Erectile Dysfunction (ED)

It is estimated that over 18 million men in the United States experience erectile dysfunction (ED), with most cases occurring in men older than 40, though it can happen at any age. ED can often result from medical conditions such as diabetes, low testosterone, high blood pressure, or an enlarged prostate. Additionally, prostate surgery can cause ED due to nerve damage or other physical trauma. Lifestyle factors like smoking, alcohol use, and certain medications, as well as stress or anxiety, can also contribute to ED. Fortunately, ED is treatable regardless of its cause. While oral medications such as Viagra or Cialis work for some men, others may not respond to them or may experience uncomfortable or dangerous side effects. In these instances, custom-compounded medications are often used to treat ED effectively. Injectable drugs such as Papaverine, Phentolamine, Alprostadil (Prostaglandin E1), or Atropine, individually or in combination, are effective treatments. While injections may seem daunting, the procedure involves minimal discomfort and is highly effective for treating ED.

Orally Disintegrating Tablet (ODT)
Injectable ED Ingredients

Papaverine is a known smooth muscle relaxant and vasodilator, working primarily as a non-specific dilator of small blood vessels. Its main side effects, such as priapism and tissue fibrosis, are significantly reduced when used in low doses or combined with other drugs like phentolamine and alprostadil.

Phentolamine can increase the release of norepinephrine, a stress hormone. When used for ED treatment, phentolamine is often paired with other drugs like papaverine to boost effectiveness, and studies show this combination induces erections sufficient for intercourse in over 90% of cases.

Alprostadil (Prostaglandin E1) relaxes smooth muscle via cAMP activation after binding to PGE receptors. Its rapid breakdown in the lungs likely explains why it doesn’t cause significant cardiovascular side effects when injected into the penis. It can also be metabolized locally in the penis.

Alprostadil is available as an intraurethral pellet (MUSE), gel, or injection, with research showing the injectable form to be more effective. Atropine is a non-selective muscarinic receptor antagonist that works by blocking acetylcholine receptors, which are involved in muscle contraction and relaxation. In the penis, this blockage helps relax blood vessels and promote erections. While not highly effective alone, atropine can reduce pain caused by PGE1 when used in combination therapies.

Injectable ED Medications

  • BiMix: A mixture of Papaverine and Phentolamine
  • Super BiMix: A more potent formulation of the traditional BiMix injection
  • TriMix: A combination of Papaverine, Phentolamine, and Prostaglandin E1
  • Super TriMix: A higher concentration of the regular TriMix injection
  • QuadMix: Super TriMix with the addition of Atropine
  • Super QuadMix: A stronger version of the regular QuadMix injection
  • Custom combinations and concentrations available

Multiple strength combinations of Tri-Mix are available:

  • Papaverine 30mg/mL, Phentolamine Mesylate 1mg/mL, Prostaglandin E1 10mcg/mL. 5 mL vial. Lyophilized.(30-1-10)
  • Papaverine 30mg/mL, Phentolamine Mesylate 2mg/mL, Prostaglandin E1 20mcg/mL. 5 mL vial. Lyophilized. (30-2-20)
  • Pharmacologic Category: Anti-erectile dysfunction preparation: vasodilator, prostaglandins, & alpha-adrenergic receptor antagonist.

General Information

TRIMIX is administered as a self-injection into the penis and is often regarded as one of the most potent treatments for erectile dysfunction. While its individual components—Papaverine, Phentolamine, and Prostaglandin E1 (PGE1)—are used to treat various other conditions, combining them has become a standard approach in sexual medicine. TRIMIX is commonly used when traditional PDE5 inhibitors, such as Viagra or Cialis, are either ineffective or unsuitable for the patient.

Indications: TRIMIX is prescribed for the treatment of erectile dysfunction in men. It combines three drugs from different therapeutic classes that work together synergistically and are mixed into a sterile injection. These drugs are:

  • PAPAVERINE: A vasodilator that promotes the expansion of blood vessels, facilitating increased blood flow to the penis, thereby enabling an erection. It stimulates the production of cyclic adenosine monophosphate (cAMP) by interacting with adenylate cyclase, which relaxes penile smooth muscle and enhances erectile function. Papaverine was among the earliest effective injectable treatments for erectile dysfunction. Its mechanism of action is complex and not fully understood, as it inhibits phosphodiesterase nonspecifically and acts through various other pathways that may be dose-dependent. Research has shown that Papaverine relaxes penile arteries, cavernosal sinusoids, and veins. Studies in dogs indicate that it reduces resistance to arterial inflow while increasing resistance to venous outflow, a finding confirmed in clinical studies. This suggests that Papaverine may work through a veno-occlusive mechanism to improve erectile function.
  • Biweekly Intracavernosal Administration of Papaverine for Erectile Dysfunction
  • Participants: 50 men aged 40 to 70
    • Administration: Injection directly into the penis
    • Dosage: 60 mg of Papaverine in 5 ml of saline, administered every two weeks
    • Results: All but one participant achieved an erection at 80% or more of normal capacity, significantly improving sexual potency.
  • Medical treatment of impotence with papaverine and phentolamine via intracavernosal injection
  • Participants: 20 men aged 32 to 72
    • Administration: Injection directly into the penis
    • Dosage: 30 mg of papaverine and 1 mg of phentolamine
    • Results: Erection occurred within 20 to 30 minutes, with 18 out of 20 participants achieving an erection sufficient for intercourse.
  • Treatment of impotence using intrapenile injections of papaverine and phenoxybenzamine: a double-blind, controlled trial
    • Participants: 39 men aged 27 to 67
    • Administration: Intracavernosal injection
    • Dosage: 60 mg of papaverine in 10 ml saline
    • Results: 35% of patients experienced full restoration of erectile function, while 65% showed partial restoration.
  • Evaluating erectile dysfunction: oral sildenafil vs. intracavernosal injection of papaverine
    • Participants: 39 men aged 21 to 65
    • Administration: Intracavernosal injection
    • Dosage: 30 mg of papaverine
    • Results: Papaverine was shown to be effective, improving both penile length and circumference, making it a viable injection therapy for erectile dysfunction.
  • PHENTOLAMINE: When injected into the penis, phentolamine promotes erection by relaxing and dilating the penile blood vessels while also increasing cardiac output.
    • Phentolamine is classified as an Alpha-Adrenoceptor Antagonist. Noradrenaline regulates the smooth muscle tone in the penile tissue, keeping the corpora cavernosa contracted. By blocking the effects of noradrenaline at the Alpha-Adrenoceptor, phentolamine allows for an erectile response. It competes with norepinephrine for binding at Alpha1 and Alpha2 adrenoceptors, with similar affinity for both. This mechanism is considered the primary way phentolamine produces its physiological effects. Additionally, phentolamine blocks 5-HT receptors, triggering histamine release from mast cells. Some studies also suggest that phentolamine may activate NOS (nitric oxide synthase), further enhancing vasodilation.
    • The role of phentolamine as an Alpha-Adrenoceptor Antagonist is considered complex. Its non-selective receptor-blocking action involves interactions with adrenergic nerves, which have not been fully understood. There may be counteracting regulation between pre- and post-junctional nerves, although how this affects phentolamine’s efficacy in treating erectile dysfunction remains unclear.
    • Animal studies have shown that phentolamine decreases penile arterial inflow resistance, indicating that its physiological action supports erectile response. However, human studies have not demonstrated a significant effect on venous outflow from penile tissues. Additionally, the pharmacokinetics of phentolamine remain under-researched.
    • Oral administration of phentolamine is not effective for treating erectile dysfunction due to its first-pass metabolism, which reduces its potency. For this reason, phentolamine must be injected. It has a half-life of 30 minutes, with effects lasting between 2.5 and 4 hours. Following a penile injection, the serum concentration of phentolamine peaks within 20 to 30 minutes before being quickly metabolized.
    • Side effects of phentolamine are rare, but cases of orthostatic hypotension, tachycardia, arrhythmias, and myocardial infarction have been reported after penile injections. Scientific studies have not clearly explained the specific mechanisms behind these side effects. Phentolamine is typically combined with papaverine or vasoactive intestinal peptide to enhance erectile response.
  • Medical treatment of impotence using papaverine and phentolamine via intracavernosal injection
    • Participants: 20 men aged 32 to 72
    • Administration: Intracavernosal injection
    • Dosage: 30 mg papaverine and 1 mg phentolamine
    • Results: Erection occurred within 20 to 30 minutes, and 18 out of the 20 participants achieved an erection sufficient for sexual intercourse.
  • Prostaglandin E1 (Alprostadil): A powerful hormone-like compound that promotes erection by relaxing the blood vessels in the penis and widening the cavernosal arteries. This dilation increases arterial blood flow into the penis while simultaneously enhancing venous outflow resistance, allowing more blood to enter the penis and reducing the amount of blood leaving.
    • Prostaglandin E1 is administered via intracavernosal injection and is typically prescribed as a second-line treatment for erectile dysfunction, especially when oral PDE5 inhibitors have been ineffective. Studies indicate that between 40% and 70% of men with erectile dysfunction respond to prostaglandin E1 treatment. The reason for non-responsiveness in some patients has not been fully explained. However, research suggests that combining prostaglandin E1 with S-nitroso glutathione may improve efficacy for those who do not respond to the drug alone.
    • In cases where patients fail to respond to prostaglandin E1, medications that activate additional relaxation pathways may be necessary, as smooth muscle relaxation is essential for erectile function. Combining prostaglandin E1 with other agents, such as S-nitroso glutathione or other erectile dysfunction treatments, might offer enhanced therapeutic benefits. When injected into penile tissue, prostaglandin E1 is quickly metabolized into compounds that promote erectile function, amplifying its effectiveness. Prostaglandin E1 has also been shown to modify noradrenaline concentrations, adding another mechanism to its action. However, its primary function is thought to be through increased cAMP synthesis via EP receptor interaction, which induces muscle relaxation.
    • Prostaglandin E1 has widespread effects on the body, influencing systemic processes such as vasodilation, preventing platelet aggregation, and stimulating intestinal activity. Due to these effects, it is rarely administered for a systemic response. While pharmacokinetic data on prostaglandin E1 is limited, studies suggest it has a short duration of action and a high rate of metabolic breakdown, with 70% of the drug metabolized during the first pass through the lungs. Because prostaglandin E1 is metabolized rapidly throughout the body, its effects are mostly localized to penile tissues, which may explain the rarity of systemic circulatory side effects.
    • Reasons to avoid this medication: Avoid using it if you have an allergy or sensitivity to any ingredients. Additionally, do not take it if you have conditions that increase the risk of priapism (a prolonged and painful erection lasting over 4 hours), such as sickle cell anemia, multiple myeloma, or leukemia. Avoid this medication if you have anatomical deformities of the penis or penile implants or if your doctor has advised against sexual activity.
    • Important warnings before use: Inform your doctor if you have any conditions or are taking medications that may affect your blood clotting ability.
    • Precautions when using this medicine: Provide your healthcare provider with a complete list of any medications, herbal supplements, over-the-counter drugs, or dietary supplements you use, as some may interact with this treatment.
    • How to properly take this medication: It’s best to administer the injection just before engaging in sexual activity. The injection is given directly into the penis (intracavernosal), usually taking effect within 5 to 20 minutes and lasting up to an hour. To avoid bruising, apply firm pressure at the injection site for five minutes afterward. The Tri-mix injection should not be used more than twice a week, and there must be at least 24 hours between doses. Remember that needle breakage is possible, so follow your doctor’s instructions carefully. If the needle breaks during injection, contact your doctor immediately.
    • What to do if you miss a dose: Do not take an extra or double dose. This medication should only be administered 5 to 20 minutes before intercourse.
    • Possible side effects: You may experience mild to moderate pain during the injection or a painful erection, as well as some minor bleeding at the injection site. If you notice redness, swelling, lumps, tenderness, or curvature of the penis during an erection, contact your doctor. If your erection lasts longer than two hours, you may take 2 to 4 pseudoephedrine (30 mg) tablets orally and apply an ice pack. If the erection persists for more than another hour, seek immediate medical help, as erections lasting over six hours can cause serious damage to penile tissue.
    • Storage instructions: Once mixed, this medication is not stable at room temperature and should be stored in a refrigerator at 2°-8°C (36°-46°F). The medication’s potency may decrease if not stored properly, though no harmful chemicals will be produced. Ensure the medication is kept out of the reach of children. Discard any unused medication after its expiration date, and do not dispose of it by flushing or pouring it down a drain.