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The search for effective nonsurgical treatment for Peyronie’s disease

Laurence A Levine
1 January, 2008  

Laurence A Levine
MD FACS
Professor of Urology
Department of Urology
Rush University Medical Center
Chicago, Illnois
USA

Peyronie’s disease is a wound-healing disorder of unclear aetiology which results in erect penile deformity (ie, curvature, shortening, indentation). It is a physically and psychologically devastating condition for the affected man. The search for effective medical treatment for Peyronie’s ­disease remains unanswered. Although there has been some progress in basic scientific research that may help us understand this unusual wound-healing disorder, the research studies and the clinical ­trials that have been published over the last decade have not led to a cure. Therefore, the practising urologist continues to face the problem as to the appropriate treatment for the male patient presenting with Peyronie’s disease. The gold standard of treatment is surgical correction, but often the patient is either not a surgical candidate because the disease is unstable or he is not psychologically ­prepared to accept surgery. Therefore, nonsurgical/medical therapy must be considered, compared with no ­treatment at all. Historically and currently, observation has been offered with the hope that the disease will undergo spontaneous resolution. This is based on subjective reports from the 1970s demonstrating that up to 30% of men had spontaneous resolution.

Treatment studies
More recent natural history studies have demonstrated that no more than 10–12% of men experience spontaneous resolution. Peyronie’s disease tends not to spontaneously resolve because, as recent research has shown, there are abnormalities in the final stages of wound healing which inhibit or ­prevent scar remodelling. This research has shown, in plaque excised during surgical reconstruction, that there appears to be an absence of effective collagenases and an abundance of inhibitors of those collagenases, both of which block scar breakdown. Therefore, an understanding of the sensible, albeit not curative, nonsurgical approaches to treat Peyronie’s disease is essential for the physician seeing men with Peyronie’s disease.

Oral treatments for Peyronie’s disease have been used since the time of de la Peyronie. The most commonly used oral therapies, including vitamin E, Potaba, colchicine and tamoxifen, have not ­demonstrated therapeutic benefit in placebo-controlled trials. On the other hand, recent anecdotal reports have suggested a potential benefit for pentoxifylline and L-arginine, which may increase circulating nitric oxide. Nitric oxide has been shown to have an antifibrotic effect in tissue culture and in the animal model studies of Peyronie’s disease. Other oral treatments have been examined in the literature, but properly performed placebo-controlled trials are lacking.

Intralesional injection therapy has been recommended since the 1950s. Unfortunately, there have been no placebo-controlled trials of steroids or orgotein. As a result, these agents are not currently recommended. Steroids have been noted to cause tissue thinning, and when they fail the surgical­ plane between the tunica albuginea and the neurovascular bundle is often ablated. Intralesional verapamil injection therapy was first introduced in 1994 and has emerged as the most scientifically ­sensible medical­ treatment. Due to the lack of industry support for a generic drug as well as difficulties­ in ­accruing patients for placebo-controlled trials of intralesional therapy, there are no large-scale, ­placebo-­controlled trials to confirm the efficacy of verapamil. In spite of this, there have been many well-­conducted studies of intralesional verapamil which demonstrate that, at a minimum, verapamil appears to stabilise disease, and in up to 60% of men there has been objectively measured improvement in deformity. Verapamil appears to be safe when given in 10–20 mg doses and is inexpensive. Typically, it is administered every two weeks for a series of 12 injections. It is important to recognise that short-term treatment (6–8 weeks) with any nonsurgical approach is unlikely to result in any reliable benefit as scar tissue changes at glacial speed. It is my practice that, if the patient does not note any improvement in his deformity following a series of six injections, either the dose of verapamil should be increased to 20 mg or surgery should be offered. Intralesional interferon alpha-2b is the only drug which has been demonstrated in a multicentre, placebo-controlled trial to be beneficial over saline. In this important and well-conducted study, 9% of patients in the saline group had measured improvement of curvature for a mean of 9°. On the other hand, in the active treatment arm 27% had measured improvement for a mean of 22°, a less robust response when compared with the noncontrolled verapamil reports. The key is that the simple injection of an inactive agent such as saline does not appear to have benefit.

Drug trials
There has been increased interest in applying energy to drive drugs such as verapamil and ­dexamethasone through the skin to the underlying plaque. Two placebo-controlled trials have demonstrated some benefit following iontophoresis with verapamil alone, or combined with dexamethasone. The improvement of deformity tends to be modest in the 10–15° range, which may be of value to the man with mild-to- moderate curvature. 

There does not appear to be any evidence of therapeutic benefit from the use of topical ­verapamil creams or gels. In addition, there is no evidence that topically applied verapamil actually reaches the target tissue of the tunica albuginea. On the other hand, studies of verapamil administrated with ­iontophoresis demonstrated that up to 70% of patients had measurable levels of verapamil. The question is what tissue concentration can be obtained with this technique and whether it will be enough to effect the desired change.

There have been multiple published reports on electrohydraulic shockwave therapy (ESWT), and the results have been difficult to interpret. Two recent reports have employed ESWT in a clever placebo-controlled fashion, and no therapeutic benefit was found in the treatment arm.

Recent study developments
Mechanical stretching therapy has been proposed for some time. Anecdotal reports suggested that ­daily application of a vacuum device could encourage remodelling. Unfortunately, there are no ­published reports with objective measures demonstrating the benefit of vacuum therapy. However, a clinical trial is in development and hopefully will answer this question. External traction devices have also recently received attention. The concept is to apply chronic stretching forces to the plaque with hopes that this will result in remodelling of the scar. When considering the mechanism of action for this treatment, we should think of an external traction device like dental braces which apply chronic forces to result in movement of bone.

Distraction osteogenesis, or callotasis, has been used since the 1960s as a treatment for long bone abnormalities. External fixation devices have also been used in patients with Dupuytren’s ­contracture either before or following fasciotomy to facilitate proper remodelling once the scar tissue is released. Therefore, it is not unreasonable to consider mechanical stretching forces with an external penile extender. The challenge is to have the patient wear the device for a minimum of two hours, but up to 8–10 hours per day, for six months. This must be done for an extended period of time to allow the remodelling process to occur. A recent pilot study of the FS external penile extender device
(fsPhysioMed Company, Aliso Viejo, CA, USA) was conducted in Chicago on 10 men with Peyronie’s disease. Penile duplex ultrasound was performed both before and at the end of treatment to measure change in erect deformity. All 10 men reported subjective reduction of curvature and had measured improvement of 10–45°. In addition, all men reported enhanced penile length and were found to have a measured increase in shaft length of 0.5–2 cm. Seventy percent of men had evidence of shaft narrowing, causing a hinge-effect. All of these men reported subjective improvement of the indentation and hinge-effect. Importantly, there was no reported change in penile sensation, skin breakdown, ulceration or new erectile dysfunction (ED).

Another recent study from Spain examined a group of men with Peyronie’s disease undergoing surgical straightening with either grafting or plication procedures. Half of the group used the Andro-Penis penile extender (AndroMedical, Madrid, Spain) for 8–10 hours per day beginning 2–3 weeks after surgery. There was meaningful preservation of penile length (1–3 cm) in those who used the device versus the control group who did not apply the stretching device. Larger-scale, multicentre trials will be necessary to confirm the apparent value of external penile traction therapy. 

My current nonsurgical treatment protocol includes:

  • Oral pentoxifylline (400 mg TID) and L-arginine (500 mg BID).
  • Intralesional verapamil therapy Q 2 weeks x 12 injections.
  • FS external penile extender therapy daily for a minimum of 2–8 hours per day for six months.

Conclusion
It is likely that other applications of penile traction therapy will emerge, including for men after radical prostatectomy, where up to 70% may lose length after surgery and possibly prior to placement of a penile prosthesis. In men with ED who may have lost shaft length, preoperative stretch therapy may allow placement of a larger internal cylinder to preserve or possibly enhance length. 

It is important that we recognise the psychologically devastating effects of Peyronie’s disease and be honest about the limitations of nonsurgical treatment, remembering that no cure is in sight, but that stabilisation or improvement is certainly possible with mechanical traction therapy and hopefully enhanced by combination therapy with oral and/or injectable agents.