Salvage of Sildenafil Failures with Cabergoline: a Randomized, Double-Blind, Placebo-Controlled Study

ORIGINAL ARTICLE Salvage of sildenafil failures with cabergoline: a randomized, double-blind, placebo-controlled study

MR Safarinejad

Urology and Nephrology Research Center, Shaheed Beheshti University of Medical Sciences, Tehran, Iran

To evaluate the safety and efficacy of cabergoline in men with erectile dysfunction (ED) who did not respond to sildenafil. Four hundred two sildenafil nonresponders aged from 21 to 59 years were included in the study. Patients were randomly divided into group 1, those who received 0.5–1 mg cabergoline weekly for 6 months and group 2, who received placebo for the same period. They underwent preliminary assessment, including medical and sexual history, self-administered International Index of Erectile Function (IIEF) and intravaginal ejaculatory latency time (IVELT) evaluation. Standard biochemistry and hematological laboratory tests, and measurement of serum testosterone and prolactin levels were also carried out. When indicated, other tests were used to establish the diagnosis of vasculogenic and neurogenic ED, including penile color duplex Doppler ultrasonography, pudendal nerve conduction test and impaired sensory-evoked potentials studies. The efficacy of two treatments was assessed every 2 weeks during treatment, at the end of the study, using responses to IIEF, IVELT evaluation, mean intercourse satisfaction domain, mean weekly coitus episodes and adverse drug effects. The trial was completed by 370 (92%) men. Positive clinical results were seen in 31.2% of patients in the cabergoline group compared with 7.1% of patients in the placebo group (P ¼ 0.04). The mean weekly intercourse episodes increased from pretreatment values of 1.4 and 1.2 to 2.2 and 1.4, for cabergoline and placebo, respectively (P ¼ 0.04). Baseline mean intercourse satisfaction domain values of IIEF 10 and 11 reached to 15 and 10 at 6-month treatment in groups 1 and 2, respectively (P ¼ 0.04). The IVELT after cabergoline and placebo gradually increased from 98 and 101 s to approximately 242 and 116 s, respectively (P ¼ 0.001). More drug-related adverse effects occurred in cabergoline group and 12 (5.9%) had to discontinue treatment (P ¼ 0.001). Cabergoline is moderately effective salvage therapy for sildenafil nonresponse. Further studies with different dosages and treatment regimens are necessary to draw final conclusions on the efficacy of this drug in ED. International Journal of Impotence Research (2006) 18, 550–558. doi:10.1038/sj.ijir.3901476; published online 20 April 2006

Keywords: erectile dysfunction; drug therapy; sildenafil; cabergoline

Introduction primary care specialists writing more than half of these prescriptions.2,3 Marketing data worldwide Normal erectile function relies on the coordination demonstrated that dropout rates for sildenafil are of neurogenic, psychologic, endocrine and vascular as high as 50% of patients treated.4 In spite of its factors. Sildenafil citrate, an orally administered effectiveness, yet, approximately 30–50% of sub- phosphodiesterase-5 (PDE-5) inhibitor generally jects receiving sildenafil do not satisfactorily re- used to treat erectile dysfunction (ED). It is the first spond to therapy.5 Proposed rationales for treatment oral medication to exhibit significant and reliable discontinuation include variations in motivation in efficacy in most patients with ED.1 Nowadays more patients incorporated in the clinical trials and those than 15 million men have used this medication with of the everyday practice, lack of reimbursement, failure to recognize patients expectations from sexual life,6 lack of a definitive cure, low efficacy, Correspondence: Dr MR Safarinejad, Department of fear of adverse events and need for sexual inter- Urology, Urology and Nephrology Research Center, PO 7,8 Box 19395-1849, Tehran, Iran. course scheduling. A panel of experts at the first E-mail: [email protected] International Consultation on Erectile Dysfunction Received 28 February 2006; revised 3 March 2006; recommended oral agents as first line treatment for 9 accepted 13 March 2006; published online 20 April 2006 ED independent of etiology. Salvage of sildenafil failures with cabergoline MR Safarinejad 551 The central nervous system controls sexual beha- 5-HT receptor activation.35 Receptor-binding studies vior and related sexual responses, for example indicate that cabergoline has also low affinity for a1- 36 erection and ejaculation in males. Pharmacological and a2-adrenergic receptors. It has been suggested researches have focused on the role of neurotrans- that central adrenergic receptors promote sexual mitters and neuropeptides involved in this central function.37 control.10 Particular attention has been made to dopa- Although there are no published reports on the use mine (DA) and, hence, to the dopaminergic D1/D2 of cabergoline as an ED pharmacotherapy, several receptor agonists. At least six different forms of the DA reports show that cabergoline is able to ameliorate receptors cloned from the brain have been reported. disorders associated with DA deficiency and hence is 38–42 The D1 class of DA receptor has been divided into an appropriate candidate for this trial. To our D1 and D5 receptor subtypes and the D2 class com- knowledge this the first study to assess the efficacy of 11,12 prises D2S-, D2L-, D3-, and D4-receptor subtypes. cabergoline in nonresponders to sildenafil. Dopamine-mediated improvement of sexual behavior was first recognized when administration of l-dopa (3,4-dihydroxyl-phenylalanine), the precur- sor to DA, to men suffering from Parkinson’s disease Materials and methods resulted in increased libido and sexual potency.13–15 This study comprised 486 married men (aged 21–59 In addition to enhancing the consummatory phase years) with ED and their wives. They were referred of sexual behavior, DA agonists also enhanced to 1 urologist (MRS) from primary care physicians or psychogenic erections and sexual motivation.16 addressed themselves disappointed by the results Other DA agonists, including apomorphine (a of sildenafil from February 2002 to March 2005. The D /D DA receptor agonist), have also been used 1 2 diagnosis of ED was established according to the to potentiate human erectile function.17 National Institute of Health statement on ED.43 All Central sexual input from the forebrain and patients were given a sildenafil instruction/safety peripheral sexual stimuli are integrated in the medial sheet prior to including the study. The instruction preoptic area and the paraventricular nucleus of the sheet emphasized the timing of sildenafil adminis- hypothalamus and transmitted via the spinal cord tration (45 min–2 h prior to sexual stimulation) as and peripheral autonomic nerves to the penis. Both well as the absolute need for sexual stimulation, structures can be activated by dopaminergic agents.18 such as visual stimulation, foreplay and hugging. In The beneficial effect of apomorphine in ED is addition, the instruction sheet stressed that silde- marginal. In a placebo-controlled study 48–53% of nafil should be used 2–3 h after a low-fat meal. patients with ED achieved and maintained an Finally, the sheet also emphasized that outcomes erection firm enough for intercourse as compared tend to get better after six to eight attempts and with 35% for placebo.19 In another study, the global success is often dose dependent. The office visit response to the apomorphine amounted to 26.1%.20 consisted of physical examination and patient We need more safe and effective drugs launched reinstruction following a review of patient history specifically for the treatment of ED, especially in and risk factors. The starting dose in all patients was nonresponders to PDE-5 inhibitors. 50 mg. They were instructed to rapidly increase the The ergot alkaloids,21,22 derivatives of lysergic dose from the 50 to 100 mg after one attempt if the acid or ergoline structures show a broad range of initial treatment was not satisfactory and there were pharmacological activities. Many of them are DA D 2 no adverse reactions, but not to exceed more than receptor agonists,23,24 but some ergoline derivatives one tablet per day. Patients were asked to use at least also interact with serotonin receptors25–27 and 12 tablets/attempts at home. Outcome measures adrenoceptors28,29 with very high affinities. Caber- were assessed using a global assessment question- goline is a selective D agonist whereas apomor- 2 naire (GAQ) (‘Did this treatment improve your phine is a non-specific D /D agonist. With its 1 2 erections?’). The effect of treatment was assessed highly specific D receptor agonism and its favorable 2 every 2 weeks during a 16-week treatment period. adverse effect profile, cabergoline may turn out to be Of the 486 patients re-educated, 56 (11.5%) particularly suitable for this indication. Its elimina- responded to sildenafil and therefore excluded from tion half-life has been estimated as about the study. The remaining 430 patients were asked to 65–110 h,30 and therefore may provide fairly steady complete the remainder study protocol. dopaminergic stimulation. It is generally assumed that selective serotonin reuptake inhibitors sexual side effects are related to increased central 5-hydroxytryptamine (5-HT, serotonin) neurotrans- Study protocol mission and activation of postsynaptic 5-HT recep- Four hundred and thirty men who were ‘non- tors.31,32 Selective serotonin reuptake inhibitors responders’ to sildenafil entered the study (mean (paroxetine, fluoxetine, sertraline) are reported to age 41.5 years, range 21–59) with a mean duration of be effective for treating premature ejaculation.33,34 penile ED of 2.8 years (range 1.9–7). All subjects As recently published, cabergoline caused potent gave their written informed consent before entering

International Journal of Impotence Research Salvage of sildenafil failures with cabergoline MR Safarinejad 552 the study, which was conducted in accordance with All of the men were asked not to consume the Declaration of Helsinki. The study was not alcoholic drinks within 6 h of sexual activity. There advertised, and no remuneration was offered. This were no statistical pre-treatment differences in study was carried out without sponsorship. None IVELT, IIEF, and mean coitus attempts per week in of the patients had received other treatment for the 2 groups. male ED for at least 4 weeks before the start of the study. Patients were eligible for inclusion in the study if they were aged 18 years or older, were Outcome measures nonresponders to sildenafil monotherapy and Theeffectoftreatmentwasassessedevery2weeks had medically documented ED to be of at least during treatment and at the end of study. For the ana- 6 months duration. The patients had to be in a stable lysis of efficacy and safety, all patients were assessed relationship with his wife for at least the previous in each visit evaluating changes in IVELTand respon- 6 months. ses to the questions from the IIEF: question 3, ‘When Exclusion criteria included penile anatomical you attempted sexual intercourse, how often were defects; a primary diagnosis of another sexual able to penetrate your partner?’ and question 4, disorder; use of psychotropic and antidepressant ‘During sexual intercourse, how often were able to medication and serious relationship problems; maintain your erection to completion of intercourse?’ poorly controlled diabetes mellitus; uncontrolled Responses to the two questions were rated on a scale congestive or ischemic heart disease, or renal or ranging from 1 to 5, with five response options: liver impairment, a history of alcohol or drug abuse; 1 ¼ almost never/never, 2 ¼ a few times (much less spinal cord injury; history of prostate cancer, than half the time), 3 ¼ sometimes (approximately neurological disorders that cause ED, and those half the time), 4 ¼ most times (much more than half unlikely to be available for follow-up. the time) and 5 ¼ almost always/always. The five All patients underwent preliminary assessment, separate response domains, erectile function, orgas- including a medical and sexual history, physical mic function, sexual desire, intercourse satisfaction examination, structured interview diagnostic of and overall satisfaction, were also used in the mental and physical disorders, self-administered assessment of efficacy. Each patient also responded International Index of Erectile Function (IIEF), a to a global efficacy question (‘Did the treatment 15-question, validated measure of ED44 and intra- improve your erections?’), and maintained an event vaginal ejaculatory latency time (IVELT) evaluation. log, in which was record the date of the medication Standard biochemistry and hematological laboratory taken, the presence of sexual stimulation, the hard- tests, and measurement of serum testosterone and ness of erections on a 4-point scale, the number of prolactin levels were also carried out. Men with low attempt at sexual intercourse and the number of testosterone or elevated prolactin levels were not attempts that were successful. All patients were eligible for enrolment. asked to indicate their sexual satisfaction on a scale When indicated, other tests were used to establish of 0–5 as proposed by Kim and Paick, with 0 being the diagnosis of vasculogenic and neurogenic ED, extremely dissatisfied and 5 extremely satisfied.45 including penile color duplex Doppler ultrasono- None of the patients underwent formal psychosexual graphy before and after intracavernosal injection of counseling. Patients were given a diary to record the 20-mg prostaglandin E , pudendal nerve conduction 1 frequency of coitus and adverse drug-related effects test and impaired sensory-evoked potentials studies. and requested to measure IVELT using a stopwatch. Of 430 ‘nonresponders’ 402 met inclusion and Adverse events were recorded at each visit and labo- exclusion criteria and agree to participate in the ratory tests were monitored throughout the study. study.

Statistical analysis Treatments Analysis was performed according to the intention The patients were randomly assigned to either of to treat. All analysis of significance were two-sided two groups of subjects. Randomization was deter- and tested at the 5% level, values of Po0.05 were mined by a computer-generated schedule. Group 1 considered to indicate significant differences. Com- was given 0.5 mg cabergoline (Dostinex; Pharmacia parison of sexual satisfaction rates of patients and & Upjohn, Milano, Italy) orally weekly initially their wives and comparison of the incidence of side followed by an increase 0.25 mg biweekly up to effects were tested using the w2 test with Yates 1 mg weekly for 6 months. Group 2 was received a correction or Fisher’s exact, when necessary. The similar regimen of placebo. The placebo was a starch Mann–Whitney test was used to compare quantita- compound with the same color and size of cabergo- tive variables. Statistical analysis was performed line. Treatment was administered in a randomized using the computer statistical package SPSS/4.0 sequence that remained unknown to the patient and (SPSS, Chicago, IL, USA) and SAS/6.4 (SAS to the physician. Institute Cary, NC, USA).

International Journal of Impotence Research Salvage of sildenafil failures with cabergoline MR Safarinejad 553 Results 192 (52%) were cigarette smokers, 91 (24.6%) had hypercholesterolemia, 87 (23.5%) had hypertension All patients were seen with their partners and and 52 (14%) had ischemic heart disease. interviewed about their sexual activity and patient’s erectile function. The wives actively participated in solving their problems. They know everything about Efficacy the study and were satisfy with it. Four hundred and Treatment with cabergoline was associated with two patients were recruited, but only 370 (92%) significantly higher scores for question 3 (frequency completed the whole randomized trial study (187 of of penetration) and question 4 (maintenance of 205 in the cabergoline group and 183 of 197 in the erection after sexual penetration) than baseline placebo group) (Figure 1). At baseline, the study and (P ¼ 0.01) (Table 2). For question 3, the mean score placebo groups were similar in demographic and was 3.3 for patients in the cabergoline group clinical characteristics (Table 1). compared with 2.0 for those in placebo group, Thirty-two patients were non-completers. Reasons which represent increases from baseline of 45.5% for non-completion included 14 adverse effects (12 (mean score at baseline, 1.8) and 15% (mean score at from cabergoline group and two from placebo baseline, 1.7), respectively. For question 4, the mean group), 12 lack of effect on ED (five from cabergoline score was 3.7 (51.4% increase from baseline mean group and seven from placebo group) and six lost for score of 1.8) for the cabergoline group compared follow-up (two from cabergoline group and four with 2 (20% increase from baseline mean score of from placebo group). The difference in dropout rates 1.6) for the placebo group. At the 6-month end point, was not significant between the groups. Mean 64 (31.2%) of 205 patients taking cabergoline with patient age was 40.5 years (range 21–59) in group 1 a mean age of 42.3 years reported positive clinical and 42.5 (range 21–59) in group 2 (P ¼ 0.1). results compared with 14 (7.1%) of 197 patients in Mean patient age was 41.5 years (range 21–59). the placebo group (P ¼ 0.04). Thirty-six percent of Mean duration of penile ED was 2.8 years. The etio- the patients reported at least one successful attempt logy of ED was arteriogenic in 132 (35.7%) patients, psychogenic in 28 (7.6%), cavernosal venous leakage in 97 (26.2%), mixed vasculogenic in 105 Table 1 Patients demographics (28.4%) and secondary to corporeal fibrosis in eight (2.2%). Of the men, 44 (12%) had diabetes mellitus, Variables Cabergoline Placebo P-value n ¼ 205 n ¼ 197

Mean age, years (range) 40.5 (21–59) 42.5 (21–59) NS Screened Patients: 486 Mean duration of ED, 2.9 (1.5–5.3) 2.7 (1.6–5.8) NS years (range)

ED etiology, no. (%) Arteriogenic 65 (31.7) 67 (34) NS Mixed vasculogenic 51 (24.9) 54 (27.4) NS Random Assignment: 402 Psychogenic 15 (7.3) 13 (6.6) NS Veno-occlusive 49 (24) 48 (24.4) NS dysfunction Corporeal fibrosis 4 (2) 4 (2) NS

Cabergoline: 205 Placebo: 197 Concomitant risk factors, no. (%) Diabetes mellitus 24 (11.7) 20 (10.2) NS Cigarette smoking 94 (45.9) 98 (49.7) NS Hypercholesterolemia 48 (23.4) 43 (21.8) NS Hypertension 44 (21.5) 43 (21.8) NS Withdrawn: 19 Withdrawn: 13 Ischemic heart disease 27 (13.1) 25 (12.7) NS Adverse Effects: 12 Adverse Effects: 2 Lack of Efficacy: 5 Lack of Efficacy: 7 Lost to Follow-up: 2 Lost to Follow-up: 4 Abbreviations: ED ¼ erectile dysfunction; NS ¼ not significant.

Table 2 Mean (s.e.) scores for questions 3 and 4 of the IIEF Followed-up: 187 Followed-up: 183 questionnaire at baseline and at the end of 6-month trial IIEF: Week 0 - month 6 IIEF: Week 0 - month 6 IVELT: Week 0 – month 6 IVELT: Week 0 – month 6 GEQ: Week 8 and month 6 GEQ: Week 8 and month 6 Question 3 Question 4

Baseline 1.8 (0.2) 1.7 (0.2) Sildenafil 3.3 (0.2)a 3.7 (0.2)a Completed Trial: 187 Completed Trial: 183 Placebo 2 (0.2) 2.0 (0.2)

Figure 1 Study design. Key: GEQ: global efficacy question; IIEF: Abbreviation: IIEF ¼ International Index of Erectile Function. a International Index of Erectile Function. P ¼ 0.01 vs baseline.

International Journal of Impotence Research Salvage of sildenafil failures with cabergoline MR Safarinejad 554 Table 3 Mean scores to questions 1, 2 and 5–15 of the International Index of Erectile Function at baseline and after 6 months of treatment with cabergoline or placebo

Mean score

Cabergoline (n ¼ 187) Placebo (n ¼ 197) Overall treatment Question Baseline Final a P-value Baseline Final a P-valueb P-valuec

1. How often were you able to get an erection during 2.1 3.0 (0.2) 0.02 2.0 2.0 (0.2) 0.10 0.01 sexual activity? 2. When you had erection with sexual stimulation, how 1.8 3.1 (0.2) 0.02 1.7 1.9 (0.2) 0.71 0.01 were your erections hard enough for penetration? 5. During sexual intercourse. How difficult was to 1.4 2.9 (0.2) 0.02 1.4 1.7 (0.2) 0.30 0.01 maintain your erection to completion of intercourse? 6. How many times have you attempted sexual 2.0 3.6 (0.2) 0.001 1.8 2.0 (0.2) 0.1 0.001 intercourse? 7. When you attempted sexual intercourse, how often was 1.8 3.5 (0.3) 0.001 1.6 1.7 (0.3) 0.34 0.01 it satisfactory for you? 8. How much have you enjoyed sexual intercourse? 1.7 3.7 (0.2) 0.001 1.7 1.9 (0.2) 0.63 0.01 9. When you had sexual intercourse, how often did you 2.7 3.7 (0.2) 0.02 2.8 3.3 (0.2) 0.50 0.002 ejaculate? 10. When you had sexual intercourse, how often did you 2.8 3.8 (0.2) 0.02 2.7 3.1 (0.3) 0.47 0.003 have the feeling of orgasm or climax? 11. How often have you felt sexual desire? 2.6 3.6 (0.2) 0.01 2.6 2.6 (0.2) 0.50 0.04 12. How would you rate your level of sexual desire? 2.3 3.4 (0.1) 0.02 2.3 2.4 (0.1) 0.91 0.02 13. How satisfied have you been with your overall sex life? 1.8 2.8 (0.2) 0.01 1.8 2.2 (0.2) 0.3 0.01 14. How satisfied have you been with your sexual 2.4 3.2 (0.2) 0.001 2.5 2.8 (0.2) 0.03 0.002 relationship? 15. How do you rate your confidence that you could get and 1.7 3.6 (0.2) 0.001 1.6 1.7 (0.2) 0.08 0.001 keep an erection?

a Least squares mean (s.e.) scores. b P-values for comparison between baseline and final scores. c P-values for overall treatment effect.

Table 4 Mean IVELT, frequency of coitus, mean intercourse satisfaction domain values of the IIEF and sexual satisfaction scores

Baseline 8-week P-value 3-month P-value 6-month P-value

Cabergoline Mean IVELT (s) 98 202 0.01 228 0.001 198 0.001 Mean no. coitus/week 1.4 2.1 0.04 2.2 0.04 2.2 0.04 Mean intercourse satisfaction domain values of the IIEF 10 14 0.04 15 0.04 15 0.04 Sexual satisfaction score 1.4 3.2 0.04 3.6 0.04 3.6 0.04

Placebo Mean IVELT (s) 101 107 NS 108 NS 116 NS Mean no. coitus/week 1.2 1.3 NS 1.1 NS 1.4 NS Mean intercourse satisfaction domain values of the IIEF 11 10 NS 10 NS 10 NS Sexual satisfaction score 1.3 1.5 NS 1.8 NS 1.8 NS

Abbreviations: IIEF ¼ International Index of Erectile Function; IVELT ¼intravaginal ejaculatory latency time; NS ¼ not significant.

at sexual intercourse in the cabergoline group as the study, from month 1 onward and at the study compared with 6% successful attempts during end point (month 6), there were significant differ- placebo treatment (P ¼ 0.02). Data from patients’ ences between the treatment groups (P ¼ 0.001) event logs showed no evidence of a treatment period (Table 4). The mean pre-treatment IVELT was effect. Mean scores for the remaining 13 questions markedly increased from baseline 98 s in the of the IIEF are shown in Table 3. The remaining cabergoline group to 242 s compared with only a 13 questions assessing other aspect of male sexual gradual and mild increase in the placebo group function, showed significant improvements for the (from 101 to 116 s) (Table 4). cabergoline group compared with the placebo group The mean pretreatment intercourse frequency was (P ¼ 0.04). 1.4 per week for cabergoline compared to 1.2 per After 6 months of treatment, the IVELT differed week for placebo. Cabergoline demonstrated super- significantly between two treatment groups. During iority in increasing mean pretreatment intercourse

International Journal of Impotence Research Salvage of sildenafil failures with cabergoline MR Safarinejad 555 frequency. The mean intercourse frequency at our results, the main recognized reason for sildenafil 6-month treatment was 2.2 and 1.4 for cabergoline failure was lack of effect. and placebo, respectively (P ¼ 0.04). Baseline and Prior studies have shown that patients preferred 6-month mean intercourse satisfaction domain oral medical therapies over invasive treatments even values of the IIEF were 10, 11 and 15, 10 in groups prior to the release of sildenafil in 1998.53,54 1 and 2, respectively. Cabergoline group reported Some men do not respond to PDE-5 inhibitors due significantly greater intercourse satisfaction than to the unknown and known reasons such as con- those in placebo group (P ¼ 0.04). comitant presence of a low androgen milieu. We Cabergoline also increased statistically significant excluded patients with hypotestosteronemia. The sexual satisfaction scores (P ¼ 0.04) (Table 4). patients may have other different deficiencies such as disorders of penile innervation or neurotransmitter release; malfunction of the enzymes adenylate cyclase or gunalyte cyclase as well as nitric oxide Adverse effects synthase or incompetence of the tunica albuginea.55 Adverse effects related to treatment were noted in Three systems are recognized as playing a major 12.2% (25/205) of patients taking cabergoline and role in modulating sexual motivation, behavior and 2% (4/197) of patients taking placebo (P ¼ 0.001). function, with both sensory stimulation and copula- Of the patients taking cabergoline, 10% reported tion-producing dopaminergic activity in all three nausea as an adverse events 2% of patients taking systems.56,57 First, the incerto-hypothalamic dopa- placebo (P ¼ 0.04); 9% taking cabergoline reported minergic system which projects to the medial headache vs 0% taking placebo (P ¼ 0.001); 9% preoptic area (MPOA) is recognized as one of the taking cabergoline reported dizziness vs 2% taking most imperative areas for the control of motivational placebo (P ¼ 0.04); and 6% taking cabergoline re- and consummatory aspects of sexual behavior. ported somnolence vs 0% taking placebo (P ¼ 0.03). Particularly, the generation of genital reflexes essen- The cabergoline generally was well tolerated, with tial for erection and ejaculation, the focusing of male side effects noted in 12.2 percent; however, only 5.9 attention on sexually related stimuli, and the percent had to discontinue treatment. increase of species-specific motor patterns during copulation are controlled by the MPOA. Second system is the mesolimbocortical dopaminergic Discussion system (MLC), which originates in the ventral tegmental area and projects to the mesial compo- Sildenafil is a novel, orally active agent that has nents of the limbic system (e.g. nucleus accumbens, long-term efficacy and safety in treating men with amygdala, mesial frontal cortex). It has a role in ED of mixed etiology.46 The approved and world- reward processes. The dopaminergic output of the wide availability of sildenafil has fostered exciting MLC is mainly responsible for appetitive/motiva- innovative research reports from independent in- tional regulation of sexual activity. This is con- vestigators around the world. Despite this pharma- firmed by stimulation of MLC DA in response to cological breakthrough this drug alone is not a sexually related sensory stimuli.58,59 Finally, the solution for all forms of ED. The sildenafil efficacy nigrostriatal dopaminergic system (NS), which ori- rate for treating male ED independent of etiology is ginates in the substantia nigra and projects primarily 65–75%.47 Steers et al. (1998) reported that only 55 to the putamen and caudate nucleus, integrate both and 59% of patients with severe ED achieved scores sensory and motor aspects of sexual behavior, of 4 or 5 to IIEF questions 3 and 4, respectively, with with NS DA enabling a state of ‘preparedness.’ 100 mg. sildenafil.48 Recent reports of tachyphylaxis Dopaminergic activity of the NS thus contributes to sildenafil have also been reported.49,50 Attempts to generation of consummatory motor functions, at sildenafil salvage by urologists and primary care such as the pursuit of a sexual partner before physicians should be considered as the first step in copulation.60 ED treatment for initial failure. In this study small Cabergoline, an ergot derivative, has been ap- numbers of nonresponders (11.5%) were responder proved for the treatment of hyperprolactinemia in after re-education. This result is lower than that in the United States. Cabergoline is a long-lasting D2 other studies that described up to 31, 40 and 55% dopaminergic receptor agonist capable of abolishing salvage of sildenafil failures through re-educa- prolactin secretion with administration once per tion.3,51,52 The reason for this difference may be week, without serious side effects.61 In healthy proper patient education and evaluation by primary young men manipulating hormonal levels to de- care providers. In our study, 82% of the patients had crease prolactin with cabergoline increases sexual received adequate administration instructions, and desire and arousal in laboratory conditions.62 It has 67% had been scheduled for a follow-up visit. An been reported that63–65 cabergoline could reduce the attempt at sildenafil salvage with re-education is length of anestrous and induce a fertile estrous necessary and useful in all patients prior to declar- period in bitches. Improved penile erections and ing that treatment has actually failed. According to libido caused by dopaminergic compounds occa-

International Journal of Impotence Research Salvage of sildenafil failures with cabergoline MR Safarinejad 556 sionally can be perceived as adverse events. These were responder to cabergoline. Of the 370 patients events, however, can be used to treat ED. With its 44 (12%) had diabetes mellitus and 230 (62%) had highly specific D2 receptor agonism and its favorable two or more vascular risk factors in addition to adverse event profile, cabergoline may be especially diabetes. Forty four patients were diabetic. Im- appropriate for this indication. Potential pharma- proved erections were reported by only 51–57% of cotherapies will probably require long half-lives patients with diabetes mellitus treated with silde- or involve methods of administration that provide nafil.67,68 Of 44 nonresponders to sildenafil, 12 steady-state delivery over long periods (as in the (27.3%) responded to cabergoline. None of these case of cabergoline). This study employed only a responders had severe vasculogenic concomitant very low dose of cabergoline (up to a maximum of risk factors. 1 mg/week). Cabergoline doses up to 6 mg/day have None of our patients had a history of spinal cord been safely used in parkinsonian patients with injury, pelvic trauma or surgery, neurological and motor fluctuations, with doses as high as 18 mg/ disorders that cause ED. day being given to particularly severe cases.66 Severe vascular lesions as arterial insufficiency Higher doses of cabergoline might give greater or cavernovenous leakage are significant factors benefit. influencing response to cabergoline treatment. The Our investigation showed the efficacy of cabergo- erectile response is more dependent on the efficacy line treatment in a group of patients who were of the corporeal veno-occlusive mechanism. Our unresponsive to sildenafil alone. Cabergoline was findings parallel the results already described as we associated with a significant increase, with respect have 78% of these sildenafil nonresponders with to baseline, in the mean-end-of-treatment scores for this problem.69,70 questions 3 and 4 of the IIEF. Also, 31% of patients Our study clearly demonstrates that ED patients taking cabergoline reported that treatment had did receive appropriate education in the use of the improved their erections compared with only 7% prescribed medication, as well as they are also of those taking placebos. adequately followed-up. While improved erectile function is the main goal Cabergoline is a potent 5-HT receptor activator.35 of ED therapy, quality of life is also enhanced as The serotonergic system has a crucial role on subjects become more satisfied with sexual activity. ejaculation function. Serotonin reuptake inhibitors We also used an inventory for analysis of satisfac- have all been shown to be effective in the treatment tion scores for the men or their wives. Satisfaction of premature ejaculation.71–74 This study demon- scores significantly improved with cabergoline. The strated that cabergoline 1 mg weekly significantly notable finding of our study is the superiority of delay ejaculation in men. Furthermore, mean cabergoline over placebo in increasing all of the weekly intercourse episodes for patients treated measured parameters (IVELT, IIEF, and mean num- with cabergoline compared to placebo were signifi- ber of coitus episodes weekly). Cabergoline provides cantly superior. We also used an inventory for also significant improvements on the overall sexual analysis of satisfaction scores for the men or their functions of the patients with the ED, suggesting wives. While improved erectile function is the main that the overall sexual functions of patients with the goal of ED therapy, quality of life is also enhanced as ED including sexual desire and partner’s satisfaction subjects become more satisfied with sexual activity. have improved. In this study, satisfaction scores were numerically Our study demonstrates that about one-third of better throughout the therapy period in subjects who nonresponders to sildenafil can be ‘salvaged’ with received cabergoline vs placebo, and by month 6 cabergoline monotherapy therapy. A response was such improvements were statistically superior in achieved by 36.4% (48 of 132) of patients with cabergoline-treated subjects. arteriogenic ED, 28% (27 of 97) with cavernosal Cabergoline was well tolerated with only 12 venous leakage and 35.2% (37 of 105) with mixed patients (5.9%) discontinuing on account of adverse vasculogenic ED. The responses were significantly event. There were no unexpected adverse events higher for patients with psychogenic ED (75%). associated with cabergoline. The dropout rate in the Patients with cavernosal venous leakage appeared cabergoline group was 9.3%, and the dropout rate less likely to respond to cabergoline monotherapy. in the placebo group was 5.6%. In our opinions a None of the patients with corporeal fibrosis had diagnostic work-up is still mandatory in the medical response to cabergoline. care process of impotent patients, especially when Clearly our study group comprised a highly select co-morbidity is present. subset of patients with severe vasculogenic erectile The results of this analysis indicate that cabergo- None of the 54 patients with cavernosal venous line, administered once weekly at a maximum dose leakage and a flow to maintain rate of X30 ml/min of 1 mg/week has therapeutic efficacy in the one- had score of 3 to both questions, whereas 27 of 43 third of nonresponders to sildenafil. Whether initial with cavernosal venous leakage and flow to main- treatment with cabergoline in de novo cases of ED tain rate of o30 ml/min achieved this score. None will increase the success rate, remains undeter- of the patients with peak systolic velocity p20 cm/s mined. A limitation of our study is that we were

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