SELF-INJECTION THERAPY WITH VASOACTIVE DRUGS

Note:The following is given for informational purposes ONLY.
It is not meant to be used to do this to yourself.

This article deals with the proceedures to inject medication into a penis in order
to give the penis an erection that is medically induced instead of from normal means.
The proceedures on how to inject the medication can also be useful to anyone that
may need to do injections into a penis for other reasons as well.

Development:

The first paper on pharmacologically induced erections appeared in the late 1970s. Domer, Wessler, Brown, and Charles (1978) were studying the autonomic nervous system's role in bladder function and noted that erections resulted from the infusion of phentolamine, phenoxybenzamine, terbutaline, and salbutamol. Their study went unnoticed until several years later, when Brindley (1983) and Virag and his associates Olirag dr Virag, 1983; Virag, Erydman, Legman, Q Virag, 1984) independently published papers reporting that intracavemosal injection of phenoxybenzamine and papaverine induced erection. These findings led to the development of home self-injection programs, in which men were taught to inject themselves and given syringes and medication for home use (Althof et al., 1987; Nellans, Ellis, Kramer Levien, 1987; Nelson, 1989; Sidi, Cameron, Duffy, 6r Lange, 1986; Sidi, 1988; Trapp, 1987; Zorgniotti & Lefleur, 1985).

Clinical investigations of intracavemosal injection have focused primarily on four medications: (1) phenoxybenzamine hydrochloride, (2) papaverine hydrochloride, (3) phentolamine mesylate, and (4) prostaglandin E, Other agents also reported to induce erection are vasoactive intestinal peptide, theophylline, thymoxamine, imipramine, verapamil, moxisylate, and nitroglycerlne (Brindley, 1983, 1986; Buvat, Lemaire, Buvat-Herbaut, QMah : colin, 1989; Lue 6t Tanagho, 1987; Virag, 1985; Willis, Ottesen, Wagner, - Sundler, 6r Fahrenkrug, 1981).

Phenoxybenzamine is an alpha-adrenergic blocking agent not available in the United States. Although it was one of the first drugs discovered to induce erection, it was painful to inject, was slow to produce turgidity, and resulted in penile enlargement for up to3 days (Brindley, 1983, 1986).

Papaverine, a smooth muscle relaxant, was less painful to inject and induced erection more rapidly and for a shorter duration than phenoxybenzamine. Zorgniotti and Leneur (1985) later showed that a combination of papaverine and phentolamine, an alpha-adrenergic blocker, was superior to papaverine alone. Most clinicians employ a combination of 15-60 mg of papaverine with 0.5-2 mg of phentolamine. A moderate erection is usually evident within 15 minutes. Turgidity further increases with sexual stimulantion, resulting in an erection that lasts for 1-4 hours (Kursh et al., 1988).

Prostaglandin E, is a smooth muscle relaxant. The first clinical trials in humans were performed independently by Ishii et al. (1989) and by Virag : and Adaikan (1987). The accepted dose levels range between 5 µg and 20 µg. µg.

Method of Action:

Papaverine relaxes the arterial and trabecular smooth muscles by inhibiting oxidative phosphorylation, blocking cyclic adenosine monophosphate phosphodiesterase, and interfering with calcium flow during muscle contraction; this increases arterial inflow and corporal veno-occlusion (Krane, Goldstein, i: Q Saenz de Tejada, 1989). It also has an antinicotinic effect on ganglionictransmission (Poch & Kubovetz, 1971; Bauer 6r Capek, 1972).

Phentolamine induces smooth muscle relaxation by blocking the alphaadrenergic receptors on cell membranes. Sexual stimulation enhances, and anxiety interferes with, the efficacy of these medications.

The mode of action of prosmglandin E, is less clear. It is thought to exert an inhibitory effect on adrenergic receptors by preventing norepinephrine release, thereby relaxing the smooth musculature (Waldhauser 6r Schramek, 1988).

Indications for Use:

Self-injection of vasoactive substances should be considered a first-line treatment for mixed, idiopathic, and organic erectile dysfunctions. It is not the treatment of choice for psychogenic impotence.

Medical-Legal Issues:

Neither papaverine, phentolamine, nos prostaglandin E1, has been approved for treating erectile dysfunction by the Food and Drug Administration (FDA). Because there is little financial incentive, it is unlikely that drug manufacturers will seek FDA approval. What this means for the clinician is not entirely clear. There is some risk involved in using a medication that goes beyond the FDA approved indications. However, what stands in the clinician's favor is a considerable body of literature that documents the efficacy and relative safety of the drugs. To minimize risk of litigation, many clinicians have their patients sign a consent form that clearly details the risks and benefits of self-injection therapy. A patient's spouse can also sign a separate form, stating that she is aware that her partner is undergoing this treatment and that she has been apprised of the gains and limitations of self-injection.

Trial Dose Procedure:

Treatment begins with the trial dose procedure. The patient comes to the doctor's office to receive physician-administered injections. At each visit, the dose of medication is increased until either the man has a satisfactory erection, or the maximum dose-fails to induce an adequate result.

The first trial dose is limited to 15 mg of papaverine. If the response is poor, a second injection of 0.5 mg of phentolamine is given during this first office visit. Thereafter, the following schedule of dose increases is often used: 30 mg papaverine and 0.5 mg phentolamine; 30 mg papaverine and 1 mg phentolamine; 30 mg papaverine and 2 mg of phentolamine; 45 mg papaverine and 1.5 mg phentolamine; 45 mg papaverine and 2 mg phentolamine; 60 mg papaverine and 1 mg phentolamine; and the ceiling dose, 60 mg papaverine and 2 mg phentolamine. Although some clinicians go beyond these dosage levels, our experience suggests that other options should be considered when the patient fails to respond at 60 mg of papaverine and 2 mg of phentolamine (Kursh et al., 1988).

Patients with neurogenic erectile dysfunction have denervation hypersensitivity to these medications and are at risk for developing prolonged erection. Therefore physicians often begin the trial dose procedure with less than 7.5 mg of papaverine.

Injections are given at the base of the penis at the 3 o'clock or 9 o'clock positions (posterolateral, away from the neurovascular bundle and urethra), using a disposable I-mi insulin syringe and a 26- or 27-gauge needle. Holding the syringe perpendicular to the penis, the patient inserts the needle through the tough tunica albuginea into the left or right corpus cavernosum (Figure 11.1). A popping is usually heard and felt as the needle passes

FIGURE 11.1. Illustration of intracavemosal injection. through the tunica into the corpora. The needle is withdrawn slightly and the medication is slowly injected. Some physicians suggest that a toumiquet be tied around the base of the penis prior to injection to reduce the venous outflow, thereby increasing the local concentration of the injected material (Sidi & Reddy, 1990).

Patients' psychological responses to the trial dose phase warrant careful attention. Because injections need to be used within 30 minutes of inter- course, and several visits to the clinic are often necessary to establish the proper dose, this may be a frusuating time for couples. Some manage these frustrations with grace, humor, and creativity; these patients joke about how they would respond to the proverbial policeman's question,'What's the hurry!", if caught speeding on the way to a motel. Others, however, are demoralized.

Case Vignette:

One couple was in the midst ofuial dosing at Christmas time. They planned to go from our offices in midtown Cleveland to a downtown hotel. Although the man had a good erection when the couple left the office, it unfortunately subsided on the way to the hotel. When asked at the next visit how things went, the wife vented her frustration by saying, "Let's put it this way, it was no miracle on 34th Streetl"

After determining the proper dose, the patient is taught how to use sterile technique, how to draw up medication, and where and how to inject himself. This process is usually accomplished in 1 hour by a nurse educator. Should the patient be unable or unwilling to inject himself the partner is invited to learn the technique. Once the nurse educator is satisfied that the patient and/or his partner can safely inject the drug, they are given a 1 month supply of medication and syringes.

Efficacy:

Self-injection of papaverine and phentolamine has been employed as a means of temporarily reversing erectile dysfunction that is due to neurogenic, vasculogenic, hormonal, and psychological factors. This alternative is most effective for patients with neurogenic problems, such as those with spinal cord injuries (Bodner, Lindan, LeMer, Kursh, & Resnick, 1987; Sidi, Camcron, Dykstra, Reinberg, & Lange, 1987); it is least effective in men with severe corporal veno-occlusive dysfunction and/or anerial insufficiency Krane et al., 1989).

We prospectively studied 42 patients who completed 1 year of self-injection with papaverine and phentolamine (Althof et al., 1987, 1991). Follow-up appointments with each patient and partner (when available) were scheduled for 1, 3, 6, and 12 months after beginning self-injection. The men injected themselves an average of five times per month; 83% of the injections produced satisfactory erections. It was difficult to discern all the factors that produced the 17% failure rate; the primary explanations appeared to be poor injection technique, outdated phentolamine (i.e., phentojlnmine that was constituted in solution more than 60 days prior to use), worsening vascular disease, and tachyphylaxis (i.e., lessening effectiveness time of the same dose because of enhanced metabolism). When pretreatment and postinjection sexual functioning were contrasted, there were stistically significant improvements in the frequencyof intercourse frequency of orgasm, and sexual satisfaction. These positive gains were evident at 1 month and persisted throughout all follow-up visits.

The efficacy of intracavemosal prostaglandin E1 was studied by Ishii et al. (1989), who reported that 62% of men achieved complete erection, 24% achieved incomplete erection, and 14% had poor responses. Waldhauser and Schramek (1988) compared erectile response to papaverine and entolamine with the response to prostaglandin E1 and found protaglandin E1 to be more effective. Reiss (1989) demonstrated that prostaglandin E1 'produced erections in men who failed to achieve or maintain a good response to papaverine.

Side Effects:

Seven potential side effects have been associated with self-injection therapy: (1) prolonged erection (priapism), (2) fibrotic nodules, (3) liver function abnormalities, (4) bruising, (5) vasovagal episodes, (6) pain, and (7) infection.

Prolonged erection from inuacavemosal injection of papaverine and/or phentolamine has occurred during the trial dose phase in 2.3% to 15% of patients (Zentgraf, Ludwig, & Ziegler, 1989). "Prolonged" is defined as continuing for more than 4 hours. Priapism occurs infrequently during home self-injection, usually because a patient experiments with his medication levels. This side effect has been reported to occur less frequently with prostaglandin E1 (Krane et al., 1989). Men with neurogenic erectile dysfunctions are most susceptible to prolonged erection. Patients are advised to return for intervention if an erection persists beyond 4 hours. Intracavernosal injection of an alpha-adrenergic receptor agonist, such as phenylephrine or epinephrine, often reverses the erectile response. If this is not effective, surgical intervention may be required.

There has been considerable variation in the reported incidence of fibrotic plaque or nodule development with papaverine and/or phentolamine. The lowest estimate is l.5% (Padma-Nathan, Goldstein, & Krane, 1986), whereas the highest is 60% (Levine et al., 1989). Krane et al. (1989) reported a lower incidence of nodule development with prostaglandin E1.

Although the origin of plaques is unknown, investigators speculate that they may be related to the low pH of papaverine, high frequency of injectic number of months on self-injection, and/or faulty injection technique et al, 1989). Clinicians are concerned that plaques may lead to a Peyronie-like penile curvature. When this occurs, cessation of self-injection is recommen Also, corporalfibrosis makes later implantation of a penile prosthesis difficult These plaques may disappear once treatment is stopped.

The incidence of reported liver function abnormalities associated papaverine and/or phentolamine varies from 0.4% (Zentgraf et al., 1989) 40% (Levine et al., 1989). In Levine et al.'s (1989) study, 40% of men had at least one abnormal value in serum glutamic-oxaloacetic transaminase, bilirubin, lactate dehydrogenase, or alkaline phosphatase. None of these patients had symptoms of hepatic disease. Because papaverine is considered potentially hepatotoxic, liver function values should be monitored while patients inject themselves (Direman, 1973). No research studies have linked prostaglandin Fl to liver function abnormalities.

From 25% to 50% of men have developed bruising, hematomas, or ecchymosis (Girdley, Bruskewitz, Feyzi, Graversen, & Gassner, 1988; Levine et al., 1989). These symptoms are usually the results of poor injection technique and do not require medical intervention.

Orthostatic hypotension has developed in 296 of patients injecting with papaverine and/or phentolamine (Sidi et al., 1986). A lower incidence of vasovagal symptoms is reported with prostaglandin E1.

Pain is an infrequently reported occurrence with papaverine and/or phentolamine. With prostaglandin E1, however, 7596 of patients report significant pain and burning during injection and while erect (Krane et al., 1989; Waldhauser & ek, 1988).

Although infection is uncommon, it is most often associated with reusing needles. The life-threatening development following intracavernosal injection of 'paverine has been reported by Hashmat and Abraham (1987). One of their patients developed a pulmonary embolism following infection secondary to prolonged erection.

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