Prior to the advent of intracorporeal pharmacotherapy, or penile injections, penile prosthesis was the only thing other than drug therapy really available. The advent of penile injections began when a scientist working with dogs found that a drug injected into the penis produced an erection.
This drug was papaverine,. Papaverine was originally marketed for use in vascular surgery to dilate vessels and additionally was taken as an oral medication to act as a vasodilator in people with lower extremity ischemia and people with vascular diseases of the legs. The off-label indication was used extensively throughout the 1980s.
Ever since Virag, in 1982, discovered that the papaverine intracavernosal injection could induce a full erection, the self-injection has no longer been regarded as an alternative treatment, and became the first therapeutical option for organic impotence.
Phentolamine is an alpha-adrenergic blocker used for hypertensive crises in pheochromocytoma. It came into reckoning for ICI when it was seen that papaverine gave better results when mixed with phentolamine.
Alprostadil was originally introduced to maintain the patency of the ductus arteriosus before definitive cardiac surgery could be undertaken. When it became apparent that it was effective in a penile self-injection program, it was then granted permission to be marketed as a treatment for erectile dysfunction.
The sympathetic nervous system normally maintains the penis in a flaccid or non-erect state. All of these vasoactive drugs, when injected into the corpora cavernosae, inhibit or override sympathetic inhibition to encourage relaxation of the smooth muscle trabeculae within the penile erectile bodies. The ensuing onrush of blood engorges the penile corpora cavernosae sinusoidal spaces with sufficient pressure to compress the emissary veins that normally drain blood from the penis. The combination of accelerated arterial inflow and impeded venous outflow from the corpora cavernosae creates an erection.
Papaverine is a nonspecific phosphodiesterase inhibitor that increases cyclic AMP and cyclic GMP concentrations in penile erectile tissue. The usual dose ranges from 15 to 60 mg. Given in doses of 7.5-90 mg, initially alone and later with phentolamine as a synergist in the ratio of 30:1, these treatments did not have a product licence but they were effective (up to 80 percent in men with psychogenic and neurogenic erectile dysfunction, but is less effective in men with vasculogenic dysfunction,36 to 50 percent), cheap, stable at room temperature and easy to use. Its major disadvantages are priapism (in up to 35 percent of cases), corporal fibrosis (in up to 33 percent of cases), and occasional increases in serum aminotransferase concentrations.
Currently, the use of isolated papaverine is not routinely used because of its unacceptably high complication rates, like priapism and systemic effects. However, its most frightening effect is corpora cavernosa fibrosis, which can occur even after a single injection.
Phentolamine is a competitive -adrenergic-receptor antagonist. When used alone, phentolamine does not produce rigid erections; when it is combined with papaverine, success rates range from 63 to 87 percent. A combination of 30 mg of papaverine and 0.5 to 1 mg of phentolamine is typically used, and the usual dose ranges from 0.1 to 1 ml. The side effects of phentolamine include hypotension and reflex tachycardia.
Alprostadil (prostaglandin E1) was given a product licence in 1994 and is supplied in 5, 10, and 20 µg doses.
Alprostadil (prostaglandin E1)'s efficacy is superior to that of papaverine and the combination of papaverine and phentolamine; it results in erections in more than 79 % of men. In addition, alprostadil is associated with a relatively low incidence of priapism (0.35 to 4 percent) and fibrosis (1 to 23 percent). Additionally, thanks to its rapid intracavernosal metabolization, priapism occurrence is lower than 1%, and the onset of corpora cavernosa fibrosis caused by prostaglandin is not frequent. The most important side effect is pain in the injection site, which occurs in up to 40% of patients. This pain, strongly intense, can last up to 3 hours after the injection, and is the main cause of treatment voluntary-cessation.
Despite the relatively high success rate, there is a very high attrition rate with self-injection when used long-term, suggesting that ICI may not be a satisfactory long term treatment for many men.
The most widely used today, known as Tri-Mix, or Goldstein solution is the combination of PGE1, phentolamine and papaverine. This combination of vasodilating substances and relaxants of the cavernosal smooth muscle has enabled the use of very small doses from each drug, attaining success rates higher than 95% for male impotence cases of any etiology, with practically no side effects. Priapism reported lower than 0.5% of the cases and there is almost no corpora cavernosa fibrosis. In addition to that, this combination does not cause penile pain.
Treatment usually starts at a dose of papaverine 30 mg, phentolamine l mg, and alprostadil 20 痢. The usual dose of trimix solution ranges from 0.1 to 0.5 ml.
The goal is to achieve an erection that is adequate for sexual intercourse but does not last for more than one hour.
The actual technique of penile injections involves the use of a fine 29 or 30 gauge needle and 1-cc syringe, which is the same type of syringe that diabetics use for insulin, to inject as small a volume of fluid as possible. Generally the injections are made in the 10:00 and the 2:00 position in the sides of the penis.
The needle is placed in a perpendicular fashion to inject the entire contents of the syringe. It is not necessary to get a return of blood in the needle. Direct pressure should be applied over the injection site for several minutes. If the patient is on blood thinners such as Coumadin or aspirin, pressure is applied to the injection site for an additional period.
Penile injection therapy must always be initiated in the hospital or a well equipped clinic setting with careful instructions and close follow up of the patient. The technique appears deceptively simple, but it is not without numerous complications and side effects. Patients are at risk for scarring if the procedure is not performed correctly, and as a consequence of scarring, patients can also develop angulation and a variant of Peyronie's disease.
Most patients should be advised to use this technique only two to three times a week.
The major side effect of intrapenile alprostadil therapy is penile pain, occurring in 50 percent. Pain is the side effect most often cited by men who discontinue ICI therapy.
Priapism, or a prolonged erection lasting more than four to six hours, is a medical emergency often requiring immediate urologic attention to evacuate blood clogged within the corpora cavernosae. Prolonged erections occur in 6 percent of men who use intrapenile alprostadil and about 11 percent of those who use intrapenile papaverine.One study evaluated the effects of prolonged priapism
Papaverine injected into the corpora cavernosae may escape into the general circulation and can be hepatotoxic; abnormal liver function tests have been reported in men using this drug for penile self-injection. In contrast, alprostadil is metabolized within the corpora and does not adversely affect the liver.
The other major side effect of intracavernous injection is fibrosis (which can lead to penile deviation, nodules, or plaque). To prevent fibrosis, routinely instruct men to compress the injection site for 5 minutes (up to 10 minutes in men taking an anticoagulant drug).
Pain is not an infrequent complication of intercavernosal injection therapy, particularly with prostaglandin. The pain tends to be an aching sensation, but most patients are able to tolerate it.
Another worrisome complication is scarring. All drugs have different cases of scarring. Prostaglandin tends to have the lowest instance of scarring, and some studies indicate that prostaglandin may actually protect the corporal smooth muscle from the development of scarring related to age. Papaverine has been associated with the most degree of scarring. This was initially thought to be related to the pH of the solution, and the occurrence is nearly 100 percent in some cases. Rare long-term side effects of scarring include curvature, similar to Peyronie's disease. Severe scarring may require a straightening procedure, much like the treatment for Peyronie's disease.
There is also a fairly high dropout rate from penile injections. Reasons include fear of the needle and medication costs. Although the treatment produces an excellent erection, it is not the ideal panacea and has drawbacks: the needle, the need for partner preparation, and frankly, the loss of spontaneity. This is probably the number one complaint from patients and their partners.
Intracavernous injection therapy is contraindicated in men with sickle cell anemia, schizophrenia or other severe psychiatric disorders, or severe venous leakage.
The other major contraindication would be an allergy to prostaglandin, papaverine, or Phentolamine. Patients who are at risk for priapism should be carefully counseled as well. Additionally, patients on anticoagulants for conditions that require thinning of the blood are advised to put extra pressure on the penis after an injection.
Finally, once the patient shows positive results with ICI therapy and after the initial injections are given in a hospital or clinic setting, he must then take the injections himself in these surroundings where medical help is instantly available. He then needs to self inject at home.
1) Hold the medication bottle so that your fingers do not touch the rubber stopper through which the needle is inserted.
2) Using a circular motion, wipe off the top of the vial with an alcohol swab.
3) Remove the needle cover. Do not allow the needle to touch anything prior to drawing the medication or before injecting the medication.
4) Draw an amount of air equal to the amount of medication to be injected into the syringe. Push the needle through the center of the stopper. Push the air into the bottle.
5) Turn the bottle and syringe upside down. Slowly draw the medication into the syringe. Tap the syringe gently to remove the bubbles.
6) Move the plunger in and out several times while gently tapping the syringe, thus removing all air bubbles.
7) Gently remove the needle from the vial and replace the cap. Remove the drawing needle and replace with the 30g injecting needle. Loosen the protective cap and place the filled syringe within easy reach prior to injection.
8) Use injection site as illustrated. This area is designated on the drawing with the crosshatch marks.
9) Locate the area of injection. Wipe off with an alcohol swab. Grasp the head of the penis, not the skin. Position the penis along your inner thigh. Maintain traction on the head after cleaning the side of the penis.
10) Grasp the syringe between the thumb and middle finger like a pen. Place the needle on the site of injection at a 90 degree angle. Push the needle in, gently but firmly, all the way down to the hub.
11) Shift your finger so that your index finger or your thumb can push in the plunger. Push the medication in slowly - over 8 to 10 seconds.
12) Remove the needle. Apply pressure with your index finger on the injection site and your thumb on the opposite side of the penis. Apply pressure for 2 minutes.