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Intracavernosal Injection

An intracavernous injection, according to the American Urologic Association, is the most effective non-surgical treatment for ED. Injections into the penis, unlike oral medications, trigger an automatic erection. Injection can be done by the individual 5 minutes prior to sexual activity and should last for no more than 1 hour. Injection is considered second line to be used if oral therapy fails. Compounds that can be injected include alprostadil, papaverine, and phentolamine. Alprostadil and phentolamine are the most common agents used as monotherapy. However, combination therapies are used to increase efficacy and decrease side effects. Combination therapy includes Tri-Mix and Bi-Mix. Both products are not commercially available and must be compounded by specialty pharmacies. Below is a description of the medications that are in Tri-Mix and Bi-Mix including mechanism, dose and side effects of each agent.
inteacavernosal injection

Despite the introduction of Viagra a few years ago and the recent FDA approvals of Levitra, Cialis and Avanafil, self-injection therapy remains a popular and very effective mode of therapy for erectile dysfunction (ED). Popularized in the early 1980′s, self-administered penile injections had an instant appeal as an alternative to the only available treatment at the time, the penile prosthesis. Although some men hesitate to think about placing a needle into their penis, and some defer their treatment to “think” about it, most men choosing injection therapy quickly realize that the benefit of the injection far outweighs that little pin-prick.

Safety of Intracavernosal Injections

A study evaluated the long-term efficacy and safety profiles of self-intracavernous injection of prostaglandin E1 (PGE1) for erectile dysfunction (ED). Four hundred and sixteen ED patients were treated with self-intracavernous injection of PGE1 from January 1998 to December 2007 in outpatient service. Follow-up was made to investigate the efficacy and side effects of this treatment. It was found that 261 patients (62.7%) felt satisfied and kept using this treatment due to its advantages of satisfactory efficacy and reasonable expense. Twenty-seven of them (6.5%) got rid of PGE1 treatment after five times injections and did not need any other drugs to maintain satisfactory sexual lives. Two hundred and fourteen (51.4%) patients kept using this treatment for over 1 year, 26 (6.2%) over 5 years, 12 (2.9%) over 8 years and 7 (1.7%) over 10 years. The major complications of self-intracavernous injection of PGE1 include fibrosis of corpus cavernosum (three cases), ecchymosis associated with vascular injury due to injection (23 cases) and pain associated with injection (295 cases). There were no patients displaying priapism. It is concluded that self-intracavernous injection of PGE1 is a safe and effective treatment for ED with various aetiologies and a broad range of severity, and no serious complications were observed after long-term application.

The original drug used for intracavernosal therapy was papaverine, a smooth muscle relaxant, often supplemented with phentolamine, an alpha adrenergic blocker. Neither is registered for treatment of erectile dysfunction in any country. Despite the wide ad hoc usage of these two drugs and their combination, there is little reliable information on their efficacy or safety. Indeed, there is doubt that these combinations are chemically compatible, stable or sterile under the usual circumstances of use. The main reason for the preference for prostaglandin E1 over the papaverine or papaverine/phentolamine combination is that these older drugs are believed to have a higher incidence of priapism and long-term penile fibrosis. The use of 3 or 4 drug cocktails represents shotgun therapy which is contrary to sound pharmacological principles

  • Alprostodil 

  • Commercially available alprostodil for monotherapy as Caverject® and Edex®
  • The FDA is considering appoving a new topical cream of Alprostodil called Vitaros.
  • Mechanism: a prostaglandin E1 that stimulates the relaxation of the smooth muscle and dilates arteries in the penis increasing blood flow
  • Studies have shown efficacy in 75% of men when injected into the penis
  • Usual dose: start at 10-15 mcg in patients who have failed oral therapy or 2.5-5 mcg in patients who have neurogenic or psychogenic ED and have failed or declined oral therapy
  • Median dose is 12-15 mcg. Benefit is not seen at doses greater than 40mcg. It is recommended to try a drug combination that includes papaverine, phentolamine or both. 
  • Side Effects
    • Priapism: prolonged erection lasting more than 4 hours- must seek medical attention
    • Penile pain- during or immediately after injection, occurs in up to 31%, may be reduced if mixed with other agents
    • Bruising at injection site- can be minimized with a 30G needle, should be minimal with proper injection technique 
    • Hypotension- occurs when drug leaks out of injected area into general circulation. Rare with alprostadil.
    • Fibrosis- scaring of penile tissue is lower with alprostadil, may result after long term use of injection therapy 
    • Occasional increase in liver function tests


  • Commercially available as Regitine®
  • Mechanism: alpha-adrenergic antagonist that produces a direct vasodilation in the arteries increasing blood flow to the penis.
  • Usual Dose: 1 to 2 mg
  • Side Effects
    • Painful prolonged erection lasting more than 4 hours
    • Fibrosis- penile scaring
    • Systemic hypotension (low blood pressure)
    • Reflex tachycardia (increase in heart rate)
    • Nasal congestion
    • Gastrointestinal upset


  • Not commercially available and must be used with phentolamine to produce hard erections.
  • Mechanism: Phosphodiesterase inhibitor that results in smooth muscle relaxation allowing for an increase in blood flow to the penis. It’s used mainly in combination with alprostadil and/or phentolamine. Although it has been used since the early 1980’s, it is not approved for ED.
  • Usual dose ranges from 5 to 30mg
  • Side effects
    • Priapism – high rate of 1-6%
    • Fibrosis-  highest rate and can present as a lump within the penis
    • Hypotension

Bi-Mix: Papaverine + Phentolamine

Bi-Mix was first introduced by a study in 1985 that showed a success rate of 71% amongst 250 patients that were given 1mg of phentolamine mixed with 30mg of papaverine. In 1987, 2 more studies were published. One study showed that phentolamine mixed with papaverine had a 72.9% success rate verse 20% with papaverine alone. In another study, papaverine mixed with phentolamine was examined for a follow up of 26 months. Only 13% of the patients failed to respond to therapy. Usual prescribed strength: Papaverine 6-25mg + Phentolamine 0.05-2.0mg/ml

Tri-Mix: Papaverine, Phentolamine, Alprostadil

Tri-Mix is a compounded medication the combine’s papaverine, phentolamine and alprostadil in one vial to achieve maximum efficacy, lower incidence of pain, and lower cost per dose. Studies have been done that have shown the efficacy of all three agents combined into one formulation. Combination therapy was first introduced in 1991 by Bennett and his colleagues who demonstrated a success rate of TriMix of 92% in 116 patients. Tri-Mix is often reserved for patients who fail alprostadil (PGE-1), fail Bi-Mix or for patients with severe penile pain from prostaglandin E1. Since Tri-Mix uses lower doses of alprostadil, penile pain often subsides. Usual prescribed strength: Papaverine 18-25mg + Phentolamine 1.0-2.0mg + Prostaglandin E1 10-25mcg/ml

Quad-Mix: Papaverine, Phentolamine, Alprostadil, Atropine

Quad-Mix includes the addition of atropine which may work synergistically to cause smooth muscle relaxation in the penis. In a study conducted by Israilov and colleagues, 13 patients that failed tri-mix had a positive response to quad-mix. Seven (53.8%) of the patients responded successfully with the addition of atropine. Usual prescribed strength: Papaverine 20-25mg + Phentolamine 1.5-2.0mg + Prostaglandin E1 20-25mcg + Atropine 0.02-0.08mg/ml

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