Intracavernosal injection (ICI) therapy is the injection of a medication into the corpus cavernosum tissue in the base of the penis to treat Erectile Dysfunction (or ED). ICI has been shown to be effective in ED caused by various medical conditions including psychogenic, neurogenic or vascular causes.
ICI helps induce an erection by injecting medications that cause smooth muscle relaxation (known as vasoactive agents) and is usually reserved for male patients who have ED and who have not had an adequate response to oral treatments with phosphodiesterase five inhibitors (PDE5-inhibtors) such as sildenafil or tadalafil (1).
The injection is performed with a small 26-30 gauge ½ inch needle (similar to what diabetic patient’s use for injecting insulin under the skin) and is usually easily performed by the patient.
Success rates with ICI are generally 60-70% but can reach 90% (2) in appropriately selected patients and what is interesting, is that when it comes to performance anxiety related ED, studies have shown that short term use of ICI can not only improve erectile function and sexual performance, but in fact, can result in resumption of normal erectile function without the need for ICI after a short course or 1 to 2 injections (3).
Adverse effects can occur and generally are dose related. Mild penile pain is the most common adverse effect, but rarely is this severe. Bleeding and fibrotic changes/plaques are rare. Prolonged erections occur in roughly 5% of cases and priapism (an erection lasting > 4 hours) is generally observed in < 2% of cases (REF 4).
Injections cannot be administered more than once in a 24-hour period and generally it is not advised to administer the injection more than three times a week. All penile injections, whether approved versions of alprostadil, or compounded forms such as Bimix or Trimix, also increase the risk of penile plaque formation which can increase with greater usage over time. This risk is low (<5%) but needs to be considered.
Appropriate counseling of injection technique and oversight over dose selection and titration by trained professionals, is key to reducing the risk of adverse effects with ICI. The vast majority of patients treated with ICI can achieve a good result in terms of erectile and sexual function without encountering significant side effects.
One important point to note, is that the ICI’s should not be used in conjunction with oral PDE5-inhibitors. Your prescribing doctor will likely suggest not using ICI within 24 hours (either before or after) of using sildenafil (Viagra), vardenafil (Levitra) or avanafil (Stenda) and 72 hours (either before or after) of using tadalafil (Cialis).
What is alprostadil?
Prostaglandin E1 (alprostadil) is the only FDA-and Health Canada-approved treatment for penile self-injection (Caverject, Edex) (1, 2).
Alprostadil and Caverject act by dilating the blood vessels in the penis, engorging the penis locally, which in turn constricts the blood vessels (veins) that normally drain blood from the penis. It is this combination of the increased inflow and reduced outflow of blood that leads to and sustains an erection.
Alprostadil typically takes 10-30 minutes to work and doctors generally advise injection 10-20 minutes prior to sexual activity. Erection duration is often dose dependent, and in some cases, may last up to an hour or longer. If erections last for 4 or more hours, the condition is termed priapism and requires urgent medical attention.
What is Caverject and what is Edex?
Two forms of alprostadil exist in North America, Caverject and Edex.
Caverject (1) is available in vials of 20 and 40 micrograms. Dosing is generally initiated at 2.5 micrograms and titrated upwards based on response. If response is partial, typically, titration is with a dose increment of 2.5 micrograms limiting injections to one per 24 hours and no more than 3 times per week. It is generally not recommended to use doses that exceed 40 micrograms and each injection requires use of a new vial to reduce risk of infection. Injections are delivered over 5-10 seconds. Strict cleaning and injection technique needs to be adhered to and must be learned prior to injection.
Edex (2) is available in vials of 10 micrograms. Dosing is generally initiated at 2.5 micrograms and titrated upwards based on response. If response is partial, typically, titration is with dose increments of 2.5 micrograms limiting injections to one per 24 hours and no more than 3 times per week. It is generally not recommended to use doses that exceed 10 micrograms and each injection requires use of a new vial to reduce risk of infection. Injections are delivered over 5-10 seconds. Like Caverject, strict cleaning and injection technique needs to be adhered to and must be learned prior to injection.
Dose selection and titration may differ depending on the prescribing MD, but it is quite typical to start at a low dose which may not result in full effect and titration to a dose that allows a good effect while still being well tolerated.
Does alprostadil work?
ICI with alprostadil can be extremely effective with good erection quality and duration achieved in over 60% and even up to 90% of cases (3, 4). Almost 90% of partners have also been reported as being satisfied with the results of alprostadil (4).
Side effects of alprostadil:
While ICI injection with alprostadil can be a very effective form of treatment, disadvantages of penile self-injection do exist. Some of the more common disadvantages or side effects include dislike of the procedure, need for a sterile technique, penile pain, risk of bleeding and a ~5% risk of priapism (defined as a sustained erection > 4 hours and generally considered a medical emergency requiring medical intervention). All penile injections, whether approved versions of alprostadil, or compounded forms such as bimix or trimix, also increase the risk of penile plaque formation which can increase with greater usage over time. This risk is low (<5%) but needs to be considered.
How is alprostadil injected?
Before injecting alprostadil, attention needs to be paid to ensuring a clean/sterile site. Your prescriber or health care nurse will teach you how to prepare the area. Injection technique is also important with injection delivered in the base of the penis into the corpus cavernosum. Injections need to be administered slowly over 5-10 seconds and cannot be administered more than once in a 24-hour period. Generally it is not advised to administer the injection more than three times a week.
Trimix vs. Alprostadil
What is Bimix and what is Trimix?
Sometimes, physicians will want to prescribe an injectable form containing two (bimix) and sometimes three (trimix) active ingredients for the treatment of ED.
Bimix includes the active medications phentolamine (an alpha blocker) and papaverine (a vasodilator).
Trimix includes these two active ingredients plus alprostadil (prostaglandin E1).
These combination injectable treatments have not gone through the regulatory process, are not approved for the ED indication and are therefore prescribed “off label”, requiring a physician prescription and a pharmacy to compound the medication.
One might ask “why use trimix or bimix”? These combination compounded versions are used over the single alprostadil form as they tend to offer improved efficacy and also provide a good ability to titrate the dosage to get to the best efficacy safely (REF 1). The combinations of two (Bimix) or three (Trimix) medications increase the degree of vasodilation (dilation of the blood vessels) in the penis allowing blood to flow in, initiating and sustaining a better erection.
Of course as with any stronger medication, the risk of adverse effects might be higher. The addition of papaverine for example has been reported to increase the risk of priapism from 5 to ~10%.
How do I inject Caverject, Edex, Bimix or Trimix?
Following instructions from your prescriber is essential to ensure the safest and most effective outcome with your intracavernosal injection of any of the injectable products available including Caverject, Edex, Bimix or Trimix.
The multiple steps can appear quite daunting initially, but men can generally learn the technique rapidly and application can thereafter be smooth and successful.
Technique for injecting Caverject can be found here:
https://labeling.pfizer.com/ShowLabeling.aspx?id=590&Section=IFU
Technique for injecting Edex can be found here:
https://www.edex.com/assets/pdf/patient_brochure.pdf
There are numerous excellent academic websites that also detail the injection technique for any intracavernosal injection (ICI) including for alprostadil (Caverject, Edex), Bimix or Trimix. A few examples are found here:
https://www.mskcc.org/cancer-care/patient-education/penile-injection-therapy
https://www.ucsfhealth.org/education/patient-guide-to-penile-injections
What are the risks of alprostadil, bimix, and trimix?
Risks and side effects of injection with alprostadil, trimix or bimix include bruising, bleeding, penile pain, rash, swelling, plaque, Peyronie’s disease, priapism.
Side effects are generally dose related and therefore titration from a lower starting dose is always recommended.
The most common adverse effect is penile discomfort or pain at or close to the injection site. This can be seen in up to 50% of injections and is usually mild and transient (1).
The most severe side effect, which again is generally dose related, is priapism, defined as an erection > 4 hours and requiring urgent medical attention and in many cases, surgical intervention. Untreated priapism increases the risk of longer term fibrosis or scarring of parts of the penis. This in turn has the potential to impact erectile function. Priapism is generally reported anywhere between 1-5% of cases.
Attention to maintaining a sterile field and to injection technique combined with a cautious dosing regimen starting at a low 2.5 microgram dose and titrating in small dose increases, can in most cases result in an effective and well tolerated treatment with high satisfaction scores in the men who inject and in their sexual partners as well.
When should men consider injectables for ED?
Intracavernosal injection therapy (ICI) has been available for almost 50 years for the treatment of erectile dysfunction (ED). These injections include single agents (alprostadil) and combination agents with papaverine or phentolamine (Bimix) or combined with alprostadil (Trimix). Bimix and Trimix are not FDA or Health Canada approved and are therefore used “off label”. All these injectable medications require physician prescription and in the case of Bimix and Trimix, also require pharmacy compounding.
The agents are not considered first line treatment for ED. They do not replace the use of phosphodiesterase 5-inhibitor (PDE5-inhibitors) such as sildenafil, tadalafil, vardenafil or avanafil. ICI is used in cases where PDE5-inhibitors are not effective or sufficiently effective to support satisfactory sexual activity. Difficult to treat ED is not uncommon and is due to various factors, including psychogenic (stress, sleep deprivation, depression, general or performance anxiety), vascular (ischemia, smoking, hypertension, diabetes), neurologic (eg spinal cord injuries or conditions such as MS) or a combination of factors.
Injectable treatment is not used first line in circumstances of low libido. Low libido is different from ED and often requires medical treatment including with testosterone replacement if clinically indicated. Men with low libido have lost interest in sexual activity for various reasons. Men with low libido may still have satisfactory erections. On the contrary men with ED, don’t generally have low libido and can feel sexual desire but are not able to initiate or sustain an erection to support satisfactory sexual performance. Injectables can certainly be helpful in men with lower libido who have ED and in these cases, can help in improving sexual performance.
Injectable treatment needs to be conducted under medical supervision initially. Patients need to learn the appropriate technique to optimize safety and efficacy. Injections should not be used more than once per 24-hour period and should not be used more than 3 times per week.
References:
Intracavernosal Injection for the Diagnosis, Evaluation, and Treatment of Erectile Dysfunction: A Review. Belew D et al., Sex Med Rev. 2015 Mar;3(1):11-23. Epub 2015 Oct 19 - https://pubmed.ncbi.nlm.nih.gov/27784568/
A review of outcomes of an intracavernosal injection therapy programme. Coombs PG et al., BJU 2012 Dec;110(11):1787-91. Epub 2012 May 7 - https://pubmed.ncbi.nlm.nih.gov/22564343/
Short-term intracavernous self-injection treatment of psychogenic erectile dysfunction secondary to sexual performance anxiety in unconsummated marriages. Lidawi G et al. International Journal of Impotence Research volume 34, pages407–410 (2022) - https://pubmed.ncbi.nlm.nih.gov/33603244/
REF 4 Efficacy and Safety of Intracavernosal Alprostadil in Men with Erectile Dysfunction. Limnet O et al. N Engl J Med 1996;334:873-877 - https://pubmed.ncbi.nlm.nih.gov/8596569/
https://www.mskcc.org/cancer-care/patient-education/penile-injection-therapy
https://www.mayoclinic.org/drugs-supplements/alprostadil-intracavernosal-route/description/drg-20067404
https://www.ucsfhealth.org/education/patient-guide-to-penile-injections
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020379s032lbl.pdf
https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020649s023lbl.pdf
