Combined Oral Therapy with Sildenafil and Doxazosin for the Treament Of

Home , Doxazosin, Phentolamine

Combined oral therapy with sildenaﬁl and doxazosin for the treament of non-organic erectile dysfunction refractory to sildenaﬁl monotherapy

AF De Rose1*, M Giglio1, P Traverso1, P Lantieri2 and G Carmignani1

1Department of Urology, S. Martino Hospital, University of Genoa, Italy; and 2Department of Medical Statistics, S. Martino Hospital, University of Genoa, Italy

The purpose of this work was to investigate the efficacy and safety of sildenafil in combination with doxazosin for the treatment of non-organic erectile dysfunction in patients who did not respond to sildenafil. We enrolled 28 patients with non-organic erectile dysfunction, for whom 3 months of sildenafil monotherapy had failed. They were divided in two random and homogeneous groups: 14 were treated with doxazosin (4 mg daily) and sildenafil (100 mg 1 h before sexual intercourse); the other 14 patients received sildenafil and placebo. The results were assessed by means of the IIEF questionnaire before the beginning of the study, after 30 days of therapy and after 60 days. Of the 14 patients treated with doxazosin and sildenafil, 11 (78.6%) showed a statistically significant increase of IIEF; in the placebo group, only one patient (7.1%) recorded a significant IIEF increase. The differences observed in the two groups were statistically very significant (P ¼ 0.0016). Blood pressure did not show significant alterations. Side effects were minimal and even present during sildenafil monotherapy. The combination therapy with sildenafil and doxazosin resulted in the safe and effective treatment of men with non-organic erectile dysfunction for whom sildenafil alone had failed. International Journal of Impotence Research (2002) 14, 50–53. DOI: 10.1038=sj=ijir=3900815

Keywords: erectile dysfunction; drug therapy, combination; administration, oral; doxazosin; sildenaﬁl

Introduction efficacy and tolerability of sildenafil are extremely high, failure rates of 30 – 35% are however reported.3,4 The prevalence of erectile disorders in the world’s The inhibitory action of the sympathetic nervous male population has reached high values: according system and of the alpha-adrenergic mediators on to recent epidemiological studies, more than 30 erection have been exhaustively documented;5–7 million men in the United States are affected by good results for ED achieved with alpha-blockers 1 erectile dysfunction (ED) of varying severity. Due to have also been reported after intracavernosal injec- progressive prolongevity, it goes without saying that tion as well as oral administration.8–12 Doxazosin is the impact of this problem will continue to grow. an alpha1-blocker commonly used in the oral The introduction of new oral drugs such as therapy for hypertension and benign prostatic sildenafil has radically transformed the therapeutic hyperplasia, and therefore considered worth trying. approach of ED, reducing the use of other therapeu- The aim of our study was to investigate the tic options such as intracavernosal pharmacother- efficacy and safety of combined sildenafil – doxazo- apy, intraurethral prostaglandin (MUSE), vacuum sin oral therapy for non-organic ED patients who did constrictor devices, vascular surgery and penile not respond to sildenafil monotherapy. prostheses. It has generally been accepted that patients presenting with ED are treated with sildenafil regardless of etiology.2 Even though the Materials and methods

During the last year, 28 patients with chronic ED *Correspondence: AF De Rose, Via Donato Somma 77, who had failed at least 12 weeks of sildenafil I-16146, Genova, Italy. E-mail: [email protected] (100 mg) therapy were enrolled in this prospective, Received 29 June 2001; accepted 29 October 2001 randomized and placebo-controlled study. The age Combined oral therapy of non-organic ED AF De Rose et al 51 of patients varied between 36 and 62 y (average 51), with sildenafil þ doxazosin compared with the one while the ED had persisted from 8 months to 3 y. All treated with sildenafil þ placebo. It should be noted patients were referred to our public andrological that the positive progression of the IIEF score vis-a`- office; all were heterosexual, 21 (75%) were married vis the assessment phases (V0, V1 and V2) is highly and 7 (25%) had a stable partner. Exclusion criteria significant (P < 0.0001) and that the response to the included patients with significant cardiovascular pharmacological association between sildenafil and disease, unbalanced diabetes mellitus, neurological doxazosin shows a significant score increases as and psychiatric disorders, previous genitourinary early as the second visit (P ¼ 0.0023). Tables 1 and 2 surgery, or a history of intolerance to alpha-blockers. show results in detail. A normal blood testosterone, a normal nocturnal In two of the 11 patients who responded penile tumescence and rigidity (evaluated by NPTR- positively to the sildenafil – doxazosin association, RigiScan) and normal dynamic duplex ultrasound it was possible to lower sildenafil dosage to 50 mg. were adopted as inclusion criteria. During the In particular, eight of the 11 positive responders dynamic tests, the intracavernosal injection of (72.2%) said that they achieved erection far more 10 mg of prostaglandin E1 (PGE1) produced an easily and without fatigue and of having managed to erection of sufficient stiffness and duration in all keep their penis constantly erect during the entire patients. On the basis of the outcomes of these intercourse. diagnostic tests, we can define the ED as ‘non- Blood pressure monitoring did not point out organic’ or ‘without an identifiable organic aetiol- significant oscillations: 130 mm Hg Æ 10=80 Æ 5at ogy’. We can not nevertheless label these patients as V0 and 120 mm Hg Æ 10=75 Æ 5 at V2. None of the suffering from psychogenic ED, because no psycho- patients mentioned lipothymic episodes. Two pa- metric tests were performed; however none of the tients in the sildenafil – doxazosin group reported patients were afflicted with psychiatric disorders or facial flushing and one a mild headache. One patient were on psychotropic medications. reported heartburn, which was treated with anta- The patients where randomized in two homo- cids. In the placebo group a patient reported mild genous groups: 14 of them received daily doxazosin headache. Of all the reported side effects, heartburn titrated to 4 mg and 100 mg of sildenafil 1 h before was the only addition to the sildenafil – doxazosin sexual intercourse; the other 14 patients, apart from association: all the others were present before the 100 mg of sildenafil before intercourse, received treatment. a placebo instead of doxazosin. The results were assessed by means of the erectile function domain of the IIEF13 questionnaire before Discussion the beginning of the study (V0), after 30 days of therapy (V1) and after 60 days (V2). During treatment, all patients had at least two sexual Today, sildenafil is the therapy of choice for patients encounters weekly. During each clinic visit blood presenting with ED regardless of etiology.2 Recent pressure measurements were taken. The IIEF scores of the two groups were statistically compared with Table 1 Statistical values of IIEF variations relative to the ANOVA; for each group the results during the erectile function during sildenafil – doxazosin therapy. Stratifi- various visits were also assessed using Friedman’s cation by IIEF groups and visit non-parametric test and the corresponding internal IIEF changes. The comparison between the frequency of IIEF cases that responded positively in the two groups groups Patients V0 V1 V2 was carried out using Fischer’s exact probability 6 – 10 3 9.33 Æ 0.58 16.67 Æ 3.21 19.00 Æ 5.00 test. 11 – 16 8 14.38 Æ 1.60 20.50 Æ 3.51 22.00 Æ 2.62 17 – 25 3 19.33 Æ 2.08 19.33 Æ 1.15 19.67 Æ 2.52 Total 14 14.36 Æ 3.69 19.43 Æ 3.30 20.86 Æ 3.23 Results

Table 2 Statistical values of IIEF variations relative to the Of the 14 patients treated with doxazosin and erectile function during sildenafil – placebo therapy. Stratification sildenafil, 11 (78.6%) showed a statistically signifi- by IIEF groups and visit cant increase of IIEF, moving on average from 13.0 (V0) to 21.2 (V2). In the placebo group, only one IIEF IIEF patient (7.1%) recorded a significant IIEF increase groups Patients V0 V1 V2 from 12 (V0) to 22 (V2), while all the others experienced no changes in the IIEF score. 6 – 10 4 9.00 Æ 0.82 9.25 Æ 0.96 9.25 Æ 0.96 Result assessment of the two groups in terms of 11 – 16 7 13.43 Æ 1.81 14.14 Æ 2.34 14.29 Æ 3.90 17 – 25 3 19.67 Æ 1.53 18.67 Æ 1.15 18.67 Æ 1.15 IIEF score highlighted a significant difference Total 14 13.50 Æ 4.13 13.71 Æ 3.85 13.50 Æ 4.13 (P ¼ 0.0016) to the advantage of the group treated

International Journal of Impotence Research Combined oral therapy of non-organic ED AF De Rose et al 52 studies have confirmed its high efficacy and ex- erections and a constant erection during the entire cellent safety. However, approximately 30 – 35% of intercourse. Side effects did not increase and blood patients treated with this drug in monotherapy did pressure showed no significant alterations. In 2000, not achieve satisfactory results in terms of an Mydlo22 reported that 60 of 65 patients (92%) with improved erectile function.3,4 Most of these silde- ED and minimal or no response to intracavernosal nafil-refractory patients seem to suffer from organic alprostadil or sildenafil monotherapy had satisfac- dysfunction, especially of vascular etiology.14 It has tory responses with combination therapy (sildenafil become acceptable to offer various second-line ED and alprostadil). In 2001, Nehra23 used a combina- treatments (such as vacuum devices, MUSE and tion of sildenafil (100 mg) and MUSE (500 mg) for intracavernosal pharmacotherapy) without further refractory ED patients and reported a 100% success evaluation to patients who do not respond to rate at 18-month follow-up. sildenafil.2 Following this principle, Padma-Nathan The sympathetic nervous system, via release of obtained very good results with intracavernosal noradrenaline and stimulation of alpha1 adrenergic alprostadil in sildenafil failures.15 However, a receptors, is considered to be the prime determinant reasonable share of sildenafil non-responders have of cavernosal smooth muscle contraction and detu- a non-organic ED: Rosen recently reported that mescence.6 The tonic activity of the sympathetic psychosexual therapy in combination with sildena- system keeps the penis in the flaccid state by means fil is effective for patients who do not respond to of the continuous stimulation of alpha adrenocep- sildenafil monotherapy.16 tors present in penile erectile tissue (helicine vessels In the light of our experience, most patients with and cavernosal trabecular smooth muscle) resulting non-organic ED refractory to sildenafil respond well in vasoconstriction. This explains the positive to the sildenafil – doxazosin association. Therefore, action of anti-adrenergic drugs on the penile erec- we believe that these refractory patients, before tion disorders, whether these are administered at starting more invasive second-line treatments, local intracavernosal level or at systemic level by should undergo diagnostic evaluations in order to means of oral administration. These drugs remove understand the etiology of their ED. In presence of the inhibitory sympathetic tone and allow the non-organic ED patients, a combined treatment with cavernosal smooth muscle cells to relax, with sildenafil, doxazosin and=or psychosexual therapy consequent increase of blood flow inside the lacunar should be used. spaces. Phentolamine, a non-specific adrenergic The rationale of combined therapy with respect to inhibitor active on both alpha1 and alpha2 adreno- monotherapy, is that of increasing the efficacy and, ceptors, has been successfully employed in intraca- at the same time, reducing the side effects of the vernosal pharmacotheraphy.8,17 Some studies have treatment itself. If we look at intracavernosal pointed out its possible role even after oral or buccal pharmacotherapy, for example, it has been shown administration. Zorgniotti reported a 42% rate of that the combination of phentolamine and prosta- full spontaneous erections after buccal administra- 9 glandin E1 (alprostadil) or of phentolamine and tion of 50 mg of phentolamine. Becker has carried papaverine may achieve better results (in terms out a double-blind placebo-controlled study in 40 of efficacy and tolerability) than monotherapy.8 men with ED treated with varying doses of phento- Pathma-Nathan even recommended the use of lamine: full erections were achieved by 20% of the triple therapy: phentolamine, alprostadil and placebo group, 30% in the group treated with 20 mg papaverine.17 and 50% in the group with 50 mg.10 Recently, In the last years, the treatment of ED was Goldstein has reported the results of large multi- revolutionized by the introduction of new drugs center, placebo-controlled pivotal phase III clinical that may be administered orally. Apart from silde- trials: the mean change in the erectile function was nafil, apomorphine,18,19 phentolamine,9 – 11 doxazo- significantly higher following use of phentolamine sin,12 yohimbine20 and vardenafil21 have recently (40 mg or 80 mg) compared to placebo and there been used. The efficacy of these drugs has not yet were no severe adverse events.11 been determined in a final way and no comparative Doxazosin is an alpha1 selective anti-adrenergic clinical trials versus sildenafil have been performed. drug; there are few studies on its oral use for ED In the past, as far as we are aware of, no articles therapy. Apart from Kaplan’s above-mentioned have been published on combined therapy that paper,12 we can report Grimm et al’s recent exclusively envisages oral drugs. In 1998, Kaplan12 experience on the study of long-term effects of five published a paper on combined therapy that antihypertension drugs on sexual dysfunction: after included oral doxazosin and intracavernosal pros- 2 y of therapy, the lower incidence of ED (2.8%) was taglandin (alprostadil) in patients with ED in whom found in the subgroups of patients treated with the mere intracavernosal pharmacotherapy proved doxazosin (compared to 5% in the group of patients to be ineffective. In these patients, the doxazosin who received a placebo).24 Doxazosin’s action on association with a dosage of 4 mg allowed for a penile alpha1-adrenergic receptors was shown with statistically significant improvement of the erectile experiments in primates, where intracavernosal deficit: in particular, patients reported quicker injection with doxazosin enabled full erections.12

International Journal of Impotence Research Combined oral therapy of non-organic ED AF De Rose et al 53 The contractile cavernosal tissue is regulated by 4 Goldstein I et al. Oral sildenafil in the treatment of erectile two systems: on the one hand the sympathetic dysfunction. Sildenafil Study Group. New Engl J Med 1998; 338: 1397 – 1404. nervous system mediated by noradrenaline with an 5 Diederichs W et al. The sympathetic role as antagonist of inhibitory action on erection (ie vasoconstriction), erection. Urol Res 1991, 19: 123 – 126. and on the other hand the non-adrenergic system 6 Andersson KE, Hedlund P, Alm P. Sympathetic pathways and with stimulating action (ie vasodilation). The re- adrenergic innervation of the penis. Int J Impot Res 2000; 12 (Suppl 1): 5 – 12. laxation of the smooth muscle cells present in the 7 Traish A, Kim NN, Moreland RB, Goldstein I. Role of alpha intracavernosal vascular structures induced by the adrenergic receptors in erectile function. Int J Impot Res 2000; non-adrenergic systems has, as the ultimate med- 12(Suppl 1): 48 – 63. iator, nitric oxide. Sildenafil’s action, by inhibiting 8 Bechara A et al. Comparative study of papaverine plus 5-phosphodiesterase, favors the release of this phentolamine versus prostaglandin E1 in erectile dysfunction. J Urol 1997; 157: 2132 – 2134. powerful vasodilator. This explains the rationale of 9 Zorgniotti AW. Experience with buccal phentolamine mesy- sildenafil – doxazosin combined therapy: doxazo- late for impotence. Int J Impot Res 1994; 6:37– 41. sin’s anti-adrenergic action reduces the inhibitory 10 Becker AJ et al. Oral phentolamine as treatment for erectile tone of the sympathetic system hence favoring dysfunction. J Urol 1998; 159: 1214 – 1216. 11 Goldstein I. Oral phentolamine: an alpha-1, alpha-2 adrener- sildenafil’s stimulation of the non-adrenergic system gic antagonist for the treatment of erectile dysfunction. Int J with a vasodilating action. This is the only way to Impot Res 2000; 12(Suppl 1): 75 – 80. possibly explain the faster erections and the more 12 Kaplan SA et al. Combination therapy using alpha-blockers constant rigidity reported by most of our patients and intracavernosal injection in men with erectile dysfunc- who positively responded to the sildenafil and tion. Urology 1998; 52: 739 – 743. 13 Rosen RC et al. The international index of erectile function doxazosin association. (IIEF): a multidimensional scale for assessment of erectile Since the efficacy and tolerability of sildenafil are dysfunction. Urology 1997; 47: 822 – 830. well known, combined therapy with doxazosin 14 Metro M, Broderick G. The penile blood flow characteristics of must not be administered as the first option for Viagra failures. Int J Impot Res 2000; 12(Suppl 3): 78. 15 Padma-Nathan H et al.Efficacy and safety of alprostadil patients with ED, but should only be used in (Caverject) in sildenafil (Viagra) failures. 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Int drug reduces penile vasoconstrictive sympathetic J Impot Res 2000; 12(Suppl 4): 67 – 73. tone enhancing the vasoactive effects of sildenafil. 20 Vogt HJ et al. Double-blind, placebo-controlled safety and The sildenafil – doxazosin association showed efficacy trial with yohimbine hydrochloride in the treatment of nonorganic erectile dysfunction. Int J Impot Res 1997; 9: 155 – neither an increase in side effects nor significant 161. blood pressure alterations. 21 Klotz T et al. Vardenafil increases penile rigidity and tumescence in erectile dysfunction patients: a RigiScan and pharmacokinetic study. World J Urol 2001; 19:32– 39. 22 Mydlo JH, Volpe MA, Macchia RJ. Initial results utilizing References combination therapy for patients with a suboptimal response to either alprostadil or sildenafil monotherapy. Eur Urol 2000; 38:30– 34. 1 NIH Consensus Development Panel on Impotence. NIH 23 Nehra A et al. Effectiveness of combination therapy of MUSE Consensus Conference. 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