Penile Rehabilitation Postprostatectomy: Is There a Role for MUSE?

Expert Commentary

RIU0393_03-20.qxd 3/20/08 9:52 PM Page 1 EXPERT COMMENTARY Penile Rehabilitation Postprostatectomy: Is There a Role for MUSE? Herbert Lepor, MD, Andrew McCullough, MD New York University School of Medicine, New York, NY [Rev Urol. 2008;10(1):1-5] © 2008 MedReviews, LLC espite the advent of nerve-sparing surgery in the early 1980s, normalization of erectile function following prostatectomy remains poor. Robotic techniques and higher-magnification equipment have done little to improve results. Herbert Lepor, MD, Professor and Martin Spatz Chairperson of Urology and Professor of Pharmacology at New York University School of Medicine and cofounder of Reviews in Urology, and Andrew McCullough, MD, Director of the Sexual Health and Male Infertility and Microsurgery Programs at New York University School of Medicine, discuss treatment options for penile rehabilitation postprostatectomy. Herbert Lepor, MD: Urologists consider nerve-sparing prostatectomy “perfect surgery,” but it needs improvement in terms of erectile function. How can we enhance results? Andrew McCullough, MD: The discovery of the nerve-sparing prostatectomy was a tremendous advance in the treatment of prostate cancer. Before that, men were universally impotent after their radical prostatectomy. In 1983, Dr. Walsh D VOL. 10 NO. 1 2008 REVIEWS IN UROLOGY 1 RIU0393_03-14.qxd 3/15/08 3:06 AM Page 2 Penile Rehabilitation Postprostatectomy continued came up with the concept of preserving the neurovascular bundle that was important for potency.1 Initially, the results were very favorable in terms of preserving erectile function. The definition of erectile function, however, confuses the issue. Was the surgery really potency preserving, or were we just minimizing the damage from the surgery? As urologists developed experience with nerve-sparing prostatectomy, we began to realize that the results were not perfect. The shortcomings of the surgery became increasingly obvious: Very few patients were as good in the long term as they were before surgery. The first study to show this in a placebo-controlled and very rigorous fashion was the Penile Rehabilitation Study, which tested sildenafil (Viagra®; Pfizer, New York, NY). Using validated instruments, we were able to show that at 1 year, or 11 months, the normalization of erectile function was rather poor. With treatment, there was a 7-fold improvement in the normalization of erectile function.2 Let me qualify that: I am not saying that 4% of men have erectile function after surgery, but when we look at our gold standard, which is normalization of erectile function, we are falling short of our goal. Urologists hoped that with robotic surgery and higher magnification we would be able to improve on those statistics. However, what we are discovering, at least in the short term, is that there is no difference in return of erectile function in robotic versus open prostatectomy. Even with a high degree of magnification, an injury occurs that is causing damage to the process of erectile function. Moreover, we do not yet know exactly which treatment regimen is best. Dr. Montorsi conducted the first study that showed that there might be some benefit to pharmacologic inter- 2 VOL. 10 NO. 1 2008 vention during the recovery phase.3 Using injection therapy for 3 months, he was able to improve the return of erectile function. The study was not placebo controlled; it is hard to do a placebo-controlled study with injection therapy. Therefore, the first pharmacologic placebo-controlled study was in fact the Penile Rehabilitation Study, which involved a relatively small series of 75 men. Again, we were able to show a 7-fold improvement in normalization of erectile function.2 Since then, there have been no placebo-controlled studies on pharmacologic intervention in penile rehabilitation. It’s a little bit difficult ethically to do a placebo-controlled study when you have already demonstrated that there’s a 7-fold difference between placebo and treatment, but nonetheless, larger studies are needed. We have probably maximized our surgical approach. We are dealing with is microneural damage occurring at the time of surgery that results in a neurapraxia and possibly a secondary myogenic or muscle injury. The problem is, as in any other neuromuscular injury, if the muscle is not rehabilitated after the nerve injury, many times, if not all the time, the muscle undergoes some degree of atrophy and fibrosis. Herbert Lepor, MD: Let’s talk about early intervention. How important is it and what have we learned? Andrew McCullough, MD: Well, we have learned that there’s a consequence of not intervening that may be detrimental in terms of long-term recovery of erectile function. We have also seen, and you certainly can see it in animal models, that without intervention, there is fibrosis that occurs within the penis.4-6 Clinically, we see this when men say to us, “Doctor, what did you do? My penis has shrunk after surgery!” REVIEWS IN UROLOGY We’re not talking about shrinkage caused by a reduction in the urethral length; we’re talking about both circumferential and length changes that occur after surgery. Therefore, the consequence of not doing anything is the potential of damage to the microarchitecture of the penis—irreversible, long-term damage. The penis is not a muscle that you can go into rehabilitation and strengthen everyday, as is done with skeletal muscle injuries. In fact, how often does the penis get used—maybe 4 to 6 times a month? The benefit of early intervention is in prevention of neuromuscular damage. Herbert Lepor, MD: What treatment options are out there right now, and do they work? Andrew McCullough, MD: Before we had Viagra or sildenafil, we had treatment options. We had the vacuum erection device. We had intraurethral alprostadil. We had penile injections and we had the penile implant. In 1998, almost 10 years ago, the US Food and Drug Administration (FDA) approved sildenafil and urologists hoped it would be a savior in terms of postprostatectomy erectile function. However, phosphodiesterase type 5 (PDE-5) inhibitors need intact neuromuscular function in order to work. Viagra and PDE-5 inhibitors work by amplifying neuromuscular activity. With the absence of neuromuscular activity, there is no efficacy. In 1998, there was a unique clinical situation because before March 27, 1998, men did not have exposure to sildenafil. Patients who had had their radical prostatectomy—1 month, 1 year, or 10 years before the approval— had not experienced PDE-5 inhibitors. On April 1, 1998, virtually all the patients who had had radical prostatectomies were calling in for a prescription. We had this unique opportunity of seeing what the effect of PDE-5 inhibitors was on this huge reserve of RIU0393_03-14.qxd 3/15/08 3:06 AM Page 3 Penile Rehabilitation Postprostatectomy patients that heretofore were not exposed to them. In the summer of 1998, we sent validated questionnaires to a large cohort of patients to see what their responsiveness was to PDE-5 inhibitors.7 These were patients on whom we had all the clinical information: disease stage, preoperative potency, prostate-specific antigen (PSA) levels, prostate weight. We had all the information on these patients because they were in our database. In addition, what we found was, as one would expect, early on there is virtually no responsiveness to PDE-5 inhibitors. Moreover, the recovery of responsiveness to PDE-5 inhibitors is virtually the same as the recovery of natural function described by Pat Walsh in his article in Urology.8 PDE-5 inhibitors are an alternative for treatment, but early on, they just do not work, which is very frustrating for the patient. Why would he want to take a medication where he sees no efficacy? In fact, in the placebocontrolled study, despite taking sildenafil at 50 mg or 100 mg every night, patients were complaining that they were on placebo.2 They also did not perceive any side effects because they were seeing no reactivity in the early months. Therefore, in the early stages after the radical prostatectomy there is no PDE-5 responsiveness in terms of erectile function. Nevertheless, there must be some benefit going on in terms of rehabilitation because we did see 7-fold improvement in return of erectile function eventually. However, it is in those first 6 to 9 months where there is not enough neurological function for the PDE-5 inhibitors to work that we have our biggest dilemma. What do we do to treat these patients? How do we get them sexually functional again? We do have other alternatives and we’re in the process of doing a study using intraurethral alprostadil. Now the advantage of intraurethral alprostadil is it works regardless of nerve status. The Costabile study, conducted after FDA approval, showed efficacy in men after radical prostatectomy, regardless of the nerve status.9 Clearly, we have another form of intervention that in the early stages after prostatectomy appears vastly superior to PDE-5 inhibitors, and it obviates the need for penile injections. Herbert Lepor, MD: It is very clear that, at least within the first 6 to 9 months, PDE-5 inhibitors are just not working. Can you talk a little bit about MUSE® (alprostadil urethral suppository; VIVUS, Inc, Mountain View, CA) and why it would work? Andrew McCullough, MD: In 1998, MUSE proved effective after radical prostatectomy. Whereas the Viagralike drugs work by amplifying the neurologic reflex, intraurethral prostaglandin acts by increasing adenylyl cyclase. The mechanism is cyclic adenosine monophosphate (cAMP) and not cyclic guanosine monophosphate (cGMP). Because it is providing direct stimulation of adenylyl cyclase, creating cAMP, you do not need intact neuromuscular function. MUSE does have the drawback of potential discomfort during administration because of prostaglandin’s direct effect on pain receptors. The use of lidocaine in the urethra obviates this discomfort at the time of administration. The pain that occurs, which is usually mild and tolerable, decreases with future treatments. When we were designing a protocol, we were looking to improve on PDE-5 results. We had 28% normalization of erectile function at 11 months.10 How can we improve on that? According to the Montorsi study using intracavernous injections,3 we thought that active oxygenation would be beneficial. Therefore, we undertook a study using sildenafil as the active control. We did not feel that it was ethical to use a placebo when we had already established that, at least in the short term, there was a disadvantage to a placebo arm. We used an active control arm and we administered intraurethral prostaglandin once every day. Why every day? The sildenafil study used that model. If we had dosed less frequently and had gotten a negative result, we risked criticism for underdosing. We felt that it was important to compare apples to apples, so we were studying nightly treatment of sildenafil and nightly treatment of intraurethral alprostadil. Then you have to ask the question, what dose do we use? The discomfort that accompanies the use of MUSE is dose dependant, and the last thing we wanted was patients dropping out of the study because they were having pain from administering the medication. A previous study done at the Cleveland Clinic suggested that 250 g of MUSE was tolerated.11 We decided that would be a good starting point. We started very early, so 1 week after surgery, after catheter removal, patients took 125 g of MUSE per night. After 1 month, they were dose escalated to 250 g, and treatment remained at 250 g for the following 8 months. What is the concept behind using MUSE or increasing blood flow? The concept is that of penile oxygenation. It is somewhat controversial, but the idea is that after a neurologic injury such as a radical prostatectomy, there is a loss of nocturnal penile erections. That results in a chronic hypoxemic state within the penis. We’re not talking about anoxia, or lack of oxygen, we’re talking about hypoxemic state. Similar to venus blood, during the period when there is no nocturnal VOL. 10 NO. 1 2008 REVIEWS IN UROLOGY 3 RIU0393_03-14.qxd 3/15/08 3:06 AM Page 4 Penile Rehabilitation Postprostatectomy continued activity following radical prostatectomy, the penis never arterializes. You have an organ that is used to getting oxygenated with arterialization of the cavernous blood through erections, or even with suberectile states of stimulation. However, the penis, rather than oxygenating, ends up in a chronic venus state. This leads to the formation of fibrosis within the penis. We thought that we would be able to oxygenate the penis, at least once a day, via the administration of MUSE. We had the opportunity to work with an FDA-approved tool called the ODISsey™ Tissue Oximeter (ViOptix, Inc, Irvine, CA), which is a tissue oxygen saturation machine. It measures the amount of oxygenated blood versus desaturated oxygenated blood by sending in 2 laser beams at different wavelengths: one at the wavelength of desaturated oxygenated hemoglobin and the other at the wavelength of saturated blood. It then compares a ratio of the 2. This is not a pulsoxymeter; this actually measures an average of a cubic centimeter of tissue below the probe. Pediatric anesthesia uses a similar concept in children that are undergoing hypothermic arrest for heart surgery. Cerebral oxygenation is monitored by use of a similar technique. Using a simple probe placed on the surface of the penis, we can measure a cubic centimeter of tissue below the skin, which is within the corporeal tissue. The first question was: What is normal oxygen saturation in the flaccid penis? Therefore, we tested a series of patients with various disease states, some not related to erectile dysfunction, and demonstrated that in fact, the resting penis was in a desaturated state. With erections induced by injections, or by MUSE, we arterialized the blood in the penis. 4 VOL. 10 NO. 1 2008 With an erection, you can in fact increase the arterialization of blood in the penis. The next question was: What about a suberectile state? Very, very few patients respond to 250 g of MUSE to the point of having an erection. So does 250 g of MUSE arterialize the blood? As part of the study, we measured corporeal oximetry before and after the administration of MUSE 125 g and MUSE 250 g, and we compared these measurements to the arterialization of blood that occurred with injection of intracorporeal prostaglandin, papaverine, and phentolamine. What we found was that even with 125 g of MUSE creating a suberectile state, we were able to arterialize blood in the penis. Now, 250 g was statistically better than 125 g, but most importantly, 250 g of MUSE was comparable to intracorporeal injection of vasoactive material. We were improving arterialization of blood with a suberectile dose of intraurethral alprostadil. Armed with that information, we felt comfortable that we were accomplishing our goal, which was to oxygenate the penis. However, what are you doing if you’re only arterializing the blood for 15 minutes, which is the half-life of alprostadil? Throughout the study, we measured corporeal oximetry in men who were in either the Viagra arm or the MUSE arm. Keep in mind that patients were dosed with sildenafil the night before. They took MUSE the night before. Therefore, what we were seeing the next day was the result of the administration of medication the night before. Amazingly, what we saw was that the arterialization of the blood that occurred the night before had a residual effect the next day. Moreover, for the first 6 months after surgery, when there was very little neuromuscular function, we saw a dramatic advantage to the suberectile REVIEWS IN UROLOGY administration of intraurethral alprostadil. There was no effect of sildenafil. Not only did a suberectile dose of MUSE create oxygenation of the penile blood, the effect carried into the next day. The concept of active treatment was validated by looking at penile oxygenation in these men. Clearly, it’s much easier for men to administer intraurethral alprostadil versus a penile injection and our compliance rate—and this was a surprise to me—were comparable for the MUSE and sildenafil arm of the study. Herbert Lepor, MD: Do urologists underutilize MUSE? Andrew McCullough, MD: I think MUSE is underutilized. I think penile injections are underutilized. A certain degree of complacency has taken place because people saw PDE5 inhibitors as replacing existing therapies. Nevertheless, if you look at efficacy of PDE-5 inhibitors, you can have improvement in your International Index of Erectile Function (IIEF) score, but improvement in IIEF does not mean an erection satisfactory for intercourse. In addition, what people have forgotten is that we have very effective ways of not only increasing IIEF, but also allowing our patients to be sexually active. That’s an important concept. Therefore, I think that MUSE has a role. I think it has a role for the primary care physician. You have to remember that prior to 1998, urologists treated 90% of erectile dysfunction because they were administering injections, intraurethral alprostadil, and vacuum devices, and performing implants. Today, primary care physicians manage 90% of erectile dysfunction. Therefore, they are managing the first-line treatment. There is no reason for the primary care physician not to administer a second-line treatment as well. Patients tolerate MUSE very RIU0393_03-14.qxd 3/15/08 3:06 AM Page 5 Penile Rehabilitation Postprostatectomy well. It is easy to administer. There is no reason why a primary care physician cannot get involved. The incident of priapism with MUSE is exceedingly low, so I think that it has a real role in the treatment of erectile dysfunction. More and more patients are PDE-5 failures. Why is that? What’s happening is the underlying disease process is progressing. Diabetes is not a stagnant condition. It progresses. Hypertension, dyslipidemia, and aging all create the potential for PDE-5 inhibitor failure. When you think about it, we have 10 years of men, 35% of whom never responded to the PDE-5 inhibitors and an increasing number of men who were exposed to the PDE5 inhibitors early on, who are no longer responding to PDE-5 inhibitors and need a second- or third-line treatment. Herbert Lepor, MD: What about combination therapy? Andrew McCullough, MD: The FDA has not approved combination therapy. Nevertheless, what we have seen clinically is that with the judicious use of combination therapy, we can salvage these PDE-5 failures. Keep in mind that you don’t need to have a neuromuscular transmission for intraurethral alprostadil to work. On the other hand, there is some evidence that suggests that the chronic administration of a PDE-5 inhibitor can improve erectile function over time. What are you doing in that situation? You are increasing the amount of cyclic GMP within the corporeal body. There are two mechanisms: a guanylate cyclase mechanism enhanced by the use of PDE-5 inhibitors and a cAMP mechanism addressed by intraurethral alprostadil. There is a physiologic rational for the use of combination therapy to salvage patients who are not responsive to PDE-5 inhibitors. Studies at the Mayo Clinic12 and at the Cleveland Clinic13 show this. By using the synergistic effect of the increase in cGMP and the increase in cAMP, we can salvage patients who have failed treatment with a single modality. PDE-5 inhibitors were a tremendous advancement in the treatment of erectile dysfunction. The approval of PDE-5 inhibitors overshadowed another important treatment that became available 1 year before: intraurethral alprostadil. Intraurethral alprostadil offers an excellent firstor second-line treatment for erectile dysfunction. In the large number of patients who have failed using PDE-5 inhibitors, this represents a viable option for treating erectile dysfunction that is tremendously underutilized. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. References 1. 2. Walsh PC, Mostwin JL. Radical prostatectomy and cystoprostatectomy with preservation of potency. Results using a new nerve-sparing technique. Br J Urol. 1984;56:694-697. Brock G, Nehra A, Lipshulz LI, et al. Safety and efficacy of vardenafil for the treatment of men with erectile dysfunction after radical retropubic prostatectomy. J Urol. 2003;170:1278-1283. 13. Montorsi F, Guazzoni G, Strambi LF, et al. Recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: results of a prospective, randomized trial. J Urol. 1997;158:1408-1410. Lakin MM, Montague DK, Schover LR. Fibrosis with intracavernous injection therapy utilizing prostaglandin E1. J Urol. 1992;147:309A. Mumtaz FH, et al. Prostaglandin E1 intracavernosal injections—longterm results and complications. Int J Impot Res. 1996;7:120. Chew KK, Stuckey BG, Earle CM, et al. Penile fibrosis in intracavernosal prostaglandin E1 injection therapy for erectile dysfunction. Int J Impot Res. 1997;9:225-229. Hong EK, Lepor H, McCullough AR. Time dependent patient satisfaction with sildenafil for erectile dysfunction (ED) after nerve-sparing radical retropubic prostatectomy (RRP). Int J Impotence Res 1999;11(suppl 1):S15-S22. Walsh PC, Marschke P, Ricker D, Burnett AL. Patient-reported urinary continence and sexual function after anatomic radical prostatectomy. Urology. 2000;55:58-61. Costabile RA, Spevak M, Fishman IJ, et al. Efficacy and safety of transurethral alprostadil in patients with erectile dysfunction following radical prostatectomy. J Urol. 1998;160:13251328. Padma-Nathan H, McCullough A, Guiliano F, et al. Postoperative nightly administration of sildenafil citrate significantly improves normal spontaneous erectile function after bilateral nervesparing radical prostatectomy [abstract]. J Urol. 2003;169(suppl 4):375. Raina R, Agarwal A, Ausmundson S, et al. Longterm efficacy and compliance of MUSE for erectile dysfunction following radical prostatectomy: SHIM (IIEF-5) analysis. Int J Impot Res. 2005;17:86-90. Nehra A, Blute ML, Barrett DM, Moreland RB. Rationale for combination therapy of intraurethral prostaglandin E(1) and sildenafil in the salvage of erectile dysfunction patients desiring noninvasive therapy. Int J Impot Res. 2002;14(1 suppl):S38-S42. Raina R, Nandipati KC, Agarwal A, et al. Combination therapy: medicated urethral system for erection enhances sexual satisfaction in sildenafil citrate failure following nerve-sparing radical prostatectomy. J Androl. 2005;26:757-760. VOL. 10 NO. 1 2008 REVIEWS IN UROLOGY 5