Multiple treatment options have been used for Peyronie's disease (PD) including intralesional injection of the calcium antagonist verapamil. The use of verapamil is based on its capacity to alter fibroblast function at several levels, including cell proliferation, extracellular matrix protein synthesis and secretion, as well as collagen degradation. Consequently, calcium antagonists may have the capacity to slow, prevent, or even reverse plaque formation and the progression of PD. The multicenter international experience with intralesional verapamil injection suggests that the majority of men with PD that receive treatment demonstrate durable reduction in pain, decrease in curvature, and improved sexual function. We review the scientific rationale, published literature, clinical experience, and technique of intralesional injection of verapamil.
Multiple treatment options have been employed for Peyronie's disease (PD) since de La Peyronie's description of induratio penis plastica.1 Although almost 250 y has elapsed since then, the disease process is not understood and its treatment remains frustrating to the practicing urologist. There are many surgical and non-surgical options available, however indications for each are not completely defined. Without a clear understanding of the etiology and pathophysiology, non-surgical management continues to be largely based on theoretical grounds. Despite these uncertainties, success has been cited with numerous non-surgical approaches including extra-corporeal shockwave therapy, radiotherapy, iontophoresis, oral agents such as vitamin E, colchicine, tamoxifen, and Potaba, and intraplaque injection of compounds including collagenase, steroids, orgotein, interferon alpha 2B, and verapamil.2,3,4,5,6,7,8,9,10,11,12,13,14 In this review, we present the scientific rationale, clinical experience, and technique of intralesional injection of verapamil.
The use of the calcium antagonist verapamil for the treatment of PD was first considered in 1991 after research regarding its effects on scar formation was applied. The early data showed that verapamil was able to alter fibroblast production of extracellular matrix macromolecules. Experiments by Kelly demonstrated that exocystosis of extracellular matrix molecules, including collagen, fibronectin, and glycosaminoglycans (primary components of a Peyronie's plaque) is a calcium ion dependent process.15 Aggeler et al demonstrated that anti-microtubular agents, calcium antagonists, and a calmodulin blocker resulted in a change in fibroblast cell shape.16 This morphogenic change resulted in alteration in the protein secretion phenotype of these fibroblasts. The affected cells were noted to alter the secretion of extracellular matrix proteins on a concentration related basis, which correlates positively with the degree of cell shape change. The change in secretion phenotype was manifest by increased extracellular matrix collagenase activity as well as decreased collagen and fibronectin synthesis and secretion. Askey et al found that verapamil specifically inhibited fibroblast secretion of a membrane impermeable probe.17
The effect of calcium antagonists specifically on fibroblasts and extracellular matrix was further investigated by Lee and Ping who reported that cultured bovine fibroblasts exposed to increasing concentrations of verapamil and nifidepine displayed a dose-dependent decrease in the incorporation of radiolabeled proline and sulfate into extracellular matrix collagen and glycosaminoglycans, indicating decreased synthesis and secretion of these cellular products.18 In addition, they noted that the therapeutic serum levels of verapamil used for the treatment of hypertension and cardiac dysrhythmias range from 0.01 to 0.2 µM. However, the concentration to retard extracellular matrix collagen synthesis in their in vitro study was approximately 100 µM. Therefore, it was concluded that direct delivery of the drug to the scar tissue was necessary to avoid toxic serum levels. In vivo studies of calcium antagonists have also been performed. Two independent animal model studies showed that treatment with verapamil produced significantly fewer peritoneal adhesions with a surgically created abdominal wound.19,20 In addition, Johnson et al reported that nifedipine resulted in improved wound healing in adriamycin-induced tissue injury.21
More recent research has also documented the capacity of verapamil to modulate extracellular matrix metabolism by inhibiting the expression of collagen as well as by increasing the proteolytic activity of collagenase, thereby enhancing matrix remodeling by human fibroblasts in burn scars22 and vascular smooth muscle cells in cell culture.23,24 Verapamil has also been shown to enhance growth of urothelial cells and decrease collagen III production by both urothelial and smooth muscle cells in the laboratory.25 In addition, verapamil and other calcium channel blockers were found to affect cytokine expression associated with the early phases of wound healing and inflammation, including platelet-derived growth factor-BB, interleukin-6, and interleukin-8.23,26 Most recently, Anderson et al were able to assess the effects of verapamil on fibroblasts derived from excised Peyronie's plaques in an in vitro model.27 They found that verapamil had the most profound inhibitory effect on cell proliferation compared to other biologic agents, including prostaglandin-E1, interferon-alpha 2β, and colchicine.
The above work indicates the importance of regulating the balance between matrix biosynthesis and degradation by fibroblasts in wound healing and scar formation. It can, therefore, be hypothesized that fibroblast exposure to a calcium antagonist such as verapamil has the potential to significantly alter fibroblast function at several levels, including cell proliferation, extracellular matrix protein synthesis and secretion, as well as collagen degradation. Consequently, calcium antagonists may have the capacity to slow, prevent, or even reverse plaque formation and the progression of PD.
Review of the literature and clinical experience
The majority of the studies on intralesional verapamil injection have been criticized for small patient populations, poor patient characteristics, absence of an objective measure of response, and most importantly, lack of a placebo-controlled comparison group. Large controlled studies have been difficult to conduct due to lack of industry support and the limited patient population seen by most urologists. In addition, it is ethically difficult to offer a placebo administered in an invasive fashion or a known non-effective treatment to the man with PD. Despite these problems, several reports have been published supporting the efficacy of intralesional verapamil therapy in men with PD.
In 1994, treatment of PD with intralesional verapamil was first reported by Levine et al in a dose-escalating trial.28 Of the 14 men who entered the study, 91% had resolution of pain, 42% had objective decrease in curvature, 58% had improved erectile dysfunction (ED), and 100% reported increased penile girth. The men were given biweekly (every two weeks) injections for six months, and doses were sequentially escalated to 10 mg of verapamil in a single sitting. A standard dose of 10 mg was established at this time since it was regarded as the highest dose one could safely give intravenously by the pharmaceutical industry during the development of verapamil, and it was found to result in the greatest tissue response in the dose-escalating trial. Arena et al reported on 39 men given biweekly injections for six months.29 They found objective improvement in curvature in 50% of those in which the diagnosis of PD was less than one year old, but in only 10.2% when the disease lasted more than one year. In addition, they reported that 91% had rapid resolution of pain. Teloken et al, however, noted no advantage to verapamil over placebo or steroids when given in a controlled fashion.30 In that study verapamil was injected around and not into the plaque, underscoring the importance of direct drug delivery to plaque fibroblasts. In another small study, 11 patients were given intralesional verapamil with a 50% subjective improvement in curvature.31 In a long-term single-blind study, Rehman et al reported on 14 patients given weekly injections for six months.32 They noted an objective decrease in curvature in 28% of patients receiving verapamil but this was not statistically significant. Erectile dysfunction was improved in 43%, 100% had increased girth, and 57% had a measured decrease in plaque volume. The authors concluded that verapamil was most effective in patients with noncalcified plaques and penile angulation less than 30 degrees. These studies confirmed the effect of intralesional verapamil with variable efficacy. The differences among results may be attributed to differences in technique, dose, frequency, and patient population since it is clear that not all patients respond.
In 1997, a subsequent report from Levine in 46 patients with PD suggested that there was a positive response to verapamil regardless of disease duration and severity.14 In that study, patients received injections every 2 weeks for a total of 12 injections. Pain resolved in 97% after a mean of 2.5 injections. Objectively, curvature was decreased in 54% and there were no differences in response to treatment based on duration of disease or within the three Kelami classification groups. In addition, 72% of men reported an improvement in sexual function. Most recently, Levine et al reported a non-randomized prospective study of 156 men who were treated with verapamil.33 Objectively, 60% of men were found to have a decrease in curvature, while 62% of men reported a subjective improvement in curvature. Increase in girth was reported by 83%, 80% described an increase in rigidity distal to the plaque, and 71% noted an improvement in sexual function. Consistent with the earlier data from 1997, there was no significant difference in response based on duration of disease or Kelami classification. In addition, there were few complications, with only 6/156 (4%) reporting any problem. Of these, three had complaints of transient nausea or lightheadedness without measured hypotension or cardiac dysrhythmia. Three men had transient pain at the injection site lasting longer than one day but less than seven days. Most men experienced mild penile ecchymosis, but none required treatment. There were no adverse cardiovascular events.
The most recent update by Levine et al also represents the largest follow-up study to date.33 The 156 men were followed for an average of over two years and as long as six years following completion of verapamil injections. In the group of men who subjectively noted improvement of erect deformity, including bending and indentations, none reported subsequent recurrence of deformity or new plaque formation.
In patients who have received verapamil injections and undergone subsequent surgery, we have not experienced increased technical difficulty or noted compromised surgical success. In fact, we have utilized verapamil in men who are planning surgical correction but still have active disease, manifest by painful erections or changing deformity, or who have extreme penile deformity in excess of 90 degrees. In these cases, four to six intralesional injections typically appear to hasten stabilization of the inflammatory process and penile deformity. Surgical intervention is then pursued when the deformity is stable for more than six months.
Criticism of the available data centers on the lack of non-randomized trials. This is an appropriate criticism since the “litmus test” of efficacy is the placebo-controlled trial. However, it is recognized that in certain circumstances this study design is not plausible or ethically just, ie when there is no effective standard of care with which to compare and when placebo treatment may be potentially painful, invasive, and/or do no good or cause harm. It is also recognized that nonrandomized designs, also known as quasi-experimental designs, are valuable additions to the literature and are statistically sound.34 In addition, much of medical treatment research today is industry-supported given the expense of medical care. When this author solicited companies in the early 1990's for support to study verapamil in a randomized placebo controlled fashion there was no support available since verapamil is inexpensive and generically available. Thus, the data presented as well as the multi-institutional experience suggests that in a majority of patients with PD, verapamil intralesional injection will improve erect penile deformity and accelerate resolution of pain (which may indicate stabilization of the inflammatory phase) with minimal adverse effects.
A standardized dose of 10 mg of verapamil (5 mg/2 cc) diluted to 10 cc total volume with injectable saline is used. The solution is distributed throughout the Peyronie's plaque using a 5/8-inch, 25-gauge needle on a standard 10 cc Luerlock syringe.14,28 A smaller gauge needle is not recommended, as this may increase the risk of needle fracture. Also, the 25-gauge needle allows for a large enough tract in which to deposit the drug. Prior to drug injection, a penile block is performed with 10 cc 0.5% bupivacaine without epinephrine. In some cases, a second penile block may be required. The plaque is grasped between index finger and thumb, and a single skin puncture is performed. The needle is then passed in and out of the plaque while leaving the drug within the needle tracts. In men with large plaques, the needle may be removed and the process repeated. After the injections are complete, the patient is asked to lightly compress the penis with both thumbs over the puncture sites to reduce the likelihood of ecchymosis and/or hematoma. Each patient's blood pressure is monitored for ten minutes after drug injection before discharge from the office. Patients are asked to abstain from intercourse for a minimum of 24 hours after each procedure.
Each set of injections is administered at an interval of two weeks with twelve total treatment sessions performed. A minimum two-week interval was established based on previous experience that a shorter interval incites an increased inflammatory response.28 Intervals of up to three and four weeks are allowed for patients' convenience. More specifically, we currently recommend that patients receive a course of six biweekly injections. If no subjective improvement of girth or curvature is noted, further injections are not encouraged. This approach is based on the finding that 75% of patients receiving verapamil injections noted some improvement by the sixth injection.14
Plaque size and shape may change significantly during the course of injections, even becoming larger than the pre-treatment size. In following patients who complete treatments, we have found plaque size to consistently diminish, indicating the persistent and slow remodeling process triggered by the verapamil therapy. We therefore suggest that changes in erect penile deformity, and not plaque size, should be monitored in patients receiving the injection protocol.
Intralesional verapamil injection for the treatment of Peyronie's disease is based on experimental findings that show that calcium antagonists may significantly affect fibroblast function on several levels, including cell proliferation, extracellular matrix protein synthesis and secretion, as well as collagen degradation. These changes may allow intralesional verapamil to retard, prevent, or possibly reverse plaque formation and progression of PD. The multicenter international clinical experience with verapamil injection supports the scientific rationale in that patients demonstrate reduction in pain, decrease in curvature, and improved sexual function. The ideal candidates for intralesional verapamil treatment include those who present with pain, decline surgery, have curvature less than 90 degrees, and have a non-calcified plaque. The efficacy of treatment seems to be independent of disease duration and Kelami classification. In men who subjectively note improvement of erect deformity, the results are durable over at least a two-year period. In addition, patients who have had verapamil injections and subsequent surgery have no evidence of compromised surgical success, and may exhibit hastened pre-surgical plaque stabilization. Thus, intralesional verapamil treatment should be considered a first-line treatment in the great majority of patients presenting with PD.
de La Peyronie F . Sur quelques obstacles qui s'opposent a l'ejaculation naturelle de la semence Mem de l'Acad Roy de Chir 1743 1: 425–434
Abdel-Salam Y et al. Treatment of Peyronie's disease by extra corporeal shockwave therapy: evaluation of our preliminary results Journal of Urology 1997 13: 549–552
Bittard H, Schraub S, Bittard M . Treatment of Peyronie's disease by a combination of radiotherapy and surgery. Apropos of 51 cases Annales d Urologie 1988 22: 67–69
Stojic M, Negrojevic M, Josic P, Stojic S . Conservative therapy of Peyronie's disease using vitamin E Medicinski Pregled 1987 40: 133–135
Akkus E et al. Is colchicine effective in Peyronie's disease? A pilot study Urology 1994 44: 291–295
Teloken C et al. Tamoxifen vs placebo in the treatment of Peyronie's disease Journal of Urology 1999 162: 2003–2005
Carson CC . Potassium para-aminobenzoate for the treatment of Peyronie's disease: is it effective? Techniques in Urology 1997 3: 135–139
Riedl CR et al. Iontophoresis for treatment of Peyronie's disease Journal of Urology 2000 163: 95–99
Treffiletti et al. Iontophoresis in the conservative treatment of Peyronie's disease: preliminary experience Archivio Italiano di Urologia, Andrologia 1997 69: 323–327
Gelbard MK, James K, Riach P, Dovey F . Collagenase vs placebo in the treatment of Peyronie's disease: a double-blind study Journal of Urology 1993 149: 56–58
Cipollone G et al. Betamethasone vs placebo in Peyronie's disease Archivio Italiano di Urologia, Andrologia 1998 70: 165–168
Primus G . Orgetein in the treatment of plastic induration of the penis (Peyronie's disease) International Urology and Nephrology 1993 25: 169–172
Ahuja S et al. A pilot study demonstrating clinical benefit from intralesional interferon alpha 2B in the treatment of Peyronie's disease Journal of Andrology 1999 20: 444–448
Levine LA . Treatment of Peyronie's disease with intralesional verapamil injection Journal of Urology 1997 158: 1395–1399
Kelly RB . Pathways of protein secretion in eukaryotes Science 1985 230: 25–32
Aggeler J, Frisch SM, Werb Z . Changes in cell shape correlate with collagenase gene expression in rabbit synovial fibroblasts Journal of Cell Biology 1984 98: 1662–1671
Askey DB et al. The effect of weak electric fields and verapamil on exocytosis in human fibroblasts Journal of Cell Biology 1988 107: 336a abstract 1905
Lee RC, Ping JA . Calcium antagonists retard extracellular matrix production in connective tissue equivalent J Surg Res 1990 49: 463–466
Kappas AM, Barsoum GH, Ortiz JB, Keighly MR . Prevention of peritoneal adhesions in rats with verapamil, hydrocortisone sodium succinate, and phosphatidylcholine European Journal of Surgery 1992 158: 33–35
Steinleitner A, Kazensky C, Lambert H . Calcium channel blockade prevents postsurgical reformation of adnexal adhesions in rabbits Obstetrics and Gynecology 1989 74: 796–798
Johnson H, Parham M, Davis E, Wise L . Preliminary study of the protective effect of the calcium channel blocker, nifedipine, on adriamycin-induced tissue injury J Invest Surg 1991 4: 313–322
Lee RC, Doong H, Jellema AF . The response of burn scars to intralesional verapamil. Report of five cases Arch Surg 1994 129: 107–111
Roth M, Eickelberg O, Kohler E, Erne P, Block LH . Ca2+ channel blockers modulate metabolism of collagens within the extracellular matrix Proc Natl Acad Sci 1996 93: 5478–5482
Stetler-Stevenson WG . Dynamics of matrix turnover during pathologic remodeling of the extracellular matrix Amer J Path 1996 148: 1345
Wolf JS Jr, Soble JJ, Ratliff TL, Clayman RV . Ureteral cell cultures II. Collagen production and response to pharmacological agents J Urol 1996 156: 2067
Rodler S, Roth M, Nauck M, Tamm M, Block LH . Ca(2+)-channel blockers modulate the expression of interleukin-6 and interleukin-8 genes in human vascular smooth muscle cells J Mol Cell Cardiol 1995 27: 2295
Anderson MS, Shankey TV, Lubrano T, Mulhall JP . Inhibition of Peyronie's plaque fibroblast proliferation by biologic agents International Journal of Impotence Research 2000 Suppl. 3 S25–S31
Levine LA, Merrick PF, Lee RC . Intralesional verapamil injection for the treatment of Peyronie's disease J Urol 1994 151: 1522–1524
Arena F . Clinical effects of verapamil in the treatment of Peyronie's disease Acta Biomed Ateneo Parmense 1995 66: 269–272
Teloken C et al. Objective evaluation of non-surgical approach for Peyronie's disease J Urol 1996 155: 633A abstract 1290
Lasser A, Vandenberg TL, Vincent MJ, Hellstrom WJ . Intraplaque verapamil injection for treatment of Peyronie's disease Journal of the Louisiana State Medical Society 1998 150: 431–434
Rehman J, Benet A, Melman A . Use of intralesional verapamil to dissolve Peyronie's disease plaque: a long-term single-blind study Urology 1998 51: 620–626
Levine LA, Goldman KE . Updated experience with intralesional verapamil injection treatment for Peyronie's disease J Urol 2000 163: 170 abstract 751
Shadish WR, Cook TD, Campbell DT . Experimental and quasi-experimental designs for generalized causal inference Houghton-Mifflin: Boston 2002
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Levine, L., Estrada, C. Intralesional verapamil for the treatment of Peyronie's disease: a review. Int J Impot Res 14, 324–328 (2002). https://doi.org/10.1038/sj.ijir.3900917
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