Comparison of the Effect of Sildenafil and Apomorphine SL on Nocturnal Erections in Healthy Volunteers: A Placebo-Controlled Study

Transcription

1 European Urology European Urology 47 (2005) Comparison of the Effect of Sildenafil and Apomorphine SL on Nocturnal Erections in Healthy Volunteers: A Placebo-Controlled Study Andrea Salonia a, *, Luigi Barbieri a, Juza Chen b, Alberto Briganti a, Federico Dehò a, Richard Naspro a, Ubaldo Del Carro c, Kostantinos Rokkas a, Vincenzo Scattoni a, Patrizio Rigatti a, Francesco Montorsi a a Department of Urology, University Vita-Salute San Raffaele, Scientific Institute H. San Raffaele, Via Olgettina, 60, Milan, Italy b Department of Urology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel c Department of Neurology, University Vita-Salute San Raffaele, Scientific Institute H. San Raffaele, Milan, Italy Accepted 15 December 2004 Available online 5 January 2005 Abstract Objective: To compare the effects of sildenafil and sublingual (sl) apomorphine on nocturnal erections. Methods: In a prospective, single-blinded, placebo-controlled at-home study we compared the effect of apomorphine sl and sildenafil on sleep-related erectile activity in 30 healthy potent volunteers (mean age, 26.4 years; range, years; Erectile Function domain of the International Index of Erectile Function 26), not reporting any subjective sleep abnormality during 4 consecutive nights with rigidity monitoring (NPTR) with the RigiScan TM device. After the first night of adaptation, they were randomized to receive placebo or apomorphine sl 2 mg or sildenafil 50 mg taken at bedtime during the following 3 consecutive nights. Results: Sildenafil increased the mean SE number of erections, overall length of erectile events, and the time of erections with rigidity >60% at both tip and base, as compared to placebo. The same parameters were reduced after administration of apomorphine sl. Similar findings were observed with regards to Rigidity Activity Units and Tumescence Activity Units. Conclusions: Our results confirm that sildenafil taken at bedtime might increase nocturnal erectile activity also in young potent men as compared to placebo. Apomorphine sl taken at bedtime seems to have the opposite effect. # 2004 Elsevier B.V. All rights reserved. Keywords: Sildenafil; Apomorphine; Nocturnal erections; RigiScan 1. Introduction Sleep is an active process, not just a default state when incoming sensory information is reduced. Throughout the sleep period there are fluctuating levels of a series of neurotransmitters. Nocturnal erections may be considered a peculiar expression of these nocturnal fluctuations; they are reported to be present from infancy to senescence and are believed to represent an intrinsic mechanism aimed * Corresponding author. Tel ; Fax: address: salonia.andrea@hsr.it (A. Salonia). at protecting the morphodynamic integrity of the corpora cavernosa [1,2]. Penile blood engorgement occurring during nocturnal and erotic erections is associated with high corporeal oxygen tension (po 2 ), which plays a key role in the maintenance of normal corporeal morphology [3]. Data from the literature suggest that nocturnal erections can involve the cyclic release of nitric oxide (NO) [4,5]. Nocturnal penile tumescence and rigidity testing by means of the RigiScan TM device (Dacomed Corporation, MN, USA) has become a widely used method for evaluating men complaining of erectile dysfunction (ED), despite the unquestionable limitations of the method /$ see front matter # 2004 Elsevier B.V. All rights reserved. doi: /j.eururo

2 A. Salonia et al. / European Urology 47 (2005) [6,7]. Normative values for potent subjects have been identified by Hatzichristou et al. [8]. We have demonstrated that sildenafil taken at bedtime in patients suffering from ED and with good quality sleep significantly improves nocturnal erectile activity [9]. More recently, Rochira et al. [10] and Yaman et al. [11] independently assessed the effect of sildenafil on nocturnal erectile function in potent volunteers and showed that bedtime sildenafil is efficacious in improving sleep-related erections even in normal men. Sublingual apomorphine, a mixed D1/D2 dopamine (DA) receptor agonist, is the first centrally acting agent officially approved for the treatment of ED [12]. Selective postsynaptic D2 receptor activation seems to promote DA agonist-induced stretching-yawing and penile erection [13,14]. Dopamine-containing nerve endings seem to impinge on oxytocinergic cell bodies in the paraventricular nucleus (PVN), which, in turn, project to extra-hypothalamic brain areas (e.g., hippocampus, the medulla oblongata, and the spinal cord), activating proerectile central neurologic pathways involving NO signaling, and finally resulting in penile erection [12,14 17]. In our placebo-controlled at-home study we prospectively assessed the effect of sildenafil or apomorphine sl on nocturnal erections in a population of young potent volunteers to compare the impact of these two oral compounds on the nocturnal, non-erotic erections that are believed to represent an intrinsic mechanism aimed at protecting the morphodynamic integrity of the corpora cavernosa. 2. Methods From January 2002 to November 2003, 30 potent men (mean age, 26.4 years; range, years) entered this prospective, single-blinded, placebo-controlled, cross-over study. Inclusion criteria were normal erectile function as defined by an erectile function domain score of the International Index of Erectile Function (IIEF) 26 [18] and the subject s willingness to undergo a 4-night RigiScan TM evaluation of nocturnal erections at home. Exclusion criteria are listed in Table 1 and included factors potentially interfering with nocturnal erections, factors known to be associated with lack of efficacy of sildenafil or apomorphine sl, and factors contraindicating the use of both sildenafil citrate and apomorphine sl. Exclusion criteria also included a history of sleep disorders as well as the use of drugs (recreational drugs, hypnotic inducers, etc.) known to possibly affect sleep quality. The experimental design of the study, approved by the Ethics Committee of our university, was thoroughly explained to volunteers who were asked to sign an informed consent form. Men considered eligible for inclusion in the study were tested during 4 consecutive nights at home. The RigiScan TM monitoring device (supplied with the RigiScan Plus software 4.0) was applied Table 1 Exclusion criteria for entering the study 1. Affecting night erections Depression History of sleep disorders Use of drugs influencing the quality of sleep (hypnotics, psychotropics, dexamethasone) Cigarette smoking Hypogonadism 2. Affecting the efficacy of sildenafil or apomorphine sl History of poor libido Hypotestosteronemia Hyperprolactinemia History of neurogenic disorders (i.e., multiple sclerosis, spinal cord injury, Parkinson disease) 3. Contraindications related to the use of sildenafil or apomorphine sl Use of nitrates Use of central dopaminergic agonists or antagonists Use of complex (3 drugs) antihypertensive regimens Use of drugs interfering with the metabolic pathway of sildenafil or apomorphine (e.g., cimetidine, erythromycin, ketoconazole, protease inhibitors) Renal or hepatic failure Known allergy to any of the drug components to the volunteer s penis to record changes in penile tumescence and radial rigidity for the entire duration of each night. The first night (night 1) served as adaptation. The subjects were instructed to go to bed at their usual bedtime; the RigiScan TM device was applied to the penis and turned to the off position, in accordance with our previous experience [9]. Volunteers were then studied for 3 subsequent nights during which the penile erectile activity was recorded. During nights 2, 3, and 4, the subjects randomly received placebo (e.g., 2 capsules: a sublingual placebo pill plus an oral placebo pill) prepared by the hospital pharmacy, or apomorphine sl (e.g., 2 capsules: an sl pill containing apomorphine 2 mg plus an oral pill containing a placebo), or sildenafil (e.g., 2 capsules: an sl pill containing a placebo plus an oral pill containing sildenafil 50 mg) in a single-blinded fashion prior to bedtime. Oral compounds were perfectly identical in appearance as were the sl pills. However, the sl preparations differed in appearance from the oral preparations for the specific purpose of administering them properly. Doses were administered at least 2 hours after the end of dinner without the intake of any alcoholic beverages or any beverages containing caffeine (i.e., coffee), theine (i.e., tea), or theobromine (i.e., chocolate). Subjects were also instructed to take no sedatives or sleeping pills such as anxiolytics and stupefacients. All volunteers were also asked not to watch any violent movies and to refrain from any form of sexual activity during the 4 nights of athome monitoring of erectile function. The morning after each of the nights of RigiScan TM recording, each volunteer was interviewed concerning any sleep disorder and adverse effects induced by placebo, apomorphine sl, or sildenafil possibly occurring throughout the night, such as nausea, vomiting, headache, hot flushing, etc. Sleep duration was determined by the completion of the patient s daily sleep diary and by means of the patient s self-report. Erectile activity during sleep was measured by determining the following parameters: number of erectile events, erection-time/ sleep-time (%), total duration of tip and base rigidity >60%, average event tumescence, event tumescence percentage greater

3 526 A. Salonia et al. / European Urology 47 (2005) Table 2 Erectile activity observed during the 3 nights of recording (mean SE; p = Kruskal Wallis test) Placebo night Apomorphine night Sildenafil night p Session duration (min) No. of erectile episodes Erectile episodes duration (min) Erection-time/sleep-time (%) Duration of tip rigidity >60% Duration of base rigidity >60% than baseline, and values of Rigidity Activity Units (RAU) and Tumescence Activity Units (TAU). The potential impact of placebo, apomorphine sl, or sildenafil pharmacokinetics was assessed by evaluating the erectile activity observed in the first half of sleep duration versus the second half during the 3 nights of recording. Statistical analysis was based on the Kruskal Wallis test for repeated measures, the ANOVA one-way analysis of variance, and the Student t-test for the direct comparison of the mean SE values. The study was conducted in accordance with the principles of research involving human subjects as expressed in the Declaration of Helsinki. 3. Results All 30 volunteers completed the protocol with a mean sleep duration longer than 6 hours; thus, they were considered eligible for evaluation of results. Table 2 details various parameters of nocturnal erectile activity observed during the 3 active nights of recording in the 30 men. The number of erectile episodes was not significantly different (ANOVA: p = 0.65; F ratio = 0.444) during the 3 nights of recording (Table 2); sildenafil induced the greatest number of erections, followed by placebo and apomorphine sl. A direct comparison showed that sildenafil was able to promote a greater number of erections than apomorphine sl (Student t test p = 0.047). Moreover, sildenafil induced a significantly greater (mean SE) duration of the erectile episodes (ANOVA: p = 0.043; F ratio = 5.07) as well as a higher duration of rigidity >60% both at the tip (ANOVA: p = 0.044; F ratio = 8.09) and at the base (ANOVA: p = 0.033; F ratio = 7.11), followed by placebo and by apomorphine sl (Table 2). Similar findings were seen in the percentage of erection-time/sleep-time (ANOVA: p = 0.040; F ratio = 10.01). Table 3 details the values (mean SE) of TAU and RAU observed during the 3 nights of recording. Mean TAU and RAU values were significantly different during the 3 nights, at the tip (ANOVA: p = 0.043; F ratio = 8.01 and p = 0.033; F ratio = 9.67, respectively, for TAU and RAU) and at the base (ANOVA: p = 0.044; F ratio = 6.41 and p = 0.044; F Table 3 Integrated time intensity area measures of tumescence (TAU) and rigidity (RAU) results observed during the 3 nights of recording (mean SE; p = Kruskal Wallis test) Placebo night ratio = 12.44, respectively, for TAU and RAU) of the penile shaft, with sildenafil promoting the greater values, followed by placebo and apomorphine sl. Overall, the administration of apomorphine sl seemed to reduce nocturnal erectile activity. No significant difference in any parameter related to nocturnal erections was found in the first half of sleep duration versus the second half during the 3 nights of recordings. One man (10%) reported slight, self-resolving nausea on awakening after the administration of apomorphine sl. 4. Discussion Apomorphine night Sildenafil night RAU tip RAU base TAU tip TAU base Sleep oscillates between rapid eye movement (REM) sleep and light sleep and deep slow-wave sleep (SWS), which are collectively called non-rem sleep. Although the physiology of nocturnal erections is not completely understood, it has been suggested that erections occurring during REM sleep can involve the release of NO from nitrergic nerves, which then activates the hemodynamic series of events leading to rigidity [4,5]. Hatzichristou et al. demonstrated that in a young, potent individual an average of 4 episodes of full penile rigidity per night are expected [8]. During these episodes of corporeal blood engorgement, it is speculated that complete oxygenation of tissues occurs, thus potentially contributing to functional penis maintenance. Spontaneous erectile activity occurs during p

4 A. Salonia et al. / European Urology 47 (2005) the early stages of the life of any individual and nocturnal erections have been reported from early infancy to late senescence. Sildenafil is a safe and effective drug for the ondemand treatment of erectile dysfunction [19]. We previously demonstrated [9] that in >70% of patients with ED the administration of sildenafil before sleep produced nighttime erections that were significantly stronger than those after administration of a placebo. Namely, both RAU and TAU values recorded at the tip and base of the penis were significantly greater with the use of sildenafil. In addition, the total duration of penile tip rigidity >60% was significantly longer after sildenafil than after placebo administration. However, the average number of erectile events was not significantly different on the 2 nights of recording. More recently, Rochira et al. reported the results of a randomized, placebo-controlled, cross-over study that assessed the effect of bedtime sildenafil 50 mg and placebo on nocturnal erectile function in 44 healthy fully potent volunteers (mean S.D. age, years) [10]. Sildenafil induced an increased total number of valid erections, total duration of rigidity 70%, total duration of increase in penile circumference 30 mm, and maximum rigidity during both the first 4 hours and the whole 8 hours of monitoring. The authors therefore concluded that bedtime sildenafil is efficacious in improving sleep-related erections also in normal men, indirectly confirming that the NO pathway is crucial in the physiology of erections during sleep. Similar findings have been independently reported by Yaman et al. [11]. A potential bias of our present analysis is that the study was only a single-blinded trial. However, we do not believe that this limitation had an influence on the data interpretation. Overall, our current results confirm the data previously published, suggesting that bedtime sildenafil significantly increases overall nocturnal erectile activity more than placebo. This was clear in the analysis of the duration of the erectile episodes, the percentage of erection-time/sleep-time, and the duration of rigidity >60% both at the tip and base of the penile shaft. The effects induced by apomorphine sl, on the contrary, suggest a potential negative interaction between this dopaminergic agonist and the nocturnal, non-erotic erections. Several studies demonstrated that dopaminergic transmission is strongly related to REM sleep. For instance amphetamine-like stimulants, the most potent wake-promoting agents, increase wakefulness by blocking DA re-uptake or by stimulating DA release or both [20]. To evaluate the relative importance of dopaminergic and noradrenergic transmission in mediating wakefulness and modulating REM sleep, Nishino et al. demonstrated that several dopaminergic uptake inhibitors dose dependently increased wakefulness in both control and narcoleptic animals [21]. Dopamine uptake inhibitors also moderately reduced REM sleep, but this effect was most likely secondary to SWS suppression, because selective DA uptake inhibitors reduced both REM sleep and SWS proportionally. These results suggested that presynaptic activation of DA transmission is critical for the pharmacologic control of wakefulness. Dopaminergic receptor agents have different effects on sleep and wakefulness depending on their affinity for dopaminergic receptor subtypes and for presynaptic versus postsynaptic receptors [20]. Indeed, Ongini et al. demonstrated that A68930, a full DA D1 receptor agonist, and SKF 38393, a partial DA D1 receptor agonist, increased waking time, reduced the amount of REM sleep, and enhanced spontaneous grooming dose dependently [22,23]. However, although several studies demonstrated that DA and the dopaminergic system have profound influences on the manifestation of wakefulness and vigilance in humans [24], Shouse and coworkers recently showed that although norepinephrine (NE) and 5-hydroxytryptamine (5-HT) concentrations declined progressively from wakefulness to SWS and then to REM sleep, the concentrations of DA did not change across the sleep-wake cycle. They concluded that the release of NE and 5-HT modulates physiologic components related to the sleep-wake cycle, whereas DA does not [25]. Another bias of the present study is the lack of a rigorous sleep evaluation at the sleep laboratory. A NPTR combined with a polysomnography including electroencephalography, electro-oculogram, submental electromyogram, anterior tibial electromyogram, oronasal airflow, thoracoabdominal movements, and oxygen saturation, would certainly be better to evaluate any sleep modifications and to correlate each period of either REM phase and wakefulness or vigilance with any penile erection. Therefore, we may only hypothesize a potential correlation between REM sleep and the effect of apomorphine sl. However, in reference to the former, several observations regarding the correlation between the dopaminergic system and the pharmacologic control of wakefulness and REM sleep seem to suggest a possible explanation for the negative impact of apomorphine sl over the nocturnal erections that we have found in our series of healthy potent volunteers. Moreover, to date, to the very best of our knowledge, this

5 528 A. Salonia et al. / European Urology 47 (2005) paper is the first to investigate the impact of bedtime apomorphine sl on the nocturnal erectile function of fully potent men. These findings, of course, do not confirm any correlation with awake erectile function showing deterioration of the ED in patients taking apomorphine sl. Surprisingly, no significant difference in any parameter related to nocturnal erections was found in the first half of sleep duration versus the second half during the 3 nights of recordings. To better clarify this aspect, we examined the potential lack of balance between the pharmacokinetics of apomorphine sl and the overall session duration as registered by the RigiScan device. The absence of those expected differences might suggest that the pharmacokinetics profile of both apomorphine sl and sildenafil can cover the entire session duration for each night examined. Furthermore, Argiolas and Hedlund [12] clearly showed that apomorphine sl 2 mg reaches its T max after 0.74 hours, with a T 1/2 of hours, which approximately covers the mean session duration of the apomorphine sl night (namely, mean SE, minutes) in our series. The same study showed that apomorphine sl is rapidly absorbed after administration, achieving measurable plasma concentrations within 10 minutes, with a subsequent apparent complete disappearance after 6 to 8 hours [12]. 5. Conclusion Our results show an active role of sildenafil in promoting an amelioration of the nocturnal erectile function profile in potent volunteers, whereas they suggest that apomorphine sl results in a deteriorative effect. Complete oxygenation of tissues occurs during each episode of corporeal blood engorgement, suggesting a contribution to functional penis maintenance; these observations may suggest that increasing total nocturnal erectile activity could be hypothesized as a potential way of preventing the deterioration that usually occurs with the aging process often worsened by associated vascular risk factors. Therefore, further studies are needed to verify whether these preliminary observations may constitute the hypothetical basis for a potential use of phosphodiesterase type 5 inhibitors to prevent ED in the normal male population. On the other hand, the reduction of nocturnal erectile activity seen following the administration of apomorphine sl seems to exclude a role for this compound in the prevention of ED. Acknowledgements The authors are grateful to Prof. Lorraine Wood for reviewing the linguistic style of the manuscript. References [1] Morales A, Condra M, Heaton JPW. The interpretation of nocturnal penile tumescence monitoring. Curr Opin Urol 1995;5: [2] Hirshkowits M, Ware CJ. Studies of nocturnal penile tumescence and rigidity. In: Singer C, Weiner WJ, editors. Sexual dysfunction: a neuromedical approach. New York: Futura Publishing; p [3] Moreland RB. Is there a role of hypoxemia in penile fibrosis: a viewpoint presented to the Society for the Study of Impotence. Int J Impot Res 1998;10: [4] Shabsigh R. The effects of testosterone on the cavernous tissue and erectile function. World J Urol 1997;15:21 6. [5] Giuliano F, Rampin O, Benoit G, Jardin A. Neural control of penile erection. Urol Clin North Am 1995;22: [6] Allen RP, et al. Comparison of RigiScan and formal nocturnal penile tumescence testing in the evaluation of erectile rigidity. J Urol 1993;149: [7] Licht MR, et al. Comparison of RigiScan and sleep laboratory nocturnal penile tumescence in the diagnosis of organic impotence. J Urol 1995;154: [8] Hatzichristou DG, Hatzimouratidis K, Ioannides E, Yannakoyorgos K, Dimitriadis G, Kalinderis A. Nocturnal penile tumescence and rigidity monitoring in young potent volunteers. J Urol 1998;159: [9] Montorsi F, Maga T, Ferini Strambi L, Salonia A, Barbieri L, Scattoni V, et al. Sildenafil taken at bedtime significantly increases nocturnal erections: results of a placebo-controlled study. Urology 2000;56: [10] Rochira V, Granata AR, Balestrieri A, Madeo B, Carani C. Effects of sildenafil on nocturnal penile tumescence and rigidity in normal men: randomized, placebo-controlled, cross-over study. J Androl 2002;23: [11] Yaman O, Tokath Z, Inal T, Anafarta K. Effect of sildenafil on nocturnal erections of potent men. Int J Impot Res 2003;15: [12] Argiolas A, Hedlund H. The pharmacology and clinical pharmacokinetics of apomorphine SL. BJU Int 2001;88(Suppl 3): [13] Drolet G, Adams M, Heaton JPW. Evidence for the central sites of action of apomorphine-induced erections. Int J Impot Res 1996;8:108. [14] Melis MR, Argiolas A, Gessa GL. Apomorphine-induced penile erection and yawning: site of action in brain. Brain Res 1987;415: [15] Argiolas A, Melis MR. Neuromodulation of penile erection: an overview of the role of neurotransmitters and neuropeptides. Prog Neurobiol 1995;47: [16] Giuliano F, Rampin O. Central neural regulation of penile erection. Neurosci Biobehav Rev 2000;24: [17] Heaton JPW. Central neuropharmacological agents and mechanisms in erectile dysfunction: the role of dopamine. Neurosci Biobehav Rev 2000;24: [18] Cappelleri JC, Rosen RC, Smith MD, Mishra A, Osterloh IH. Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function. Urology 1999;54: [19] Salonia A, Rigatti P, Montorsi F. Sildenadil in erectile dysfunction: a critical review. Curr Med Res Opin 2003;19: [20] Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM. Dopaminergic role in stimulant-induced wakefulness. J Neurosci 2001;21:

6 A. Salonia et al. / European Urology 47 (2005) [21] Nishino S, Mao J, Sampathkumaran R, Shelton J. Increased dopaminergic transmission mediates wake-promoting effects of CNS stimulants. Sleep Res Online 1998;1: [22] Ongini E, Bonizzoni E, Ferri N, Milani S, Trampus M. Differential effects of dopamine D-1 and D-2 receptor antagonist antipsychotics on sleep-wake patterns in the rat. J Pharmacol Exp Ther 1993;266: [23] Trampus M, Ferri N, Adami M, Ongini E. The dopamine D1 receptor agonists, A68930 and SKF 38393, induce arousal and suppress REM sleep in the rat. Eur J Pharmacol 1993;235:83 7. [24] Nicholson AN, Pascoe PA. Dopaminergic transmission and the sleepwakefulness continuum in man. Neuropharmacology 1990;29: [25] Shouse MN, Staba RJ, Saquib SF, Farber PR. Monoamines and sleep: microdialysisfindingsinponsandamygdala. BrainRes2000;860: Editorial Comment Eric J. Meuleman, Nijmegen, The Netherlands e.meuleman@chello.nl e.meuleman@uro.umcn.nl The authors should be congratulated for their original and robust study design, using nocturnal penile tumescence and rigidity testing to compare the efficacy of sildenafil and apomorphine sl in normal men, which in my opinion is the most objective methodology to date to prove and compare efficacy of erectogenic drugs. This academic study is a true relief in the current era of preference trials sponsored by the pharmaceutical industry and introducing a host of subjective data and biased results. In the academia it is generally accepted that the best method to establish the efficacy of erectogenic medication is during sleep in normal men. However, most efficacy trials have been performed during audiovisual sexual stimulation in men with a broad spectrum of erectile dysfunction. Under these conditions, variables such as the extend of vascular and neural impairment as well as inhibition of the erectile response by psychological factors such as nervousness, embarrassment and distraction from the erotic stimuli form a significant bias in the interpretation of the results. The more because, at least in our laboratory, the response rate to audiovisual erotic stimuli is steadily decreasing, due to an overexposure to erotic stimuli in the media. This study confirms earlier studies of the same research group that sildenafil is effective to facilitate night time erections that are significantly stronger than those after administration of a placebo. This finding and the knowledge that night time erections represent phases of cavernous oxygenation and therefore improve the prognosis for recovery of spontaneous erections following radical prostatectomy (RP), currently contributes to the believe that daily dosing of a PDE5 inhibitor may be beneficial in men following RP. On the contrary, the effects induced by 2 mg apomorphine sl in this study suggest a potential negative interaction between this dopaminergic agonist and nocturnal, non-erotic erections. Although a rigorous sleep evaluation in a sleep-lab is lacking, the authors hypnotize that the negative interaction is mediated by the relative role of dopaminergic and noradrenergic transmission in mediating wakefulness and reducing REM sleep. Two facts are certain: (1) two mg apomorphine sl does not improve cavernous perfusion during sleep and (2) this study does not show that apomorphine sl negatively impact on awake erectile function.