What Is Tri-mix & How Does it Work?

Erectile dysfunction (ED), the inability to achieve or maintain penile erection long enough for sexual activity, is a disorder that affects men primarily between the ages of 40 and 70. About 20 million men in the United States suffer from this condition, and this number is projected to increase to greater than 300 million by the year 2025.1 The standard first-line treatment for this condition is oral phosphodiesterase type 5 (PDE5) inhibitors such as Sildenafil and Tadalafil; these work by inhibiting the catabolism of cyclic Guanosine- 3', 5'- Monophosphate (cGMP) which leads to the relaxation of the corpus cavernosum inside the penis and consequently, penile erection.2

There are some individuals, however, who may not tolerate PDE5 inhibitors for any number of reasons or are poorly responsive to this class of medications. In these individuals an alternative option that has been used with promising results in the management of ED is Tri-Mix. Tri-Mix is considered to be a second-line medication used to treat ED in men for whom PDE5 inhibitors are not an acceptable option.

Components of Tri-mix

Tri-Mix is so named because it is a compounded drug comprised of a mixture of three drugs namely phentolamine, papaverine and alprostadil in varying concentrations. This drug is not readily available in traditional retail pharmacies but must be specially made at compounding pharmacies. The components of Tri-Mix have been shown to exert a synergistic effect in causing sustained penile erections in individuals suffering from ED. In contrast to the first-line drug treatment of ED, PDE5 inhibitors, which are administered orally, Tri-Mix is an injectable medication which is administered locally into the penis. This medication is typically compounded at dosages that are tailored to the requirements of each individual. Discussed below are more details about the components of Tri-Mix injection.

1) Phentolamine

Phentolamine belongs to the class of drugs known as alpha-adrenoceptor antagonists; they block the effects of epinephrine and norepinephrine on the alpha receptors in the human body. In the corpus cavernosum of the penis, norepinephrine and epinephrine cause vasoconstriction of the vessels, resulting in penile detumescence. Phentolamine blocks the alpha receptors such that epinephrine and norepinephrine can no longer bind with them and exert their vasoconstrictive effects; this assists in penile erection.34

Phentolamine has a rapid onset of action when administered by injection, ranging anywhere between 5 and 20 minutes, with its peak effect occurring about 10 minutes after its administration. It has a half-life of about 30 minutes and its effects typically last anywhere between 1 and 4 hours.

2) Alprostadil

Alprostadil, also known as Prostaglandin E1, is another drug that has been shown to be of benefit in the management of ED. It is a potent vasodilator, and it exerts its effect by dilating the vessels of the corpus cavernosum. When administered locally into the penis, it relaxes the smooth muscles of the corpus cavernosum and dilates the cavernosal arteries, thereby leading to penile tumescence. It is metabolized quickly, with over 80 percent of it being metabolized after circulating round the body just once. Additionally, it has a short half-life, lasting about 5 – 10 minutes.6

3) Papaverine

This is an alkaloid which has vasodilatory effects and smooth muscle relaxing effects in the human body. Similar to standard PDE5 inhibitors, it works by inhibiting the catabolism of cyclic Adenine Monophosphate as well as cyclic Guanosine Monophosphate; it also has an inhibitory effect on voltage-gated calcium channels. Through these mechanisms, the smooth muscles of the corpus cavernosum undergo relaxation, allowing for increased blood flow to this area, which can assist with penile erection.7

How Does Tri-mix Work?

As earlier stated, Tri-Mix is a compounded drug that works synergistically. Each of its individual components may have some effect in causing a penile erection. However, when these components are compounded together into one drug, they can enhance each other's positive effects. The combined effect of these drugs can be significantly greater than what each of them would have manifested by itself. Once injected into the penis, Tri-Mix may cause the relaxation, expansion, and filling of the corpus cavernosum with blood. This may result in satisfactory penile erections that lasts throughout the duration of sexual intercourse.8

Who Needs Tri-mix

Tri-Mix is a drug that is specifically made to be used only by men; there are no indications for its use in women. Even though its individual components may have a variety of therapeutic uses, as a compound drug Tri-Mix is only indicated in men who present with signs and symptoms of ED. Even so, individuals with ED should not consider using Tri-Mix right away. Patients should initially trial and fail traditional therapeutic methods such as PDE5 inhibitors to manage ED before exploring intracavernosal injection therapy.

There are two primary reasons that men with ED may consider using Tri-Mix:

•  They do not achieve satisfactory results using first-line therapy such as PDE5 inhibitors
•  They experience hypersensitivity or other reactions to PDE5 inhibitors

Injectable Tri-Mix has been shown to be efficacious in the management of ED. Studies have indicated that Tri-Mix has an approximate overall success rate of 80 – 90 percent.9

How Safe is Tri-mix?

Tri-Mix has been demonstrated to be generally safe to use by most men. This class of drugs has undergone extensive research and analysis since it was first developed over two decades ago. However, there are some groups of men who should exercise some caution before using Tri-Mix as their preferred treatment for ED. This group of men in whom the use of Tri-Mix may be absolutely or relatively contraindicated may include the following:

•  Men who have demonstrated hypersensitivity to any of the components of Tri-Mix
•  Men taking medications such as blood thinners or other medications that may affect blood clotting
•  Men who experience priapism (prolonged erections) or have medical conditions that may predispose to their developing priapism
•  Men who have a deformity with the anatomy of their penis
•  Men who have medical conditions such as leukemia, sickle cell anemia, or multiple myeloma
•  Active infections or open sores on the penis

There are no conclusive studies regarding the risks of administering Tri-Mix while taking oral ED medications. Generally, it is not advisable to take oral ED medications and Tri-Mix within 18 to 24 hours of each other to minimize the likelihood of developing significant side effects. Recommendations and advice from a health care provider should be obtained before taking these two classes of medications together.

How to Safely Store Tri-mix

To ensure that Tri-Mix does not quickly lose its potency and effectiveness, it should be stored under its labeled conditions. Lyophilized (freeze dried) Tri-Mix can be stored at room temperature. Once reconstituted, Tri-Mix should be stored under refrigeration. In its liquid form Tri-Mix should not be stored at room temperature as this may alter the stability and the potency of the drug. If traveling over long distances, liquid Tri-Mix should be stored in an ice pack, whereas it can be stored at room temperature if the drug is still in its powdered (lyophilized) state.

Tri-Mix is an odorless, colorless, and slightly yellow liquid. If the medication becomes cloudy-looking, or particles become present in the liquid, it should not be used further. If this occurs patients should have a discussion with their health care provider or pharmacist.

How to Self-Administer 

As has been mentioned previously, Tri-Mix is an injectable that can be self-administered locally into the penis. It may be injected up to three or four times a week but there must be an interval of at least 24 hours between injections. Even though some men may feel anxious or squeamish about self-injecting themselves, this is a relatively painless procedure if done properly with correct technique. Discussed below are the steps that are needed to safely self-administer the Tri-Mix injection.1011

•  Wash hands thoroughly with soap and water or an alcohol-based solution to maintain proper hygiene.
•  Wipe the top of the rubber stopper thoroughly with an alcohol pad.
•  Insert a syringe into the vial through the rubber stopper and draw out the prescribed amount of Tri-Mix into the syringe. Ensure that there are no air bubbles by tapping the syringe.
•  Find an injection site on the penis. Do not inject at the top or the bottom of the penis. Also avoid injecting directly into any visible veins or arteries on the penis, as well as along the midline. The optimal locations to administer the Tri-Mix injection are at the sides of the penis. Avoid using the same spot repeatedly for injections as this may result in the scarring of penile tissue.
•  Once an injection site has been found, thoroughly wipe it with a fresh alcohol swab.
•  Insert the needle into the penis and slowly depress the plunger to release the Tri-Mix medication into the corpora cavernosa of the penis. Remove and carefully dispose of the syringe when this completed.
•  Apply pressure to the injection site and massage the penis to ensure thorough distribution of the medication throughout the tissues inside the penis.

The effects of Tri-Mix become evident about 5 – 15 minutes after its injection into the penis as it induces a penile erection. Its duration action typically varies depending on the individual, ranging anywhere between half an hour to an hour. However, its effects should not last longer than 3 hours; the prescribing physician should be consulted immediately if the erection becomes prolonged.

Benefits of Tri-mix 

Compared to other drugs that are used in the treatment of ED, some benefits of using Tri-Mix injections include the following:

•  Effects manifest quickly and are long-lasting
•  Administration is simple and relatively painless
•  Studies have indicated that Tri-Mix has a high success rate

Side Effects  

Even though Tri-Mix can be a generally safe medication to administer, some men may experience some side effects with its use. Some side effects that may occur are:

•  Pain at the injection site which may occur if proper techniques are not followed while administering the injection. Topical anesthetics solutions may be used to reduce the likelihood of pain.
•  Bleeding may occur at the injection site if a vein is inadvertently punctured while administering the Tri-Mix injection.
•  Temporary swelling of the penis skin may occur if proper injection technique is not adhered to.
•  A prolonged erection, known as priapism, may occur. This requires prompt medical intervention as it is a medical emergency.

Where can Tri-mix be Obtained?

A prescription is required from a healthcare provider before Tri-Mix may be used. This medication is a compound drug that has to be specially prepared by a pharmacist at a compounding pharmacy or outsourcing facility. The ratio of the various components of Tri-Mix used in its preparation may vary depending on the needs of the individual and the prescription written by the healthcare provider. View our Tri-mix Injection Page for more details.

• 1. Bernie, H.L., Segal, R., Le, B., Burnett, A., Bivalacqua, T.J., "An Empirical vs Risk-Based Approach Algorithm to Intercavernosal Injection Therapy: A prospective Study". Sexual Medicine, vol.5 issue 1. March 2017. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302379/ 
• 2. Hatzimouratidis, H, "Sildenafil in the treatment of erectile dysfunction: an overview of the clinical evidence", Clinical Interventions in Aging, vol.1 issue 1, pp.403-414. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699643/ 
• 3. Traish, A.M., Moreland, R.B., Huang, Y.H., Goldstein, I., "Expression of functional alpha2-adrenergic receptor subtypes in human corpus cavernosum and in cultured trabecular smooth muscle cells", Receipt Signal Transduct, vol.7 issue 1, pp.55-67. Available: https://pubmed.ncbi.nlm.nih.gov/9285531/ 
• 4. Wespes, E., Rondeux, C.,"Effect of phentolamine on venous return in human erection", British Journal of Urology, vol.63 issue 1, pp. 95-97. January 1989. Available: https://pubmed.ncbi.nlm.nih.gov/2920269/ 
• 6. "Alprrostadil", Drug Bank. Available: https://go.drugbank.com/drugs/DB00770 
• 7. "Papaverine", Drug Bank. Available: https://go.drugbank.com/drugs/DB01113 
• 8. Sami, S., Stern, N., Pierdomenico, A.D., Katz, B., Brock, G., "Erectile Dysfunction: A Primer for in  Office Management", Medical Sciences (Basel), vol.7 issue 9, pp.90. September 2019. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780163/ 
• 9. Hanash, K.A., "Comparative results of goal oriented therapy for erectile dysfunction", Journal of Urology, vol.157 issue 6, pp.2135-2138. Available: https://pubmed.ncbi.nlm.nih.gov/9146600/ 
• 10. "Successful Self Penile Injection Hints, Questions and Answers", UCSF Medical Center: Your Health Matters. Available: https://urology.ucsf.edu/sites/urology.ucsf.edu/files/uploaded-files/attachments/successful_self_penile_injection_2.pdf 
• 11. "Penile Injection Therapy". Available: https://www.hopkinsmedicine.org/brady-urology-institute/patient-information/Penile_injection_teaching_tool.pdf