Intracavernosal injection therapy for erectile dysfunction

Case scenario

Dale, 58 years old, has come in to obtain a repeat prescription for tadalafil and asks if he can have a chat. You note that this appears to be the second type of PDE5 inhibitor he has been prescribed recently. After inviting him into your consult room, he tells you that despite following all the instructions he still can’t seem to ‘get it up’ in the bedroom. He has recently been referred to a urologist by his GP to discuss alternative options. He has heard that he might be given an injection to try and wants to know more.

After reading this article, pharmacists should be able to: Describe the physiology of an erection  Discuss the use of intracavernosal injections in managing erectile dysfunction  Explain how pharmacists can help assist patients experiencing erectile dysfunction. Competency standards (2016) addressed: 1.1, 1.4, 1.5, 2.2, 3.1, 3.5 Accreditation number: CAP2410SYPTS Accreditation expiry: 30/09/2027

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Introduction

Erectile dysfunction (ED) is defined as difficulty in gaining or maintaining a penile erection sufficient for sexual activity.¹ It is often measured and graded using a questionnaire titled ‘International Index of Erectile Function’.² Around 1 in 5 Australian males over 40 years of age have a problem with erections,³ and the impact of this can be significant.⁴ It has been shown that ED can increase the risk of depression,⁴ reduce a patient’s sense of masculinity and self,⁵ and adversely affect relationships.⁶

Fortunately, many effective treatments exist to assist with ED.⁷ Factors such as comorbidities, other medicines, condition severity, cost, availability and patient preference can all influence choice of treatment.⁷

Physiology of erections

In a healthy functioning male, an erection will begin with a sexual stimulus. A signal triggered by the stimulus is sent from the brain down the spinal cord and eventually through to the nerve and endothelial cells in the penile tissue, called the corpora cavernosa.⁸ These cells release nitric oxide synthase (NOS), which catalyses the synthesis of nitric oxide.^8,9 Nitric oxide is responsible for activating guanylate cyclase, an enzyme that is able to convert guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP).⁹ A build-up of cGMP causes a cascade of biological processing events that ultimately leads to the desired response as it causes smooth muscle relaxation and arterial dilation in the corpus cavernosum.⁹

Aetiology of erectile dysfunction

Many health conditions can increase a person’s risk of ED. Comorbidities that can affect nerve function, blood flow or hormone levels are all common culprits.⁷ Examples include diabetes, cardiovascular disease, multiple sclerosis, Parkinson’s disease and anxiety disorders.⁷ Local trauma such as injury, surgeries and radiation treatment are also common
risk factors.⁷

Drug-induced ED should also not be ignored. Some relevant medicines to be wary of include selective serotonin reuptake inhibitors (SSRIs), serotonin noradrenaline reuptake inhibitors (SNRIs), androgen deprivation therapies (commonly used in the treatment of prostate cancer), and 5-a reductase inhibitors.⁷

Lastly, a significant proportion of cases of ED are at least partially psychogenic in nature. Anxiety and depression are often involved, and if not initially, they can develop as a result of experiencing ED.⁷

First-line management

Underlying comorbidities contributing to the presenting issue of ED should be optimally treated and controlled as a matter of importance.⁷ ED may in fact serve as a motivating factor to improve overall health, particularly if the impact of these comorbidities can be articulated in a way that the patient can understand. For example, a patient with diabetes may not realise that their poor blood glucose control can increase their risk of sexual dysfunction. Opportunistic conversations explaining the connection between these conditions may result in significant improvement to their broader health.

Oral therapies

While working to achieve control of these conditions, it is reasonable to also commence treatment for ED. According to guidelines, first-line therapy includes oral phosphodiesterase type five (PDE5) inhibitors if suitable for the individual.

PDE5 inhibitors include avanafil, sildenafil, tadalafil and vardenafil.¹⁰ These medicines elicit a clinical effect by inhibiting the enzyme responsible for converting cGMP to GTP, therefore allowing a greater build-up of cGMP and subsequently improving erectile function.⁹ Considering the mechanism of action, a degree of normal function is crucial for PDE5 inhibitors to work.¹⁰ 

PDE5 inhibitor molecules are manufactured into a variety of tablet strengths.¹¹ They can be differentiated by their pharmacodynamic and pharmacokinetic properties, as well as their adverse effect profiles.¹¹ For instance, tadalafil has a relatively slow time to peak effect of 2 hours, but also has a clinical effect lasting up to 36 hours.¹⁰ In comparison, avanafil has a peak effect after 30–45 minutes while only lasting around 6 hours once swallowed.¹⁰ Common adverse effects for PDE5 inhibitors are dose-dependent and include headache, flushing, dyspepsia, dizziness and nasal congestion.¹⁰

Clinical decision-making between first-line treatment options should take all of these factors into consideration. Furthermore, if well tolerated and use is appropriate for the individual, at least two different PDE5 inhibitors should be trialled, each at least three times before PDE5 inhibitors are determined as a failure. This, among other considerations, such as whether it was taken as directed, sexual stimulation was attempted, dose was appropriate and medicine was sourced appropriately (e.g. not purchased online or overseas), should be evaluated before moving onto second-line therapies.⁷

These medicines have an absolute contraindication in people taking nitrates due to the risk of fatal hypotension.¹⁰

Second-line management

Vacuum erection devices

Vacuum erection devices are a drug-free, surgery-free option. When operated correctly, these devices work by exposing the penis to external negative pressure.¹² This is achieved by placing a tubular chamber over the penis, forming a seal against the body.¹² Air is then drawn out of the chamber either via a battery-operated motor, or a manual pump.¹² As air is pumped out of the device, the penile tissue expands to fill the void, forcing a stretch in the blood vessels which subsequently fill with blood.¹² In order to maintain the erection, a constriction ring is placed around the base of the penis and the vacuum device removed.¹² This action will occlude the venous outflow and therefore maintain tumescence (swelling).¹² Constriction rings are considered safe to use in this way for up to 30 minutes.¹²

Beyond the potential adverse effects such as pain, bruising and anejaculation, there are also several noticeable differences between an organic erection and that formed via a vacuum device.¹² Differences include the veins becoming more pronounced, the penis being colder to the touch, and a ‘hinging’ effect.¹²

Some patients may consider this method too burdensome and difficult to incorporate into sexual activity, but it is an important option to be aware of.¹²

Intracavernosal injections   

Intracavernosal injections (ICIs) or penile injections, a treatment option which is often overlooked, can provide an effective and reliable second-line treatment option for those with ED.^7,10 This therapy requires a patient to inject a prescribed dose of medicine directly into the corpus cavernosum of the penis.^10,13 Common molecules and combinations of molecules typically used in ICIs are discussed in detail below. It is important to note that in contrast to oral PDE5 inhibitors, medicines given via ICI usually do not require any baseline erectile function in order to elicit a response.¹³

Products currently available in Australia include alprostadil and papaverine.¹⁴ Other ICIs mentioned below (and combination products) are not available as a proprietary product in Australia and may be considered for compounding by specialist sterile compounding pharmacies, if clinically and legally appropriate.

Alprostadil

Alprostadil is the preferred monotherapy for intracavernosal injection in ED.¹⁰ It is a synthetic form of prostaglandin E₁ (PGE₁), binding to PGE₁ receptors in the corpus cavernosa, thus inducing smooth muscle relaxation allowing for an influx of blood into this tissue.^11,13 As pressure builds, venous outflow is reduced and eventually blocked in a similar way to the process of a normal physiological erection.^11,13 A penile erection can therefore be gained and importantly maintained if using a suitable dose.

The doses of alprostadil required to achieve a satisfactory response are typically in the range of 2.5–20 micrograms.^11,13 Some patients may require a higher dose, and this may be prescribed under specialist supervision.¹³ Alternative ingredients or compounded combination products may also be recommended by specialist prescribers.¹³

Compared to phentolamine and papaverine, alprostadil has a lower risk of cavernosal fibrosis and prolonged erections (priapism).¹⁰

Papaverine

Papaverine is an injectable PDE5 inhibitor and is noted as being the first injectable medicine for the treatment of ED.¹³ Its action prevents the breakdown of cyclic adenosine monophosphate (cAMP) in the adenosine triphosphate (ATP) pathway thus causing smooth muscle relaxation.¹³ It is worth noting that this mechanism is different to the action of the oral PDE5 inhibitor formulations, as these prevent the breakdown of cGMP in the neuronal pathway rather than cAMP.^11,13 Papaverine is generally only used in combination with other agents such as alprostadil and phentolamine.¹³ It is not recommended for use as monotherapy.¹⁰

Phentolamine

Phentolamine works directly on the smooth muscle of the corpus cavernosum.¹³ It is a non-selective alpha-adrenergic receptor antagonist, targeting both alpha₁ and alpha₂ receptors.¹³ Antagonism of these receptors promotes relaxation and therefore enhanced blood flow into the tissue to form an erection.¹³ It is generally not recommended as a monotherapy¹⁰ and has a weak clinical effect. Phentolamine may enhance clinical outcomes if used in combination with alprostadil, papaverine or aviptadil.¹³

Aviptadil

Aviptadil is a synthetic vasoactive intestinal peptide (VIP).¹³ Clinical effect is achieved through activation of adenylate cyclase, an enzyme responsible for converting ATP to cAMP.¹³ A build-up of cAMP then results in smooth muscle relaxation and penile erection¹³ as described previously. Aviptadil may be used as monotherapy or combined with phentolamine.¹³

Atropine

Atropine is another agent generally only used in combination with other active ingredients.¹³ Tissue response is dose-dependent, and is generally given in relatively high doses to stimulate the release of a key neurotransmitter in the erectile process called endothelium-derived relaxing-factor.¹⁵ As the name suggests, this neurotransmitter causes smooth muscle relaxation and therefore penile erection.¹⁵ Atropine is typically used in combination with other ingredients such as alprostadil, phentolamine and papaverine.¹³

Combination therapies

Common intracavernosal preparations containing two or more active components include¹³:

• papaverine + phentolamine
• aviptadil + phentolamine
• alprostadil + papaverine + phentolamine
• alprostadil + papaverine + phentolamine + atropine

Note: concentrations of each ingredient within these formulations may be altered to suit various patient factors, as combinations are currently formulated by specialist sterile compounding facilities.¹³

Dosing technique for intracavernosal injection

The method of delivery is particularly pertinent to intracavernosal injection therapy. When a patient is being initiated on this therapy, the first dose should be administered by an experienced medical practitioner, then a self-administered dose given under supervision.^10,12 Preparing the dose may vary depending on whether a proprietary product or a compounded product has been prescribed, and product information should be followed closely.^10,12 Before use, the patient is first shown how to prepare a dose (for compounded products, this often means drawing up a dose from a multi-dose vial).¹² Once the dose is prepared, the patient is taught how to inject according to the supplied product information.¹²

The optimal injection sites are at the mid-shaft of the penis, at either the 2 o’clock or 10 o’clock position when imagining a cross-section of the penis, taking care to avoid any veins and the urethra.¹² Injection sites should be alternated each time a dose is administered, and a patient should not exceed more than one injection within 24 hours, or more than 3 injections per week.¹²

Expectations and outcomes

Once a prescribed dose has been administered, it takes time before a full effect is reached (e.g. between 5 and 20 minutes for alprostadil).¹⁰ Doses are often titrated to achieve an optimal dose, which should lead to an erection that will last no more than 1 hour.¹⁰

Initial injections are often given at a cautiously low dose and therefore the response may be suboptimal in both firmness and duration. If this is the case, up-titration of the dose is necessary.¹⁰

If the dose administered is too high, or the patient is particularly sensitive to the medicine, they might experience priapism (prolonged erection), which is a medical emergency.¹⁰ If a prolonged erection continues 2 hours after injection, treatment should be initiated. This includes contacting the treating practitioner or after-hours contact, taking 120 mg of immediate-release pseudoephedrine,  taking a cold shower and gentle exercise.¹⁰ If the erection is still present after 4 hours, the patient should seek urgent medical assistance at the local emergency department.¹⁰ If deemed appropriate to continue ICI treatment, the subsequent dose should be down-titrated.¹⁰

Patients are often apprehensive about administering a self-injection into their penis.¹⁶ However, in 2022 researchers showed that patients undergoing their first intracavernosal injection experience significantly less pain than they initially expect.¹⁶ Predicted pain on a scale from 0–10 was estimated at an average of 5.45 prior to the injection.¹⁶ Post-injection on the same scale, the pain experienced was described at an average of 1.20.¹⁶ Knowledge of the discrepancy between perception and reality of injection pain may assist in reducing apprehension towards the therapy for many patients and is therefore a valuable counselling point for pharmacists.¹⁶

Troubleshooting in practice

If poor response is reported, it should first be ascertained that¹²:

• The medicine has been stored correctly and has not expired.
• An appropriate needle gauge (G) and length are being used (e.g. Mulhall and Jenkins recommend 29 G, 12.7 mm length for ICI).
• Injection technique is correct, as each and every step in the process is paramount to achieving a positive response.

Dose adjustment of the ICI may then occur under the supervision of a trained healthcare professional.¹²

Finally, if all of the aforementioned points have been addressed and clinical response is still suboptimal, a formulation with higher concentration or alternative active ingredients can be considered.^12,13

Pain is reported in around 10% of patients using alprostadil injections.^10–12 If pain is experienced, injection technique should first be reviewed, then it would be reasonable for a urologist to consider changing to an alternative formulation that may cause less injection pain, such as combination products papaverine + phentolamine or alprostadil + papaverine + phentolamine.^12,13

Knowledge to practice

Pharmacists play a key role in patient education and optimising therapies, with a goal of minimising the impact the condition has on people’s lives. Pharmacists can assist patients by creating a safe space in which to share their experience with first-line therapies; providing education on the existence of second-line therapies; and discussing concerns about injections, expectations for onset, efficacy, administration and adverse effects.

Conclusion

ED may stem from a variety of causes, but can have a major impact on a person’s life regardless of the origin. While first-line therapies may be effective for some patients, they are not always suitable or may not achieve the desired response. As such, second-line therapies such as intracavernosal injections are a welcome option for some patients. Plenty of opportunity exists for pharmacists to assist in educating and optimising these treatments.

Case scenario continued You advise Dale that there are other therapies available, including injections that go directly into the penis to help initiate and maintain an erection. You advise that the specialist will likely assess if an injection called alprostadil is suitable for him to try. After initial administration and training under the urologist’s supervision, he can then be trained to self-administer at home. You discuss how it works and let him know that you are happy to discuss it further with him after his specialist appointment. Dale is relieved that there are other therapies available and is looking forward to his appointment with the urologist.

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Key points

• Erectile dysfunction can have a significant impact on an individual.
• First-line therapies are limited and may not be suitable for all patients.
• Intracavernosal injections are often a very effective second-line option for erectile dysfunction.
• Pharmacists are well placed to educate patients and help optimise intracavernosal injection therapy.

References

1. Montorsi F, Adaikan G, Becher E, et al. Summary of the recommendations on sexual dysfunctions in men. J Sex Med 2010;7(11):3572–88.
2. Rosen RC, Riley A, Wagner G, et al. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997;49(6):822–30.
3. Healthy male. Erectile dysfunction. 2020. At: www.healthymale.org.au/mens-health/erectile-dysfunction
4. Liu Q, Zhang Y, Wang J, et al. Erectile dysfunction and depression: a systematic review and meta-analysis. J Sex Med 2018;15(8):1073–82.
5. Chambers SK, Chung E, Wittert G, et al. Erectile dysfunction, masculinity, and psychosocial outcomes: a review of the experiences of men after prostate cancer treatment. Transl Androl Urol 2017;6(1):60–8.
6. Prostate cancer foundation of Australia. Proscare: a psychological care model for men with prostate cancer. 2013. At: www.pcfa.org.au/media/195765/proscare_monograph_final_2013.pdf
7. Shoshany O, Katz D, Love C. Much more than prescribing a pill – assessment and treatment of erectile dysfunction by the general practitioner. Australian Family Physician 2017;46(9).
8. Burnett AL. The role of nitric oxide in erectile dysfunction: implications for medical therapy. J Clin Hypertens (Greenwich) 2006;8(12 Suppl 4):53–62.
9. Burnett AL. The science and practice of erection physiology: story of a revolutionary gaseous molecule. Trans Am Clin Climatol Assoc 2019;130:51–9.
10. Therapeutic Guidelines. Erectile dysfunction. 2024. At: https://tg.org.au
11. eMIMs. 2024. At: www.emims.com.au
12. Mulhall JP, Jenkins LC. Atlas of office based andrology procedures. 2017.
13. Duncan C, Omran GJ, Teh J, et al. Erectile dysfunction: a global review of intracavernosal injectables. World J Urol 2019;37(6):1007–14.
14. Rossi S, ed. Australian medicines handbook. 2024. At: https://amhonline.amh.net.au/
15. Montorsi F, Guazzoni G, Bergamaschi F, et al. Effectiveness and safety of multidrug intracavernous therapy for vasculogenic impotence. Urology 1993;42(5):554–8.
16. Baird B, Wajswol E, Ericson C, et al. Pre- and post-Injection needle pain in patients undergoing first intracavernosal injection. J Sex Med 2022;19(4):590–3.

Our author

Tim Stewart MPharm, BPharmSci, JP is a clinical men’s health pharmacist and director of Mens Health Downunder in Deakin, ACT. He was recognised as the MIMs/Guild Intern of the Year in 2017 for his work in urological health and has since consulted with patients from every state and territory in Australia.

Our reviewer

Hana Numan (she/her) BPharm (NZ), PGDipClinPharm (NZ), MPS (NZ)

Conflict of interest declaration:

Tim Stewart is the director of Men’s Health Downunder in Deakin, ACT.