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Blackwell Publishing IncMalden, USAJSMJournal of Sexual Medicine1743-6095 2007 International Society for Sexual Medicine200742477484Original ArticlesTopical Treatment of Peyronies DiseaseFitch et al.
ORIGINAL RESEARCH—PEYRONIE’S DISEASE
Topical Verapamil HCl, Topical Trifluoperazine, and Topical
Magnesium Sulfate for the Treatment of Peyronie’s Disease—
A Placebo-Controlled Pilot Study
William P. Fitch, III, MD,* W. Jerry Easterling, RPH,† Robert L. Talbert, PharmD,‡Michael J. Bordovsky, RPH,§ and Michael Mosier, PhD¶ *Urology Consultants, P.A., San Antonio, TX, USA; †PDL, San Antonio, TX, USA; ‡University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; §Private Consultant, San Antonio, TX, USA; ¶Washburn University, Topeka, KS, USA A B S T R A C T
Introduction. Transdermal and intralesional verapamil has been reported to be useful in the treatment of Peyronie’s
Disease. This study evaluates a topically applied calcium channel blocker (verapamil hydrochloride 15% gel), a
topically applied calmodulin blocker (trifluoperazine), and a topically applied weak calcium channel blocker (mag-
nesium sulfate), each incorporated in a transdermal vehicle.
Aim. This pilot study was conducted to assess the efficacy of a 15% verapamil gel applied topically to the penile
shaft twice daily for the treatment of Peyronie’s Disease.
Main Outcome Measure. To assess improvement in curvature, plaque size, resolution of painful erections, and
improvement in erection quality.
Methods. Two simultaneous, three armed, double blinded, placebo-controlled studies were conducted. After ran-
domization into one of four groups, patients were treated for 3 months. At the end of 3 months’ treatment using
blinded drug, each patient was treated with open label topical verapamil for 6 months. The studies were completed
after each patient had been treated and evaluated for 9 months after randomization.
Results. Fifty-seven patients were randomized. In total, 94.4% of patients treated for 9 months with topical
verapamil experienced improvement in curvature with an average percent curvature change of 61.1% compared
with 43.6% curvature improvement at 3 months. At 9 months the average percent plaque change was 84.7%
compared with 55% at 3 months. Pain resolution at 9 months was 100% compared with 87.5% at 3 months. Patient
perception of erection quality also increased at 9 months to 81.8% compared with 72.7% at 3 months.
Conclusions. Topical verapamil gel proved effective in eliminating pain on erection, decreasing the size of plaque,
decreasing curvature, and improving erection quality in patients with Peyronie’s Disease. Treatment results
improved significantly after 9 months’ treatment as compared with 3 months’ treatment. Fitch WP III, Easterling
WJ, Talbert RL, Bordovsky MJ, and Mosier M. Topical verapamil HCl, topical trifluoperazine, and topical
magnesium sulfate for the treatment of Peyronie’s Disease—A placebo-controlled pilot study. J Sex Med
2007;4:477–484.
Key Words. Peyronie’s Disease, Calcium Channel Blocker; Topical Verapamil; Placebo
Introduction
[1]. The fibrotic process is characterized by palpa-ble fibrotic plaque, penile curvature, pain with ibrosis of the penile tunica albuginea was first erections, and decreased quality of erection. The described by Francois de la Peyronie in 1743 incidence of Peyronie’s Disease in the general 2006 International Society for Sexual Medicine male population has been reported to be as high The sample sizes for this trial were small. Because Aggeler et al. demonstrated that antimicrotu- of the small sample size, the comparison of pro- bular agents, calcium antagonists, and calmodulin portions between treatments (such as the propor- blockers resulted in a change in fibroblast cell tion of patients showing improvement on clinical shape [5]. Kelly demonstrated with in vitro exper- endpoints) was conducted using Fisher’s Exact iments the importance of calcium in fibroblast Test, rather than the more common chi-squared test. Expected counts for some cells in each con- Levine et al. reported that intralesional vera- tingency table are certainly less than 5, making the pamil injection of Peyronie’s plaque resulted in an 84% resolution of pain, improvement in curvature Comparisons between treatments of the aver- in 62% of patients, and improved sexual perfor- age percent change in clinical endpoints were per- formed using the Wilcoxon Rank Sum Test. This The purpose of this study was to evaluate a nonparametric procedure provides valid inference topically applied calcium channel blocker (vera- regardless of the distribution of the variables pamil hydrochloride), a topically applied calm- which cannot be adequately assessed with limited odulin blocker (trifluoperazine), and a topically applied weak calcium channel blocker (magne- For the treatment comparisons of verapamil at sium sulfate), each incorporated in a transder- 3 months with verapamil at 9 months, methods mal vehicle for the treatment of Peyronie’s appropriate for paired data were used. For pro- portions of patients achieving improvement,McNemar’s test was used. For average changefrom baseline endpoints, the Wilcoxon Signed Two simultaneous three armed, double blindedplacebo-controlled studies were conducted in this pilot study. The first study was a comparison oftopical verapamil 15% vs. topical trifluoperazine Fifty-seven patients with Peyronie’s Disease were 10%, and topical placebo. The second study com- evaluated and randomized into one of six sub- pared topical verapamil 15% vs. topical magne- sium sulfate 10% and placebo. After signing aninformed consent, patients were assigned a proto- col number by drawing. Each group had similar • Topical verapamil 15% (10 patients).
demographics, symptoms, and duration of symp- • Topical trifluoperazine 10% (seven patients).
toms. After randomization into one of four groups, patients were treated for 3 months. Thedrug preparations were applied to the entire penile Note: because of serious side effects (anxiety, shaft (excluding the glans) twice daily. The 0.5 mL agitation, blurred vision, insomnia, and depres- dose was measured with a paper dosimeter.
sion) with trifluoperazine 10%, enrollment was Patients were seen and evaluated at 1-month terminated after enrolling seven patients.
intervals. Plaque was measured with calipers and the surface area calculated. The person measuringplaque size was blinded as to active treatment vs.
• Topical verapamil 15% (10 patients).
placebo. Pain was measured by a “Yes” or “No” • Topical magnesium sulfate 10% (10 patients).
answer as the treatment objective was the total elimination of pain. Degree of curvature and erec-tion quality were described.
At the end of 3 months’ treatment using The patients’ ages ranged from 30 years to 83 years blinded drug, each patient was treated with open with the mean age being 56.3 years (Tables 1–4).
label verapamil gel for an additional 6 months.
Fifty-three patients completed the study.
Patients continued to be seen and evaluated at 1-month intervals. The study was completed after each patient had been treated and evaluated for Of the 20 patients randomized to topical vera- pamil, two patients (11.1%) experienced contact Topical Treatment of Peyronies Disease patients was 55% after 3 months’ treatment withtopical verapamil. Of the 11 patients with dimin- ished quality erections and treated with topical verapamil, eight patients (72.7%) experienced In comparing patients with Peyronie’s Disease with less than 6 months’ duration with patients with greater than 12 months’ duration, we saw no statistical significant difference in results related toduration of disease.
Topical TrifluoperazineOf the seven patients started on topical trifluoper- azine, five (71.4%) had serious side effects includ- ing anxiety, agitation, blurred vision, insomnia, and depression. Three patients (42.9%) with cur- vature experienced improvement of curvature.
The duration of symptoms prior to randomization ranged from The average improvement in degrees of curvature 2 months to 15 years with a mean of 3.35 years.
was 9.5%. Five patients (71.4%) had plaque reduc-tion. The average plaque reduction was 15.8%. Ofthe three patients with pain, two (66.7%) had total pain relief. Three (50%) of the six patients with decreased quality of erection had improvement with topical trifluoperazine. In comparing triflu- operazine with placebo, there was no statistically significant difference in results. Because of the severity of side effects, treatment with topical tri- Of these 57 patients, 56 had palpable Peyronie’s plaque, 56 patients fluoperazine was discontinued prior to completion complained of penile curvature, 20 patients complained of painful erections, and 39 patients reported decreased quality of erections.
Topical Magnesium SulfateOf the 10 patients initially treated with topical dermatitis, and subsequently one of these patients magnesium sulfate, three (30%) had improvement withdrew from the study. One patient was lost in curvature while six (60%) experienced a to follow up. At 3 months, 87.5% of the eight decrease in plaque size. The average improvement patients with pain experienced complete pain res- in degrees of curvature was 14.1%. The average olution. Of the 18 patients with curvature, 14 decrease in plaque size was 20.3%. Only one (77.8%) had reduction in curvature. The average patient randomized to topical magnesium sulfate improvement in degrees of curvature after initially complained of pain, and this patient expe- 3 months of treatment with topical verapamil was rienced complete resolution of pain after treat- 43.6%. Of the 18 patients with palpable plaque, ment with topical magnesium sulfate. Three 18 (100%) had reduction in plaque size after patients (50%) of the six patients who complained 3 months’ treatment with topical verapamil. The of diminished erection quality experienced im- average reduction in plaque size in this group of provement. In comparing magnesium sulfate with Characteristics placebo vs. verapamil treated patients Topical verapamil vs. placebo at 3 months (percentage improved) Patients with erection quality improvement *Fisher’s Exact Test.
†Wilcoxon Rank Sum Test.
placebo, there was no statistically significant dif- four (25%) experienced improvement. Of the eight patients complaining of pain and treatedwith topical placebo, three patients (37.5%) expe- The placebo effect may appear unrealistic. How- Finally, it is possible that one or more of the ever, the small number of patients, along with the chemical excipients that make up the placebo may dramatic results achieved by five of the patients, have a positive treatment affect on the scar tissue.
indicates that additional studies need to be per- The fatty layer of the protective stratum corneum formed with much larger placebo populations. For is reversibly modified to allow the carrier and example, one patient experienced an 83% curva- active drug to traverse the stratum corneum and ture improvement and an 87% plaque improve- deposit in the diseased underlying tissue. Further research will be conducted to investigate this curvature improvement and a 64% curvature possible positive treatment effect of the placebo.
improvement. Another patient experienced a 33% Tissue remodeling is complex, and it is not incon- curvature and a 100% plaque improvement.
ceivable that one of the chemical excipients could Another patient experienced a 100% curvature affect one or more of the glycosaminoglycans, improvement along with an 84% plaque improve- proteoglycans, growth factors, or cytokines in- ment, but only had a 5-degree curvature at the volved in the healing and remodeling process Eighteen patients were treated with placebo.
The data pertaining to the use of topical Two patients immediately discontinued the study.
verapamil for 9 months was compared with the After 3 months of using topical placebo, five 3-month data (Table 6). After using topical vera- patients (29.4%) of 17 patients with curvature pamil for 9 months, 17 (94.4%) of patients expe- experienced decreased penile curvature. The aver- rienced a decrease in curvature compared with 14 age improvement in degrees curvature was 18.5%.
patients (77.8%) after 3 months of treatment. The Six patients (33.3%) had decreased plaque size average curvature reduction in degrees was 61.1% while three patients had increased plaque size.
at 9 months compared with 43.6% at 3 months.
The average reduction in plaque size was 5%. Of One patient (5.6%) had total resolution of curva- the 16 patients complaining of decreased quality ture at 3 months. Four patients (22.2%) had total erections who were treated with topical placebo, resolution of curvature at 9 months. One hundred Topical verapamil at 3 months vs. 9 months Patients with erection quality improvement *McNemar’s Test (for paired proportions).
†Wilcoxon Signed Rank Test (for paired data).
For completeness, statistical tests were performed for all endpoints comparing verapamil at 3 months to verapamil at 9 months, even though in some cases theuse of a statistical test is clearly not needed. For example, when nearly all patients showed improvement at 3 months, there is no room left for further improvementat 9 months. Such a “ceiling effect” will cause the statistical comparison of the two time points to be nonsignificant, even though there is very clear evidence ofan effect at 3 months, which is sustained through 9 months.
Topical Treatment of Peyronies Disease percent of patients using topical verapamil for clinical question related to erectile dysfunction is 9 months had decreased plaque size. The average “does the treatment worsen the erectile dysfunc- plaque size decrease at 9 months was 84.7% com- tion?” Our data clearly show that it does not.
pared with 55% at 3 months. Seven patients Perhaps the International Index of Erectile Func- (38.9%) experienced complete resolution of tion questionnaire should be utilized in future plaque at 9 months compared with five patients (27.8%) at 3 months. One hundred percent of the Important observations made during this study patients experiencing pain secondary to Peyronie’s Disease had complete resolution of pain at • Based on the data shown in Table 5 comparing 9 months compared with 87.5% at 3 months.
Nine patients (81.8%) who experienced dimin- should be treated with topical verapamil as long ished quality of erections had improvement in as there is continued measurable improvement erection quality after treatment with topical vera- in pain, plaque size, curvature, and erection pamil for 9 months compared with 72.7% at • There may be a significant reduction in plaque prior to observed improvement incurvature.
Discussion
• Successful treatment is directly related to patient compliance and physician follow-up.
Some feel that ultrasonic measurements of plaque We suggest that physicians examine patients should be performed while others prefer palpation after 1 month of treatment with follow-up every and physical measurement. We unsuccessfully attempted ultrasound on 10 patients with palpableplaque. We found that calculating area using mea- The results reported using topical verapamil 15% surements with calipers was the most accurate and are better than the reported results obtained by using intralesional verapamil injections for several We felt that a simple “Yes” or “No” for the presence of pain was more objective than a visual • Multiple injections into the plaque are trau- analog pain scale which would have been appro- matic and may cause an increase in inflamma- priate had we been evaluating degrees of pain reduction as opposed to complete elimination of • The plaque’s density prevents adequate entry Curvature can be measured by patient estima- • Patients oftentimes do not return for follow-up tion, with photography, and by using intracavern- treatment and observation because of the pain osal injection of vasoactive drugs. Photography and trauma experienced with the first injections.
can be misleading because of varying camera posi-tion. Vasoactive drug injection involves risks such Specific data are presented in Table 7.
as priapism, fibrosis of the tunica albuginea, and Topical verapamil is administered to the entire fibrosis of the cavernosal smooth muscle. Cavern- shaft of the penis. In addition to treating observed osal injection may cause problems in enrolling and plaque, this also may reverse any undiagnosed retaining patients in studies. We utilized patient fibrotic tissue that could be subject to injury. Addi- estimation of curvature because error in patient tionally, a uniform concentration of verapamil is estimation of curvature is diluted by the number maintained throughout the entire plaque forma- of patients in the study. The most important tion rather than randomly as administered by aspect in quantifying curvature change is the patient perception of improvement or absence of because it has been formulated and designed to Measurement of erection quality may be the allow only negligible concentrations of active drug most controversial. While the baseline patient into the circulation and to allow for the majority estimate may not be totally accurate, the patient of absorption and concentration of the active drug and his partner certainly are able to discern the into the invading plaque. In 1990 Lee and Ping presence or absence of improvement. The treat- noted that the therapeutic serum levels of vera- ment was designed to lessen curvature and elimi- pamil used for the treatment of hypertension and nate pain as the primary outcomes. The important cardiac arrhythmias range from 0.01 to 0.2 μM.
Topical veraparmil vs. intraplaque verapamil injection On the other hand, the concentration necessary to packaged in a material that is nonreactive chemi- inhibit extracellular matrix collagen synthesis in cally or physically to the active ingredient or any their in vitro study was in the 100 μM range [8].
Because of this comparatively high dose, it appears The authors state that it is unlikely that vera- necessary to administer verapamil locally to avoid pamil would be found in fibrotic scar tissue. How- systemic toxicity while exposing fibroblasts within ever, treating fibrotic connective tissue is the the plaque to an adequate verapamil concentra- essence of transdermal treatment and should lead tion. In order to maintain a 100 μM concentra- tion, a sustained release of active drug must be Verapamil is extensively metabolized by cyto- maintained first to establish therapeutic drug equi- chrome P4503A4, and only 3–4% is excreted librium and thereafter to maintain therapeutic unchanged in the urine. Based on the reported equilibrium. The Dow Pharmaceutical Science urinary concentration of 46 ng/mL, and using data skin absorption study data of the product utilized provided by Saseen et al. [10] the back extrapo- in this study indicate that the product meets this lated plasma concentration would have to be 1400 ng/mL to achieve the reported urinary con- Martin et al. reported that the transdermal centration, and the estimated dose to produce this application of verapamil gel to the penile shaft fails plasma concentration is approximately equivalent to infiltrate the tunica albuginea [9]. The accuracy to an oral dose of 960 mg daily. The observed of this study is questionable for the following rea- urinary verapamil is most likely due to contamina- sons: only eight patients were studied; none of the tion. The conclusions noted in Martin’s publica- patients studied had Peyronie’s Disease. Verapamil tion were addressed to and published by The was applied twice before surgery and was removed Journal of Urology, Volume 173, p. 1830, May prior to surgery. It is highly unlikely that two applications would result in equilibration between The verapamil 15% formulation utilized in our epidermal tissue and the tunica albuginea. Appli- study was evaluated by Dow Pharmaceutical Sci- cation occurred over only the sides of the penile ences. The bioavailability of this topically applied shaft and not the entire penile shaft as described drug formulation of verapamil HCl was assessed utilizing an in vitro percutaneous absorption test.
Furthermore, few details are provided concern- Radiolabeled (3H) verapamil HCl absorption ing active ingredient, and no information is pro- was measured utilizing Bronaugh flow-through vided regarding whether verapamil or verapamil diffusion cells and evaluated for potential effec- hydrochloride was used. Verapamil hydrochloride tiveness in the topical treatment of Peyronie’s is preferred because of its stability. Drug vehicle and compounding technique are critical. The Human abdominal skin was dosed with the sub- vehicle must be designed to traverse the stratum ject formulation, and the absorption characteris- corneum to the extent that it reaches subdermal tics were evaluated every 6 hours for 24 hours.
connective tissue but at the same time minimizes The kinetic profile of the drug’s penetration was studied by plotting dose penetration vs. time. Epi- dermal, dermal, and receptor solution samples ducible and must provide a product of consistent were assessed. In total, 87.58% of the applied dose characteristics such as viscosity, particle size, pH.
was recovered. The receptor solution concentra- Stability is essential. The drug must be protected tion correlates with the amount of drug systemi- from light to prevent degradation, and it must be cally available following the application of a Topical Treatment of Peyronies Disease clinically relevant dose to normal, non-occluded ease. This conclusion is reinforced by the 9-month data presented and supports the fact that an The PDLabs 15% topical verapamil HCl com- extended treatment period (more than a year) is pound resulted in very low levels in the receptor necessary for some patients to experience optimal solution (0.028%). This predicts very low levels of verapamil HCl systemic exposure following topi- This was a pilot study, and the patient numbers cal application, which is one desired characteristic were small, but the results were encouraging.
of the product as the targeted area of treatment Multicenter, randomized, double-blinded studies lies very close to the dermis of the skin. Untoward comparing verapamil with placebo should be systemic effects are minimized. Dermal and epi- performed in the future utilizing a larger patient dermal levels of deposition suggest that the vehicle and the drug to a large degree partition in theepidermis, thereby creating a significant reservoirfor sustained release of verapamil HCl from Acknowledgments
human skin without the use of mechanical depotsof drug such as those manufactured in sustained Conception and design: William P. Fitch, III, MD and W. Jerry Easterling, RPH; analysis and interpretation This combination of high dose loading and of data: William P. Fitch, III, MD, W. Jerry Easterling, high epidermal deposition, following the applica- RPH, Michael J. Bordovsky, RPH, and Robert L. Tal-bert, PharmD; statistical expertise: Michael Mosier, tion to skin, indicates that the PDLabs formula- PhD and William J. Cady, PharmD; percutaneous skin tion of 15% verapamil HCl should result in penetration studies: Dow Pharmaceutical Sciences; effective, sustained delivery of the verapamil HCl administrative, technical or logistic support: Janice K.
Orem; study coordinators: Judy Lochte, Virginia Von The mechanism of action involved with the Lehmden; provision of study materials: Prescription use of topically applied calcium channel blockers and calmodulin blockers to treat fibrotic connec-tive tissue disorders is not fully understood. How- Correspondence Author: William P. Fitch, MD,
ever, the proposed mechanism of action involves Urology Consultants, P. A, 8038 Wurzbach Suite 430, blocking the cellular entry of divalent calcium or San Antonio, TX 78229, USA. Tel: (210) 616-0410;Fax: (210) 615-1295; E-mail: janice@urologyconsults.
inhibiting the binding of calmodulin antagonists to calmodulin binding protein within the cell.
The result appears to be a tissue remodeling Conflict of Interest: None declared.
effect that involves the production of a metallo-proteinase (MMP) or serine protease thatdegrades matrix proteins such as collagen, lami- References
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