11 and 12) 11) How often have you felt sexual desire? 12) Over the past 4 weeks, how would you rate your level of sexual desire? Overall satisfaction (13 and 14) 13) How satisfied have you been with you overall sex life? 14) How satisfied have you been with your sexual relationship with your partner? Erection scale (range1 = poor, 10 excellent) Sexual Health Inventory for Men (SHIM) questionnaire also called International Index of Erectile Function composed of 5 questions = IIEF(5) Each of the 5 questions has 5 possible responses with a score ranging from 1(lowest) to 5 (highest). Presence of erectile dysfunction if the total score was 21 or less. 1) How do you rate your confidence that you could keep an erection? 2) When you had erections with sexual stimulation, how often were your erections hard enough for penetration (entering your partner)? 3) During sexual intercourse, how often were you able to maintain your erection after you had penetrated (entered) your partner? 4) During sexual intercourse, how difficult was it to maintain your erection to completion of intercourse? 5) When you attempted sexual intercourse, how often was it satisfactory for you?

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Figure 1 Flow chart of clinical study selection criteria.

attempt at sexual intercourse. The most frequently utilized tool for the specific assessment of erectile function is the International Index of Erectile Function composed of 15 questions (IIEF15) [20]. This is a 15-item, self-administered questionnaire that includes questions designed to explore five domains of sexual function (erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction). Particular emphasis was placed on two specific questions from this index that explore erectile function: question 3 (frequency of penetration) and question 4 (maintenance of erection after penetration). For each question, a five-point scale was used with a higher score equaling a better response. Per definition, patients with an IIEF(15) erectile function domain score < 26 suffer from various degrees of erectile dysfunction. Table 1 includes the main outcome measures used by the various authors to evaluate erectile function. Results

General Results The literature searchers identified 32 potentially relevant articles of which 28 were included in this review. Two clinical studies were excluded because a single dose of sildenafil 50 mg was used once to see the effect on ED, and the other simply to deter-

mine the side effects of the drug on SCI patients with ED [21,22]. Regarding the reliability of the studies, one article was excluded because the authors did not report the dosage of sildenafil used for treating individuals with SCI and ED, and there was a possible bias based on the fact that 10 out of the 16 were concomitantly treating their ED with intracavernous alprostadil injection [23]. Another article focusing on patients with PD was excluded due to lack of credibility. It is unlikely that of all the PD patients assessed for eligibility by this author (N = 284), only 34 patients (11.9%) were excluded because of co-morbidities for ED [24]. In reality, depression alone affects 30–40% of all Parkinson patients [25]. A flow chart of the clinical studies selection process is reported in Figure 1. Only patients with SCI, PD, MS, MSA, and spina bifida (SB) were included in this review (see Figure 2A) because no data were found on the efficacy and safety of PDE5 for head trauma patients, and those suffering from ED with acquired brain pathology, epilepsy, stroke, and Alzheimer’s disease. SCI patients with ED comprised the largest group using PDE5 (see Figure 2B). Twenty-one articles focused on SCI patients, where all three PDE5 were explored. Moreover, two review studies analyzed the use of PDE5 for J Sex Med 2012;9:970–985

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Figure 2 Articles on each PDE5 for erectile dysfunction according to neurological diseases. Total number of patients included for each PDE5 according to neurological illness. PDE5 = Phosphodiesterase type 5 inhibitors; SCI = Spinal Cord Injury; PD = Parkinson’s Disease; MS = Multiple Sclerosis; MSA = Multiple System Atrophy; SB = Spina Bifida.

ED, again only with regard to subjects with SCI [26,27]. A meta-analysis of the data examining the efficacy and safety of each PDE5 was not possible for any of the neurological categories due to the following reasons: small number of studies available for review, the different study designs, the large and diverse outcome measures used by various authors for evaluating erectile function, heterogeneous study population, and missing or incomplete information needed to perform this statistical procedure. Spinal Cord Injured Patients

Study Population The patients selected were all men 18 or older. Mean age was less than 40 years, except in one clinical trial where the mean age was 41.5 years J Sex Med 2012;9:970–985

(range 20–71) [28]. More than 80% of the patients reported trauma as the etiology of SCI. Injury levels from cervical (C1-C8) to lumbosacral (L1S5) were included, except for one clinical study including only SCI with lesions below dorsal T5 and with a residual reflexive erection minimum of 2 according to a five-point qualitative scale for the subjective erectile assessment score (EAS) varying from 0 = No response, up to 4 = Completely hard [29]. Instead, Ergin et al. selected patients with a residual reflexogenic erection of a minimum of 1 [30]. The American Spinal Injury Association Impairment Scale (AIS) was used to classify the subjects according to the their impairment grade: complete (AIS A) vs. incomplete (AIS B–D) [31]. AIS A varied from 18% to 83% [32,33]. In the other clinical studies with no residual erection, psychogenic and reflexogenic (0 score using EAS) were included, though the percentage was not

Treating Neurogenic ED with PDE5 always reported. Percentages varied from 5% to 23% [34,35]. The length of time from injury to initiation of therapy varied from less than 1 year (6–12 months) to more than 15 years [36,37].

Efficacy of PDE5 on Erectile Function and Their Impact on Quality of Life Table 2 shows the study design and main results of 10 out of the 11 clinical studies that exclusively used sildenafil to treat SCI patients with ED. In the one clinical study not represented in the table, authors reported that 36 out of 40 patients claimed to have erections sufficient for intercourse after 50 or 100 mg of sildenafil, though no statistical analysis was given [34]. In five out of six clinical studies adopting the IIEF(15) to detect sexual function, significant statistical improvement using the oral drug was reached both for erectile function as well as at least one other domain, except for the Gans et al. clinical study where significant statistical improvement was reported for single questions of the IIEF(15) [30,35,38,39]. Sánchez Ramos et al. actually demonstrated statistically significant enhancement for each of the five IIEF(15) domains [40]. However, only one author who used the IIEF(15) reported the percentage of patients achieving a minimum score of 26 in the erectile domain [39]. Moreover, the same author showed that chronic sildenafil use (median 10-year followup) did not result in treatment resistance; instead, therapeutic efficacy was maintained [39] (see Table 2). Giuliano et al. showed that remarkable clinical improvement on erectile function was supported by statistical analysis, using all three categories of erectile outcome measures for erectile function [41]. Hutling et al., using the same sample of patients as Giuliano et al., highlighted that sildenafil’s positive effect on erection led to statistically significant improvement on quality of life (QoL). The Medical Outcomes Survey Short Form comprised of 12 questions (MOS-SF12) and the Psychological General Well-Being (PGWB) questionnaire were utilized to measure QoL. Statistically significant improvement was demonstrated in the SF-12 mental health component summary score, consisting of five questions, and in the summary scores of depression (four questions), positive well-being (two questions), and anxiety domains (five questions) of the PGWB [42]. Statistically significant improvement on treatment satisfaction for the couple using sildenafil was the focus of the Ergin et al. study (see Table 2). The focus of the Ergin et al. study

975 was the couples’ treatment satisfaction using sildenafil and measured by the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire: 11 items for men and 5 for their partners. All items are scored from 0 (no satisfaction or dissatisfaction) to 4 (high satisfaction). The mean satisfaction score is calculated and multiplied by 25 so that EDITS scores may range from a low of 0 (extremely low treatment satisfaction) to a high of 100 (extremely high satisfaction) [30]. Authors of all three tadalafil clinical studies demonstrated that remarkable clinical benefits on erectile function were reached, compared to baseline erection or placebo [28,43,44]. The clinical improvement on erection was significantly supported by statistical analysis (see Table 3). Two out of 3 clinical studies reported the percentage of patients obtaining a minimum score of 26 for the IIEF(15) erectile function domain [43,44]. As for the three clinical studies on vardenafil, only Kimoto et al. did not provide a statistical analysis of clinical findings [45–47]. The other two clinical trials using the same patient population showed that vardenafil significantly and statistically favors both erectile function and anterograde ejaculation (see Table 3). Soler et al. selected three groups of homogenous SCI patients and each group was treated with one of the PDE5. Only the sildenafil group showed a striking statistical improvement in orgasm measured by questions 9 and 10 of the IIEF(15) [33] (Table 4). Del Popolo et al. reported via SEP2 and SEP3 that patients who used both a fixed dose of tadalafil 10 mg and sildenafil 50 mg, found tadalafil to be superior in aiding satisfactory sexual intercourse 12–24 hours post-dosing [34] (see Table 4).

Predictable Parameters for the Efficacy of PDE5 Drugs A number of authors conducted a sub-analysis of data on the efficacy of the PDE5 treatments, evaluating various parameters, qualitative or quantitative, that might predict the success of these therapies on erectile function. The upper motoneuron lesion referring to injuries above the level of the sacral spinal segments (cervical and dorsal levels up to T12) is the most frequent favorable parameter, both for the success of these oral drugs and their efficacy at a low dosage [33,37,39,41,44]. The preservation of residual erection with a score above 2 on the EAS, and incomplete lesions (AIS A versus incomplete AIS B-D) represented other positive foreseeable factors to consider in that J Sex Med 2012;9:970–985

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R-DB-PC PC-M-R-DB—2 way CO

P-OL-CS Case series

R-DB-PC

Case series

Case series 1st Phase

2nd Phase

Case series

R-DB-PC 2-way CO

Derry et al. [26] Ergin et al. [30]

Moemen et al. [32] Schmid et al. [35]

Khorrami et al. [37]

Gans et al. [38]

Lombardi et al. [39]

Lombardi et al. [39]

Sánchez Ramos et al. [40]

Giuliano et al. [41]

178 (25–100 mg)

170 (50–100 mg)

178

NA

NA

113 (50–100)

34 (50–100)

NA

46

NA NA

14 50

Placebo

17 (25–100)

59 (50–100 mg)

60 (25–100 mg) 41 (25–100 mg)

13 (50 mg) 50 (50–100 mg)

Number of patients (dosage of drugs)

6 weeks

N.R.

10 years

4–8 weeks

Mean 5.3 months

6 months

1–2 months 3 months

33 days 16 weeks

Duration of the treatment Results

*GEQ (1) *% SSS ; **% SIA IIEF(15): *EF (1,5–15) only for the 20 patients with incomplete lesions. **OS 13–14); **EDITS **IIEF(5) IIEF(15): *EF (1,5–15); *SS (6–8); *OS (13–14) IIEF(5): *Only for patients with UMNL (37/45 patients using sildenafil versus 7/27 treated with placebo) IIEF(15): *For each of the following questions: 2,4,5,7,15 IIEF(15): 75 out of 113 patients reached a minimum score of 26 with EF (1,5, 15) and only those entered the second phase of the study IIEF(15): *EF (1,5, 15); *SS (6–8); *OS (13,14) IIEF(15): **All 5 domains **EF (3–4) **GEQ(1) and GEQ(2) **% SIA IIEF(15): **EF (3,4); **OS (13–14)

*P < 0.05; **P < 0.01 M = multicenter; R = randomized; DB = double-blind; B = blind; P = placebo; PC = placebo- controlled; OL = open label; PG = parallel group; CO = crossover; CS = comparative study; NA = not applicable; GEQ 1 = global efficacy question number 1; GEQ2 = global efficacy question number 2; % SIA = percentage of successful intercourse attempts; % SSS = percentage of successful sexual stimulation; UMNL = upper motoneuron lesion; IIEF(5) = international Index of erectile function composed of 5 questions; IIEF(15) = international Index of erectile function composed of 15 questions; EF (3,4) = erectile function using questions3 and 4; EF (1,5–15) = erectile function domain using questions 1 to 5 and 15); SS (6–8) = intercourse sexual satisfaction domain using questions 6 to 8; OF (9,10) = orgasmic function using questions 9 and 10; OS (13–14) = overall satisfaction domain using questions 13 and 14; EDITS = erectile dysfunction inventory of treatment satisfaction questionnaire

Study design

Summarizes the study design and results for spinal cord injured patients with erectile dysfunction using sildenafil exclusively

SILDENAFIL Authors

Table 2

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Treating Neurogenic ED with PDE5 Table 3

Summarizes the study design and the main results of clinical studies using tadalafil and vardenafil

Tadalafil Authors

Study design

Morgentaler A M-OL et al. [28]

Number of Duration of patients (dosage) Placebo treatment 49 (10–20 mg)

NA

Giuliano et al. [43]

M-R-DB-PC-FD-PG 142 (10–20 mg)

44

Lombardi et al. [44]

First phase

103 (10–20 mg)

NA

Lombardi et al. [44]

Second phase

74 (10–20 mg)

NA

Vardenafil Authors

Results

12 weeks

**SEP (1–5) IIEF(15): **EF (1–5, 15); **SS (6–8) **OS 13–14) 12 weeks **GEQ (1) and GEQ(2); **SEP(2) IIEF(15): **EF (1–5, 15); **EJ (9) **EF (1,5,15) ⱖ26 (54% of the patients using tadalafil versus 11.6% with placebo) 12 weeks IIEF(15): EF (1–5, 15) of IIEF(15) ⱖ26: (38 pts using 10 mg and 36 with 20 mg entered in phase 2 of the study) About 3 years **SEP(2) and SEP(3) IIEF(15): **EF (1–5, 15); **SS (6–8); **OS (13–14)

Study design

N° pts (dosage)

Placebo

Duration of treatment

Giuliano et al. [46]

M-DB-PC, PG

207 (5–20 mg)

211

12 weeks

Giuliano et al. [46]

M-DB, PC- PG

207 (5–20 mg)

211

12 weeks

Results **SEP(2) and SEP(3) IIEF(15): **EF (1,5, 15); **EF (1,5, 15) ⱖ26 (52% of patients using vardenafil compared to 9% with placebo) IIEF(15): **EJ (9); **OF(10)

P < 0.05; **P < 0.01 M = multicenter; R = randomized; DB = double-blind; PC = placebo-controlled; FD = flexible dose; OL = open label; PG = parallel group; CS = comparative study; P = prospective; NR = not reported; NA = not applicable, GEQ 1 = global efficacy question number 1; GEQ 2 = global efficacy question number 2; SEP2 = sexual encounter profile question 2; SEP3 = sexual encounter profile question 3; SEP(1–5) = sexual encounter profile questions 1 to 5; IIEF(15) = international index of erectile function composed of 15 questions; EF (1,5–15) = erectile function domain using questions 1 to 5 and 15; EJ (9) = ejaculation frequency using question 9; SS (6–8) = sexual satisfaction domain using questions 6 to 8); OF(10) = orgasmic function using question 10; OS(13–14) = overall satisfaction domain using questions 13 and 14; n° = number; pts = patients

significant statistical support (P < 0.05 or P < 0.01) was documented on the efficacy of the oral therapies [30,39,40,44].

Adverse Events and Analysis of Safety Typically, the adverse effects reported in patients taking the oral drugs were mild to moderate and transient; in fact, these effects were usually attenuated with continuing doses. No author cited autonomic dysreflexia. Autonomic dysreflexia is a syndrome affecting persons with spinal cord injuries at or above the level of T6 by possible hypertension, bradycardia, severe headaches, pallor below and flushing above the cord lesions, and convulsions. It is the result of impaired function of the autonomic nervous system caused by simultaneous sympathetic and parasympathetic activity, such as may occur with bowel or bladder distension. Priaprism or deaths correlated with the use of these therapies were not documented. The most frequent side effect caused by PDE5 is headache. Moemen et al. reported that during the first week of the 4-week treatment with

sildenafil 50 mg 41.7% (25 out of 60 patients) suffered from headache, while only 10% (6 out of 60 subjects) experienced headache during the last week of treatment [32]. Lombardi et al. documented a higher percentage (15%) of headache using tadalafil (11 out of 74 patients), while Giuliano et al. reported that 15% (15 out of 200) of individuals with SCI treated with vardenafil suffered from headache [44,46]. The second most frequent drawback for all PDE5 was flushing (maximum 10% using sildenafil), reported in 4 out of 40 patients [30]. Six out of 200 patients (3%) had flushing with vardenafil, 5% (4 out of 74) with tadalafil [44,46]. Ten patients left the sildenafil clinical studies due to drawbacks correlated to treatment. Of those, Giuliano et al. reported that three subjects discontinued because of headache and conjunctivitis, one headache and nausea, and one headache, flushing and dyspepsia [41]. One patient left the Gans et al. clinical study due to hypotension; Sanchez et al. reported unbearable abdominal pain prompting one discontinuation, and Lombardi et al. reported that headache and J Sex Med 2012;9:970–985

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*P < 0.05; **P < 0.01 PDE5 = phosphodiesterase 5 type inhibitors; O = open; BE = before, AS = after study R = randomized; B = blind; PC; CO=crossover; SEP2 = sexual encounter profile question 2; SEP3 = sexual encounter profile question 3; IIEF(15) = international index of erectile function composed of 15 questions; EF (1,5–15) = erectile function domain using questions 1 to 5 and 15; SS (6–8) = sexual satisfaction domain using questions 6 to 8); OF(9,10) = orgasmic function using question 9 and 10;; n° = number; pts = patients

O-BE-AS Soler et al. [33]

30 (50 mg)

12 weeks / 30 (10 mg)

IIEF(15): sildenafil, tadalafil and vardenafil *EF (1–5, 15); *SS(6–8); *OS 13–14) Only sildenafil *OF (questions 9,10) **Efficacy of tadalafil versus sildenafil evaluated through SEP(2 and 3) at 12–24 hours post dosing Mean 9.7 months Second phase 12 (10–20 mg)

NR 7 days in the clinic 66 (10–20 mg) O-BE-AS Soler et al. [33]

First phase 120 (50–100 mg) Second phase 57 (50–100 mg)

First phase 54 (10–20 mg) Second phase 21 (10–20 mg)

Results Duration of treatments N° pts (dosage Vardenafil) N° pts (dosage Tadalafil) N° pts (dosage Sildenafil) Study design Two or more PDE5 Study

Table 4

Summarizes the two clinical studies using two or more PDE5 in spinal cord injured patients suffering from erectile dysfunction

Lombardi et al. flushing caused two subjects to abandon the study, while visual disturbances prompted another to leave [38–40]. Two patients dropped out of the tadalafil clinical study, one due to headache and facial flushing, and one due to muscle pain [44]. In the end, adverse events correlated to the use of vardenafil caused four of Giuliano’s et al. patients to leave the clinical trial: two because of hypotension, one back pain, and one hypotension, back pain, and chest pain [46]. Parkinson’s Disease

Study Population The median age was less than 60 years for all three topics, with a maximum of 72.8 years [48]. Hussain et al. did not report the treatment for PD at the start of the study [49]. In the other two studies, all patients used L dopa for treating PD, except for one patient in the Zesiewicz study [48,50]. The severity of PD was measured according to the modified Hoehn–Yahr stages by one author, and their PD stage was between 1 and 3 [48]. The modified Hoehn and Yahr scale is a commonly used system for describing how the symptoms of Parkinson’s disease progress. The scale varies from 0: no sign of disease, to stage 5: needing a wheelchair or bedridden unless assisted [51]. Mean duration of ED was reported by all three authors, with a maximum time of 5.7 years [49]. Raffaele et al. included all the PD patients suffering from depression according to the Diagnostic and Statistical Manual of Mental Disorders 4th Edition Revised (DSM-IV). Moreover, the authors reported that in 67% of the cases, the etiology of ED was vascular [50]. One author excluded PD patients with depression from their study [48]. Efficacy of Therapy on Erectile Function and Depressive Symptoms For each of the three clinical studies, remarkable clinical improvement on erectile function was shown using various outcome measures for erectile function. Significant statistical analysis of the results was reached (minimum P < 0.05) (see Table 5). Raffaele et al. demonstrated that the improvement in erectile function led to concomitant clinical benefits for Parkinson’s depressive symptoms. This improvement is supported by statistical analysis (P < 0.05) comparing the mean scores pre- and post-treatment of the Unified Parkinson’s Disease Rating Scale (UPDRS) and the Beck Depression Inventory (BDI) scale [50]. The

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Treating Neurogenic ED with PDE5 Table 5

Reports the study design and main results for Parkinson’s patients with erectile dysfunction using sildenafil

Authors

Zesiewicz et al. [48]

Hussain et al. [49]

Raffaele et al. [50]

Study design Duration of study Drugs and dosages Number of patients GEQ1 IIEF(15): EF (3–4) IIEF(15): EF (1,5,15) IIEF(15): SS (6–8) IIEF(15) OF (9–10) IIEF(15) DES (11–12) IIEF(15): OS (13,14) Total SHIM score* Ability to achieve erection** Ability to maintain erection** Satisfaction with sexual desire** Ability to reach orgasm** Overall sexual satisfaction** LSCL(8) (Only sex life question)

OL-FD 2 months Sildenafil (50–100 mg) 10

R-DB-PC-CS 6 months Sildenafil (25–100 mg) 12

OL-FixD 4 months Sildenafil (50 mg) 33 P < 0.01 P < 0.01

P < 0.05

P < 0.01 P < 0.01 P < 0.01 P < 0.01 P < 0.01 P = 0.01 P = 0.02 P = 0.03 P = 0.04 P = 0.04 P = 0.03 P = 0.007,3

*Score between 5–25 with lower number indicating better function; **All items are on a five-point scale (1–5) with lower number indicating better function R = randomized, DB = double blind; PC = placebo controlled; CS = comparative study; FD = flexible doses; OL = open label; FixD = fixed dose; SHIM = sexual health inventory for men questionnaire; GEQ 1 = global efficacy question number 1; LSCL(8) = life satisfaction check list composed of 8 questions; IIEF(15) = international index of erectile function composed of 15 questions; EF(3–4) = erectile function evaluation using question 3 and 4; EF (1,5–15) = erectile function domain using questions 1 to 5 and 15; SS (6–8) = sexual satisfaction domain using questions 6 to 8; OF (9,10) = orgasmic function using questions 9 and 10; DES(11,12) = desire domain using questions 12 and 13; OS (13–14) = overall satisfaction domain using questions 13 and 14

UPDRS is a questionnaire comprised of 42 questions with multiple answers for each question, generally 5, with the lowest score (0) indicating absence of any limitation due to the neurological disease. The questionnaire is divided into 4 domains: mentation, behavior, and mood (4 questions), activities of daily living (13 questions), motor examination (13 questions) and therapy complications (11 questions). The Beck Depression Inventory (BDI, BDI-II) is a 21-question multiple-choice self report inventory measuring the severity of depression. Each answer is scored on a scale value of 0 to 3. Higher total scores indicate more severe depressive symptoms. Zesiewicz did not reveal significant statistical variation after treatment on UPDRS and BDI compared to baseline [48].

Side Effects of the PDE5 Treatment emergent adverse events were mild and transient. The most frequent side effect reported in all three topics was headache, observed in 1 out of 12 patients (8.3%) to 6 out of 33 patients (18.2%) [49,50]. The second most frequent side effect was flushing. Raffaele et al. recorded the

maximum percentage (18.2%), affecting 6 out of 33 patients [50]. Multiple Sclerosis

Study Population Mean age ranged from 41 to 46 years. Residual disability levels were ranked according to the Kurtzke Extended Disability Status Scale (EDSS), with 3–4 constituting the most common score [52]. This scale is based on the neurological exam data and the patient’s ability to walk. Scores range from 0 (indicating no neurological abnormality) to 10 (death caused by MS). All MS patients included in these clinical studies had an EDSS score of less than 6. Mean duration of MS was around 11 years, while the mean duration of ED was roughly 6 years. Only Safarinejad excluded MS patients with possible co-morbidity conditions for ED such as diabetes, hypertension, or chronic smoking (more than 10 cigarettes/day for more than 3 years) [53]. Efficacy of Oral Therapies on Erectile Function and Their Impact on QoL Table 6 shows that two out of three clinical studies indicated significant statistical improvement in J Sex Med 2012;9:970–985

J Sex Med 2012;9:970–985 R-DB- PC Maximum 6 months Sildenafil (50–100 mg) 102

Study design

Duration of study Drugs and dosages Number of patients IIEF(15): EF (3–4) GEQ 1 GEQ2 IIEF(15): EF (1–5,15) IIEF(15): OS (13,14) SEP (2) SEP 3 IIEF(15): ORG (9–10) IIEF(15): DES (11–12) EDS Mean total score LISAT(8) Satisfaction with life Sexual life Family life Partner relationship Social contacts Discontinuation for side effects correlated to the treatment Placebo 101

P = 0.000,2

P < 0.01

P < 0.01 P < 0.01

First phase R- DB- PC-FD 12 weeks Sildenafil (25–100 mg) 104 P < 0.01

Fowler et al. [54]

Placebo 113

P = 0.01 P < 0.01 P = 0.03 P = 0.01 P = 0.03 1. Pre syncopal episodes 1. Lymphopenia

P < 0.01

Second phase OLE 48 weeks Sildenafil (25–100 mg) 206

1. Headache 1. Tachycardia

P < 0.05 P < 0.05 P < 0.05

P < 0.01 P < 0.01

P < 0.01

P < 0.01

8 weeks Tadalafil (10–20 mg) 96

Case series- FD

Lombardi et al. [55]

R = randomized; DB = double blind; PC = placebo control; FD = flexible doses; OLE = open label extension; GEQ 1 = global efficacy question number 1; GEQ2 = global efficacy question number 2; SEP2 = sexual encounter profile question number 2; SEP3 = sexual encounter profile question number 3; IIEF(15) = international index of erectile function composed of 15 questions; EF (1,5–15) = erectile function domain using questions 1 to 5 and 15; EJ (9) = ejaculation frequency using question 9; SS (6–8) = sexual satisfaction domain using questions 6 to 8; OF (9,10) = orgasmic function using questions 9 and 10; OS (13–14) = overall satisfaction domain using questions 13 and 14; LISAT(8) = life satisfaction check-list questionnaire composed of 8 questions EDS = erectile distress scale questionnaire

1. Coronary artery disease requiring triple by-pass 1. Cerebrovascular accident

Safarinejad et al. [53]

Reports the study design and main results for multiple sclerosis patients with erectile dysfunction using sildenafil or tadalafil

Authors

Table 6

980 Lombardi et al.

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Treating Neurogenic ED with PDE5 erectile function evaluated by various outcome measures [54,55]. Instead, the Safarinejad study showed no significant statistical improvement using various ED efficacy measures, in part because the statistical value taken into consideration was P < 0.01 compared to other clinical trials that used P < 0.05 [53]. Two authors confirmed statistically significant improvement in patients’ QoL through several of the eight questions on the life satisfaction checklist (LISAT-8) questionnaire. The eight questions regard: Life as a whole, My sexual life, My partnership relation, My family life, My contacts with friends and acquaintances, My leisure situation, My vocational situation, and My financial situation. Each question score varied from 1 (very dissatisfying) to 6 (very satisfying) [54,55]. Moreover, Fowler et al. documented an improvement in the QoL with PDE5 using the Erection Distress Scale (EDS). This 5-question survey addresses the patient’s erection concerns. Responses to each question were scored from 1 (none of the time) to 6 (all of the time). The total mean score for the disease-specific EDS increased 43% from baseline for the sildenafil group compared to 13% for the placebo group [54] (see Table 6).

Predictable factors for the success of oral PDE5 Residual reflexogenic response was reported by two authors as the principal reason for the high response to PDE5 [54,55]. However, in both studies, responders and non-responders were not statistically analyzed considering the presence or absence of residual reflexogenic erection or in comparing their degree of residual reflexogenic erection (1–2 vs. 3–4) according to the EAS. Side Effects

Fowler et al. reported headache as the most frequent drawback correlated to treatment during phase 1 of their study, occurring in 27 out of 104 patients (20.2% of), followed by flushing which affected 13 out of 104 subjects (12.5%). In phase 2 of the study, lasting 48 weeks, of the MS patients given placebo in the first phase of the study and then switching to sildenafil, 19 out of 206 suffered from headache (9.2%); the second most frequent drawback was flushing reported in 15 out of 206 subjects (7.3%). No patient discontinued the oral drug because of drawbacks related to sildenafil in phase 1 [54]. Similarly, the most frequent side effect in Safarinejad’s clinical trial was headache, affecting 15 out of 102 patients (14.7%), followed

by flushing reported in 10 out of 102 subjects (9.8%). Additionally, 6 out of 102 patients (5.9%) left the study due to side effects but the reasons were explained only for the 2 who discontinued because of severe problems [53] (see Table 6). Lombardi et al. reported that 22 out of the 96 MS patients (22.9%) who used tadalafil experienced adverse events, and of the 63 overall adverse events correlated to treatments, the most frequent was headache (23) and the second flushing (17) [55]. Spina Bifida

A prospective, blinded, randomized, placebocontrolled, dose-escalation, crossover study in 17 patients with SB and ED with mainly thoracic spinal lesion (5 patients) was discovered [56]. Fifteen completed the study, while 2 abandoned the follow-ups. Median age was between 19 to 35 years old. All were assigned to take four sets of tablets, five tablets per set, in random order. All patients took 25 and 50 mg of sildenafil and two identical looking sets of corresponding placebo. An erectile score of P < 0.05 was reached based on a scale from 0 (lowest response) to 10 (best response), patient self-evaluation of duration of rigid erection, frequency of erection evaluated via question 1 of the IIEF(15), and the level of confidence to get and maintain an erection (question 15 of the IIEF [15]). Of the five patients who reported side effects, two experienced mild hematological changes that reverted to baseline after study completion [56]. Multiple System Atrophy

Only 1 clinical study was found related to multiple system atrophy. Hussain et al. selected 12 patients with ED and MSA, mean age of 54 years (range 46–61) [49]. The mean duration of ED was 57 months (range 24–90). Six out of 12 patients did not meet the inclusion criteria because their systolic pressure <90 and/or diastolic <50 mm Hg. Three out of 6 patients suffered a severe blood pressure plunge 1 hour after sildenafil was administered (systolic <65 and diastolic <55). Overall, four patients concluded the clinical trial with significant statistical improvement on erectile function, measured via questions 3 and 4 of the IIEF(15) questionnaire. Discussion

Data show that PDE5 represent first-line ED therapy only for individuals with SCI. A large J Sex Med 2012;9:970–985

982 amount of data, especially concerning sildenafil for treating SCI, compared to other CND diseases, confirmed their high percentage efficacy using various outcome measures for erectile function compared to baseline or placebo, and side effects were largely slight, moderate and transient for each of the three oral PDE5. The results are comparable to or better than a population of patients with mixed etiology ED (72–79%) and markedly higher than in patients with diabetes mellitus (48– 72%), whose poorly preserved vasculature might be the main reason for low efficacy [54,57,58]. Moreover, only SCI studies documented medium and long-lasting efficacy and safety using the oral drugs [39,44]. However, we were unable to evaluate the treatment results through meta-analysis even for SCI patients. Additionally, specific research on individuals with SCI and ED is needed to establish the choice of a starter treatment; in fact, manifest definite characteristics of these drugs such as earliest time to onset of action, longer duration of action, capacity for improving orgasmic function, safety, and therapy cost remain to be further demonstrated. At this time, it is difficult for the clinician to differentiate among the three agents and to select a PDE5 appropriate for the needs of the couple, or to switch to another oral drug if the initial therapy is unsuccessful or poorly tolerated. A manifest result of this review is the remarkable gap in literature on the use of PDE5 for ED by individuals with SCI compared to patients with other neurological pathologies and ED. The reasons may be multiple and diverse according to the neurological disease. Essentially, ED may depend on the interaction of many factors on CND [1,6,7,13]. An intriguing fact is that the majority of SCI patients suffer the onset of ED at the time of SCI (primary effect) and, therefore, the use of oral PDE5 is appropriate. Another reason for the limited use of PDE5 for other CND may be explained by studies that report the most frequent sexual dysfunction is a decrease of libido for those with PD, MS, stroke, and cerebral trauma [59–62]. Instead, the literature did not focus on the loss of libido for those with SCI, and the Cardoso study did not show a considerable difference in sexual desire between samples of subjects with and without SCI [63]. A study on MS reported the prevalence of decreased libido in 80.5% [62]. Loss of libido was reported in 65.6% of men with PD, 42.6% of whom suffered from concomitant ED [59]. Thus, libido loss can sometimes be the main cause of ED. This matter must be analyzed before deciding on appropriate treatment, keeping in J Sex Med 2012;9:970–985

Lombardi et al. mind that PD-induced depression represents the main cause of libido impairment [7,59]. The high frequency of depression in the CND population should motivate the evaluation of blood testosterone in that depressive symptoms are often associated with low testosterone levels that may be the main cause of sexual dysfunctions, including erectile impairment. As a result, PDE5 are not indicated as major therapy, rather testosterone administration may improve depressive symptoms and sexual function in hypogonadal men [64–66]. In the same way, missing data on the use of oral PDE5 for ED in epileptic patients may be explained, in part, by low testosterone levels as the principle cause of ED, though at this time, literature reports contrasting data regarding the role of sexual hormones on ED in this neurological population [67,68]. The possibility of dramatic drawbacks of using PDE5 to treat ED may represent another possible explanation for the scarce or absent data on PDE5 use on the CND population [69–71]. In the only clinical trial on multiple system atrophy, 50% of the patients who used sildenafil for ED had a severe drop in blood pressure; this drawback was not experienced by those with SCI using sildenafil, or in subjects with lesions above dorsal T5 [49,72,73]. Moreover, information is currently insufficient to speculate whether PDE5 may promote epileptic seizures in previous non-epileptic subjects, while an increased risk of seizure frequency in pharmacologically well-controlled seizure disorders should be investigated [74]. Though a host of variables should be taken into account before starting PDE5 treatment for PD, MS, and SB patients, the existing results are encouraging. Thus in the future, adopting PDE5 to treat ED in these subjects can be anticipated. The greater efficacy of sildenafil and tadalafil, particularly for MS patients, may be due to the fact that reflexogenic erection was preserved because sacral segmental pathways were still intact [54,55]. Palmer et al. promoted the use of sildenafil in SB patients suffering from ED [56]. The expanding use of PDE5 in this group may favor an earlier start to sexual activity as well, as one study reported only 24% of these adult patients were sexually active [75]. Immediately during initial recovery most men with SCI deal with their sexuality issues within spinal units, rehabilitation centers, or neuro-urology departments. Currently, however, there are no medical reference centers available to help other CND patients confront their sexuality problems. Many authors high-

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Treating Neurogenic ED with PDE5 lighted that the neurological department that routinely followed up on patients treated for their neurological dysfunctions became the point of reference for their sexuality needs. Consequently, professional support with at least some sexology education is needed within neurological clinics and should be able to recognize the particular aspects of each neurological pathology correlated to ED, identify the presence and degree of sexual dysfunctions by means of validated surveys such as the IIEF(15) questionnaire, and competently prescribe opportune diagnostic investigation, or therapies for ED including PDE5. The physician in the neurological department should also collaborate directly with external professional figures such as neuro-urologists and endocrinologists in order to provide personalized programmable interventions for these patients. Conclusions

The existing body of literature suggests that PDE5 are the first line therapy to treat ED in patients with SCI because they are highly effective and well tolerated in medium- and long-term follow-ups. Instead, the data on other CND patients with ED are partial or insufficient. The chief reasons for the limited use of the oral PDE5 in other CND classes are multiple: neurological pathology does not represent the main cause of erectile impairment; concomitant sexual dysfunctions, especially libido; the high presence of co-morbidities for ED, mainly depression; risk of dramatic side effects using PDE5; and sexual hormonal deficiencies as the main root of ED. Further studies are required to determine the effects of PDE5 on CND patients suffering from ED, by employing sexuality experts in the neurological departments where patients are routinely checked for their neurological dysfunctions. Corresponding Author: Giuseppe Lombardi, MD, Via Largo Palagi 1, Florence 50141, Italy. Tel: +390557948327; Fax: +390557948307; E-mail: [email protected] Conflict of Interest: None. Statement of Authorship

Category 1 (a) Conception and Design Giuseppe Lombardi; Federico Nelli; Maria Celso; Marco Mencarini; Giulio Del Popolo (b) Acquisition of Data Giuseppe Lombardi; Federico Nelli; Maria Celso; Marco Mencarini; Giulio Del Popolo

(c) Analysis and Interpretation of Data Giuseppe Lombardi; Federico Nelli; Maria Celso; Marco Mencarini; Giulio Del Popolo

Category 2 (a) Drafting the Article Giuseppe Lombardi; Federico Nelli; Maria Celso; Marco Mencarini; Giulio Del Popolo (b) Revising It for Intellectual Content Giuseppe Lombardi; Federico Nelli; Maria Celso; Marco Mencarini; Giulio Del Popolo

Category 3 (a) Final Approval of the Completed Article Giuseppe Lombardi; Federico Nelli; Maria Celso; Marco Mencarini; Giulio Del Popolo

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