Curr Urol Rep (2014) 15:415 DOI 10.1007/s11934-014-0415-4
MEN'S HEALTH (R CARRION AND C YANG, SECTION EDITORS)
Update on Medical Management of Peyronie’s Disease Ronny B. W. Tan & Premsant Sangkum & Gregory C. Mitchell & Wayne J. G. Hellstrom Published online: 17 April 2014 # Springer Science+Business Media New York 2014
Abstract The treatment of Peyronie’s disease (PD) is a challenge for the clinician. In the quest to straighten the penis, alleviate pain, prevent further shortening, and restore erectile function, many non-surgical treatments have been offered in lieu of an operative approach, which is still considered the gold standard for definitive treatment. This communication is an update on the different approaches used in the minimally invasive management of this frustrating and yet intriguing condition. Keywords Peyronie’s disease . Oral . Topical . Intralesional . Ionotophoresis . Radiotherapy . Shockwave therapy . Penile traction devices . Stem cell therapy
Introduction Peyronie’s disease (PD), or induratio penis plastica, as it was originally known, was further described by, and later eponymously named after, Francios Gigot de La Peyronie [1] in 1743. The disease is characterized by the development of fibrous tunical plaque(s) and is usually associated with some degree of penile curvature. PD has been described as having a significant psychological component, as approximately 48 % of PD patients become clinically depressed [2]. Its prevalence is reported to range from 3 % to 9 % in the adult male population, and the most frequent age of presentation is during the fifth decade [3]. In considering the natural history of PD, 1 year postdiagnosis, 40 % of men report curvatures that remain unchanged, approximately 45 % report progressive curvature, and less than 15 % of men with PD report spontaneous
resolution [4]. PD is often associated with prior penile trauma, but this history is not universal. The uncertainty about the pathogenesis and natural history of PD adds to the difficulty of managing men who present with this condition.
Pathophysiology Recently, PD has been conceptualized as a wound healing disorder. A common presentation is a fibrous, inelastic scar or plaque of the tunica albuginea that appears following trauma to the penis [5]. It is postulated that trauma causes increased TGF-β1 levels [6], which results in an intense proinflammatory, profibrotic cascade with subsequent deposition of collagen, resulting in the hallmark of the disease: plaque formation and penile curvature. Studies have shown that inducible nitric oxide levels are quenched by reactive oxygen species (ROS) creating peroxynitrite, a highly toxic and profibrotic compound [7, 8]. Although the pathophysiology of PD is still poorly understood, attempts at manipulating the levels of TGF-β1 and ROS could theoretically alter the natural history of PD, which forms the basis of many of our current medical therapies [9]. As a general rule, the aim of medical management of PD is to alter the wound healing process, preventing plaque formation. Medical therapy for PD (or minimally invasive management) can be subdivided into oral, topical, iontophoretic, intralesional, radio therapeutic, shockwave therapy, penile traction, or any combination of the above. There is also a recent interest in including stem cells for the treatment of PD. This article reviews the current literature pertaining to the non-surgical treatment options available for men who have PD (Tables 1 and 2).
This article is part of the Topical Collection on Men’s Health R. B. W. Tan Department of Urology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore e-mail: [email protected] P. Sangkum : G. C. Mitchell : W. J. G. Hellstrom (*) Department of Urology, Tulane University School of Medicine, 1430 Tulane Ave. SL-42 Room 3520B, New Orleans, LA 70112, USA e-mail: [email protected]
Oral Therapies Vitamin E (Tocopherol) Vitamin E is a highly favored initial treatment by urologists in the United States [10]. Vitamin E is a fat-soluble compound
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Table 1 Summary of randomized controlled trials performed for oral agents for the treatment of PD Study
Therapy
Mode of Type of Study Delivery
Safarinejad et al., 2007 300 mg Vit E po bid, 1 g propionyl-L-carnitine Oral bid, or combination compared with placebo Weidner et al., 2005 3 g Potaba po qid compared with placebo Oral Teloken et al., 1999
20 mg tamoxifen po bid compared with placebo Oral
Safarinejad et al., 2004 2.5 mg colchicine po od compared with placebo Oral Safarinejad et al., 2010 400 mg pentoxifylline po bid compared with placebo Safarinejad et al., 2010 300 mg CoQ10 po od compared with placebo
Oral Oral
RCT—double blind, placebo controlled RCT—double blind, placebo controlled RCT—double blind, placebo controlled RCT—double blind, placebo controlled RCT—double blind, placebo controlled RCT—double blind, placebo controlled
Effectiveness
No statistically significant improvement in treatment arm Stabilizes PD and prevents progression of penile curvature No statistically significant improvement in treatment arm No statistically significant improvement in treatment arm Significantly improves penile curvature and plaque volume Statistically significant improvements in curvature, penile pain, and IIEF score
po, per os; bid, twice daily; od, once daily; qid, four times daily; RCT, randomized, controlled trial
that was first introduced for the treatment of PD in 1949 [11]. It acts as a natural antioxidant and free-radical scavenger, thereby decreasing penile fibrosis [12, 13]. Clinical trials of vitamin E for the treatment of PD show conflicting results. Most of the studies demonstrate no clinical evidence to support treatment of PD with vitamin E [14, 15]. However, two recent reports using combination treatment of vitamin E with other agents revealed significant improvement in plaque size and penile curvature in the vitamin E group [16, 17]. Despite the equivocal evidence regarding vitamin E in the treatment of PD, its low cost, wide availability, and low rate of adverse events make it a continually popular therapy with many urologists [18]. Potassium Para-aminobenzoate (Potaba) Potassium para-aminobenzoate was introduced for treatment of PD in 1959 [19]. The mechanism of its action is hypothesized to be both anti-inflammatory and anti-fibrotic via stabilization of serotonin-monoamine oxidase activity [18, 20]. A recent double-blind, placebo-controlled trial has shown that para-aminobenzoate showed a response rate of 74.3 % over placebo 50.0 % (p = 0.016). These studies suggest that Potaba might stabilize PD and prevent progression of penile curvature [20]. Unfortunately, Potaba is relatively expensive, and dosing large tablets four times daily are potential drawbacks to the medicine. The most commonly reported adverse events are gastrointestinal upset and skin photosensitization [12, 21]. Tamoxifen Tamoxifen is a non-steroidal estrogen receptor antagonist that modulates the release of TGF-β1 from fibroblasts and blocks TGF-β receptors, resulting in diminished fibrogenesis [22]. In
clinical trials, 20 mg tamoxifen twice daily failed to show any statistical significant improvement in pain, curvature or plaque size as compared to placebo [23]. Colchicine Colchicine down-regulates TGF-β expression [24], inhibits tubulin movement, reduces leukocyte action, and diminishes wound contracture [12, 25]. In a pilot study, colchicine decreased plaque size and improved penile curvature [25]. However, a more recent randomized, double-blind, controlled study concluded that 4 months of therapy with up to 2.5 mg colchicine daily in patients with PD had no benefit when compared to placebo [26]. Moreover, combination therapy between vitamin E and colchicine for PD revealed conflicting results [27, 28]. Despite a lack of clear, undisputed evidence, colchicine is the most common choice for non-surgical treatment by American urologists [10]. Carnitine Propionyl-L-carnitine (PLC) is a short-chain acyl derivative of carnitine that has an antiproliferative effect on human endothelial cells [14]. Carnitine is more effective than tamoxifen in reducing pain and inhibiting disease progression in a clinical trial [29]. In another study, PLC significantly reduced penile curvature, plaque size, cavernosal artery end-diastolic velocity, and the need for surgery when combined with concurrent intralesional verapamil injection [30]. However, a recent study demonstrated that PLC, when taken alone (1 g orally, twice daily) or combined with vitamin E, did not lead to significant improvement in pain, curvature or Peyronie’s plaque size when compared to placebo when taken alone (1 g orally, twice daily) or combined with vitamin E [14].
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Table 2 Summary of randomized, controlled trials performed forother forms of treatment/combination therapy for PD Fitch et al., 2007 Topical verapamil 15 % vs. topical trifluoperazine 10 % vs. topical magnesium sulfate 10 % vs. placebo applied to penile shaft bid
Topical gel
Di Stasi et al., 2004
Iontophoresis
Greenfield et al., 2007
5 mg verapamil + 8 mg dexamethasone in 5 ml of water compared with lidocaine as control, 20 sessions 10 mg verapamil in 4 ml of saline vs. 4 ml of saline, 24 sessions
RCT—double blind, Statistically significant placebo controlled improvements (greatest in verapamil group) in curvature compared with placebo RCT Significant reduction in penile curvature and pain relief
Iontophoresis
RCT
Intralesional injection
Soh et al., 2010
10 mg nicardipine/10 mL H2O vs. 10 ml H2O every other week for a total of 6 injections
Hellstrom et al., 2006
5 MU interferon alpha-2b vs. 10 ml Intralesional injection saline injections biweekly for 12 weeks 5 MU interferon alpha-2b injections Intralesional injection weekly ×12 combined with 400 IU Vit E po bid for 6 months vs. 5 MU interferon alpha-2b injections weekly ×12 vs. 400 IU Vit E po bid for 6 months 0.58 mg collagenase C. histolyticum Intralesional injection injections, 6 weekly, up to 8 injections vs. placebo
Inal et al., 2006
Gelbard et al., 2013
Palmieri et al., 2009
Once weekly shockwave session with 2,000 shocks compared with sham
Chitale et al., 2010
Once weekly shockwave session with 3,000 shocks compared with sham
Paulis G et al., 2013
600 mg Vit E po od + 10 mg Verapamil injection every 2 weeks (12 total injections – the first injection 5 mg) + iontophoresis with 5 mg daily (excluding the day of injection) + 160 mg blueberries po od + 600 mg propolis po od + topical diclofenac sodium 4 % gel/twice a day compared to same regime but without Vit E
No statistically significant improvements in treatment arm RCT—single blind, Statistically significant placebo controlled improvements in pain and IIEF score in treatment group; improvement of curvature in both groups RCT—single blind, Statistically significant decrease placebo controlled in penile curvature and plaque size RCT No statistically significant improvement in the subjective parameters among the three groups
RCT—double blind, Statistically significant placebo controlled improvement in penile curvature, symptom bother score Shockwave therapy RCT—double blind, Statistically significant placebo controlled improvements in pain, IIEF score, and QOL; stabilization of curvature Shockwave therapy RCT—double blind, No statistically significant placebo controlled improvement or difference in curvature, pain, or IIEF score between groups Combination therapy RCT Statistically significant (oral Vit E + intralesional improvement in plaque verapamil + iontophoresis size and penile curvature verapamil)
po, per os; bid, twice daily; od, once daily; RCT, randomized, controlled trial
Phosphodiesterase Type 5 Inhibitors Inducible nitric oxide synthase, nitric oxide, and cyclic GMP have antifibrotic activity, preventing collagen deposition by inhibiting TGF-β1, oxidative stress and myofibroblast accumulation [31, 32]. Phosphodiesterase type 5 (PDE-5) inhibitors are known to increase cyclic GMP levels. In rat models of TGF-β1induced PD, arginine, sildenafil and pentoxifylline were shown to reduce plaque size and stimulate fibroblast apoptosis. Vardenafil was also shown to partially reverse PD-like plaques
[8]. In a retrospective study of seven PD patients using sildenafil for treatment of erectile dysfunction, no patients reported worsening of PD deformity or increasing penile pain. In a study where subjects took 2.5 mg of tadalafil daily, resolution of the septal scar was recorded in 69 % when compared to 10 % in the control group. As expected, post treatment International Index of Erectile Function (IIEF-5) scores increased significantly, and no significant side effects were reported [32]. Although these preliminary results appear promising, further research is needed before PDE-5i become standard therapy for PD.
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Pentoxifylline
analysis of tunica albuginea after topical verapamil failed to show any measurable drug in the PD plaque.
Pentoxifylline (PTX) is a nonselective phosphodiesterase inhibitor with anti-inflammatory properties. It is shown to inhibit fibroblast proliferation and attenuate both collagen fiber deposition as well as elastogenesis in vitro [33]. PTX downregulates TGF-β and increases fibrinolytic activity [34]. A retrospective cohort study showed that treatment with PTX appeared to stabilize or reduce calcium content in PD plaques [35]. In a randomized trial, giving pentoxifylline sustained-release 400 mg twice daily for 6 months significantly improved penile curvature and plaque volume compared to the placebo. The authors concluded that PTX is moderately effective in reducing penile curvature and plaque volume in patients with early chronic PD [34]. Omega-3 and Coenzyme Q10 Omega-3 is a polyunsaturated fatty acid that stimulates the production of collagenase. The only prospective, randomized, double-blind, placebo-controlled study evaluating its efficacy in PD was performed by Safarinejad, and it showed no significant improvements in penile curvature, penile pain during erection, or erectile function with the use of Omega-3 fatty acids [36]. Coenzyme Q10 (CoQ10) is a very potent antioxidant. In a double-blinded, placebo-controlled study, early chronic PD patients taking CoQ10 300 mg daily for 24 weeks demonstrated statistically significant reductions in plaque size, as well as improvements in both penile curvature and erectile function [37].
Topical Therapies The Fitch study [38] is a seminal study investigating topical therapy for PD. In this trial, three agents with purported actions in the wound-healing process (as well as suggested beneficial alterations to the extracellular matrix) were compared to placebo in a randomized, double-blinded, controlled trial. These agents were 15 % verapamil, trifluoperazine, and magnesium sulfate. Patients in the chronic phase of PD, with a mean duration of disease prior to therapy of 3.5 years, were included. Patients who underwent verapamil therapy had the best results, with at least 75 % of patients at 3 months having complete pain resolution, some reduction in curvature, or both. In the trifluoperazine treatment group, 43 % and 66 % of patients experienced improvement in curvature and pain, respectively. In the magnesium sulfate group, 30 % of patients noted improvement in curvature. The authors of this study suggested that the long-term use of topical verapamil is superior to intralesional verapamil injections. Despite these encouraging results, delivery of the drug to the PD plaque is questionable. Studies [39] have shown that histological
Iontophoresis Iontophoresis, transdermal electromotive drug administration (TEA), or electromotive drug administration (EMDA) all refer to a process where an electrical current is used to charge molecules of a topically applied drug in order to expedite drug delivery through the skin and into an area of interest (i.e. a Peyronie’s plaque). Since topically applied drugs must traverse the skin, the fascial layers of the penis, and the tunica albuginea before entering a PD plaque, the interest in this technology is understandable. Iontophoresis has been used to treat other medical conditions such as hyperhydrosis, onchomycosis, and plantar fasciitis, and it has also aided in the diagnosis of cystic fibrosis [40]. The first drugs to be delivered via iontophoresis for the treatment of PD were glucocorticoids [41]. Verapamil in combination with dexamethasone has also been administered in this fashion. In a randomized, controlled trial [42] comparing the iontophoretic delivery of 5 mg verapamil and 8 mg dexamethasone in 5 ml of water (47 patients), compared with lidocaine as control (49 patients), in 24 20-min sessions over 6 weeks, researchers observed a 22° median reduction in penile curvature. Of note, all patients reported pain relief with therapy, the relief being more durable in the treatment group. In another double-blind trial [43], 24 men (randomly selected) received 10 mg of verapamil in 4 ml of saline (treatment group) compared to 19 men (randomly selected) who received 4 ml of saline (control) in 24 sessions over 3 months. The results suggested that adding verapamil to saline does not improve penile curvature. Thus, the effectiveness of iontophoresis as a beneficial treatment for PD is still unclear.
Intralesional Therapies It stands to reason that intralesional administration of a drug (or the targeted delivery of a drug with a hypodermic needle) should result in the delivery of that drug at a higher concentration than would be possible by systemic or topical administration. Several drugs have been intralesionally injected for the treatment of PD, with mixed results. Corticosteroids Corticosteroids have been considered because they have been widely used in medicine for their anti-inflammatory and immunosuppressive effects. The use of intralesional corticosteroids was first described in the 1950s [44], and it was reported
Curr Urol Rep (2014) 15:415
that it decreased plaque size and penile pain. Subsequently, other studies [45, 46] failed to replicate the earlier findings suggesting measurable benefit with ILI of corticosteroid. Investigators determined that the effects were either no different than the natural history of the condition, or otherwise reflected the mechanical effects of the injection rather than drug action alone [47]. Corticosteroid use carries a risk of tissue atrophy and obliteration of native penile tissue planes, making future surgical correction (if needed) more challenging [48, 49]. In light of the risks of ILI corticosteroid therapy, as well as its equivocal effectiveness, it is not currently recommended for the treatment of PD. Calcium Channel Blockers Calcium channel blockers inhibit production of the extracellular matrix proteins collagen and TGF-β. Levine and colleagues introduced intralesional verapamil therapy in 1994 [50]. These uncontrolled trials provided early evidence that verapamil functions to reduce penile curvature significantly. Sixty percent of patients had a statistically significant decrease in penile curvature, measured by protractor, after pharmacologically induced erection. In this study, at least 90 % of the patients experienced some pain relief, with at least 75 % experiencing complete relief. Similarly, 71 % of patients reported subjective improvements in erectile function [51]. This agent is relatively safe and well-tolerated [52]. Some researchers believe the acute phase of PD to be the optimum time for intralesional verapamil. Clinically, standard dosing is 10 mg of verapamil in 10 ml of normal saline administered by intralesional injection every 2 weeks for 12–24 weeks [51]. Verapamil decreased penile curvature in 26 % of men, reduced plaque volume by 57 %, and improved erectile function in 43 % of patients in another study [52]. In contrast, later investigations have shown less dramatic results [53, 54]. Although Rehman [53] found that men receiving active therapy noted decreased plaque size and subjective improvements in erectile function (both statistically significant), no significant improvements in penile curvature were seen. Nicardipine, another calcium channel blocker, has been evaluated for intralesional therapy. A recent single-blind, randomized clinical trial [55] of 74 men with at least a 12-month duration of PD with persistent penile pain, received either six injections of 10 mg nicardipine in 10 ml of distilled water or 10 ml of normal saline every other week over a 10-week period. The results of this randomized trial suggest that intralesional nicardipine could improve penile pain and erectile function, but does not improve penile curvature more than intralesional injections of saline. Few randomized, double-blinded, placebo-controlled trials have assessed the efficacy of intralesional calcium channel blockers in the treatment of PD. Although certain studies suggest improvement in disease progression parameters such
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as penile curvature and erectile function, we await larger controlled trials to investigate the therapeutic potential and optimal duration of active treatment with intralesionally injected calcium channel blockers. Interferon Interferons are cytokines that modulate the normal immune system. Interferon α-2b (IFN-α-2b) was shown to decrease fibroblast proliferation and extracellular matrix production, thereby improving a model for the wound healing process in vitro [56]. Several observational studies in the 1990s demonstrated cessation of PD progression and softening of plaques [57, 58]. The only multicenter randomized study demonstrated a significant decrease in penile curvature and plaque size in men treated with intralesional IFN-α-2b. This study [59] compared intralesional injections of 5×106 units of IFN-α-2b in 10 ml of saline (injected biweekly for 12 weeks) to placebo alone. The 103 men included in this study had PD for at least 12 months, a single plaque, and at least 30° curvature. Although patients in the control group had measurable decreases in penile curvature, those in the interferon arm had greater improvements in penile curvature (4.5° vs. 13.5°, p12 vs.
MEN'S HEALTH (R CARRION AND C YANG, SECTION EDITORS)
Update on Medical Management of Peyronie’s Disease Ronny B. W. Tan & Premsant Sangkum & Gregory C. Mitchell & Wayne J. G. Hellstrom Published online: 17 April 2014 # Springer Science+Business Media New York 2014
Abstract The treatment of Peyronie’s disease (PD) is a challenge for the clinician. In the quest to straighten the penis, alleviate pain, prevent further shortening, and restore erectile function, many non-surgical treatments have been offered in lieu of an operative approach, which is still considered the gold standard for definitive treatment. This communication is an update on the different approaches used in the minimally invasive management of this frustrating and yet intriguing condition. Keywords Peyronie’s disease . Oral . Topical . Intralesional . Ionotophoresis . Radiotherapy . Shockwave therapy . Penile traction devices . Stem cell therapy
Introduction Peyronie’s disease (PD), or induratio penis plastica, as it was originally known, was further described by, and later eponymously named after, Francios Gigot de La Peyronie [1] in 1743. The disease is characterized by the development of fibrous tunical plaque(s) and is usually associated with some degree of penile curvature. PD has been described as having a significant psychological component, as approximately 48 % of PD patients become clinically depressed [2]. Its prevalence is reported to range from 3 % to 9 % in the adult male population, and the most frequent age of presentation is during the fifth decade [3]. In considering the natural history of PD, 1 year postdiagnosis, 40 % of men report curvatures that remain unchanged, approximately 45 % report progressive curvature, and less than 15 % of men with PD report spontaneous
resolution [4]. PD is often associated with prior penile trauma, but this history is not universal. The uncertainty about the pathogenesis and natural history of PD adds to the difficulty of managing men who present with this condition.
Pathophysiology Recently, PD has been conceptualized as a wound healing disorder. A common presentation is a fibrous, inelastic scar or plaque of the tunica albuginea that appears following trauma to the penis [5]. It is postulated that trauma causes increased TGF-β1 levels [6], which results in an intense proinflammatory, profibrotic cascade with subsequent deposition of collagen, resulting in the hallmark of the disease: plaque formation and penile curvature. Studies have shown that inducible nitric oxide levels are quenched by reactive oxygen species (ROS) creating peroxynitrite, a highly toxic and profibrotic compound [7, 8]. Although the pathophysiology of PD is still poorly understood, attempts at manipulating the levels of TGF-β1 and ROS could theoretically alter the natural history of PD, which forms the basis of many of our current medical therapies [9]. As a general rule, the aim of medical management of PD is to alter the wound healing process, preventing plaque formation. Medical therapy for PD (or minimally invasive management) can be subdivided into oral, topical, iontophoretic, intralesional, radio therapeutic, shockwave therapy, penile traction, or any combination of the above. There is also a recent interest in including stem cells for the treatment of PD. This article reviews the current literature pertaining to the non-surgical treatment options available for men who have PD (Tables 1 and 2).
This article is part of the Topical Collection on Men’s Health R. B. W. Tan Department of Urology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore e-mail: [email protected] P. Sangkum : G. C. Mitchell : W. J. G. Hellstrom (*) Department of Urology, Tulane University School of Medicine, 1430 Tulane Ave. SL-42 Room 3520B, New Orleans, LA 70112, USA e-mail: [email protected]
Oral Therapies Vitamin E (Tocopherol) Vitamin E is a highly favored initial treatment by urologists in the United States [10]. Vitamin E is a fat-soluble compound
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Table 1 Summary of randomized controlled trials performed for oral agents for the treatment of PD Study
Therapy
Mode of Type of Study Delivery
Safarinejad et al., 2007 300 mg Vit E po bid, 1 g propionyl-L-carnitine Oral bid, or combination compared with placebo Weidner et al., 2005 3 g Potaba po qid compared with placebo Oral Teloken et al., 1999
20 mg tamoxifen po bid compared with placebo Oral
Safarinejad et al., 2004 2.5 mg colchicine po od compared with placebo Oral Safarinejad et al., 2010 400 mg pentoxifylline po bid compared with placebo Safarinejad et al., 2010 300 mg CoQ10 po od compared with placebo
Oral Oral
RCT—double blind, placebo controlled RCT—double blind, placebo controlled RCT—double blind, placebo controlled RCT—double blind, placebo controlled RCT—double blind, placebo controlled RCT—double blind, placebo controlled
Effectiveness
No statistically significant improvement in treatment arm Stabilizes PD and prevents progression of penile curvature No statistically significant improvement in treatment arm No statistically significant improvement in treatment arm Significantly improves penile curvature and plaque volume Statistically significant improvements in curvature, penile pain, and IIEF score
po, per os; bid, twice daily; od, once daily; qid, four times daily; RCT, randomized, controlled trial
that was first introduced for the treatment of PD in 1949 [11]. It acts as a natural antioxidant and free-radical scavenger, thereby decreasing penile fibrosis [12, 13]. Clinical trials of vitamin E for the treatment of PD show conflicting results. Most of the studies demonstrate no clinical evidence to support treatment of PD with vitamin E [14, 15]. However, two recent reports using combination treatment of vitamin E with other agents revealed significant improvement in plaque size and penile curvature in the vitamin E group [16, 17]. Despite the equivocal evidence regarding vitamin E in the treatment of PD, its low cost, wide availability, and low rate of adverse events make it a continually popular therapy with many urologists [18]. Potassium Para-aminobenzoate (Potaba) Potassium para-aminobenzoate was introduced for treatment of PD in 1959 [19]. The mechanism of its action is hypothesized to be both anti-inflammatory and anti-fibrotic via stabilization of serotonin-monoamine oxidase activity [18, 20]. A recent double-blind, placebo-controlled trial has shown that para-aminobenzoate showed a response rate of 74.3 % over placebo 50.0 % (p = 0.016). These studies suggest that Potaba might stabilize PD and prevent progression of penile curvature [20]. Unfortunately, Potaba is relatively expensive, and dosing large tablets four times daily are potential drawbacks to the medicine. The most commonly reported adverse events are gastrointestinal upset and skin photosensitization [12, 21]. Tamoxifen Tamoxifen is a non-steroidal estrogen receptor antagonist that modulates the release of TGF-β1 from fibroblasts and blocks TGF-β receptors, resulting in diminished fibrogenesis [22]. In
clinical trials, 20 mg tamoxifen twice daily failed to show any statistical significant improvement in pain, curvature or plaque size as compared to placebo [23]. Colchicine Colchicine down-regulates TGF-β expression [24], inhibits tubulin movement, reduces leukocyte action, and diminishes wound contracture [12, 25]. In a pilot study, colchicine decreased plaque size and improved penile curvature [25]. However, a more recent randomized, double-blind, controlled study concluded that 4 months of therapy with up to 2.5 mg colchicine daily in patients with PD had no benefit when compared to placebo [26]. Moreover, combination therapy between vitamin E and colchicine for PD revealed conflicting results [27, 28]. Despite a lack of clear, undisputed evidence, colchicine is the most common choice for non-surgical treatment by American urologists [10]. Carnitine Propionyl-L-carnitine (PLC) is a short-chain acyl derivative of carnitine that has an antiproliferative effect on human endothelial cells [14]. Carnitine is more effective than tamoxifen in reducing pain and inhibiting disease progression in a clinical trial [29]. In another study, PLC significantly reduced penile curvature, plaque size, cavernosal artery end-diastolic velocity, and the need for surgery when combined with concurrent intralesional verapamil injection [30]. However, a recent study demonstrated that PLC, when taken alone (1 g orally, twice daily) or combined with vitamin E, did not lead to significant improvement in pain, curvature or Peyronie’s plaque size when compared to placebo when taken alone (1 g orally, twice daily) or combined with vitamin E [14].
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Table 2 Summary of randomized, controlled trials performed forother forms of treatment/combination therapy for PD Fitch et al., 2007 Topical verapamil 15 % vs. topical trifluoperazine 10 % vs. topical magnesium sulfate 10 % vs. placebo applied to penile shaft bid
Topical gel
Di Stasi et al., 2004
Iontophoresis
Greenfield et al., 2007
5 mg verapamil + 8 mg dexamethasone in 5 ml of water compared with lidocaine as control, 20 sessions 10 mg verapamil in 4 ml of saline vs. 4 ml of saline, 24 sessions
RCT—double blind, Statistically significant placebo controlled improvements (greatest in verapamil group) in curvature compared with placebo RCT Significant reduction in penile curvature and pain relief
Iontophoresis
RCT
Intralesional injection
Soh et al., 2010
10 mg nicardipine/10 mL H2O vs. 10 ml H2O every other week for a total of 6 injections
Hellstrom et al., 2006
5 MU interferon alpha-2b vs. 10 ml Intralesional injection saline injections biweekly for 12 weeks 5 MU interferon alpha-2b injections Intralesional injection weekly ×12 combined with 400 IU Vit E po bid for 6 months vs. 5 MU interferon alpha-2b injections weekly ×12 vs. 400 IU Vit E po bid for 6 months 0.58 mg collagenase C. histolyticum Intralesional injection injections, 6 weekly, up to 8 injections vs. placebo
Inal et al., 2006
Gelbard et al., 2013
Palmieri et al., 2009
Once weekly shockwave session with 2,000 shocks compared with sham
Chitale et al., 2010
Once weekly shockwave session with 3,000 shocks compared with sham
Paulis G et al., 2013
600 mg Vit E po od + 10 mg Verapamil injection every 2 weeks (12 total injections – the first injection 5 mg) + iontophoresis with 5 mg daily (excluding the day of injection) + 160 mg blueberries po od + 600 mg propolis po od + topical diclofenac sodium 4 % gel/twice a day compared to same regime but without Vit E
No statistically significant improvements in treatment arm RCT—single blind, Statistically significant placebo controlled improvements in pain and IIEF score in treatment group; improvement of curvature in both groups RCT—single blind, Statistically significant decrease placebo controlled in penile curvature and plaque size RCT No statistically significant improvement in the subjective parameters among the three groups
RCT—double blind, Statistically significant placebo controlled improvement in penile curvature, symptom bother score Shockwave therapy RCT—double blind, Statistically significant placebo controlled improvements in pain, IIEF score, and QOL; stabilization of curvature Shockwave therapy RCT—double blind, No statistically significant placebo controlled improvement or difference in curvature, pain, or IIEF score between groups Combination therapy RCT Statistically significant (oral Vit E + intralesional improvement in plaque verapamil + iontophoresis size and penile curvature verapamil)
po, per os; bid, twice daily; od, once daily; RCT, randomized, controlled trial
Phosphodiesterase Type 5 Inhibitors Inducible nitric oxide synthase, nitric oxide, and cyclic GMP have antifibrotic activity, preventing collagen deposition by inhibiting TGF-β1, oxidative stress and myofibroblast accumulation [31, 32]. Phosphodiesterase type 5 (PDE-5) inhibitors are known to increase cyclic GMP levels. In rat models of TGF-β1induced PD, arginine, sildenafil and pentoxifylline were shown to reduce plaque size and stimulate fibroblast apoptosis. Vardenafil was also shown to partially reverse PD-like plaques
[8]. In a retrospective study of seven PD patients using sildenafil for treatment of erectile dysfunction, no patients reported worsening of PD deformity or increasing penile pain. In a study where subjects took 2.5 mg of tadalafil daily, resolution of the septal scar was recorded in 69 % when compared to 10 % in the control group. As expected, post treatment International Index of Erectile Function (IIEF-5) scores increased significantly, and no significant side effects were reported [32]. Although these preliminary results appear promising, further research is needed before PDE-5i become standard therapy for PD.
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Pentoxifylline
analysis of tunica albuginea after topical verapamil failed to show any measurable drug in the PD plaque.
Pentoxifylline (PTX) is a nonselective phosphodiesterase inhibitor with anti-inflammatory properties. It is shown to inhibit fibroblast proliferation and attenuate both collagen fiber deposition as well as elastogenesis in vitro [33]. PTX downregulates TGF-β and increases fibrinolytic activity [34]. A retrospective cohort study showed that treatment with PTX appeared to stabilize or reduce calcium content in PD plaques [35]. In a randomized trial, giving pentoxifylline sustained-release 400 mg twice daily for 6 months significantly improved penile curvature and plaque volume compared to the placebo. The authors concluded that PTX is moderately effective in reducing penile curvature and plaque volume in patients with early chronic PD [34]. Omega-3 and Coenzyme Q10 Omega-3 is a polyunsaturated fatty acid that stimulates the production of collagenase. The only prospective, randomized, double-blind, placebo-controlled study evaluating its efficacy in PD was performed by Safarinejad, and it showed no significant improvements in penile curvature, penile pain during erection, or erectile function with the use of Omega-3 fatty acids [36]. Coenzyme Q10 (CoQ10) is a very potent antioxidant. In a double-blinded, placebo-controlled study, early chronic PD patients taking CoQ10 300 mg daily for 24 weeks demonstrated statistically significant reductions in plaque size, as well as improvements in both penile curvature and erectile function [37].
Topical Therapies The Fitch study [38] is a seminal study investigating topical therapy for PD. In this trial, three agents with purported actions in the wound-healing process (as well as suggested beneficial alterations to the extracellular matrix) were compared to placebo in a randomized, double-blinded, controlled trial. These agents were 15 % verapamil, trifluoperazine, and magnesium sulfate. Patients in the chronic phase of PD, with a mean duration of disease prior to therapy of 3.5 years, were included. Patients who underwent verapamil therapy had the best results, with at least 75 % of patients at 3 months having complete pain resolution, some reduction in curvature, or both. In the trifluoperazine treatment group, 43 % and 66 % of patients experienced improvement in curvature and pain, respectively. In the magnesium sulfate group, 30 % of patients noted improvement in curvature. The authors of this study suggested that the long-term use of topical verapamil is superior to intralesional verapamil injections. Despite these encouraging results, delivery of the drug to the PD plaque is questionable. Studies [39] have shown that histological
Iontophoresis Iontophoresis, transdermal electromotive drug administration (TEA), or electromotive drug administration (EMDA) all refer to a process where an electrical current is used to charge molecules of a topically applied drug in order to expedite drug delivery through the skin and into an area of interest (i.e. a Peyronie’s plaque). Since topically applied drugs must traverse the skin, the fascial layers of the penis, and the tunica albuginea before entering a PD plaque, the interest in this technology is understandable. Iontophoresis has been used to treat other medical conditions such as hyperhydrosis, onchomycosis, and plantar fasciitis, and it has also aided in the diagnosis of cystic fibrosis [40]. The first drugs to be delivered via iontophoresis for the treatment of PD were glucocorticoids [41]. Verapamil in combination with dexamethasone has also been administered in this fashion. In a randomized, controlled trial [42] comparing the iontophoretic delivery of 5 mg verapamil and 8 mg dexamethasone in 5 ml of water (47 patients), compared with lidocaine as control (49 patients), in 24 20-min sessions over 6 weeks, researchers observed a 22° median reduction in penile curvature. Of note, all patients reported pain relief with therapy, the relief being more durable in the treatment group. In another double-blind trial [43], 24 men (randomly selected) received 10 mg of verapamil in 4 ml of saline (treatment group) compared to 19 men (randomly selected) who received 4 ml of saline (control) in 24 sessions over 3 months. The results suggested that adding verapamil to saline does not improve penile curvature. Thus, the effectiveness of iontophoresis as a beneficial treatment for PD is still unclear.
Intralesional Therapies It stands to reason that intralesional administration of a drug (or the targeted delivery of a drug with a hypodermic needle) should result in the delivery of that drug at a higher concentration than would be possible by systemic or topical administration. Several drugs have been intralesionally injected for the treatment of PD, with mixed results. Corticosteroids Corticosteroids have been considered because they have been widely used in medicine for their anti-inflammatory and immunosuppressive effects. The use of intralesional corticosteroids was first described in the 1950s [44], and it was reported
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that it decreased plaque size and penile pain. Subsequently, other studies [45, 46] failed to replicate the earlier findings suggesting measurable benefit with ILI of corticosteroid. Investigators determined that the effects were either no different than the natural history of the condition, or otherwise reflected the mechanical effects of the injection rather than drug action alone [47]. Corticosteroid use carries a risk of tissue atrophy and obliteration of native penile tissue planes, making future surgical correction (if needed) more challenging [48, 49]. In light of the risks of ILI corticosteroid therapy, as well as its equivocal effectiveness, it is not currently recommended for the treatment of PD. Calcium Channel Blockers Calcium channel blockers inhibit production of the extracellular matrix proteins collagen and TGF-β. Levine and colleagues introduced intralesional verapamil therapy in 1994 [50]. These uncontrolled trials provided early evidence that verapamil functions to reduce penile curvature significantly. Sixty percent of patients had a statistically significant decrease in penile curvature, measured by protractor, after pharmacologically induced erection. In this study, at least 90 % of the patients experienced some pain relief, with at least 75 % experiencing complete relief. Similarly, 71 % of patients reported subjective improvements in erectile function [51]. This agent is relatively safe and well-tolerated [52]. Some researchers believe the acute phase of PD to be the optimum time for intralesional verapamil. Clinically, standard dosing is 10 mg of verapamil in 10 ml of normal saline administered by intralesional injection every 2 weeks for 12–24 weeks [51]. Verapamil decreased penile curvature in 26 % of men, reduced plaque volume by 57 %, and improved erectile function in 43 % of patients in another study [52]. In contrast, later investigations have shown less dramatic results [53, 54]. Although Rehman [53] found that men receiving active therapy noted decreased plaque size and subjective improvements in erectile function (both statistically significant), no significant improvements in penile curvature were seen. Nicardipine, another calcium channel blocker, has been evaluated for intralesional therapy. A recent single-blind, randomized clinical trial [55] of 74 men with at least a 12-month duration of PD with persistent penile pain, received either six injections of 10 mg nicardipine in 10 ml of distilled water or 10 ml of normal saline every other week over a 10-week period. The results of this randomized trial suggest that intralesional nicardipine could improve penile pain and erectile function, but does not improve penile curvature more than intralesional injections of saline. Few randomized, double-blinded, placebo-controlled trials have assessed the efficacy of intralesional calcium channel blockers in the treatment of PD. Although certain studies suggest improvement in disease progression parameters such
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as penile curvature and erectile function, we await larger controlled trials to investigate the therapeutic potential and optimal duration of active treatment with intralesionally injected calcium channel blockers. Interferon Interferons are cytokines that modulate the normal immune system. Interferon α-2b (IFN-α-2b) was shown to decrease fibroblast proliferation and extracellular matrix production, thereby improving a model for the wound healing process in vitro [56]. Several observational studies in the 1990s demonstrated cessation of PD progression and softening of plaques [57, 58]. The only multicenter randomized study demonstrated a significant decrease in penile curvature and plaque size in men treated with intralesional IFN-α-2b. This study [59] compared intralesional injections of 5×106 units of IFN-α-2b in 10 ml of saline (injected biweekly for 12 weeks) to placebo alone. The 103 men included in this study had PD for at least 12 months, a single plaque, and at least 30° curvature. Although patients in the control group had measurable decreases in penile curvature, those in the interferon arm had greater improvements in penile curvature (4.5° vs. 13.5°, p12 vs.
