Developmental Status of Topical Therapies for Erectile and Ejaculatory Dysfunction

Developmental status of topical therapies for erectile and ejaculatory dysfunction

A Morales1*

1Queen's University, Department of Urology, Kingston General Hospital, Kingston, Ontario, Canada

The most common of the sexual dysfunctions in men are premature ejaculation and impotence. Large strides have been made in the treatment of erectile disturbances but only limited and temporary successes have been achieved in the therapy of ejaculatory abnormalities. This manuscript examines the realm of topical therapy, its current limitations and the challenges that must be addressed if topical therapy is ever to have a niche in the urologist's treatment armamentarium. Topical agents for the treatment of premature ejaculation include anesthetics and herbal medications. The limited nature of the studies reported to date does not yet permit a reliable assessment of their ef®cacy. For the treatment of erectile dysfunction, some of the drugs administered by various other systemic routes appear to have some ef®cacy when delivered transdermally. Again, the studies and results are too limited for the urologist to develop a clear opinion about their ef®cacy. Further investigation of these drugs with the use of absorption enhancers is needed. International Journal of Impotence Research (2000) 12, Suppl 4, S80±S85.

Keywords: erectile dysfunction; premature ejaculation; topical therapy; review

Introduction Oral,1 intraurethral2 and sublingual3 administration of drugs have opened new and more acceptable avenues of therapy for ED. In the case of PE, the The most common sexual complaints in men are picture is different. Oral medications have produced premature ejaculation (PE) and erectile dysfunction only limited and temporary success and topical (ED). Both problems create signi®cant dif®culties for agents, usually anesthetics, have enjoyed waxing the sufferer and his partner, but the causal mechan- and waning interest because they have proven to be isms and therapeutic management of these condi- too cumbersome, ineffective, or tend to cause diffuse tions are dissimilar. This review will present, genital anesthesia which is not conducive to a separately, the current knowledge about topical satisfying experience. agents used to treat these two conditions. Topical (from the Greek, topicos: relative or related to a speci®c site, in this case, the penis) agents have not fared well in either the treatment Premature ejaculation of ED or PE. New compounds have offered initial promising initial results but demand further study to establish their effectiveness. Premature ejaculation or premature orgasm is The search for effective, non-invasive pharmaco- de®ned as the persistent or recurrent ejaculation of logical therapy for ED led to the exploration of semen with minimal sexual stimulation before, various routes of administration for compounds that upon or shortly after vaginal penetration and before are capable, by a number of mechanisms, of the person or his partner desires it.4 It is the most inducing or enhancing smooth muscle relaxation widespread form of male sexual dysfunction with an in the corporal bodies. Ultimately, the relaxant estimated prevalence in `normal' men of between 30 effect on smooth muscle should result in a satisfac- and 40%.5 It is commonly accepted that the normal tory penile erection. Although the search has been intravaginal ejaculatory latency time (IVELT) should enthusiastic, effective and safe medications have be no less than 2 min. The cause(s) of the dysfunc- only recently been evaluated and only a few of them tion are not thoroughly understood but it is have become part of the clinician's armamentarium. recognized that the neurological aspects of ejaculation involve two re¯ex mechanisms. The ®rst *Correspondence: A Morales Queen's University, Kingston (afferent) re¯ex is initiated by stimulation of the General Hospital, Kingston, Ontario, Canada. genital receptors, then travels through the pudendal E-mail: [email protected] nerves to the sacral cord with a ®nal destination at Topical therapies for erectile and ejaculatory dysfunction A Morales S81 the limbic lobe and the hypothalamus. The second Encouraging results utilizing this product were also re¯ex is transmitted from the urethra to the reported recently by Porst.15 Uncontrolled studies, ejaculatory center (segments S2 ± 4). Efferent ®bers however, offer little information about the ef®cacy of of pudendal parasympathetic nerves broadcast sig- a medication used to treat this condition in which nals to the ganglia; these signals result in the release emotional factors play such a signi®cant role. of neurotransmitters which, by depolarizing peri- Furthermore, without bene®t of further assessment neal muscles, translate into rhythmic contractions or follow-up, the promising results of these limited and seminal emission.6 studies are called into question, leaving the true Behavioral therapy has been commonly used to ef®cacy of the compound uncon®rmed. Research treat PE. Treatment paradigms have generally been methods are also in need of improvement. For empirical and the proposed underlying emotional example, although the IVELT may indeed improve abnormalities have not been reliably documented. following treatment, this approach to evaluating Successes of behavioral therapy are limited and drug ef®cacy carries some signi®cant drawbacks: it almost invariably have been temporary; most of the requires a 30 min application, the use of a condom, post-therapy bene®ts are lost within 3 y of treat- the cost is relatively high, and the patient must ment.7 This monumental failure of behavioral endure numbness of the entire penis. therapy, not surprisingly, has led to an increasing We have recently embarked upon a study of a `medicalization' of the treatment of PE. proprietary metered-dose aerosol formulation of the Systemic pharmacotherapy is another pillar of the same agents (prilocaine lidocaine) in a formula- treatment for PE. Adrenergic antagonists have tion known as a `eutectic mixture' that causes both demonstrated ef®cacy in a few small studies.8 drugs to remain in liquid form at room temperature. Similar remarks can be applied to the use of Since penetration of most drugs is inversely propor- gamma-amino butyric acid (GABA), a neurohor- tional to the percentage of drug in ionized or mone that inhibits neural pathways. The lack of charged form, the delivery of pure base drug will follow-up studies suggests that their ef®cacy theoretically provide the best penetration of the (although not their cost) is comparable to that of compound. The main advantage is that the agent can behavioral therapy. Serotonin reuptake inhibitors be delivered to a speci®c, limited area (in this currently enjoy much popularity. The non-selective situation, to the glans penis). Furthermore, the blocker clomipramide,9 and the selective blockers, slightly oily nature of the drug combination ensures ¯uoxetine10 and paroxetine11 are reported to in- that it stays at the site (residency). Its effect is crease the IVELT for up to 10 min. All of these prompt (10 ± 15 min) and once the glans is anesthe- compounds required continuous dosing and are, not tized, the thin ®lm can be wiped off with a damp surprisingly, associated with side effects (dizziness, cloth, avoiding the need for a condom to prevent dry mouth, fatigue, diarrhea). partner contamination. The initial results are Men with PE exhibit abnormal autonomic re¯ex encouraging16 but further experience is needed. pathways for the ejaculatory process. The reported abnormalities are, most commonly: lower vibratory threshold to ejaculation; shorter bulbocavernous Herbal extracts latency time, and higher bulbocavernosus evoked potentials.12,13 Such ®ndings provide the rational The SS cream (Cheil Jedang Corporation, Seoul, background for dampening the sensory input from Korea) is a proprietary preparation consisting of the glans that could return these men to a baseline extracts of nine herbal medicines: Bufonis venenum, circuitry and increase the IVELT. Therapeutic Angelicae gigantis radix, Cistanchis caulis, Torilis intervention with topical agents, believed to be semen, Ginseng radix alba, Zanthoxylli fructus, capable of correcting the heightened genital sensi- Asiasari radix, Caryophylli ¯os and Cinnamoni tivity, is presently limited to the agents described cortex.17 It is applied to the glans about 1 h prior below. to intercourse and then removed with a wet towel shortly before foreplay and vaginal penetration. Initial claims of ef®cacy were positive and, more Topical anesthetics (TA) recently, a controlled study has supported these claims. In a double-blind, randomized, multicenter trial of 106 patients, Choi et al18 reported that `the The rationale mentioned above makes the use of TA mean ejaculatory latency was signi®cantly an appealing possibility for treating patients with prolonged after the application of SS-creams PE. Unfortunately, TAs have been used indiscrimi- (10.92 Æ 9.83 min) (placebo: 2.45 Æ 2.95). Prolonga- nately and the literature offers very few credible tion of ejaculatory latency more than 2 minutes than studies. Berkovitch et al14 reported a marked im- that of the screening period were 82.2% after the provement in IVELT with the use of a prilocaine application of SS-cream (10.3% in placebo)'. The lidocaine cream (EMLATM, Astra Pharmaceuticals, adverse effects are mild, mostly due to local irritation Wayne, PA) in nine of 11 men treated for PE. (80%), and disappear spontaneously within 1 h of

International Journal of Impotence Research Topical therapies for erectile and ejaculatory dysfunction A Morales S82 application. Although the rate of success appears to Papaverine be signi®cant, it offers no cure, and the patients need to apply the cream in a repetitive manner. These data appear to support the ef®cacy and This phosphodiesterase inhibitor was the ®rst agent safety of the SS-cream, which compares favorably to to achieve wide acceptance as an effective intraca- recent reports about more orthodox systemic phar- vernosal agent for the treatment of ED.21 For topical macotherapy.10,11 Until the study published by Choi application, papaverine was formulated as a gel et al, all reports on the ef®cacy of the herbal cream (also containing the skin permeation enhancer had been initiated by its developers. Justi®able cyclodextran) both as the hydrochloride salt and as interest exists for these promising observations to the base at concentrations ranging from 133 to be con®rmed by independent investigators. 500 mg.22 The relatively large molecule (molecular weight 376 D) did not readily cross the dermal barrier despite the large area of skin smeared with the preparation (penis, scrotum and perineum). Erectile dysfunction Predictably, the results were unsatisfactory: three patients in the placebo group and three in the papaverine groups developed erections (total of only As mentioned above, topical treatment for ED is 17 men). However, the erections in the papaverine extremely appealing for its simplicity and its limited group lasted longer than those in the placebo group. or absent systemic distribution. Many agents that are Because of its molecular size, it is doubtful that capable of inducing smooth muscle relaxation when enhancers would improve the penetration of papa- administered by their intended routes (eg oral or verine through the stratum corneum. Considering parenteral) have also been examined for their that no further reports have appeared from these or potential ef®cacy when applied topically. Following from other investigators, it is safe to assume that the is a review of the reports on the ef®cacy of various concept of topical papaverine gel was impractical compounds that have been used topically for and that its use has been curtailed. treating ED. The review does not attempt to be exhaustive as it is limited to a Medline search of peer-reviewed publications and conference proceed- ings. Not surprisingly, most of the drugs discussed Prostaglandin E1 below are vasoactive pharmacological agents that either initiate or enhance a penile erection by Among the vasoactive agents for the treatment of ED, various mechanisms resulting in corporal smooth prostaglandin E1 (PGE1) has enjoyed a long and muscle relaxation. distinct reputation for safety and ef®cacy.23 Not surprisingly, however, the injectable intracavernosal route has not been particularly inviting to patients, their partners or their physicians. Once again, the Glyceryltrinitrate (GTN) or nitroglycerin topical route for drug delivery was explored. Under the strict de®nition of `topical', the intraurethral (IU) This agent has long been recognized as a powerful route of administration would qualify for inclusion coronary vasodilator and this property made it a in this review, but PGE1 administered by the IU natural, early candidate as an erectogenic agent. It route is thoroughly discussed elsewhere in this was initially used topically on the penis for a issue.24 diagnostic purpose in an effort to eliminate the need for an injection during evaluation of the vascular 19 penile bed by Doppler ultrasonography. Although Androgens the administration of GTN 2% paste (1 inch applied to the penile shaft) was shown to induce arterial vasodilatation, it frequently resulted in tumescence Investigators have concentrated their efforts in episodes but rarely in penile rigidity of adequate topical delivery of drugs to the genitals to those quality for intercourse; this study was performed with vasodilatory activity. Topical testosterone is under laboratory conditions by the author and his the only drug that has been successfully used to colleagues. This same group of investigators next deliver a systemic dose of drug by the transdermal explored the usefulness of GTN as an erectogenic route. An adequate hormonal milieu is fundamental agent, also under laboratory conditions but supple- for proper sexual function and in hypogonadism mented with erotic visual stimulation.20 Once again, both sexual desire and performance may be ad- tumescence was achieved in 18 of 26 the men versely affected. The oral and parenteral routes have treated but no signi®cant rigidity was observed. been used for effective normalization of androgen Further experiments with this compound have since levels and, more recently, testosterone patches for been abandoned. transdermal delivery have become available.

International Journal of Impotence Research Topical therapies for erectile and ejaculatory dysfunction A Morales S83 Because this subject is discussed at length in used to bypass the skin's formidable barrier to the another article in this issue,25 it will suf®ce to passage of therapeutic compounds. The main inter- mention here that both transdermal routes (scrotal est has focused on SEPA, the acronym for, `soft and non-scrotal) are effective, imitate closely the enhancer for percutaneous absorption'. This com- circadian levels of testosterone and are safe, with the pound is capable of temporarily modifying the lipid exception of local skin problems.26 structure of the keratinized layer of the skin (stratum corneum), allowing passage of externally applied molecules.34 Only low molecular weight com- Other miscellaneous agents pounds can enjoy the effects of this enhancer, while those of higher molecular weight and microbes cannot. A recent preliminary study conducted A variety of other vasodilators have been reported to by McVary et al35 also reported an encouraging be effective when administered topically. These response for the PGE1=SEPA formulation, ie sig- agents are mentioned brie¯y for the sake of com- ni®cantly better than placebo at doses of 0.5, 1 and pleteness, but have either not progressed past the 2.5 mg. The same proprietary formulation of initial positive results or such results have been PGE1 SEPA (TopiglanTM, MacroChem Corporation, refuted in subsequent studies. Lexington, Massachusetts, USA) was used in a Minoxidil was reported by Cavallini27 not only to randomized, double-blinded, single-institution be effective transcutaneously but superior to GTN. study under laboratory conditions.36 In this parti- When his results could not be reproduced,28 a cular study, patients were exposed to neutral and remarkable response was reported by the same erotic ®lms and were assessed frequently by an investigator with the combination of minoxidil and investigator. Outcome measures included a self- capsaicin.29 Diligent literature searches for further report by the subject, the investigator's report and a positive results on minoxidil alone or in combination photograph of the patient while standing in front of have been fruitless. a protractor in order to measure the angle of erection Yohimbine appears to have erectogenic activity from the vertical. Twelve of the 31 patients (38.8%) when administered by the oral route.30 Although its receiving topical PGE1 SEPA developed an erec- large molecular size and pharmacological action tion probably suf®cient for vaginal penetration does not make it a logical candidate for the while only two of 29 (6.9%) of those receiving intracavernosal or topical (penile) route, there was placebo developed an adequate erection. Adverse a single report indicating that it was effective when events were minimal and temporary (mild warmth applied chronically (for 2 months) to the balano- and burning and, rarely, tingling or coolness). These prepucial sulcus. The reported difference in re- results are certainly encouraging and even more so sponse was signi®cantly better for yohimbine than when one considers the conditions under which the placebo.31 Again no further reports have appeared to study was conducted. The subjects, whose mean age con®rm these initial surprising results. was not speci®ed, were dealing with a `white-coat effect' and with intrusive visits every 15 min to assess the degree of local irritation, the degree of Use of penetration enhancers erection and were photographed. In the author's opinion, only powerful medication and particularly effective visual and vibratory stimulation could With the notable exception of nitroglycerin, which overcome such conditions and demonstrate effec- readily crosses all skin barriers, all other com- tiveness. Unfortunately, these type of `drillings' are pounds confront a formidable obstacle in reaching mandatory in phase I studies designed to evaluate the penile corporal tissue. The barriers are the skin safety and ef®cacy of new drugs. A multicenter, epidermis and its strati®ed squamous epithelium dose ± response study using the same preparation and the tunica albuginea of the corpus cavernosum. and a very similar study protocol but with a Application of medications to the penile shaft faces larger population (n 114) reported similar positive the ®ercest resistance. After histological studies results.37 characterized the skin layers of the glans,32 an Signi®cant hemodynamic changes were reported alternative approach using penetration enhancers by Becher et al38 following the application of PGE1 has been considered for applying agents to the with another permeation enhancer (NextActTM, penis. NextMed Inc. Commerce, California), the nature of The application of transdermal PGE1 with pene- which was not speci®ed in the report. In this very tration enhancers and visual sexual stimulation met limited study with only 10 subjects, it was found with remarkable success (67%) in patients with that the preparation produced hemodynamic mild arteriogenic erectile dysfunction. Evidence has changes undistinguishable from those induced by been published presenting objective increases in intracavernous injections of alprostadil. This author local vascular activity as measured by Doppler is unaware of further published reports about this sonography.33 More recently, medications have been preparation. A novel, topical, lipid-based delivery

International Journal of Impotence Research Topical therapies for erectile and ejaculatory dysfunction A Morales S84 system for PGE1 was reported to exhibit erectogenic achieving an appealing, simple, effective and safe capacity.39 However, the response rate in the PGE1 form of drug delivery to the target organ in question. group was quite low (10% vs 0% for the placebo) There is a long siege ahead yet. and the study was insuf®ciently powered to be interpretable. Further investigations of the PGE1 combined with permeation-enhancers in natural settings are desir- able and, hopefully, are already in progress. Until References convincing results with home use of the topical PGE1 are reported, a very cautious approach to the 1 Goldstein I et al. Oral sildena®l in the treatment of erectile modality is appropriate. dysfunction. New Engl J Med 1998; 338: 1397 ± 1404. 2 Padma-Nahan H et al. Treatment of men with erectile dysfunction with transurethral alprostadil. New Engl J Med 1997; 336: 1±7. The Borges procedure 3 Heaton JPW et al. Recovery of erectile function by oral administration of apomorphine. Urology 1995; 45: 200 ± 203. 4 Masters W, Johnson V. Human Sexual Inadequacy, London: This operation is mentioned here because it was Churchill, 1970. 5 Reading A, Weist W. An analysis of self-reported sexual developed as a means to cirumvent the obstacle to behavior in a sample of normal males. Arch Sex Behav 1984; drug penetration of the tunica albuginea. The 13: 69 ± 83. procedure consists of making a small window on 6 Vickers MA. The forgotten dysfunction: a pharmacological the tunica exposing the corpus cavernosus. The approach to premature ejaculation. In: Morales A, ed., Erectile defect is then covered with a patch of the super®cial Dysfunction: Issues in Current Pharmacotherapy, London: Martin Dunitz, 1998, pp 253 ± 267. 40 dorsal vein of the penis. The Borges technique was 7 DeAmicis L et al. Clinical follow-up of couples treated for reported to increase the response to GTN but no sexual dysfunction. Arch Sex Behav 1985; 14: 467 ± 489. responses were detected following the application 8 Beretta G et al. Effect of an alpha-blocking agent (phenox- of PGE1. It should be noted, however, that the PGE1 ybenzamine) in the management of premature ejaculation. Acta Eur Fert 1986; 127: 43 ± 45. was used alone (without enhancer) or mixed with 9 Girgis S, El-Haggar S, El-Harmouzy S. A double blind trial of 50% dimethyl sulfoxide which is readily absorbed clomipramine in premature ejaculation. Andrologia 1982; 14: but is not a carrier molecule. Despite the fact that the 364 ± 368. results have not been replicated either by the 10 Kara H et al. The ef®cacy of ¯uoxetine in the treatment of original author or other investigators, it may be premature ejaculation: a double blind placebo control study. J Urol 1996; 156: 1631 ± 1632. worth considering because of its relative simplicity 11 McMahon CG, Touma K, Johnston H. Treatment of premature when transdermal compounds are investigated. ejaculation with paroxetin hydrochloride. Int J Impot Res 1998; 10(Suppl 3): S38. 12 Vignoli G. Premature ejaculation: new electrophysiological approach. Urology 1978; 11: 81 ± 82. Conclusion 13 Xin Z et al. Somatosensory evoked potentials in patients with primary premature ejaculation. J Urol 1997; 158: 451 ± 455. 14 Berkovitch M, Karesteci A, Koren G. Ef®cacy of prilocaine ± One of the most memorable episodes in the history lidocaine cream in the treatment of premature ejaculation. J Urol 1995; 154: 1360 ± 1361. of human con¯ict is that of the Trojan war, not for its 15 Porst H. Management of sexual (erectile and ejaculatory) geopolitical signi®cance nor for its historical trans- disorders of the aging male. Aging Male 2000; 3: 19. cendence but for its romantic overtones and the 16 Henry R, Morales A. Unpublished observations. demonstration of human ingenuity and foolishness. 17 Product Insert of SS Cream. Cheil Jedang Corporation, Seoul, The root of the con¯ict, according to legend, was Korea. 18 Choi HK et al. A double blind randomized placebo controlled Helen of Troy, but probably there were more serious multicenter phase III clinical study of SS-cream in patients issues in dispute: commerce, land, beliefs. Even- with primary premature ejaculation. Int J Impot Res 1998; tually, the Athenians established the siege of Troy 10(Suppl 3): S22. lasting several years, but the defenses of the city 19 Heaton JPW et al. Topical glyceryltrinitrate causes measurable proved to be impenetrable. After more than 9 y, after penile dilatation in impotent men. J Urol 1990; 143: 729 ± 731. 20 Owen JA et al. 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Appendix Dr Morales: It's available in the States and it's used by pediatricians before doing a venipuncture in children. The problem in premature ejaculation is Open discussion following Dr Morales' presentation that you pass it to the partner and it produces anesthesia of the penis, so it decreases the sensation. And you have to use a condom. Dr Morales: I would like to comment about the use of topicals for the treatment of premature ejacula- Dr Porst: It decreases the sensation, but I tell the tion. Many of you have heard of a physician in males that they have to clean the penis of the EMLA Argentina who had done a penectomy for the before they engage in sexual intercourse. And it only treatment of premature ejaculation. There is another works when you have a prepuce. In circumcised one from Brazil who has a series of patients with males, EMLA does not work, and I tell them to apply premature ejaculation and cancer of the penis. EMLA and to put on a condom over and then it These patients underwent a partial penectomy. It's works. Either you have a prepuce or, when you are very interesting that, even following the penectomy, circumcised, you have to apply a condom for about they continued to have premature ejaculation. I 20 min. There are no prospective GCP studies on don't know if there is such a thing as a phantom premature ejaculation, but that makes me wonder this. about the effectiveness of local therapies. Dr Porst, Dr Wyllie: There's at least a couple of studies you are familiar with the use of EMLA. where penetration enhancers were used with GTN topically, to increase the transport of the glycerol Dr Porst: I use it a lot and quite successfully. trinitrate. But, unfortunately, they found if you EMLA is a combination of prilocaine and lidocaine, increase the transport, you get a full systemic and is very common in Germany for premature vascular effect and vascular headache. Tumescence ejaculation. Apply it 20 min before and its success and rigidity were quite reasonable, but the side rate is between 40 and 50%. effect pro®le was unacceptable.

International Journal of Impotence Research