madman
Super Moderator
Current status of intracavernosal injection therapy in erectile dysfunction (2023)
Bobo W. Elena, Melchiode Zachary, Pavaluri Haritha, Bobo A. Graham & Hellstrom J.G. Wayne
Abstract
Introduction
Erectile dysfunction (ED) is defined as the inability to attain and/or maintain a penile erection. The first introduction of intracavernosal injection (ICI) for the treatment of erectile failure was in 1982 by Virag who reported the positive effects of papaverine on erectile tissue, followed by Brindley concurrently conducting research on ICI therapy with alpha blockade. ICI remains a viable option for the treatment of ED, even after FDA approval of phosphodiesterase type 5 inhibitors in 1998. The American Urological Association (AUA) and the European Association of Urology (EAU) both recommend ICI as a second-line therapy for the treatment of ED. We herein provide an overview of the current state of ICI therapy for the treatment of ED.
Areas covered
We performed a literature review from 1977-2022, using PubMed and the current AUA and EAU guidelines to discuss the current state of ICI for the treatment of ED.
Expert opinion
Although other oral agents are considered the first line for the treatment of ED, the current guidelines and literature demonstrate that ICI is a safe and effective option for patients; however, careful patient selection and counseling should be performed to maximize the effectiveness and safety of this ED treatment.
1. Introduction
Erectile dysfunction (ED) is defined as the consistent or recurrent inability to attain and/or maintain a penile erection sufficient for satisfactory sexual performance [1]. The incidence of ED in the general population increases with age, and it is estimated that approximately 52% of men over the age of 40 experience some degree of ED [2]. There is a multitude of etiologies for ED, including vasculogenic, neurogenic, psychogenic, endocrinologic, and medication-induced ED. The treatment of ED largely consisted of surgery, vacuum erection devices, and psychosocial interventions prior to the introduction of pharmacologic agents [3].
The first introduction of intracavernosal injection (ICI) for the treatment of erectile failure was in 1982 by Dr. Ronald Virag, a cardiovascular surgeon, who reported the positive effects of papaverine on erectile tissue [4]. Dr. Giles Brindley was concurrently conducting research on the effectiveness of phenoxybenzamine as an ICI therapy for ED [5]. His findings were published shortly after Virag; however, Brindley is most famous for his personal demonstration of ICI therapy’s efficacy while at the 1983 American Urological Association’s (AUA) Annual Meeting in Las Vegas, where he performed ICI on himself, using various vasoactive agents prior to his speech to give visual proof to his hypothesis.
During a normal erection after sexual stimulation, parasympathetic nerve endings release nitric oxide, which activates guanylate cyclase (GC) in the smooth muscle (SM) cell. In turn, GC converts guanosine triphosphate to cyclic guanosine monophosphate (cGMP), which decreases the amount of intracellular calcium by activating protein kinase G, leading to the phosphorylation of potassium and calcium channels. This causes dilation of arterioles and relaxes the trabecular SMs, leading to an erection [Figure 1]. The increased pressure within the sinusoidal spaces in the cavernosal tissues presses against the tunica albuginea and prevents venous outflow of blood, allowing for the erection to be maintained. Phosphodiesterase (PDE), especially PDE type 5 (PDE5), is in high concentration within the cavernosal tissues and decreases the levels of cGMP, thus causing the contraction of the SM needed for detumescence. PDE5 inhibitors impede this pathology, thereby promoting the erectile response. Pharmacotherapies used in the treatment of ED take advantage of these physiologic pathways [6].
ICI remains a viable option for the treatment of ED, even after the introduction and FDA approval of oral PDE5 inhibitors in 1998 [7]. The AUA and the European Association of Urology (EAU) both recommend ICI as a second-line therapy for the treatment of ED after the use of PDE5 inhibitors or if PDE5 inhibitors are contraindicated. We herein provide an overview of the current state of ICI for the treatment of ED [1,8].
2. Overview of the Market
The therapeutic agents that are currently available for the treatment of ED include those administered orally, transurethrally, and by ICI. Of these agents, PDE5 inhibitors are consistently used as first-line agents, followed by those administered transurethrally and by ICI. The agents discussed in this review can be used as a single agent; however, they are often used in combination for a synergistic effect. The main concerns regarding ICI therapies are the unwanted side effects, such as prolonged erection/priapism, pain, hematoma, and cavernosal fibrosis. Further research on improving the efficacy of these agents, via clinical trials, is needed in addition to FDA approval and dosage standardization to limit side effects.
3. Introduction of compounds
There are a multitude of therapeutic agents and combinations that are currently available for the treatment of ED via ICI. In this section, we provide a brief introduction to these available agents, which will be discussed further throughout this manuscript [16-30] [Table 1]
4. Pharmacodynamics
4.1.1 Alprostadil
Alprostadil is a prostaglandin E1 (PGE1) synthetic analog that binds as an agonist to prostaglandin (PG) receptors, activating AC and thus leading to the accumulation of cAMP. This increase in cAMP leads to a reduction in the influx of calcium, which is responsible for the pharmacologic effects, including SM relaxation, vasodilation, bronchodilation, and inhibition of platelet aggregation [9]. Alprostadil induces erection by relaxation of trabecular SM and by dilation of cavernous arteries. This leads to the expansion of lacunar spaces and entrapment of blood by compressing venules against the tunica albuginea. Alprostadil has also been demonstrated to act at presynaptic α-adrenergic receptors (ARs) to decrease the release of noradrenaline release and thus decrease the sympathetic response that normally leads to detumescence [10].
4.1.2 Papaverine
Papaverine is a benzylisoquinoline alkaloid of opium that acts as a nonspecific PDE inhibitor in SM cells, thereby causing an increase in intracellular cAMP and cGMP. This pathway induces SM relaxation with a subsequent increase in arterial flow into the corpora cavernosa and a decrease in venous outflow, leading to penile erection [11].
4.1.3 Phentolamine
Phentolamine mesylate is an α1- and α2-selective AR antagonist, thus causing vasodilation via SM relaxation. Phentolamine, through α-adrenergic inhibition, blocks the sympathetic pathway to detumescence, but, as a monotherapy, it does not induce an erection [12].
4.1.4 Aviptadil
Aviptadil is a synthetic vasoactive intestinal polypeptide that increases the activity of AC, leading to cavernosal SM relaxation with the subsequent filling of the cavernous sinuses [13].
4.1.5 Bimix
Bimix is the result of the combined properties of both papaverine and phentolamine. Phentolamine supplements the action of papaverine by decreasing arterial resistance and promoting vasodilation through both pathways in congruence [14].
4.1.6 Trimix
Trimix consists of a combination of papaverine, phentolamine, and alprostadil. Mechanistically, Trimix is like Bimix with the addition of alprostadil’s accumulation of cAMP and reduction in the influx of intracellular calcium. This leads to greater SM relaxation and vasodilation [14].
4.1.7 Quadmix
Quadmix consists of a combination of papaverine, phentolamine, alprostadil, and atropine. Atropine sulfate, at high doses, is hypothesized to assist in the release of endothelium-derived relaxing factor, which is formed from L-arginine in endothelial cells. Acting through soluble GC in the vascular SM cells with the production of cGMP, Quadmix causes vasodilation and inhibits platelet adhesion and aggregation [15].
5. Pharmacokinetics
The pharmacokinetic principles of these agents, including absorption, distribution, metabolism, and excretion, are briefly listed in Tables 2 and 3 [16-30]. Due to the limited literature on the pharmacokinetics of these combination agents, further investigation into these agents is needed.
6. Clinical Efficacy
6.1.1 Alprostadil
Alprostadil is currently the only FDA-approved injectable medication for ED and is available in two formulations (alprostadil-alfadex and alprostadil sterile powder) [31]. At dosages of 10-20 mcg, alprostadil produces full erections in 70-80% of patients with ED [24,32]. Linet et al. performed three separate multi-institutional, prospective studies evaluating the efficacy and tolerability of alprostadil [33]. In one of the studies, the causes of ED were multifactorial in nature, and the assessment of satisfactory sexual activity was ascertained by both the study participant and the partner. Of the 13762 injections given to the 683 men enrolled, 11924 resulted in satisfactory sexual activity. Porst also demonstrated a response rate of over 70% in 4577 men who used intracavernosal alprostadil [34]. Of note, combination therapies have been found to be about twice as effective as PGE1 alone, more cost-efficient, and usually without the discomfort associated with intracavernosal PGE1 injections; thus, the use of combination therapy is increasing when compared to alprostadil monotherapy.
6.1.2 Papaverine
Papaverine, as an intracavernosal monotherapy, is approximately 60% effective in promoting penile erection [32]. In a study by Yasumoto et al., a total of 6 patients were injected with 40 mg/ml of papaverine hydrochloride monotherapy, with 4 of the patients having a nonfunctional expansion. The monotherapy of papaverine was compared to PGE1, which was given to the same 6 patients. All patients demonstrated incomplete functional erections [35]. Papaverine is not approved for monotherapy by the FDA and is typically injected in combination formulations, as the risk for adverse events was demonstrated to be worse when administered alone. However, papaverine is administered alone in developing countries.
6.1.3 Phentolamine
Phentolamine is often administered in combination with other medications, such as alprostadil or papaverine, due to its weak efficacy as a monotherapy and its lack of FDA approval [36]. As a competitive antagonist at both α1- and α2-ARs, phentolamine’s erectogenic effect is mediated by blocking the (anti-erectile) postsynaptic α1-AR [37]. Because of its potential for inhibition of the prejunctional α2-AR, which interferes with norepinephrine reuptake, the drug's erectogenic effect is believed to be antagonized [38]. This dual effect of the drug probably accounts for its limited success when administered intracavernosal as a sole agent [39]. Oral phentolamine at doses of 40 or 80 mg has demonstrated improvement in erectile function when evaluated with the International Index of Erectile Function (IIEF-5). Approximately 59% of men were able to achieve vaginal penetration in a randomized controlled trial [36]. Due to these positive results, oral phentolamine is available in many South American countries.
6.1.4 Aviptadil
Aviptadil has had disappointing effects when administered alone; however, when separately combined with other drugs, such as papaverine and phentolamine, erectile responses were elicited [13,40]. Aviptadil, in combination with phentolamine, is currently being sought for regulatory approval in the United States; however, it has been approved in Europe since 2000 [30]. In an open, multicenter, randomized crossover study comparing the efficacy and preference of alprostadil to aviptadil/phentolamine, 187 men were enrolled, and both agents were found to elicit comparable penile erections satisfactory for penetration [41]. A favorable side-effect profile with this combination was reported, as the incidence of priapism, pain, and fibrosis was low at 0.06, 0.5, and 0%, respectively, after a 12-month follow-up. Aviptadil/phentolamine is also effective in patients who do not respond to other single monotherapy injections, with efficacy rates of 67–73% [30]. Aviptadil/phentolamine has been clinically approved in the United Kingdom, Denmark, and in New Zealand.
6.1.5 Bimix
Zorgniotti and Lefleur established the popularity of Bimix with the results of their study in 1986. During in-office testing, they observed an increased average response rate of 60-70% [42] when compared with monotherapy injections of alprostadil. In a recent multicenter study evaluating Bimix in 157 men, Bernie et al. noted a 94% efficacy rate, with a 0.9% to 2.6% side-effect incidence of priapism, pain, or hematoma [43]. The combination of phentolamine and papaverine, though not FDA-approved in the United States, is approved and available for use in many European countries.
6.1.6 Trimix
Bernie et al., in a prospective study with 175 men enrolled, compared Trimix to PGE1 monotherapy. Trimix produced a longer-lasting, satisfactory erection but also increased the risk of priapism [43]. The study participants were evaluated via the IIEF-5, Quality of Erection Questionnaire, Sexual Quality of Life, and Erectile Dysfunction Inventory of Treatment Satisfaction, which indicated that combination therapy was non-inferior to PGE1 alone. Interestingly, the group, that was treated with the higher dosage of Trimix, exhibited the largest risk of priapism [43]. Kulaksizoglu et al. noted that patients obtained comparable satisfactory penile erections with Trimix when compared to PGE1, but patients preferred Trimix therapy [43]. A clinical double-blind study by Shenfeld et al. recorded that Trimix was superior to Bimix when administered to 20 impotent patients [45]. Bennet et al. described rigid erections in 50 to 62% of nonresponders to oral medications, suggesting that Trimix can offer treatment benefits for individuals who failed to respond to monotherapy with alprostadil or combination therapy with Bimix [46].
6.1.7 Quadmix
Hatzimourtidis reported that 95% to 100% of patients with ED achieved sustained rigidity after dose titration with Quadmix [47]. Montorsi et al. demonstrated that 96% of their patients with vasculogenic ED reported sustained erections suitable for penetration. Montorsi et al., who administered Quadmix to 56 patients with corporal veno-occlusive ED, also noted that 95% of their patients achieved rigid and sustained erections. [12]. One study observed less impressive results, with no statistically significant difference between pharmacologic injections enriched with or without atropine [15]. The hypothesis is that the addition of atropine increases the synergism of the Trimix combination, continuing to enhance SM relaxation within the cavernous sinusoids and helicine arteries. As demonstrated by Baniel et al., the addition of atropine resulted in the improvement of several measurable hemodynamic events during an erection, including arterial dilation, venous compression, and sinusoidal relaxation [48].
7. Safety and Tolerability
7.1.1 Alprostadil
The use of ICI of alprostadil can cause a variety of adverse reactions, with penile pain as the most commonly reported. This was noted in 37% of patients who underwent treatment for up to 18 months [49, 50]. Other adverse reactions include priapism, penile fibrosis, injection-site hematoma, ecchymosis, penile rash, and penile edema [33]. These reactions were reported by 4% or less of patients who underwent treatment. Other noted symptoms include penile numbness, irritation, sensitivity, pruritus, erythema, skin tearing, and discoloration. Patients also experienced systemic adverse reactions, including hypotension, dizziness, and headache. Contraindications include sickle cell anemia or trait, multiple myeloma, and leukemia, conditions that would increase the risk of priapism. Other contraindications include those with fibrotic penile conditions, such as anatomical deformation, angulation, cavernosal fibrosis, Peyronie’s disease, or penile implants [24].
7.1.2 Papaverine
As demonstrated by Moemen et al., priapism and corporal fibrosis were more commonly observed with papaverine when compared to PGE1 and Trimix [51]. However, a noted risk to consider with ICI of papaverine is hepatotoxicity. A study analyzing the incidence of hepatotoxicity with ICIs of papaverine revealed that 2 out of 71 patients developed elevated liver function tests (LFTs) during treatment. This study recommended monitoring LFTs every 6 months [52].
7.1.3 Phentolamine
Due to similar mechanistic outcomes including SM relaxation and vasodilation, adverse reactions of phentolamine are similar to those of alprostadil [40]. Common side effects associated with this drug include systemic hypotension, reflex tachycardia, nasal congestion, and gastrointestinal upset when given both orally and intracavernosal [30].
7.1.4 Aviptadil
In addition to having similar adverse reactions to the above-mentioned medications, aviptadil injections can also cause transient facial flushing. This adverse effect was reported by 33.9% of patients in a study evaluating the side-effect profile and efficacy of aviptadil injections [53].
7.1.5 Bimix
Adverse reactions to Bimix injections are similar to those of the above-mentioned medications. Short-term effects include priapism and penile pain, while a long-term side effect is cavernosal fibrosis. As Bimix is a combination of papaverine and phentolamine, hepatotoxicity is an adverse reaction to consider [54].
7.1.6 Trimix
Trimix has adverse reactions similar to the above-mentioned adverse reactions. The prevalence of penile pain is reduced relative to alprostadil injections, as there are decreased levels of PG. Trimix also requires more complicated storage as well as preparation, which is important to consider [55].
7.1.7 Quadmix
Adverse reactions are similar to Trimix. Additionally, Quadmix also requires relatively more complex preparation and storage similar to Trimix. Other adverse effects more specifically attributed to Quadmix include dizziness, plaque formation (7%), and subcutaneous hemorrhage (4%) [12]. In one study, small nodules were also reported in 57% of patients after more than 12 months of use [56,57].
8. Conclusion
ED is a condition that affects a multitude of men and is multifactorial in its etiology. There are numerous treatments for ED, including conservative lifestyle measures, medicinal agents, and surgical therapy. A thorough history, physical exam, laboratory workup, and an overall health assessment should be performed to provide the best treatment options. Although conservative measures are considered a viable treatment option per the AUA and EAU guidelines, there is a lack of sufficient evidence to support any one lifestyle modification as a definitive treatment option [1]. If conservative measures fail to improve erectile failure, then medical therapy is indicated.
Of the therapeutic agents used in the treatment of ED, oral PDE5 inhibitors are considered first-line therapy in both the AUA and EAU guidelines. In men who continue to experience ED after the use of oral agents or who have contraindications to the use of PDE5 inhibitors (eg, nitrates), ICI is considered second-line therapy, with penile prosthesis placement considered a third-line option. Of the agents used for ICI, alprostadil is the only FDA-approved agent for the treatment of ED. As discussed, combination therapies have demonstrated even greater efficacy than alprostadil alone. Specifically, Trimix has demonstrated a success rate of 92% and has a lower incidence of penile pain than alprostadil alone [8]. Although combination therapies have proven their efficacy, there is currently no FDA approval for any of these agents, making dosing and standardization of treatment difficult. ICI therapy has also demonstrated a high treatment withdrawal rate up to 79.9 percent. Reasons for withdrawal include poor treatment response, adverse event(s), and inconvenience of use [58]. Despite this, after a review of the guidelines and literature regarding treatment for ED, it is clear that ICI can be an effective treatment option for patients experiencing significant ED.
9. Expert Opinion
In regard to ICI therapy in the treatment of ED, we believe that the key areas of improvement, including future directions of research, should concern the obtainment of FDA approval and the dosage standardization of these agents. To date, alprostadil is the only FDA-approved agent. In addition, the only ongoing trials involving ICI therapy for ED include experimental agents, such as platelet-rich plasma, umbilical cord mesenchymal cells, stem cells (SCs), and botulinum toxin. Further research into this field would expand the use of this therapy and potentially improve the efficacy of these agents by optimizing the current drug combinations and minimizing any side effects. Oral PDE5 inhibitors, unless contraindicated, are considered first-line therapy for ED. However, in a substantial proportion of patients (30%), the effectiveness of PDE5 inhibitors is unsatisfactory, with 46% of patients quitting oral medication largely due to the lack of efficacy [2]. This demonstrates a need for ICI therapy to aid patients who are refractory to oral agents.
Although the findings of this study indicate a promising modality for ED, there are limitations in the use of SC therapies. More specifically, in this study, the process of collecting and shipping the sample to the lab was time-consuming, with a total processing time of 10 days [59]. If this therapy were to acquire FDA approval for this indication, it could be inaccessible and unrealistic for many patients due to the time commitment and the shipping expenses associated with this type of collection. However, this study demonstrates the concept that ICI of SCs, even after a single dose, could potentially circumvent the need for surgery. This finding is equally promising, as the current medical treatment of ED involves the use of on-demand administration to achieve desired effects. If SC therapies were to become widely available to patients, they could change the landscape of the treatment of ED by reducing the frequency of treatments.
Our position is that the treatment of ED with ICI will continue to expand and improve over the course of the next decade. As demonstrated in our review, these agents are a safe and effective option for the appropriately selected patient and provide a unique niche in the treatment of ED. As discussed, the ICI of SCs is a promising novel therapy and may become more widely available for the treatment of ED, especially as technologies continue to improve. However, prior to incorporating the ICI of SCs into the algorithm of ED treatment, further studies regarding their mechanism of action are needed. The future of this area of pharmacology is encouraging, and continued research may significantly impact the treatment of ED by providing another medical modality, reducing the need for surgical options, and decreasing the need for on-demand agents to achieve spontaneous erections.
Bobo W. Elena, Melchiode Zachary, Pavaluri Haritha, Bobo A. Graham & Hellstrom J.G. Wayne
Abstract
Introduction
Erectile dysfunction (ED) is defined as the inability to attain and/or maintain a penile erection. The first introduction of intracavernosal injection (ICI) for the treatment of erectile failure was in 1982 by Virag who reported the positive effects of papaverine on erectile tissue, followed by Brindley concurrently conducting research on ICI therapy with alpha blockade. ICI remains a viable option for the treatment of ED, even after FDA approval of phosphodiesterase type 5 inhibitors in 1998. The American Urological Association (AUA) and the European Association of Urology (EAU) both recommend ICI as a second-line therapy for the treatment of ED. We herein provide an overview of the current state of ICI therapy for the treatment of ED.
Areas covered
We performed a literature review from 1977-2022, using PubMed and the current AUA and EAU guidelines to discuss the current state of ICI for the treatment of ED.
Expert opinion
Although other oral agents are considered the first line for the treatment of ED, the current guidelines and literature demonstrate that ICI is a safe and effective option for patients; however, careful patient selection and counseling should be performed to maximize the effectiveness and safety of this ED treatment.
1. Introduction
Erectile dysfunction (ED) is defined as the consistent or recurrent inability to attain and/or maintain a penile erection sufficient for satisfactory sexual performance [1]. The incidence of ED in the general population increases with age, and it is estimated that approximately 52% of men over the age of 40 experience some degree of ED [2]. There is a multitude of etiologies for ED, including vasculogenic, neurogenic, psychogenic, endocrinologic, and medication-induced ED. The treatment of ED largely consisted of surgery, vacuum erection devices, and psychosocial interventions prior to the introduction of pharmacologic agents [3].
The first introduction of intracavernosal injection (ICI) for the treatment of erectile failure was in 1982 by Dr. Ronald Virag, a cardiovascular surgeon, who reported the positive effects of papaverine on erectile tissue [4]. Dr. Giles Brindley was concurrently conducting research on the effectiveness of phenoxybenzamine as an ICI therapy for ED [5]. His findings were published shortly after Virag; however, Brindley is most famous for his personal demonstration of ICI therapy’s efficacy while at the 1983 American Urological Association’s (AUA) Annual Meeting in Las Vegas, where he performed ICI on himself, using various vasoactive agents prior to his speech to give visual proof to his hypothesis.
During a normal erection after sexual stimulation, parasympathetic nerve endings release nitric oxide, which activates guanylate cyclase (GC) in the smooth muscle (SM) cell. In turn, GC converts guanosine triphosphate to cyclic guanosine monophosphate (cGMP), which decreases the amount of intracellular calcium by activating protein kinase G, leading to the phosphorylation of potassium and calcium channels. This causes dilation of arterioles and relaxes the trabecular SMs, leading to an erection [Figure 1]. The increased pressure within the sinusoidal spaces in the cavernosal tissues presses against the tunica albuginea and prevents venous outflow of blood, allowing for the erection to be maintained. Phosphodiesterase (PDE), especially PDE type 5 (PDE5), is in high concentration within the cavernosal tissues and decreases the levels of cGMP, thus causing the contraction of the SM needed for detumescence. PDE5 inhibitors impede this pathology, thereby promoting the erectile response. Pharmacotherapies used in the treatment of ED take advantage of these physiologic pathways [6].
ICI remains a viable option for the treatment of ED, even after the introduction and FDA approval of oral PDE5 inhibitors in 1998 [7]. The AUA and the European Association of Urology (EAU) both recommend ICI as a second-line therapy for the treatment of ED after the use of PDE5 inhibitors or if PDE5 inhibitors are contraindicated. We herein provide an overview of the current state of ICI for the treatment of ED [1,8].
2. Overview of the Market
The therapeutic agents that are currently available for the treatment of ED include those administered orally, transurethrally, and by ICI. Of these agents, PDE5 inhibitors are consistently used as first-line agents, followed by those administered transurethrally and by ICI. The agents discussed in this review can be used as a single agent; however, they are often used in combination for a synergistic effect. The main concerns regarding ICI therapies are the unwanted side effects, such as prolonged erection/priapism, pain, hematoma, and cavernosal fibrosis. Further research on improving the efficacy of these agents, via clinical trials, is needed in addition to FDA approval and dosage standardization to limit side effects.
3. Introduction of compounds
There are a multitude of therapeutic agents and combinations that are currently available for the treatment of ED via ICI. In this section, we provide a brief introduction to these available agents, which will be discussed further throughout this manuscript [16-30] [Table 1]
4. Pharmacodynamics
4.1.1 Alprostadil
Alprostadil is a prostaglandin E1 (PGE1) synthetic analog that binds as an agonist to prostaglandin (PG) receptors, activating AC and thus leading to the accumulation of cAMP. This increase in cAMP leads to a reduction in the influx of calcium, which is responsible for the pharmacologic effects, including SM relaxation, vasodilation, bronchodilation, and inhibition of platelet aggregation [9]. Alprostadil induces erection by relaxation of trabecular SM and by dilation of cavernous arteries. This leads to the expansion of lacunar spaces and entrapment of blood by compressing venules against the tunica albuginea. Alprostadil has also been demonstrated to act at presynaptic α-adrenergic receptors (ARs) to decrease the release of noradrenaline release and thus decrease the sympathetic response that normally leads to detumescence [10].
4.1.2 Papaverine
Papaverine is a benzylisoquinoline alkaloid of opium that acts as a nonspecific PDE inhibitor in SM cells, thereby causing an increase in intracellular cAMP and cGMP. This pathway induces SM relaxation with a subsequent increase in arterial flow into the corpora cavernosa and a decrease in venous outflow, leading to penile erection [11].
4.1.3 Phentolamine
Phentolamine mesylate is an α1- and α2-selective AR antagonist, thus causing vasodilation via SM relaxation. Phentolamine, through α-adrenergic inhibition, blocks the sympathetic pathway to detumescence, but, as a monotherapy, it does not induce an erection [12].
4.1.4 Aviptadil
Aviptadil is a synthetic vasoactive intestinal polypeptide that increases the activity of AC, leading to cavernosal SM relaxation with the subsequent filling of the cavernous sinuses [13].
4.1.5 Bimix
Bimix is the result of the combined properties of both papaverine and phentolamine. Phentolamine supplements the action of papaverine by decreasing arterial resistance and promoting vasodilation through both pathways in congruence [14].
4.1.6 Trimix
Trimix consists of a combination of papaverine, phentolamine, and alprostadil. Mechanistically, Trimix is like Bimix with the addition of alprostadil’s accumulation of cAMP and reduction in the influx of intracellular calcium. This leads to greater SM relaxation and vasodilation [14].
4.1.7 Quadmix
Quadmix consists of a combination of papaverine, phentolamine, alprostadil, and atropine. Atropine sulfate, at high doses, is hypothesized to assist in the release of endothelium-derived relaxing factor, which is formed from L-arginine in endothelial cells. Acting through soluble GC in the vascular SM cells with the production of cGMP, Quadmix causes vasodilation and inhibits platelet adhesion and aggregation [15].
5. Pharmacokinetics
The pharmacokinetic principles of these agents, including absorption, distribution, metabolism, and excretion, are briefly listed in Tables 2 and 3 [16-30]. Due to the limited literature on the pharmacokinetics of these combination agents, further investigation into these agents is needed.
6. Clinical Efficacy
6.1.1 Alprostadil
Alprostadil is currently the only FDA-approved injectable medication for ED and is available in two formulations (alprostadil-alfadex and alprostadil sterile powder) [31]. At dosages of 10-20 mcg, alprostadil produces full erections in 70-80% of patients with ED [24,32]. Linet et al. performed three separate multi-institutional, prospective studies evaluating the efficacy and tolerability of alprostadil [33]. In one of the studies, the causes of ED were multifactorial in nature, and the assessment of satisfactory sexual activity was ascertained by both the study participant and the partner. Of the 13762 injections given to the 683 men enrolled, 11924 resulted in satisfactory sexual activity. Porst also demonstrated a response rate of over 70% in 4577 men who used intracavernosal alprostadil [34]. Of note, combination therapies have been found to be about twice as effective as PGE1 alone, more cost-efficient, and usually without the discomfort associated with intracavernosal PGE1 injections; thus, the use of combination therapy is increasing when compared to alprostadil monotherapy.
6.1.2 Papaverine
Papaverine, as an intracavernosal monotherapy, is approximately 60% effective in promoting penile erection [32]. In a study by Yasumoto et al., a total of 6 patients were injected with 40 mg/ml of papaverine hydrochloride monotherapy, with 4 of the patients having a nonfunctional expansion. The monotherapy of papaverine was compared to PGE1, which was given to the same 6 patients. All patients demonstrated incomplete functional erections [35]. Papaverine is not approved for monotherapy by the FDA and is typically injected in combination formulations, as the risk for adverse events was demonstrated to be worse when administered alone. However, papaverine is administered alone in developing countries.
6.1.3 Phentolamine
Phentolamine is often administered in combination with other medications, such as alprostadil or papaverine, due to its weak efficacy as a monotherapy and its lack of FDA approval [36]. As a competitive antagonist at both α1- and α2-ARs, phentolamine’s erectogenic effect is mediated by blocking the (anti-erectile) postsynaptic α1-AR [37]. Because of its potential for inhibition of the prejunctional α2-AR, which interferes with norepinephrine reuptake, the drug's erectogenic effect is believed to be antagonized [38]. This dual effect of the drug probably accounts for its limited success when administered intracavernosal as a sole agent [39]. Oral phentolamine at doses of 40 or 80 mg has demonstrated improvement in erectile function when evaluated with the International Index of Erectile Function (IIEF-5). Approximately 59% of men were able to achieve vaginal penetration in a randomized controlled trial [36]. Due to these positive results, oral phentolamine is available in many South American countries.
6.1.4 Aviptadil
Aviptadil has had disappointing effects when administered alone; however, when separately combined with other drugs, such as papaverine and phentolamine, erectile responses were elicited [13,40]. Aviptadil, in combination with phentolamine, is currently being sought for regulatory approval in the United States; however, it has been approved in Europe since 2000 [30]. In an open, multicenter, randomized crossover study comparing the efficacy and preference of alprostadil to aviptadil/phentolamine, 187 men were enrolled, and both agents were found to elicit comparable penile erections satisfactory for penetration [41]. A favorable side-effect profile with this combination was reported, as the incidence of priapism, pain, and fibrosis was low at 0.06, 0.5, and 0%, respectively, after a 12-month follow-up. Aviptadil/phentolamine is also effective in patients who do not respond to other single monotherapy injections, with efficacy rates of 67–73% [30]. Aviptadil/phentolamine has been clinically approved in the United Kingdom, Denmark, and in New Zealand.
6.1.5 Bimix
Zorgniotti and Lefleur established the popularity of Bimix with the results of their study in 1986. During in-office testing, they observed an increased average response rate of 60-70% [42] when compared with monotherapy injections of alprostadil. In a recent multicenter study evaluating Bimix in 157 men, Bernie et al. noted a 94% efficacy rate, with a 0.9% to 2.6% side-effect incidence of priapism, pain, or hematoma [43]. The combination of phentolamine and papaverine, though not FDA-approved in the United States, is approved and available for use in many European countries.
6.1.6 Trimix
Bernie et al., in a prospective study with 175 men enrolled, compared Trimix to PGE1 monotherapy. Trimix produced a longer-lasting, satisfactory erection but also increased the risk of priapism [43]. The study participants were evaluated via the IIEF-5, Quality of Erection Questionnaire, Sexual Quality of Life, and Erectile Dysfunction Inventory of Treatment Satisfaction, which indicated that combination therapy was non-inferior to PGE1 alone. Interestingly, the group, that was treated with the higher dosage of Trimix, exhibited the largest risk of priapism [43]. Kulaksizoglu et al. noted that patients obtained comparable satisfactory penile erections with Trimix when compared to PGE1, but patients preferred Trimix therapy [43]. A clinical double-blind study by Shenfeld et al. recorded that Trimix was superior to Bimix when administered to 20 impotent patients [45]. Bennet et al. described rigid erections in 50 to 62% of nonresponders to oral medications, suggesting that Trimix can offer treatment benefits for individuals who failed to respond to monotherapy with alprostadil or combination therapy with Bimix [46].
6.1.7 Quadmix
Hatzimourtidis reported that 95% to 100% of patients with ED achieved sustained rigidity after dose titration with Quadmix [47]. Montorsi et al. demonstrated that 96% of their patients with vasculogenic ED reported sustained erections suitable for penetration. Montorsi et al., who administered Quadmix to 56 patients with corporal veno-occlusive ED, also noted that 95% of their patients achieved rigid and sustained erections. [12]. One study observed less impressive results, with no statistically significant difference between pharmacologic injections enriched with or without atropine [15]. The hypothesis is that the addition of atropine increases the synergism of the Trimix combination, continuing to enhance SM relaxation within the cavernous sinusoids and helicine arteries. As demonstrated by Baniel et al., the addition of atropine resulted in the improvement of several measurable hemodynamic events during an erection, including arterial dilation, venous compression, and sinusoidal relaxation [48].
7. Safety and Tolerability
7.1.1 Alprostadil
The use of ICI of alprostadil can cause a variety of adverse reactions, with penile pain as the most commonly reported. This was noted in 37% of patients who underwent treatment for up to 18 months [49, 50]. Other adverse reactions include priapism, penile fibrosis, injection-site hematoma, ecchymosis, penile rash, and penile edema [33]. These reactions were reported by 4% or less of patients who underwent treatment. Other noted symptoms include penile numbness, irritation, sensitivity, pruritus, erythema, skin tearing, and discoloration. Patients also experienced systemic adverse reactions, including hypotension, dizziness, and headache. Contraindications include sickle cell anemia or trait, multiple myeloma, and leukemia, conditions that would increase the risk of priapism. Other contraindications include those with fibrotic penile conditions, such as anatomical deformation, angulation, cavernosal fibrosis, Peyronie’s disease, or penile implants [24].
7.1.2 Papaverine
As demonstrated by Moemen et al., priapism and corporal fibrosis were more commonly observed with papaverine when compared to PGE1 and Trimix [51]. However, a noted risk to consider with ICI of papaverine is hepatotoxicity. A study analyzing the incidence of hepatotoxicity with ICIs of papaverine revealed that 2 out of 71 patients developed elevated liver function tests (LFTs) during treatment. This study recommended monitoring LFTs every 6 months [52].
7.1.3 Phentolamine
Due to similar mechanistic outcomes including SM relaxation and vasodilation, adverse reactions of phentolamine are similar to those of alprostadil [40]. Common side effects associated with this drug include systemic hypotension, reflex tachycardia, nasal congestion, and gastrointestinal upset when given both orally and intracavernosal [30].
7.1.4 Aviptadil
In addition to having similar adverse reactions to the above-mentioned medications, aviptadil injections can also cause transient facial flushing. This adverse effect was reported by 33.9% of patients in a study evaluating the side-effect profile and efficacy of aviptadil injections [53].
7.1.5 Bimix
Adverse reactions to Bimix injections are similar to those of the above-mentioned medications. Short-term effects include priapism and penile pain, while a long-term side effect is cavernosal fibrosis. As Bimix is a combination of papaverine and phentolamine, hepatotoxicity is an adverse reaction to consider [54].
7.1.6 Trimix
Trimix has adverse reactions similar to the above-mentioned adverse reactions. The prevalence of penile pain is reduced relative to alprostadil injections, as there are decreased levels of PG. Trimix also requires more complicated storage as well as preparation, which is important to consider [55].
7.1.7 Quadmix
Adverse reactions are similar to Trimix. Additionally, Quadmix also requires relatively more complex preparation and storage similar to Trimix. Other adverse effects more specifically attributed to Quadmix include dizziness, plaque formation (7%), and subcutaneous hemorrhage (4%) [12]. In one study, small nodules were also reported in 57% of patients after more than 12 months of use [56,57].
8. Conclusion
ED is a condition that affects a multitude of men and is multifactorial in its etiology. There are numerous treatments for ED, including conservative lifestyle measures, medicinal agents, and surgical therapy. A thorough history, physical exam, laboratory workup, and an overall health assessment should be performed to provide the best treatment options. Although conservative measures are considered a viable treatment option per the AUA and EAU guidelines, there is a lack of sufficient evidence to support any one lifestyle modification as a definitive treatment option [1]. If conservative measures fail to improve erectile failure, then medical therapy is indicated.
Of the therapeutic agents used in the treatment of ED, oral PDE5 inhibitors are considered first-line therapy in both the AUA and EAU guidelines. In men who continue to experience ED after the use of oral agents or who have contraindications to the use of PDE5 inhibitors (eg, nitrates), ICI is considered second-line therapy, with penile prosthesis placement considered a third-line option. Of the agents used for ICI, alprostadil is the only FDA-approved agent for the treatment of ED. As discussed, combination therapies have demonstrated even greater efficacy than alprostadil alone. Specifically, Trimix has demonstrated a success rate of 92% and has a lower incidence of penile pain than alprostadil alone [8]. Although combination therapies have proven their efficacy, there is currently no FDA approval for any of these agents, making dosing and standardization of treatment difficult. ICI therapy has also demonstrated a high treatment withdrawal rate up to 79.9 percent. Reasons for withdrawal include poor treatment response, adverse event(s), and inconvenience of use [58]. Despite this, after a review of the guidelines and literature regarding treatment for ED, it is clear that ICI can be an effective treatment option for patients experiencing significant ED.
9. Expert Opinion
In regard to ICI therapy in the treatment of ED, we believe that the key areas of improvement, including future directions of research, should concern the obtainment of FDA approval and the dosage standardization of these agents. To date, alprostadil is the only FDA-approved agent. In addition, the only ongoing trials involving ICI therapy for ED include experimental agents, such as platelet-rich plasma, umbilical cord mesenchymal cells, stem cells (SCs), and botulinum toxin. Further research into this field would expand the use of this therapy and potentially improve the efficacy of these agents by optimizing the current drug combinations and minimizing any side effects. Oral PDE5 inhibitors, unless contraindicated, are considered first-line therapy for ED. However, in a substantial proportion of patients (30%), the effectiveness of PDE5 inhibitors is unsatisfactory, with 46% of patients quitting oral medication largely due to the lack of efficacy [2]. This demonstrates a need for ICI therapy to aid patients who are refractory to oral agents.
Although the findings of this study indicate a promising modality for ED, there are limitations in the use of SC therapies. More specifically, in this study, the process of collecting and shipping the sample to the lab was time-consuming, with a total processing time of 10 days [59]. If this therapy were to acquire FDA approval for this indication, it could be inaccessible and unrealistic for many patients due to the time commitment and the shipping expenses associated with this type of collection. However, this study demonstrates the concept that ICI of SCs, even after a single dose, could potentially circumvent the need for surgery. This finding is equally promising, as the current medical treatment of ED involves the use of on-demand administration to achieve desired effects. If SC therapies were to become widely available to patients, they could change the landscape of the treatment of ED by reducing the frequency of treatments.
Our position is that the treatment of ED with ICI will continue to expand and improve over the course of the next decade. As demonstrated in our review, these agents are a safe and effective option for the appropriately selected patient and provide a unique niche in the treatment of ED. As discussed, the ICI of SCs is a promising novel therapy and may become more widely available for the treatment of ED, especially as technologies continue to improve. However, prior to incorporating the ICI of SCs into the algorithm of ED treatment, further studies regarding their mechanism of action are needed. The future of this area of pharmacology is encouraging, and continued research may significantly impact the treatment of ED by providing another medical modality, reducing the need for surgical options, and decreasing the need for on-demand agents to achieve spontaneous erections.
