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Keywords:

  • dexamethasone;
  • intralesional injection;
  • Peyronie's disease;
  • transdermal electromotive administration;
  • verapamil

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

To compare the efficacy of transdermal electromotive administration and intra-lesional injection of verapamil plus dexamethasone for the treatment of Peyronie's disease. Patients with Peyronie's disease of less than 2-year duration were randomized into two groups of transdermal electromotive administration and intra-lesional injection of verapamil plus dexamethasone. During the 6-week therapy period, a single weekly dose of 10 mg verapamil and 4 mg dexamethasone solution was administered to 30 patients in each group either by transdermal electromotive method or via the conventional injection method by a syringe connected to a 25 G needle. Evaluations of plaque length, width, and volume, penile curvature, erectile dysfunction and penile deviations were carried out before and after 1 and 3 months of the interventions. Erectile pain was reduced in the electromotive group from a mean of 5.1–1.0 in scale of 10 and from 5.4 to 3.6 in the injection group (= 0.006). Regarding plaque length, plaque width, penile curvature plaque volume and erectile dysfunction, the electromotive administration group showed better results which, however, were not statistically significant. (p > 0.05). Transdermal electromotive drug administration yielded comparable results as against current conventional intra-lesional injection technique and fared better in controlling erectile pain.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Peyronie's disease is characterized by acquired penile curvature, pain on erection, decreased erectile capacity and difficulty in vaginal penetration that are thought to be correlated to local inflammation and subsequent fibrous plaque formation in the tunica albuginea (Gelbard et al., 1990; Tefekli et al., 2001; Mulhall et al., 2004; Tuygun et al., 2009). The pathophysiology of the disorder is not fully understood (Levine et al., 2003); however, some interesting theories such as multiple penile micro traumas, disorders of wound healing, or autoimmune mechanisms have been incriminated (Gingell & Desai, 1989; Hellstrom & Bivalacqua, 2000). The incidence of Peyronie's disease has been reported to be as high as 3–9% in the general population (Schwarzer et al., 2001; Tefekli et al., 2001; Mulhall et al., 2004).

Because the aetiology of the disease is not quite clear, a variety of therapeutic methods have been proposed by different researchers (Fitkin & Ho, 1999; Tunuguntlas, 2001). In addition to oral medications such as vitamin E, colchicine, potassium para-aminobenzoate, or tamoxifen there is a growing body of evidence emerging in favour of using remodelling techniques applied by the patient himself or by means of vacuum devices, whereas in severe cases, surgery has proved to be the best option (Bour, 1984; Ralph et al., 1992; Akkus et al., 1994; Carson, 1997). Unfortunately oral medications have not been promising so far ascribable to unpleasant side effect profiles of the drugs (Di et al., 2004; Tuygun et al., 2009). On the other hand, many patients may refuse to undergo surgery despite its efficacy (Di et al., 2004). Therefore, researchers have been seeking new therapies for the treatment of Peyronie's disease with minimal complications.

Recently, the intra-lesional injection of verapamil has been shown to be an effective therapy for the treatment of Peyronie's disease in a few randomized, controlled trials (Levine, 1997; Rehman et al., 1998; Levine et al., 2002). The primary advantage of this method is the delivery of high concentrations of the drug at the disease site with minimal side effects (Di et al., 2004). Nevertheless, multiple injections need to be performed at the site of the plaque, which of course is uncomfortable and sometimes may worsen the scarring process (Di et al., 2004; Tuygun et al., 2009). Transdermal electromotive administration (TEA), which effectively delivers up to 70% of the drug to the target site seems to be an intriguing option. The efficacy of TEA of verapamil and dexamethasone has been evaluated in a few uncontrolled studies and has proved to be a safe drug delivery system in the penis (Montorsi et al., 2000; Di Stasi et al., 2003, 2004; Greenfield et al., 2007; Tuygun et al., 2009). However, no randomized, controlled surveys have been carried out so far to compare the efficacy of transdermal electromotive administration as against the intra-lesional injection of a combination of verapamil and dexamethasone. Therefore, a prospective randomized, controlled trial was designed to compare the efficacy of the aforementioned therapies for the treatment of Peyronie's disease in terms of both subjective and objective variables.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

After obtaining local research committee approval, from June 2010 to June 2011, patients with Peyronie's disease who were referred to the urology clinic of Sina Hospital were enrolled after obtaining written informed consent. The inclusion criteria were disease period of less than 2 years, presence of pain on erection, penile deviation of less than 45° and the ability to perform vaginal intercourse. The exclusion criteria were the presence of calcified plaque as assessed using ultrasonography, ventral curvature and erectile dysfunction referable to psychological, neurological, hormonal or vascular causes, contraindications to the use of verapamil or dexamethasone, history of diabetes mellitus, congenital penile curvatures or chordee with hypospadias.

The participants were block randomized to receive 6 weekly doses of a solution containing 10 mg verapamil and 4 mg dexamethasone diluted in 2 mL of distilled water either by TEA (group1) or intra-lesional injection in group 2. The solution was then put into a plastic reservoir connected to the anode and placed over the plaque. The anode was connected to the current generator, while the cathode was connected to a dispersive electrode placed on the lower abdomen. Afterwards, the current generator supplied a pulsed direct current with an intensity of 2.4 mA and a frequency of 1500 Hz for 20 min. In each therapy session, the heart rate and blood pressure of the patients were regularly monitored. A 25 G needle was used in conventional intra-lesional injection group.

Prior to intervention, pain on erection on visual pain scale of 1–10, satisfaction with vaginal penetration according to IIEF5 and plaque size and volume as assessed again using ultrasonography (in case more than one plaque was present, the total size and volume of all plaques) were recorded in every patient. The same parameters were assessed again after 1 and 3 months of interventions. The dropouts were four patients in each of the groups and were substituted by new enrolments.

The following formula was applied for estimating the sample size, taking into consideration unpublished data of previously conducted studies by the authors in Iranian men, regarding the prevalence of erectile dysfunction among Iranian Peyronie's disease patients. Sample size calculations yielded 60 participants, 30 in each group.

  • display math(1)

SD2 = 6.3, SD1 = 7.1, β = 80%, α =5%, d = 10.

Block randomization method was used with only the statistician in charge of randomization aware of the type of intervention being assigned to each new participant. Blinding was not possible attributable to the different apparatuses used, and both the urologists and the patients were aware of the type of intervention after allocation.

Before conducting the statistical analyses, the collected data were coded to avoid unwanted bias during the analysis. Descriptive statistics and repeated ANOVA were used to analyse the data. A level of significance was assumed to be <0.05. At the end of the statistical analysis, the data were decoded, enabling us to assign the findings to the relevant groups.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Of 75 patients assessed, 60 participants complied with the inclusion criteria. Seven patients with plaque calcifications were excluded and eight patients – four in each group – needed to be enrolled later in the study course due to dropouts. The groups had the same disease characteristics regarding age (54.6 vs. 57.1 p = 0.6), plaque size (p = 0.3) and mean disease period (11 vs. 13 months p = 0.4).

Majority of the participants were in their mid fifties with the disease duration of approximately 12 months.

The outcome measures for the eligible patients in each group before and after the intervention are depicted (Table 1). Erectile pain decreased more significantly in the TEA group from 5.1 to 1.6 and 1.0 on scale of 10 compared to the injection group from 5.4 to 4.0 and 3.6 as noted after 1 and 3 months of the intervention respectively (= 0.006).

Table 1. Outcome measures before and after the interventions
VariableTimeMean (SD) in TEA group (= 30)Mean (SD) in II group (= 30)p-value repeated measurement ANOVA
Plaque length (mm)Before10.0 (4.6)9.0 (2.6)0.592
1 month6.8 (4.3)7.8 (2.8)
3 month6.1 (4.2)7.5 (3.4)
Plaque width (mm)Before6.8 (4.3)7.8 (2.8)0.124
1 month3.7 (2.4)4.7 (1.6)
3 month3.3 (2.1)4.6 (1.7)
Plaque volume (mm3)Before220.3 (162.3)169.8 (100.0)0.573
1 month76.4 (89.1)130.5 (81.7)
3 month68.9 (118.6)105.5 (73.0)
Erectile dysfunctionBefore13.2 (4.5)13.5 (4.4)0.170
1 month17.1 (5.0)14.9 (4.4)
3 month18.2 (5.5)15.3 (5.4)
Erectile painBefore5.1 (3.5)5.4 (3.2)0.006
1 month1.6 (1.9)4.0 (3.0)
3 month1.0 (1.7)3.6 (2.8)

Plaque volume in the TEA group decreased from 220.3 to 76.4 mm3 and 68.9 mm3 1 and 3 months after the intervention respectively; corresponding plaque volume values for the second group were 169.8, 130.5 and 105.5 mm3 respectively. However, this difference was not statistically significant (p = 0.573).

The mean IIEF score was increased in both groups from 13.2 to 18.1 in TEA and 13.5–15.3 in the injection group (p = 0.12).

Improvements in penile curvature were noted in both groups and the shift from 30° to 60° curvature towards the <30° was more pronounced in the TEA group, but the difference was not statistically significant. Curvatures recorded at baseline and at 3 months after the treatment are presented (Table 2).

Table 2. Penile curvatures at baseline and 3 months post-treatment
 ElectromotiveConventional
  1. a

    = 0.12.

Baseline cure<30° group1517
3 months follow-up2620
Baseline curve 30°–60° group1513
3 months follow-up38
Baseline >60 group00
3 months follow-upa12

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

The aim of this study was to compare transdermal electromotive administration vs. intra-lesional injection of verapamil and dexamethasone for the treatment of Peyronie's disease in Iranian men. Erectile pain was surprisingly better controlled in the TEA group, but other disease characteristics were not much different between the two treatment modalities although all were in favour of TEA as insignificant differences were noted regarding the reduction of plaque length, width, volume and erectile dysfunction compared to the intra-lesional method.

The effectiveness of intra-lesional injection method for the treatment of Peyronie's disease has been reported in different studies (Levine, 1997; Rehman et al., 1998; Levine et al., 2002). A randomized, single-blinded, placebo-controlled trial conducted by Rehman et al. (1998)on 13 patients in two groups found a statistically significant difference (p < 0.04) in plaque volume reduction between verapamil and saline placebo groups (57% of the patients and 28% of the controls). Erectile dysfunction improvements were noted in 42.87% of the patients in the verapamil group, compared to none in the control group (p < 0.02).There was a marked reduction of the penile curvature in the verapamil group, although the difference was not significant (p < 0.07). The authors concluded that the intra-lesional injection of verapamil is most effective for patients with non-calcified plaques and penile deviation <30°.

Levine et al. (2002) studied 156 patients with the intra-lesional injection of verapamil. 60% of the patients had objectively decreased penile curvature, 62% reported subjective decrease in penile curvature and 71% reported improved sexual function. It was finally concluded that the method is effective regarding improvements in sexual function and erectile capacity, and is believed to very be clinically safe attributable to few complications as compared to surgery.

The effectiveness of transdermal electromotive administration of verapamil and dexamethasone has been explored by a few uncontrolled and controlled studies. In the first uncontrolled study conducted by Montorsi et al. (2000) on 25 patients, all the patients reported a reduction in penile pain. Plaque volume was significantly decreased in 90% of the patients. 88% of the patients had notable improvements in penile deformity, and 80% reported improvements in penile rigidity. In another uncontrolled study (Di Stasi et al., 2003), the plaque disappeared altogether or decreased in volume in 82% of the patients. Penile curvature had resolved or else decreased in 84% of the patients, and 88% of the patients reported no penile pain after the treatment. Erectile capacity and vaginal penetration had improved in 59% and 73% of the patients respectively. Transdermal electromotive administration of verapamil and dexamethasone was then concluded to be clinically safe and effective for the treatment of Peyronie's disease. Finally, in the most recent uncontrolled study conducted by Tuygun et al. (2009), noticeable reductions were observed in plaque volume and penile deviation in 24% and 26% of the patients respectively. Completely resolved sexual dysfunction and erectile pain were observed in 55% and 80% of the patients, respectively. Attributable to the slightly different findings compared with the first two mentioned studies, the authors concluded that this method is more effective for the relief of subjective symptoms rather than objective symptoms. This small contradiction can be attributed to a difference in sample size in the above-mentioned studies, different patients' characteristics, such as disease duration and severity of the disease, enrolled in different studies, or different methodologies applied in different studies.

Results of the two controlled trials conducted to assess the efficacy of transdermal electromotive administration of verapamil and dexamethasone are inconsistent. In the first study conducted by Di et al. (2004), 73 patients were included in the study. Plaque volume and penile deviation decreased significantly in the treatment group, although no changes were observed in the control group. Penile pain disappeared permanently in the treatment group, whereas it was temporary in the control group. However, Greenfield et al. (2007) did not find statistically significant differences between the treatment and control groups in any of the disease implications, although more promising results were observed in the treatment group, especially pertaining to penile deviation. The authors believed that this inconsistency was primarily referable to the different methodologies applied or different placebo groups, whereas this can also be attributed to different patients' characteristics, and more importantly, to the significantly less patients enrolled in the second study, which could possibly have prevented the researchers in arriving at possible differences.

Finally, it is noteworthy that our study directly compared the efficacy of two drug delivery methods for the administration of verapamil in the treatment of Peyronie's disease. However, the only limitation of our study was its limited number of subjects. This was probably the main reason why we could not observe significant differences between the two groups with respect to plaque length, plaque width, plaque volume, and erectile dysfunction, nevertheless, the first group yielded better results.

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Improvements were seen in patients of both treatment groups regarding the objective variables. In addition, transdermal electromotive administration was found to be more effective than intra-lesional injection of verapamil and dexamethasone in decreasing the erectile pain. Our data could not statistically support the priority of the first method in controlling size, although better results were observed for this method especially in erectile dysfunction. Further studies with a large number of patients of different ethnic groups and environmental conditions are warranted.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

The authors wish to thank Professor Zahed Hossein Khan and Mrs. Bita Pourmand for editing the final manuscript and the Tehran University of Medical Sciences for financial support. The authors also declare that there is no conflict of interest. The registration number for survey at research development department of TUMS was 197.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References