Pharmacotherapy in the Treatment of Male Sexual Dysfunction.

The past ten years have witnessed significant advances in the treatment of men's sexual dysfunctions, many of which can be attributed to the introduction of effective pharmacologically-based therapies. Pharmacotherapy offers a range of proven options that can be used to treat sexual problems of varied and even unidentified causes. Of equal significance, these methods may be changing the way in which both patients and health professionals approach men's sexual problems--greater responsibility (and thus the need for expertise) is shifting to the medical profession, and, within the medical profession itself, to the primary care physician (Kloner, 1999). Furthermore, the new pharmacopiea seems to be altering the social milieu surrounding sexual dysfunction. With promise of a revitalized sex life, men with sexual dysfunctions appear to be seeking help and hope at unprecedented levels. Indeed, the recent introduction of sildenafil has heightened the public awareness of and discourse about men's sexual dysfunction (e.g., Handy, 1998; Watson et al., 1998). Although perhaps only temporary, it is reminiscent of the publicity and individual testimonials that accompanied the introduction of the first antidepressant agents in the mid-50s, a process that helped destigmatize depression.

In this paper, we focus on recent advances in the pharmacological treatment of the two major sexual dysfunctions in men, erectile dysfunction (ED) and premature ejaculation (PE). As part of this discussion, we describe the efficacy, mechanism of action, and problems regarding specific drugs, as well as the populations that stand to benefit most from them. In a later section, we discuss broader issues surrounding the use of drugs in the treatment of sexual problems, including the potential value of taking a multidisciplinary approach to achieve high outcome satisfaction on the part of the patient and his partner.

THE DRUG TREATMENT OF ERECTILE DYSFUNCTION

General Background

Erectile dysfunction (ED), commonly known as impotence, has entered the spotlight in recent years as its medical importance has become increasingly appreciated and as clinical applications to treat the disorder have been rapidly advanced. Indeed, new therapies that promise to overcome the limitations of traditional biomedical offerings have revolutionized the management of ED. Past treatments have been perceived as too unnatural or invasive or, if less invasive, were found largely ineffective or unsatisfying to use. Medically-based treatment options have evolved from surgically implanted penile prostheses or externally applied devices (e.g., vacuum pump) that mechanically create a rigid penis to a host of simply administered pharmacotherapies that reliably elicit a naturally appearing and useable erection. Much of this progress stems from a better understanding of the complex physiological and molecular mechanisms underlying the erectile process as well as the pathogenic factors associated with ED.

Erectile dysfunction is typically defined as the inability to achieve an erection sufficient for penetration or to maintain an erection following intromission. It is hardly an uncommon problem, affecting as many as 30 million American men and approximately 30% of all men between the ages of 40 and 70 (National Institutes of Health Consensus Conference, 1993). Its significance is all the more compelling given the implications of sexual failure and its associations with anxiety, depression, marital discord, and even violence. Given the prevalence of ED, the recognition of its impact on the quality of life, and the advent of an expanded range of treatment options, the climate is ready for all clinicians and therapists, not just those who regularly treat sexual dysfunctions, to understand the mechanisms of the problem and the various treatment options (Burnett, 1998). Indeed, all clinicians should be reasonably able to conduct a basic assessment of the problem and then competently proceed to discuss treatment options, make referrals, or, when appropriate and qualified, initiate their use.

Current pharmacotherapies for ED range from local (e.g., intracavernosal, intraurethral, topical) to systemic (e.g., subcutaneous, oral) options. This diversity reflects the imaginable routes of administration of medications as well as the pervasive belief that different therapies may be necessary to treat ED, of varying type and severity. It also acknowledges that patients differ in their choice of therapies according to their aptitudes and inclinations towards the various options. Patients may commonly feel that available options still do not adequately meet all the requirements for the ideal treatment, including convenient delivery, minimal or absent side effects, low cost, and reliable and on demand efficacy (Morales, Heaton, Johnston, & Adams, 1995).

Mechanisms of Erection

Prior to considering available pharmacotherapies and their implementation, a basic familiarity with the physiologic process of penile erection is helpful. Penile erection is a vascular process involving increased arterial inflow to the penis, penile engorgement with blood, and decreased venous outflow from the organ; these processes result in sufficient rigidity for sexual intercourse (Lue, 1992) (see Fig 1). Whether the penis is erect or flaccid depends upon the physiology of corporal smooth muscle tone, that is, the equilibrium between proerectile and antierectile mechanisms controlling, respectively, relaxant and contractile responses of the smooth muscle cells comprising the penile blood vessels and cavernous tissue (see Table 1). Specifically, the erect penis results from relaxation of smooth muscle cells--the vasculature (arteries, arterioles, and capillaries) in the penis opens to allow the increased necessary for engorgement. The flaccid penis is characterized by contraction of smooth muscle cells--constricted vasculature limits the blood flow to the penis.

[Figure 1 ILLUSTRATION OMITTED]

Table 1. Basic Physiology of Penile Erection

System                            Proerectile         Antierectile

Smooth muscle tone                Relaxation          Contraction

                                  [down arrow]        [down arrow]

Vasculature and erectile tissue   Dilation            Constriction

                                  [down arrow]        [down arrow]

Erectile response                 Penile erection     Tonic
                                                      flaccidity

The erectile mechanisms operating at the level of the smooth muscle cells in the penis are quite complex (Andersson & Wagner, 1995; Christ, 1995; Giuliano, Rampin, Benoit, & Jardin, 1995; Saenz de Tejada, 1992). At the extracellular level, neurotransmitters, hormones, and locally released substances from penile tissue both originate and modulate the biochemical signals that produce erection. At the cell membrane and the intracellular level, second messenger molecules (e.g., cGMP or cAMP) and ions carry out the signal via the action of receptor proteins or enzyme pathways. At the intercellular level, the ion channels and gap junctions propagate the signal from one cell to the next. The cumulative input of these factors in response to an erectile stimulus then produces a coordinated physiological response in the penis.

The above processes are regulated primarily by the neurological system. This system exerts both proerectile and antierectile actions at the central and peripheral levels through adrenergic, cholinergic, and nonadrenergic noncholinergic (NANC) neurotransmitters (Burnett, 1999; Giuliano et al., 1995)(see Table 2). At the central level, several spinal and supraspinal sites have been implicated in the control of penile erection--these operate through various ascending and descending neuronal circuits and involve such neurotransmitters as monoamines, amino acids, neuropeptides, and gaseous molecules. At the peripheral level (autonomic nervous system), the gaseous molecule nitric oxide released primarily from parasympathetic nerve endings coursing to the penis serves as the major proerectile mediator by relaxing smooth muscle cells. In contrast, the sympathetic neurotransmitter norepinephrine released from adrenergic nerve terminals in the penis serves as the major antierectile mediator by contracting smooth muscle cells.

Table 2. Factors and Mechanisms Affecting Erectile Response Commonly Altered Through Pharmacotherapy Directed at Penile Physiology

Source                         Proerectile

Peripheral autonomic nervous
  system component             Parasympthathetic
Postganglionic nerve           Cholinergic
Conventional transmitter at
  neuromuscular junction       Acetylcholine
Nonadrenergic-noncholinergic
  (NANC) neural mechanisms     Nitric oxide
Vasculature endothelium        Nitric oxide (EDRF)
Intracellular mechanisms       Promote nucleotides
                                 (adenylate or guanylate cyclases)

Source                         Antierectile

Peripheral autonomic nervous
  system component             Sympathetic
Postganglionic nerve           Adrenergic
Conventional transmitter at    Norepinephrine
  neuromuscular junction         ([alpha.sub.1]-receptors)
Nonadrenergic-noncholinergic
  (NANC) neural mechanisms     Neuropeptide Y (and others)
Vasculature endothelium        Endothelin
Intracellular mechanisms       Break down nucleotides
                                 (phosphodiesterases)

Note. This simplified table does not incorporate many other presumed or known factors involved in erection. In general, agents stimulating factors and mechanisms on the left side (often acting as agonists), or inhibiting factors and mechanisms on the right (often acting as antagonists), promote erection.

In addition to neurological control, several factors released locally from the corporal tissue of the penis help maintain a tonic flaccid state through vascular constriction (these factors are opposed by vasodilatory substances such as nitric oxide released from vascular endothelium, also known as endothelium-derived relaxation factor [EDRF]: see Tables 2 & 3). Specifically, at the level of the corporal smooth muscle cell, second messenger molecule systems are responsible for stimulating specific biochemical or ionic processes that alter the responsiveness of corporal smooth muscle. Enzymatic pathways (e.g., phosphodiesterase) within the muscle cell may inactivate signal transduction pathways across the cell membrane to suppress erectile function. Intracellular ion homeostasis (i.e., the relative balance between sodium, potassium, chloride, calcium, etc.) may also regulate corporal smooth muscle tone by affecting the membrane potential of the smooth muscle cells.

Table 3. Putative Mediators of Penile Erection

Regulatory site   Proerectile

Brain             Dopamine
                  Oxytocin
                  Nitric oxide
                  Glutamic acid
                  Aspartic acid
                  Adrenocorticotropin
                  Acetylcholine
                  Norepinephrine

Spinal cord       Serotonin (5-[HT.sup.2c])
                  Oxytocin
                  Nitric oxide

Penile nerves     Nitric oxide
                  Acetylcholine
                  Vasoactive
                  intestinal peptide
                  Calcitonin
                  generelated peptide
                  Substance P
                  Adenosine
                  triphosphate

Corporal tissue   Nitric oxide
                  Prostaglandins
                  Bradykinin

Regulatory site   Antierectile

Brain             Opioid peptides
                  Prolactin

Spinal cord       Serotonin ([5HT.sup.2], [5HT.sup.1A])
                  GABA
                  Dopamine

Penile nerves     Norepinephrine
                  Neuropeptide Y

Corporal tissue   Endothelin
                  Angiotensin II
                  Thromboxane
                  Histamine

Pharmacological Principles of Managing ED

Pharmacotherapeutic strategies for ED either promote proerectile mechanisms or suppress antierectile mechanisms, or do both. These objectives are based on the knowledge that the erectile state represents a finely controlled equilibrium between proerectile and antierectile mechanisms that influence corporal smooth muscle tone. Promoting proerectile action can be achieved by either (a) inducing smooth muscle relaxation through cell-receptor agonists or direct activators of tissue relaxant pathways (e.g., stimulating second messenger cyclic nucleotide [cGMP or cAMP] synthesis) or (b) inhibiting the deactivation of smooth muscle relaxation pathways (see Tables 2 & 3). In the latter strategy, for example, inhibition of phosphodiesterases, enzymes that inactivate cAMP or cGMP, results in the accumulation of these nucleotides which in turn diminishes contractility of smooth muscle tissue and thus maintains the muscle relaxation necessary for erection. Suppressing antierectile action can be achieved by decreasing smooth muscle contraction through receptor antagonists of tissue contractile pathways (e.g., [alpha.sub.1]-adrenergic [norepinephrine] inhibitors).

Treatment approaches may also be directed towards the central nervous system (i.e., brain or spinal cord). Similar to peripheral mechanisms, these either promote proerectile pathways (e.g., agonists of dopaminergic [D.sub.2] receptors in the medial hypothalamus) or suppress antierectile pathways (e.g., antagonists of 5-[HT.sub.1A/2] [serotonergic] receptors in the spinal cord).

Options for Treatment

This section presents a number of options that are currently available or are imminently expected to be approved by the Food and Drug Administration (FDA) for the pharmacotherapeutic management of ED (see Table 4). Endocrine therapies are omitted in recognition of the fact that endocrinopathy is an uncommon primary cause of erectile dysfunction except perhaps in aging men (see Schiavi, 1996). For convenience, the discussion is organized according to routes of administration.

Table 4. Pharmacotherapies for Erectile Dysfunction

Route           Trade Name              Drug

Intravenous     Caverject               Alprostadil
                Edex                    Alprostadil
                Bi-mix                  Alprostadil + Phentolamine
                Bi-mix Androskat (EU)   Papaverine + Phentolamine
                Tri-mix                 Alprostadil + Papaverine
                                        + Phentolamine
                Invicorp                VIP + Phentolamine
                Thymoxamine             Moxisylyte

Intraurethral   MUSE                    Alprostadil
                ALIBRA                  Alprostadil + Prazosin

Topical         Minoxidil               Minoxidil
                --                      Glyceryltrinitrate
                --                      Nitroglycerine
                --                      Alprostadil
                --                      Papaverine

Oral            Viagra                  Sildenafil
                Spontane                Apomorphrine
                Vasomax                 Phentolamine
                Yolon                   Yohimbine
                Desyrel                 Trazodone

Route           Trade Name              Dosages

Intravenous     Caverject               5-40 ug/ml
                Edex                    5-40 ug/ml
                Bi-mix                  20 ug/ml + 0.5 mg/ml
                Bi-mix Androskat (EU)   30 mg/ml + 0.5 mg/ml
                Tri-mix                 10 ug/ml + 30/mg/ml
                                        + 1.0 mg/ml
                Invicorp                NA
                Thymoxamine             NA

Intraurethral   MUSE                    125, 250, 500, 1000 ug
                ALIBRA                  125, 250, 500, 1000 ug
                                        + 250, 500, 1000, 2000 mg

Topical         Minoxidil               --
                --                      --
                --                      --
                --                      --
                --                      --

Oral            Viagra                  25, 50, 100 mg
                Spontane                2, 4, 6 mg
                Vasomax                 40, 80 mg
                Yolon                   5.4 mg tid x 1 month
                Desyrel                 50-200 mg gd x 1 month

Route           Trade Name              Efficacy

Intravenous     Caverject               <70% intercourse
                Edex                    <70% intercourse
                Bi-mix                  <90% intercourse
                Bi-mix Androskat (EU)   <90% intercourse
                Tri-mix                 <90% intercourse
                Invicorp                82% intercourse
                Thymoxamine             68% intercourse

Intraurethral   MUSE                    <40% intercourse
                ALIBRA
                                        70% intercourse

Topical         Minoxidil               --
                --                      --
                --                      --
                --                      --
                --                      --

Oral            Viagra                  46-69% intercourse
                Spontane                46-60% intercourse
                Vasomax                 40% improvement
                Yolon                   = placebo
                Desyrel                 = placebo

Intracavernosal pharmacotherapy using vasoactive substances. The inauguration of medical therapy for treating erectile dysfunction followed the discovery in 1982 that vasoactive agents delivered by injection to the penis induced erections (Virag, 1982; Zorgniotti, 1990). Since that time, there has been an explosion of basic scientific and clinical research leading to the development and use of various vasoactive medications. Three medications are now used regularly for intracavernosal injection: papaverine, phentolamine, and prostaglandin [E.sub.1]. Two others, moxisylyte (Costa et al., 1993) and a combination of vasoactive intestinal peptide (VIP) and phentolamine (Hackett et al., 1998; McMahon, 1996), may soon be FDA-approved. Although all act locally by promoting smooth muscle relaxation of the penile blood vessels, each does so in a different way.

Prostaglandin [E.sub.1], a naturally occurring compound that has been synthesized in the exogenous form as alprostadil (Prostin VR), is the only currently FDA-approved (in June 1995) medication for ED and is marketed for intracavernosal pharmacotherapy by the trade names Caverject and Edex (Buvat et al., 1998; Linet & Ogrinc, 1996; Porst, 1996). Prostaglandin [E.sub.1] binds with specific receptors on smooth muscle cells and activates intracellular adenylate cyclase to produce cyclic adenosine monophosphate (cAMP) which in turn induces tissue relaxation through a second messenger system (Palmer et al., 1994). Papaverine, an alkaloid isolated from the opium poppy, prevents the inactivation of cAMP by acting as a nonspecific phosphodiesterase inhibitor--in preventing the degradation of cAMP and cyclic guanosine monophosphate (cGMP), concentrations of these nucleotides in smooth muscle cells begin to accumulate and increasingly promote relaxation (Kukovetz, Poch, & Wurm, 1975). Papaverine also blocks voltage-dependent calcium channels along the membrane wall, thus impairing calcium influx to the cell, a process known to trigger smooth muscle contraction (Brading, Burdyga, & Scripnyuk, 1983; Sunagane, Ogawa, Uruno, & Kubota, 1985). Phentolamine methylate (Regitine) is a competitive, nonspecific alpha-adrenoceptor antagonist that presumably produces smooth muscle relaxation by blocking the (antierectile) postsynaptic [alpha.sub.1]-adrenergic receptor (Juenemann, Lue, Fournier, & Tanagho, 1986). That is, this drug blocks the antierectile effects of norepinephrine, thereby inducing a proerectile effect. However, phentolamine exerts some antierectile effects as well; it blocks norepinephrine reuptake, increasing norepinephrine action and consequently blocking smooth muscle relaxation. This dual effect of phentolamine probably accounts for the limited erectile response occurring with the clinical administration of this drug when used solely (Juenemann et al., 1986). Moxisylyte (Thymoxamine) is a competitive blocker of [alpha.sub.1]-adrenoceptors (i.e., decreases norepinephrine action) with impressive erectogenic effects (Buvat, Buvat-Herbaut, & Marcolin, 1989). VIP, a hormone having 28 amino-acids originally isolated from the small intestine, was proposed early on to be the elusive nonadrenergic noncholinergic (NANC) mediator of penile erection because of its potent vasodilatory effects in various tissues (Adaikan, Kottegoda, & Ratnam, 1986). Its mechanism of action in smooth muscle is achieved through specific protein receptor binding and activation of adenylate cyclase, thereby promoting synthesis of cAMP and subsequent tissue relaxation (Andersson & Wagner, 1995).

Vasoactive substances are typically self- or other-administered through a single injection to the corpus cavernosum. These agents have been used both individually and in combination. Alprostadil used as monotherapy is the initial intracavernosal treatment offered to the majority of men presenting with erectile dysfunction. Available concentrations are 5, 10, 20, and 40 ug/mL. Phentolamine is used only in combination with other drugs, whereas papaverine may be used as monotherapy or more commonly in combination with other drugs. Phentolamine is produced in a powder form and dissolved in a concentration of 5 mg/mL. Papaverine is produced in a concentration of 30 mg/mL. A commonly used bi-mix solution consists of alprostadil at 20 ug/mL and phentolamine at 0.5 mg/mL. Another is papaverine at 30 mg/mL and phentolamine at 0.5 mg/mL (known as Andrsoskat in Europe). A tri-mix solution contains alprostadil at 10 ug/mL, papaverine at 30 mg/mL, and phentolamine at 1.0 mg/mL. In-office titration of any vasoactive therapy is recommended to determine the dosage that yields an erection of sufficient rigidity for sexual intercourse yet lasts no more than an hour. This standard may vary according to the man's type and severity of ED.

Alprostadil monotherapy is approximately 70% successful in enabling sexual intercourse (Barada & McKimmy, 1994; Linet & Neff, 1994). Combination therapies have achieved success rates in the order of 90% (Barada & McKimmy, 1994). Intracavernosal VIP alone has poor erectile efficacy (Kiely, Bloom, & Williams, 1989; Roy, Petron, & Said, 1990), although in combination with phentolamine (Invicorp) it has produced an 82% success rate (Hackett et al., 1998). Intracavernosal moxisylyte has produced success rates in 68% of patients (Buvat, Buvat-Herbaut, Lemaire, & Marcolin, 1993). Despite these efficacies, long-term use of intracavernosal pharmacotherapies is poor, with dropout rates typically ranging from 50 to 80% (Barada & McKimmy, 1994; Rowland, Boedhoe, Dohle, & Slob, 1999). Reasons for discontinuation include declining sexual interest, inconvenience, cost, and preference for a less invasive form of treatment (Barada & McKimmy, 1994). In a limited number of instances, dropout can be traced to the return of erectile function (Rowland et al., 1999). Nevertheless, as long as there are contraindications for the new generation of oral medications, intracavernosal vasoactive therapy will remain an important option for a subpopulation of men with ED.

Vasoactive therapy is contraindicated for men with psychological instability, a history of or risk for priapism, histories of severe coagulopathy or unstable cardiovascular disease, reduced manual dexterity (although the partner can be trained in the injection technique), and use of monoamine oxidase inhibitors (because of the risk of precipitating a life-threatening hypertensive crisis in the event that an intracavernosal alpha-adrenergic agonist is used to reverse a priapic episode) (Sharlip, 1998). In-office testing (as well as incorporating visual sexual stimulation for those who feel comfortable with the procedure; see Slob, Steyvers, Lottman, Hop, & van der Werff ten Bosch, 1998) and proper and adequate training in the technique prior to home use are important to confirm efficacy, avoid potential complications (Barada & McKimmy, 1994), and reduce the likelihood of attrition. Risks of complications include priapism (less than 1% of men), penile fibrosis at the penile injection site (5 to 10% of men), local trauma such as hematoma (10% of injections), and penile pain (10% of men) (Barada & McKimmy, 1994).

Intraurethral pharmacotherapy. The administration of vasoactive drugs via the urethral channel of the penis has recently been explored with the hope of affording a less invasive procedure than intracavernosal needle injections to induce erection. This technique relies on the absorption of medication through the urethral mucosal lining into the surrounding corpus spongiosum, with passage via small vascular channels into the main erectile bodies, the corpora cavernosa. The transfer of drug from the urethra to the cavernous tissue varies across men according to anatomical variability. Following an initial trial which demonstrated that prostaglandin [E.sub.2] was effective in inducing full tumescence in 30% of patients and partial tumescence in 40% of patients (Wolfson, Pickett, Scott, DeKernion, & Rajfer, 1993), a synthetic formulation of prostaglandin [E.sub.1] was developed and FDA-approved in November 1996 as MUSE (Medicated Urethral System for Erection) (Hellstrom et al., 1996; Padma-Nathan et al., 1997). MUSE employs a suppository inserted into the urethral opening that dispenses a pellet of alprostadil (125, 250, 500, and 1000 [micro]g dosages) into the urethra. Several technical procedures optimize the success of the treatment including properly depositing and manually distributing the medication into the penis and the patient's remaining in the upright position for several minutes after its application.

In an initial report with MUSE, 996 of 1511 men (65.9%) with ED of various organic causes achieved erections deemed sufficient for sexual intercourse based on in-office testing (Padma-Nathan et al., 1997). In-office responders were then randomized to receive either treatment or placebo at home for 3 months, with 64.9% of those receiving treatment reporting successful intercourse compared with 18.6% of those receiving placebo. These figures establish a final responder rate of approximately 40%. Among those responding to treatment, approximately 70% of administrations resulted in successful sexual intercourse. Despite these positive indications, this treatment in a routine clinical setting of 100 patients produced about a 7% well-sustained rigid erection rate and a 30% rate of erection with partial rigidity (Werthman & Rajfer, 1997). These data have supported common clinical experiences that responses with MUSE are seldom completely rigid and are particularly difficult in men experiencing significant cavernous dysfunction (formerly described as venous leakage syndrome whereby incomplete occlusion of the veins that drain the penis prevents attainment of a rigid erection). Subsequent efforts to rectify this problem have led to the combined use of an adjustable penile constriction band (ACTIS), designed and FDA-approved to enhance the local retention and effect of the medication (Lewis, 1998). Recently, a new transurethral bi-mix (ALIBRA) consisting of alprostadil and the [alpha.sub.1]-adrenergic antagonist prazosin was introduced and in a multicenter trial of nearly 400 patients was shown to increase the at-home responder rate for successful sexual intercourse from 47% (alprostadil alone) to 70% (ALIBRA) (Costabile, 1998).

The most common side effects of MUSE include local urogenital pain (29% of patients) and minor urethral bleeding (5%) (Labasky, 1998). Other complications such as hypotension (3%), dizziness (4%), and priapism (0.1%) have been observed as well. Preliminary in-office testing with MUSE offers the advantage of patient monitoring and making dosage adjustments. MUSE is contraindicated in patients with known hypersensitivity to alprostadil, abnormal penile anatomy, and conditions that increase the risk of priapism. MUSE seems safe for female partners, producing only a 5.8% incidence of vaginal burning or itching, although it should not be used for intercourse with a pregnant woman without a condom.

Topical pharmacotherapy. The appeal of noninvasive treatments has long fueled the enthusiasm to apply vasoactive agents directly to the surface of the penis in topical (transdermal) form. The glans penis is the preferred site of application since the medication can enter the corpus spongiosum directly and then be absorbed much like drugs delivered into the urethra. Agents applied directly to the penile shaft have been largely ineffective since the anatomical barriers, including the tunica albuginea surrounding the corpora cavernosa, interfere with absorption.

An early topical investigation involved minoxidil sulfate (Minoxidil).This compound is a potassium channel opener that reportedly exerts a vasodilatory (relaxant) effect by stimulating adenosine triphosphate-dependent potassium channels at the smooth muscle cell membrane to permit the outflow of potassium ions. Ultimately, this process prevents the contractile effect on smooth muscle associated with the opening of the calcium channels and the subsequent influx of calcium to the cell (Andersson & Wagner, 1995). In a small double blind trial on 33 men, Minoxidil applied topically to the glans penis produced greater penile rigidity than either placebo or nitroglycerine (Cavallini, 1991). Other recent studies have shown positive results for topical ointments containing nitric oxide donors (Heaton, Morales, Owen, Saunders, & Fenemore, 1990; Roy, Petrone, & Agha, 1996), prostaglandin [E.sub.1] (Kim & McVary, 1995), and papaverine (Kim, El-Rashidy, & McVary, 1995). To enhance these drug effects, improved absorption through the skin has become a significant objective--permeation enhancers (Becher, Borghi, Momesso, & Montes de Oca, 1998; McVary, Polepalle, Riggi, & Pelham, 1998) and iontophoresis (i.e., introduction of ions into tissue using small electical currents; see Dugan et al., 1996) are both under investigation. Presently, topical therapies have not entered into the mainstream of ED treatments. Significantly more clinical development is needed before establishing their role, along with better understanding of possible adverse effects on the partner due to vaginal absorption of the medication.

Oral pharmacotherapy. As pharmacotherapies have evolved, the oral route of administration has consistently secured a highly attractive role since this form offers the least-invasive route of delivery. However, many traditional oral therapies have been relatively ineffective and thus they have created significant patient dissatisfaction (Hanash, 1997; Jarow, Nana-Sinkam, Sabbagh, & Eskew, 1996). With the recent availability of therapies that are minimally-invasive and increasingly effective, patient satisfaction will undoubtedly change for the better.

Sildenafil citrate (Viagra), approved by the FDA in March 1998, can be credited with accelerating the movement to treat ED with oral therapies. This medication inhibits phosphodiesterase type 5 that deactivates cGMP. As a result, cGMP remains active in increasing amounts to exert corporal smooth muscle relaxant effects (Boolel et al., 1996; Jeremy, Ballard, Naylor, Miller, & Angelini, 1997). The medication is formulated as 25, 50, or 100 mg dosages and is optimally taken orally 1 hour prior to desired sexual activity with an effect that occurs only in the presence of sexual stimulation. Sildenafil has been shown to produce a 69% successful sexual intercourse rate among men with ED (Goldstein et al., 1998). This rate diminishes to 46% when the treatment is applied to those with severe organic ED (Steers, 1998), yet still reflects a high success rate in comparison to other oral pharmacological treatments or to behavioral therapies. Subsequent investigations indicate potential efficacy for men with a broad spectrum of etiologies, including diabetes mellitus (Lipschultz & Kim, 1999), prostatectomy (Zippe, Kedia, Kedia, Nelson, & Agarwal, 1998), and antidepressant-induced impotence (Balon, 1998). A meta-analysis of safety and tolerability in more than 4000 patients using the treatment for up to 1 year has indicated the primary side effects of headache (16%), facial flushing (10%), and digestive problems (7%), although these were mostly transient and mild or moderate in severity (Morales, Gingell, Collins, Wicker, & Osterloh, 1998). Additional visual disturbances (3%) such as photophobia and appearance of a blue-green haze have been reported and considered also to be transient effects. While sildenafil is favorably indicated for the contemporary treatment of ED, several precautions are advised. An absolute contraindication is the concomitant use of nitrate drugs, which may result in severe and possibly fatal consequences owing to a profound systemic vasodilatory effect of the two drugs acting synergistically (Pfizer Inc., 1998). Such standards suggest that patients carrying any significant cardiovascular risk may be best counseled to avoid using this medication. The use of sildenafil in patients with retinal disorders such as retinitis pigmentosa or diabetic retinopathy is also concerning, though not contraindicated, because of the unknown long-term risk of retinal damage associated with this drug's effect on type 6 phosphodiesterase expressed in the retina (Food and Drug Administration Resources Page, 1998).

Apomorphine, scheduled to be marketed by the trade name Spontane with FDA approval expected soon, represents an alternative oral therapy for men with ED. This dopaminergic agonist reportedly acts through central pathways, indicating its particular relevance in the treatment of men with psychogenic ED (Lal et al., 1987). Apomorphine is designed to be taken in sublingual form and requires a narrow dosage range to limit side effects such as nausea, vomiting, drowsiness, and yawning (Heaton, Morales, Adams, Johnston, & El-Rashidy, 1995). In clinical trials involving ED men without a major organic component, a successful sexual intercourse rate was best achieved for the 6 mg dosage (59.6% vs. 45.8% and 52% for 2 and 4 mg dosages, respectively) although nausea occurred in 39% of users (compared with 2.1% and 19.5% for 2 and 4 mg dosages, respectively) (Padma-Nathan, Fromm-Freeck, Ruff, McMurray, & Rosen, 1998). The substantial side-effects of apomorphine raise concerns about its eventual clinical usefulness in other than low dosages that would be useful only in men with mild ED.

Phentolamine, currently used for intracavernosal injection and scheduled to be marketed with the trade name Vasomax once FDA approved, is under development as an oral therapy. Its role as an alpha-adrenergic antagonist mimics that associated with its intracavernosal administration. Recent clinical trials suggest an efficacy rate in men with minimal ED of approximately 40% (Goldstein, 1998). Oral phentolamine appears relatively safe, with less than 10% of patients using the 40 mg dosage experiencing headaches, facial flushing, or nasal congestion. However, further investigation is required before determining whether this drug will produce erectile responses of sufficient quality for reliable sexual intercourse, particularly in men with more severe ED.

Yohimbine (Yocon), an alkaloid derived from the bark of the yohimbe tree, reportedly exerts central effects on the mediation of penile erection as an [alpha.sub.2]-adrenergic receptor antagonist (i.e., it antagonizes the action of the antierectile neurotransmitter norepinephrine: see Clark, 1991). This drug has long been touted as an erectogenic and aphrodisiac agent, although only recently has it been seriously investigated as a treatment for ED. Conventionally, the medication is used at an oral dosage of 5.4 mg three times daily with observation for improvement over at least a month. A meta-analysis of all randomized, placebo-controlled trials involving yohimbine suggested a superior effect for the medication compared with placebo (Ernst & Pittler, 1998). However, the drug does not appear to enable successful sexual intercourse any better than placebo in men with confirmed organic ED (Montague et al., 1996; Teloken, Rhoden, Sogari, Dambros, & Souto, 1998). Adverse effects appear to be relatively infrequent but include hypertension, anxiety, tachycardia, and headache. While yohimbine may be well tolerated, its modest results suggest that the drug may be best limited to men with psychogenic ED.

Trazodone (Desyrel) is an antidepressant that was observed to cause priapism, leading to its investigation as a possible treatment for ED. According to mechanisms described at the spinal cord level, the active metabolite of trazodone acts as an agonist of the proerectile 5-[HT.sub.2c] receptor through reuptake inhibition; it also shows some affinity for the 5-[HT.sub.2A] receptor. It may also exert effects as an antagonist of antierectile 5-[HT.sub.1A] receptors (Andersson & Wagner, 1995; Giuliano et al., 1995). In clinical use at dosages typically ranging from 100 to 200 mg orally at bedtime, efficacy rates for erectile improvement were initially reported between 60 and 78% (Kurt et al., 1994; Lance, Albo, Costabile, & Steers, 1995). More rigorous evaluation, however, has shown that the drug at a 50 mg daily dosage for 3 months is probably no more effective in eliciting erectile responses than placebo (Costabile & Spevak, 1998). While the medication appears to be relatively well tolerated and safe with minimal side effects of drowsiness (31%), fatigue (19%), and dry mouth (1%), the overall lack of clinical efficacy for trazodone raises questions about its role in the treatment for erectile dysfunction in all but perhaps anxious or depressed men.

Other oral therapies, subjected to limited clinical investigations thus far, have been considered as treatments for ED. These therapies include L-arginine (the amino acid precursor of nitric oxide), l-dopa (dopamine precursor), limaprost (prostaglandin [E.sub.1]), and naltrexone (opioid antagonist). Each of these agents offers some promise in that their mechanisms of action to induce erections seem plausible. However, the actual clinical place for these agents remains to be established.

Summary

Recent advances have prompted new practical approaches to the management of ED. It is, for example, no longer considered appropriate to offer penile prosthesis surgery as first line therapy for most men presenting with ED. The introduction of effective, minimally-invasive treatment options suggests that rational steps can be followed while achieving successful outcomes for nearly all presentations. Given their low invasiveness and increasing efficacy rates, oral agents have emerged as a first line option for most patients. Sildenafil has shown significant promise, and other oral therapies may soon become available. When sildenafil is ineffective or contraindicated, patients should be offered other nonsurgical treatments such as intraurethral alprostadil, intravcavernosal therapy, and vacuum constriction devices (these devices use a nonpharmacological, mechanical means to produce an erection with a vacuum cylinder temporarily placed externally around the penis). Penile prostheses (devices implanted within the penis), while potentially quite successful, represent a surgical alternative which should be considered only after nonsurgical options have been found ineffective or unacceptable. Penile revascularization surgery is beneficial only to a small minority of patients having a vascular lesion of probable traumatic origin that is treatable using vascular bypass techniques. Thus, as pharmacologic approaches are increasingly effective, they are assuming a more central role in the treatment of ED, relegating mechanical and surgical interventions to secondary roles.

THE DRUG TREATMENT OF PREMATURE EJACULATION

General Background

Premature ejaculation (PE), reportedly occurring in 10-30% of men at some point in their lifetime (Laumann, Gagnon, Michael, & Michaels., 1994; Spector & Carey, 1990), is the persistent inability to control the timing of ejaculation such that it occurs with minimal stimulation before, during, or shortly after vaginal intromission (American Psychiatric Association, 1994). This rapid ejaculation brings coital activity to an abrupt end and interferes with the sexual satisfaction of both the man and his partner. Unlike erectile dysfunction, PE is typically defined within the context of a sexual relationship--its "dysfunctional" status arises from its adverse effect on the sexual enjoyment of both the patient and his partner.

No consensus exists regarding the operational criteria for PE, but ejaculation prior to or following 1 to 2 minutes of intravaginal thrusting and a perceived lack of control over ejaculation appear to be among its more reliable indicators (Rowland, Cooper, Slob, & Houtsmuller, 1997). A subset of men with PE report concomitant erectile problems--their inability to achieve or maintain an erection typically results in ejaculation without full penile tumescence.

Mechanisms of Ejaculation and Causes of PE

Although ejaculation typically occurs after penile tumescence is achieved, the ejaculatory process is distinct from and largely independent of the erection process. Ejaculation is the efferent (motor) component of a reflex that typically begins with afferent (sensory) input from stimulation of the glans penis. This input traverses the pudendal nerve and enters the spinal cord at the sacral level. The motor component of the reflex involves both autonomic and somatic responses. Regarding autonomic response, sympathetically-controlled [alpha.sub.1]-adrenergic neurons arising from the thoracolumbar region of the spinal cord elicit smooth muscle contractions in the vas deferens, seminal vesicles, and prostate to effect bladder neck closure and seminal emission. As seminal fluid enters and dilates the urethral duct, thereby inducing the sensation of ejaculatory inevitability, a second reflex--a somatic response--is triggered. This component of the response involves rhythmic contractions of the striate bulbocavernosus and ischiocavernosus muscles and results in seminal expulsion (ejaculation). Cholinergic motor neurons of the pudendal nerve mediate this endpoint, which is associated with the subjective experience of orgasm.

Ejaculation has been induced in men with spinal cord transections, indicating that the reflex can bypass central mediation (Brackett et al., 1998; Ohl, Sonksen, Menge, McCabe, & Keller, 1997). However, centrally-mediated processes presumably play a modulating role, either facilitatory or inhibitory, in most men. Although the physiological mechanisms underlying brain and spinal influence over ejaculation are poorly understood, studies from nonhumans suggest that descending signals from the brain overcome the prevailing spinal inhibition over the ejaculatory reflex (Marson & McKenna, 1992). At the levels of both the brain and spinal cord, serotonergic mediation has been implicated. Specifically, in male rats activation of 5-[HT.sub.1A] neurons in limbic regions of the brain shortens ejaculatory latency (Fernandez-Guasti, Escalante, Ahlenius, Hillegaart, & Larsson, 1992), and serotonergic receptors of spinal origin may be involved as well. Nevertheless, many questions remain unanswered. It is not clear how serotonergic brain and spinal systems might interact with each other, or with neurons utilizing other neurotransmitters (e.g., dopamine receptors have been implicated in ejaculation). Furthermore, the extent to which the ejaculatory process in the male rat serves as a sufficient or complete model for human ejaculation has yet to be clarified. While the mechanics of human ejaculation may parallel those of nonhumans (Pfaus, 1996), the overall processes may not. For example, in contrast with most other species, the timing of human ejaculation is influenced by complex and purposeful psychological processes such as attentional focus, cognitions and fantasy, and overall subjective sexual arousal. The physiological/biochemical systems underlying these processes may add a layer of complexity to human ejaculation which cannot be readily investigated with animal models.

In contrast with ED, research has failed to identify specific causes or mechanisms underlying PE. Current thinking suggests that PE may stem from either inherent or acquired somatic factors, from psychological factors, or from some combination thereof. Although an unequivocal and exclusive somatic or psychological cause for PE is occasionally identified (e.g., after spinal cord injury: Kuhr, Heiman, Cardenas, Bradley, & Berger, 1995), such cases are unusual. In most instances, PE probably results from a mix of psychogenic and organogenic factors (Strassberg, Kelly, Carroll, & Kircher, 1987) which may interact with each other to exacerbate the problem. For example, a purely somatic etiology that leads to sexual failure may induce anxiety about sexual performance and further maintain the dysfunction (Bancroft, 1989). Whatever the cause of PE, recent data suggest that the typical balance between sympathetic and parasympathetic systems during sexual response may be upset in men with this disorder. Specifically, sexual response in men without PE is characterized by parasympathetic dominance during erection but sympathetic dominance during ejaculation (DeGroat & Booth, 1980; Kedia, 1983). However, men with PE may show heightened sympathetic activation very early in the sexual response cycle. Strong sympathetic action at this point may slow the erectile process and trigger the ejaculatory reflex "prematurely" (Ertekin, Colakoglu, & Altay, 1995; Rowland, Strassberg, deGouveia Brazao, & Slob, 2000).

Nonpharmacological Treatments for PE

Even though a physiological basis for some types of PE has been suspected by researchers and clinicians for years (e.g., Damrav, 1963; Pasini, 1984), treatment options until recently relied quite heavily on behavioral and psychological procedures. The reasons for this are understandable. First, psychological factors such as anxiety and negative affect had frequently been associated with the occurrence of various sexual dysfunctions, including PE (Kaplan, 1983, 1989); in contrast there had been little or no evidence pointing to a physiological mechanism that might underlie PE. Second, until recently, few tested and well tolerated biologically-based therapeutic measures were available to clinicians for the treatment of PE. And third, the cognitive-behavioral strategies for treating PE were at least moderately successful in alleviating the dysfunction (Levine, 1992).

Two cognitive-behavioral strategies have enjoyed substantial popularity among sex therapists. The first is the stop-squeeze method, developed by Semans (1956) and later adopted by Masters & Johnson (1970) in their sex therapy clinic. The second method, advocated by Kaplan (1983), is the stop-pause method. Both methods suppress the urge to ejaculate by stopping sexual stimulation, but the former substitutes a squeeze of the glans penis for a pause in stimulation at the point of impending ejaculation. These behavioral strategies, which often incorporate instruction on optimal intercourse positions, are typically combined with a variety of other strategies, including increasing the range of sexual expression to extend beyond intercourse, developing greater awareness of the association between visceral sensations and ejaculation, and relying on imagery and cognitive strategies to increase control over the ejaculatory process (Thexton, 1992; Zilbergeld, 1992).

When effective, the cognitive-behavioral approach is attractive for a number of reasons. The treatment is specific to the problem, is neither harmful nor painful, produces minimal or no adverse side effects, encourages open communication about sexuality in the couple which is likely to lead to a more satisfying sexual relationship (Verhulst & Heiman, 1988; Wincze & Carey, 1991), and has a permanent quality about it--once the techniques have been learned and incorporated into lovemaking, PE men will continue to have access to strategies that help them control their ejaculation. At the same time, there are drawbacks to this approach: it is time-consuming, often requires substantial resources of both time and money, lacks immediacy, requires the partner's cooperation, and has mixed (and less well-documented) efficacy (see Hawton, 1992; Heiman & Meston, 1997, for reviews).

Pharmacotherapeutic Approach to PE

Where cognitive-behavioral treatments for PE have fallen short, pharmacological strategies have compensated. Pharmacotherapy combines ease, immediacy of effect, and minimal effort with documented efficacy and reasonably low cost. Thus, it is not surprising that many clinicians are increasingly turning to drug therapy to treat PE: in some instances to enhance psycho-behavioral therapy, in others to replace it entirely. Three approaches fall under the pharmacological treatment of PE. Each relies on the use of drugs to alleviate PE, but they have little else in common. The ensuing discussion is therefore organized upon the strategy used to deal with the PE: reducing sensory input to the penis; preventing penile detumescence after ejaculation; and pharmacologically interfering with ejaculation. Table 5 summarizes many of these pharmacotherapeutic effects.

Table 5. Pharmacotherapies for Premature Ejaculation

Strategy/route      Trade Name   Drug

Topical             --           lidocaine-prilocaine

                    SS cream     herbal extracts
                                 (proprietary)

Pharmaco-erection   --           papaverine (30 mg) +
                                 phentolamine
Oral ejaculation
retardants

  Tricyclics        Anafranil    clomipramine

  SSRIs             Prozac       fluoxetine
                    Paxil        paroxetine
                    Zoloft       sertraline
                    Luvox        fluvoxamine

  Alpha-blockers    --           phenoxibenzamine
                    --           alphuzosine
                    --           terazosine

  Beta-blockers     --           propanolol

Strategy/route      Drug                   Dosages

Topical             lidocaine-prilocaine   2.5 g
                                           (25 mg/g each)

                    herbal extracts        0.1 g 1 hr prior
                    (proprietary)

Pharmaco-erection   papaverine (30 mg) +   0.2-0.4 mi
                    phentolamine           (1 g)

Oral ejaculation
retardants

  Tricyclics        clomipramine           25 mg
                                           25 mg
                                           (5-24 hr prior)
                                           50 mg

  SSRIs             fluoxetine             20-40 mg
                                           60 mg
                    paroxetine             20-40 mg
                    sertraline             50-200 mg
                                           100 mg
                    fluvoxamine            100 mg

  Alpha-blockers    phenoxibenzamine       20 mg/day
                    alphuzosine            2 x 3 mg/day
                    terazosine             5 mg/day

  Beta-blockers     propanolol             120 mg/day

                                           Efficacy
                                           (% satisfaction or
                                           [up arrow] ejaculation
Strategy/route      Drug                   latency)

Topical             lidocaine-prilocaine   80% (ejac lat = 10 min)
                                           (30 min prior)

                    herbal extracts        80% (ejac lat = 10 min)
                    (proprietary)

Pharmaco-erection   papaverine (30 mg) +   100% satisfaction with
                    phentolamine           effect via erection

Oral ejaculation
retardants

  Tricyclics        clomipramine           2-4 min
                                           2 1/2-7 min
                                           6-7 min

  SSRIs             fluoxetine             1-3 min
                                           8-9 min
                    paroxetine             3-10 Min
                    sertraline             2-5 min
                                           (87% response rate)
                                           15 min
                    fluvoxamine            1 min

  Alpha-blockers    phenoxibenzamine       50% satisfied
                    alphuzosine            50% satisfied
                    terazosine             50% satisfied

  Beta-blockers     propanolol             no effect

Topical anesthetics. Anesthetizing ointments or creams may be applied directly to the penis to retard ejaculation. The effect is peripheral and local, the goal being to attenuate genital sensory input and thus reduce the likelihood of triggering the ejaculatory reflex. A number of recent investigations suggest creams containing prilocaine-lidocaine or other local anesthetics applied prior to intercourse can delay ejaculation in many men up to several minutes (Berkovitch, Keresteci, & Koren, 1995; Xin, Choi, Lee, & Choi, 1997). This approach, however, is not appropriate for men who ejaculate before vaginal intromission. Furthermore, it necessitates a condom to protect the partner from potential irritating and desensitizing effects of the cream or, alternatively, wiping the cream off prior to intercourse. In addition, the long term efficacy of these ointments is not known. Nevertheless, given the parsimony of this approach (simple, direct, specific, and inexpensive), it warrants consideration as an aid to delaying ejaculation in some men.

Pharmacostimulation of erection. A second approach has employed intracavernosal (penile) injection of papaverine (Fein, 1990), a vasoactive agent that induces erection and has been associated most with the treatment of erectile dysfunction. Few studies have approached the treatment of PE from this angle--the treatment does not delay ejaculation but enables the man with PE to maintain an erection long after ejaculation has occurred. The increased duration of erectile response allows greater enjoyment and satisfaction of coitus by the partner. Intracavernosal injection appears to have limited value in the treatment of PE, although this and other various proerectile oral treatments (yet to be investigated) may provide options for men who have concurrent erectile problems and are concerned primarily with their partner's satisfaction. The prolonged erection may also enable the man with PE to enjoy a second orgasm after an initial one involving short latency.

Oral retardants of ejaculation. The third and most common pharmacological approach to treating PE involves the use of oral medications that interfere with the ejaculatory process, thereby increasing latency. Most of these medications were originally developed for the treatment of mood disorders and emotional problems. Astute clinicians and patients noted that these antidepressant drugs had the side effect of delaying or inhibiting ejaculation (Beaumont, 1973; Yassa, 1982). Even with today's large selection of antidepressants, many of which operate via different pharmacological mechanisms, only a few are reportedly free of this side effect, and this attribution may reflect an incomplete evaluation of the drug rather than a lack of effect on ejaculation. Because the ejaculatory-inhibiting action of antidepressants was considered a side effect to the drugs' intended use, extensive testing to determine the effects of these drugs on PE using large clinical trials has generally not been carried out.

Although the ejaculation-retarding effects of antidepressants have led to periodic case studies in PE men for well over 25 years (Eaton, 1973; Goodman, 1980), the past decade has witnessed an enormous increase in their use. The reason for this surge is undoubtedly related to a number of developments: the introduction of classes of antidepressant agents having fewer deleterious side effects (i.e., selective serotonin reuptake inhibitors, or SSRIs); long-awaited investigations of the orgasm-delaying effects of various antidepressants in adequately controlled studies; recent reports that at least some agents could achieve their desired effect when taken on an as-needed (p.r.n.) basis as opposed to chronically; and the continuing economic pressure on the medical profession to use proven strategies that require minimal cost.

Having been on the market for several decades, clomipramine (Anafranil) has been the focus of a number of well-controlled studies relating tricyclic antidepressants to delayed ejaculation. Most have used doses between 10 and 50 mg (per day, when taken chronically), with a typical dose response curve occurring from 25 to 50 mg. These doses are fairly low in comparison to those used in the treatment of depression, which may reach 100-250 mg/day.

At the dose of 25 mg/day taken chronically, average increases in latencies have been reported from 2 to 4 min; at the higher dose of 50 mg, the increases have consistently been around 6 to 7 min (Althof, Levine, Corty, Risen, Stern, & Kurit, 1995; Segraves, Saran, Segraves, & Maguire, 1993). Interestingly, when 25 mg clomipramine is taken on an as-needed basis 12 to 24 hr prior to anticipated intercourse (rather than chronically), it is at least as effective as when it is taken chronically, and may even be more so. Under this regimen, latencies reportedly increase by about 6 min--results comparable to twice the dose when taken chronically (Haensel, Rowland, Kallan, & Slob, 1996). This paradoxical finding may stem from higher tolerance that results from chronic administration. Even when taken as needed only 4 to 6 hr prior to intercourse, 25 mg is effective in increasing latencies by 2.5 min (Strassberg, deGouveia Brazao, Rowland, Tan, & Slob, 1999). From the user's perspective, being able to take a drug such as clomipramine on an as-needed basis may represent a critically important benefit, since even chronic low doses of tricyclic antidepressants have substantial unpleasant side effects, which raises issues of compliance for couples who engage in sex relatively infrequently.

Although the overall effectiveness of clomipramine in delaying ejaculation has been well documented, a number of qualifications are worth noting. All studies report a portion of individuals who do not respond to the drug, a percentage that may range from 10 to 30% or higher. For example, when clomipramine is taken 4 to 6 hr prior to intercourse, the men least likely to improve are those whose ejaculation latencies were typically the shortest ([is less than] 1 min) prior to treatment. This lack of efficacy appears to be partly, though not entirely, related to the magnitude of the dose and when the drug is taken (i.e., the number of hours prior to intercourse). Some nonresponders might well show positive effects under higher doses (e.g., 75-100 mg), but at these levels most men begin to experience side effects severe enough to lead to voluntary termination of the treatment. In addition, men whose PE is complicated by erectile insufficiency are not likely to benefit from the ejaculation-inhibiting effects of clomipramine, and in some instances, may suffer further decline in erectile capacity. Clomipramine makes it more difficult for a man to achieve and maintain an erection; in fact, at doses used for the treatment of depression it induces erectile problems in about 20% of sexually functional men.

At the doses used for the treatment of PE, clomipramine is a safe drug. However, it is contraindicated for men who are taking MAO inhibitors, with serious outcomes possible, including seizure, coma, and death. Common side effects include drowsiness, tremors, dizziness, headaches, various digestive disorders (dry mouth, dyspepsia, constipation), and general fatigue.

Compared with clomipramine, SSRIs induce fewer and less serious side effects. Within the past five years, the number of studies investigating the influence of various SSRIs on ejaculation latency has burgeoned. Of the SSRIs tested, nearly all have been found to exert at least some delaying effect on ejaculation. Fluoxetine (Prozac), in lower doses of 20 to 40 mg/day has only moderate effects, delaying ejaculation by about 1 to 2 min (Kim & Seo, 1998; Lee, Song, Kim, & Choi, 1996; Waldinger, Hengeveld, Zwinderman, & Olivier, 1998), although higher doses up to 60 mg/day reportedly delay ejaculation by nearly 8 min (Kara, Aydin, Agargun, Odabas, & Yilmaz, 1996). At doses of 20 to 40 mg/day, paroxetine (Paxil) increases latencies anywhere from 3 to over 10 min (Ludovico et al., 1996; Waldinger, Hengeveld, & Zwinderman, 1994, 1997;). At doses of 50 to 200 mg/day, sertraline (Zoloft) seems to consistently delay ejaculation by about 2 to 5 min (Kim & Seo, 1998; McMahon, 1998a; Mendels, Camara, & Sikes, 1995; Waldinger et al., 1998), although one study reports increases up to 15 min with 100 mg/day (McMahon, 1998b).

The general benefits and limitations of the SSRIs are worth noting. On the negative side, even though SSRIs produced fewer serious side effects than clomipramine, most studies report at least some patient attrition due to unpleasant effects. While generally considered safe drugs, particularly at the moderate-low doses used to treat PE, common complaints include gastrointestinal and digestive disorders, headache, dizziness, insomnia, and drowsiness. Also, SSRIs should not be used in combination with MAO inhibitors. Furthermore, a percentage of SSRI study samples, usually about 10 to 15%, reports no effect at all. And perhaps of greatest concern, one study suggests that the inhibitory effects of SSRIs begin to wane after 5 weeks of daily administration (Waldinger et al., 1998). This latter point argues for investigation of SSRI efficacy for use on an as-needed basis. On the positive side, SSRIs have fewer unpleasant side effects and appear to be less disruptive of sexual desire and erectile response than clomipramine. Indeed, at least one study indicates that fluoxetine may be useful in delaying ejaculation not only in men having PE, but also in those having concomitant erectile problems (Haensel, Klem, Hop, & Slob, 1998).

Studies comparing SSRI's have also been carried out. In a series of investigations comparing the ejaculation-inhibiting effects of daily fluoxetine, paroxetine, and sertraline, Waldinger et al. (1994, 1997, 1998) report the greatest effects from fluoxetine (20 mg) and paroxetine (20 mg). Both increased latencies from less than a minute to 4 to 4.5 minutes. Sertraline (50 mg) was slightly less effective, with an increase to only 3 minutes. Fluvoxamine (Luvox), also tested, was found to be minimally effective. In contrast with these results, Kim & Seo (1998) found sertraline (100 mg/day) substantially more effective than fluoxetine (40 mg/day)--sertraline increased latencies by about 3.5 min whereas fluoxetine increased latencies by only about 1.5 min, not much better than placebo.

So which SSRI is most effective? Comparisons across SSRIs are not easily interpreted. For one, it is difficult to ascertain dose effect equivalency from one drug to the next. Each of the SSRIs tested above have different effective dose ranges when used in the treatment of depression. Specifically, fluoxetine's recommended doses range from 20 to 80 mg/day; paroxetine's from 20 to 50 mg/day, and sertraline's from 50 to 200 mg/day. More importantly, dose response curves for SSRI effects on ejaculatory response have simply not been carried out to the extent that they are needed. While most SSRIs tested have been moderately effective at fairly low doses, the lack of equivalence among the doses makes it impossible to recommend a specific SSRI at a specific dose in order to achieve maximal results. Moreover, different methods of drug testing (some use placebo groups or conditions, others do not), measuring outcomes (e.g., some are based on ejaculatory latencies, others on global measures of improvement), and inclusion criteria for patients have sometimes prevented direct comparisons across studies. As a result, experimentation with various SSRIs at doses within the ranges presented herein appears to be the best strategy when considering an SSRI for the treatment of PE.

Although it is too early to draw definite conclusions, SSRIs in general may not be as effective as clomipramine in delaying ejaculation. Kim and Seo (1998), in comparing daily clomipramine (50 mg) with sertraline (100 mg) and fluoxetine (40 mg), report slightly greater latencies and higher patient satisfaction from clomipramine. Using similar paradigms to test the effects of fluoxetine and clomipramine (although in different subjects and different studies), Haensel et al. (1996, 1998) have found stronger effects from clomipramine, although the higher efficacy of clomipramine (25 mg) may be related to the fact that it was taken on an as-needed basis while the fluoxetine (5 to 10 mg) was taken daily. Nevertheless, these findings raise the possibility that the very actions that make clomipramine less tolerable (e.g., adrenergic effects) also contribute to its stronger delaying effects on ejaculation.

In summary, from a purely pharmacological perspective, the aforementioned antidepressants appear quite effective in delaying ejaculation. Furthermore, they can be used safely by most men and are appropriate for men who ejaculate before vaginal intromission. Clomipramine seems to be a highly effective choice for inhibiting ejaculatory response, but is generally not tolerated well by many men. Its use on an as-needed basis, either 6 or 12 hours prior to coitus, may offset this negative effect, particularly for couples who engage in sex relatively infrequently. Such a regimen, however, requires planning for intercourse, a condition that may detract from its enjoyment for some couples. Specific SSRIs also appear promising (McMahon, 1998). There is little doubt that SSRIs are better tolerated and appear more suitable for men having mild erectile problems, although they too have the potential to interfere with potency. Until their effectiveness has been demonstrated on an as-needed basis, however, resistance to chronic use may result in low patient compliance and thus diminished satisfaction.

Drugs other than antidepressants have been used to treat PE with moderate success. [Alpha.sub.1]-adrenergic blockers such as phenoxybenzamine, alphuzosine (3 mg t.i.d.), and terazosine (up to 5 mg per day) appear effective in delaying ejaculation in about 50% of men with psychogenic PE compared to 25% of men receiving placebo (Beretta, Chelo, Fanciullacci, & Zanollo, 1986; Cavallini, 1995; Shilon, Paz, & Homannai, 1984). In comparison with antidepressant drugs, the efficacy of alpha-blockers is difficult to evaluate since few studies have been carried out, and they have emphasized patient satisfaction over statistical analysis of actual changes in ejaculatory latency. Effects on ejaculation occur after 1 to 2 weeks of treatment and presumably result from decreased sympathetic muscle tone in the pelvic region. Beta-adrenergic blockers such as propanolol have not been effective in delaying ejaculation (Cooper & Magnus, 1984).

Side effects of alpha blockers vary, with phenoxybenzamine having the most serious. As might be expected, autonomic-related side effects are common in these sympathetic blockers. Therefore patients with cardiovascular risk need to be screened carefully.

Mechanism of Action of Oral Retardants of Ejaculation

There is little understanding of the mechanism through which SSRI and tricyclic antidepressants inhibit ejaculation. Indeed, there is no consensus regarding the neurotransmitter systems that might be involved, or even whether the effects are mediated at the level of the brain, the spinal cord, or the peripheral nervous system. Clues about the pharmacological mechanism are suggested by the known neurotransmitter actions of the drugs on the one hand, and the presumed neurotransmitter systems involved in ejaculation on the other. For example, most antidepressants associated with inhibition of serotonergic reuptake inhibit orgasm in both men and women, and this pattern has led to the hypothesis that increased central serotonergic activity at the postsynaptic terminal inhibits peripherally-mediated ejaculation through the alpha-adrenergic system. The fact that MAO inhibitors and tricyclic antidepressants such as clomipramine, which impact all the monoaminergic systems (serotonin, dopamine, norepinephrine), are effective in delaying ejaculation (see Balon, 1998; Clayton & Shen, 1998; Gitlin, 1994; Segraves, 1995) has been attributed to their serotonergic rather than catecholaminergic (dopamine, norepinephrine) effects. Circumstantial evidence for this conclusion in humans has been obtained from studies which indicate successful reversal of anorgasmia with agents such as cyproheptadine, an antihistamine with antiserotonergic properties (see Gitlin, 1994, for review). Furthermore, the finding that drugs facilitating alpha-adrenergic activity can overcome the ejaculatory failure caused by serotonergic antidepressants is also consistent with the idea of serotonergic mediation (see Segraves, 1995). Evidence from nonhumans may bolster the serotonergic hypothesis. The 5-[HT.sub.1A] agonist 8-OH-DPAT induces rapid ejaculation latency in rats (Ahlenius et al., 1981; Rowland & Houtsmuller, 1998), an effect linked to stimulation of serotonergic autoreceptors which in turn ultimately decreases serotonergic transmission.

Clearly, the above explanation of pharmacological processes is oversimplified and will need further clarification. There are sufficient findings inconsistent with the hypothesis that increased serotonin leads to inhibition of ejaculation to indicate the tenuous nature of this explanation. For example, at least one SSRI (Luvox) performs barely better than placebo in its capacity to delay ejaculation (Waldinger et al., 1998). Another, nefazodone (Serzone), may actually induce rapid ejaculation, although this effect may result from the fact that this drug also blocks 5-[HT.sub.2] receptors (Michael & Ramana, 1996; Preskorn, 1995). Furthermore, the fact that there is evidence implicating serotonergic systems in ejaculation latency does not preclude a role for other neurotransmitter systems. It may be that tricyclic and MAD-inhibiting antidepressants (which affect dopamine and norepinephrine in addition to serotonin) exert additional inhibition of ejaculation by blocking peripheral [alpha.sub.1]-adrenergic receptors (see Gitlin, 1994). The fact that a number of antidepressants having no known effect on serotonergic systems (e.g., buproprion, known as Wellbutrin) can inhibit ejaculation and orgasm also suggests the involvement of other neurotransmitter systems.

Until the specific serotonin receptors (there are about 15 thus far) have been identified, the complex dynamics of inhibiting reuptake are understood (e.g., reuptake inhibition may have substantially different immediate and long-term effects on postsynaptic activity), and the neural sites in the human brain and/or spinal cord are pinpointed, discussion about the serotonergic hypothesis relating to human ejaculation remains largely theoretical. Furthermore, the tendency to view pharmacological actions only as a series of physiological steps acting via brain, spinal cord, and efferent pathways which are unconnected to relevant psychological constructs involved in ejaculatory control in humans may ignore important avenues of investigation. For example, most antidepressants reduce libido and some attenuate sexual arousal as well (see Clayton & Shen, 1998; Rowland & Slob, 1997). These psychologically-mediated effects, not surprising in view of the fact that antidepressants are known for their moderating effects on both emotional and arousal response, may play an important role by lowering sexual desire and arousal and thus increasing the man's distance from the ejaculatory threshold (Rowland & Slob, 1997). Although such effects are ultimately mediated through biochemical mechanisms in the brain, they underscore the importance of analyzing other components of the sexual response cycle when determining the effects of various drugs on ejaculatory latency.

In contrast with antidepressant drugs, the mechanism of the action of [alpha.sub.1]-blockers on ejaculation latency appears straightforward. These agents act peripherally to interrupt sympathetic activation in the pelvic region of the smooth muscle response necessary for ejaculation.

Summary

Cognitive-behavioral approaches to the treatment of PE have been moderately effective, although for unspecified reasons (e.g., perhaps waning interest or effort) their long term efficacy seems less certain. Such treatment may be augmented or substituted with various pharmacological options. Topical anesthetics provide a simple and reasonably effective means of delaying ejaculation for some men, but this approach is not suitable for men who ejaculate prior to intromission or whose partners find the cream invasive or irritating when coitus occurs without a condom. Data from pharmacological studies support the increasing use of oral retardants in the treatment for PE. In particular, antidepressant drugs such as SSRIs and clomipramine are effective at low doses and yet achieve reasonably high efficacy and satisfaction among patients. Because some antidepressants interfere with erectile capacity, not all may be appropriate for use by PE men with concomitant erection problems. In such cases, complementary use of pharmacostimulants of erection may be considered. Use of available alpha-blockers will continue to be limited due to less-documented efficacy and to their side effects; however, the development of alpha-blockers with effects targeted to the pelvic area may offer significant promise for future treatment.

ISSUES SURROUNDING THE PHARMACOLOGICAL TREATMENT OF MALE SEXUAL DYSFUNCTION

Cause-effect Issues.

It is erroneous to assume that because pharmacotherapy can alleviate sexual dysfunction in most men the cause of the their problem is thus rooted in aberrant or dysfunctional biological systems. Quite the contrary, sexual dysfunction caused by any number of different somatic, psychological, or interpersonal factors may all respond positively to pharmacotherapy. Specifically, any intervention targeted at the "mechanics" of erection or ejaculation is likely to be highly effective in rectifying the genital component of the problem, independent of its cause (Rowland, 1998).

In one sense, sexual dysfunctions such as ED and PE might be viewed as "symptoms" of various underlying physiological (e.g., cardiovascular) and/or psychological (e.g., performance anxiety) factors. Inasmuch as this symptom (i.e., a problem with genital functioning) is the source of annoyance or distress within the sexual dyad, the pharmacological approach may be highly suited to the problem--in restoring sexual capacity the distress may be significantly diminished and sexual satisfaction greatly enhanced.

Several studies lend support to this idea. PE men treated with drugs that inhibit ejaculation report increased sexual and relationship satisfaction, as well as improvements in emotional well-being (Althof et al., 1995). Studies of our own and others (Haensel et al., 1996, 1998; Kim & Seo, 1998) suggest that the magnitude of increase in relationship satisfaction is related to the extent of amelioration of the problem, with clomipramine, the more effective agent, showing greater gains than fluoxetine. Since PE is partly a partner-defined problem, positive effects may accrue for the partner as well. Partner response to pharmacological treatment of PE has generally been positive, with sexual satisfaction (though not necessarily relationship satisfaction) showing significant improvements.

Parallel outcomes on satisfaction appear with drugs that enhance erectile capacity. Men in whom intracavernosal (penile) injection induces strong erectile response typically report high levels of sexual satisfaction compared with less-responsive counterparts (Rowland et al., 1999). The use of oral medication such as sildenafil has also been associated with improved sexual satisfaction (Goldstein et al., 1998). Thus, to the extent that restored genital function and thus revitalized sexual activity have the potential to facilitate physical interaction and intimacy within couples, treatment of the dysfunctional mechanics of the genitals may impart significant psychological and interpersonal benefits to the patient and his partner.

Broader Psychological and Relationship Issues

Although the ease of pharmacotherapy has led to record numbers of men seeking treatment for their sexual problems, it has also underscored a tenet long held by sex therapists and counselors. Namely, although improved genital functioning and improved sexual/relationship satisfaction are often related, they are not synonymous. Indeed, this fact raises an important point regarding the desired outcome of any kind of therapy for a sexual problem--that of defining an appropriate endpoint and providing a treatment strategy that is most likely to achieve that endpoint. An implicit goal in the treatment of a "genital" dysfunction (PE or ED) is improved sexual satisfaction and perhaps even relationship satisfaction--indeed, restoration of genital function in the absence of these broader outcomes would seem pointless. Nevertheless, as sexual problems increasingly fall within the domain of medicine, the tendency to focus exclusively on genital outcomes may be augmented (Rowland, 1998; Teifer, 1996). This course of events is more likely to arise within a medical setting because of the strong attention given to the physical component of the problem by both the patient and the physician, sometimes to the exclusion of relevant psychological and interpersonal factors. Specifically, sexually dysfunctional men typically focus heavily on genital issues--the sexual problem is often seen as stemming from a hypofunctional penis, so the solution is identified as one that makes the penis functional once again (e.g., Zilbergeld, 1992). Moreover, physicians often assume their role is limited to the physical component of the problem and, although overall patient satisfaction is important to medical treatments, issues of general sexual satisfaction may not be addressed directly in the medical clinic. Likewise, medical personnel often feel unprepared professionally to address issues regarding the overall quality of the sexual interaction. Although understandable, such mindsets on the part of the patient and/or physician may overlook important psychological and relationship issues critical to optimizing sexual satisfaction within the dyadic relationship.

Indeed, for many couples, a sexual dysfunction may not only interfere with the sex act but also significantly alter the dynamics of the relationship (Hawton, 1998). To assume that correcting the genital problem will restore a healthy relationship dynamic ignores the negative fallout that might arise from the dysfunction (Lamberg, 1998). On the part of the patient, these may include a sense of inadequacy, diminished control, and a retreat from emotional and physical intimacy, with subsequent reactions on the part of the partner involving perceived loss of attractivity and desirability, loss of intimacy, and even frustration and anger. Negative consequences such as these may not be readily reversed by attending only to the genital problem--such situations may call for a more integrated treatment approach that addresses both the biological and psychosocial realms of the problem (e.g., Althof, 1995; Rowland, 1999).

The Value of a Multidisciplinary Approach

Regarding the treatment of sexual dysfunction, the health provider's goal lies in achieving satisfactory outcomes that are in the best interest of the patient. Such outcomes, which should not overlook improved sexual satisfaction and relationship functioning, can be optimally achieved by considering the full range of existing treatment options and selecting those (individually or in combination) likely to have the greatest impact. This process may require health care providers (whether counselor, physician, or otherwise) to inquire about the sexual problem in ways that extend beyond their own areas of expertise, to suggest in constructive ways treatment approaches that lie outside their area of competence, and if necessary to make the proper referrals.

Appropriate treatment strategies for sexual dysfunctions may thus include pharmacotherapy and individual or couples counseling, or elements of all three. The choice of the specific therapeutic strategy will depend on a variety of factors, including (a) the biological, psychological, and relationship issues that impinge on the dysfunction; (b) the risks and benefits of the various treatment options; and (c) the patient's and partner's values and attitudes about those options (see Rowland, Cooper, & Slob, 1998). Thus, in a situation where the man's sexual dysfunction is secondary to radical prostatectomy, where a healthy sexual relationship existed presurgically, and where risk from drug use is minimal, pharmacotherapy might offer an expedient and effective option. In contrast, in situations where relationship issues might be salient or where the patient is reluctant or ill-advised to use certain drugs because of their documented side effects, emphasis might be placed on combining counseling with minimal drug therapy. Even when indicators suggest minimal or no need for counseling, partner involvement in the choice of therapy, openness and communication about sex within the dyad, and exploration of alternatives to intercourse for achieving sexual enjoyment (all counted among the goals of sex therapy) represent factors typically associated with high treatment satisfaction (Hawton, 1998). In sum, clinic settings that offer or combine multiple approaches to the treatment of sexual problems, that recognize the respective roles of biological, psychological, and interpersonal factors to achieving sexual and relationship satisfaction, and that invite the patient and his partner to explore a variety of economically-feasible treatment options in a nonstigmatizing manner are most likely to be successful in achieving overall satisfaction on the part of the patient and his partner.

CONCLUSION

The number of pharmacological therapies introduced for the treatment of men's sexual problems has increased tenfold since the early 1980s. Many of these therapies are highly effective in alleviating sexual dysfunctions, and although they vary in their ease of use and the satisfaction they produce, the man with a sexual problem today has far more options from which to choose than previously. With greater understanding of the mechanisms of erection, ejaculation, and their dysfunction, pharmacotherapies will undoubtedly become yet more sophisticated and specific, and more prevalent as the treatment of choice. As restoration of genital function is achieved with greater success, clinicians might afford more attention to salient psychological and interpersonal factors that contribute to overall sexual and relationship satisfaction.

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