Side Effects of Trimix Therapy

Wayne J. G. Hellstrom, MD, FACS


September 25, 2002


I have a patient who is using Triple P as intercavernosal injection for erectile dysfunction. He found an article describing possible side effects (not Peyronie's) such as scarring and fibrosis. Is there evidence or concern for this outcome?

Fred Freedman, MD

Response from Wayne J. G. Hellstrom, MD, FACS

Professor of Urology, Tulane University Medical School, New Orleans, Louisiana; Chief, Section of Andrology and Male Infertility, Tulane University Hospital Medical Center, New Orleans, Louisiana

Over the past 2 decades, self-injection therapy has proven to be both safe and efficacious, and is considered the best second-line drug therapy for the management of erectile dysfunction. The 3 vasoactive agents commonly used alone or in combination are papaverine, phentolamine, and prostaglandin E1 (PGE1 alprostadil).

PGE1 (Edex/Viridal; Schwarz Pharma; Monheim, Germany, or Caverject; Pharmacia Corporation; Peapack, New Jersey) is the most widely used vasoactive agent because it is FDA-approved and the most researched. In the event of pain, which occurs in 30% of patients taking PGE1, or inadequate penile rigidity, clinicians may resort to off-label synergistic combinations, such as papaverine and phentolamine (bimix), or papaverine, phentolamine, and PGE1 (trimix).

Fibrotic reactions with intracavernous injection therapy have been observed since the early 1980s. A variety of reactions, ranging from subcutaneous nodules, intracavernosal fibrotic areas, and penile plaques, have been reported. The occurrence of fibrotic reactions with the use of papaverine alone or papaverine/phentolamine combinations has ranged from 0.5% to 31% and appears to be correlated with the number of injections and duration of therapy.

In addition to instructing patients to alternate the side and site of injection, there is a growing body of evidence that suggests that PGE1 causes less fibrosis. It is postulated that fibrosis is caused by production of key cytokines, with transforming growth factor beta 1 (TGFB1) being the most important. Of significance, recent studies have demonstrated that PGE1 suppresses the production of TGFB1, reducing the amount of fibrosis.

Notwithstanding, patients on trimix combinations need proper instruction on the penile injection technique and routine clinical follow-up to identify new onset of fibrosis. In most cases, penile nodules that occur with injection therapy disappear within a few months of stopping.


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