The Treatment of Erectile Dysfunction in Patients With Neurogenic Disease

Anand N. Shridharani; William O. Brant

Disclosures

Transl Androl Urol. 2016;5(1):88-101. 

In This Article

Local Therapies

Intracavernosal Injections (ICI)

Intracavenosal therapy involves injection of a vasoactive agent into the corpora cavernosa to effect smooth muscle relaxation and tumescence.

In 1983, Brindley injected the corpora of several SCI men with phentolamine.[85] Two out of the three men had a sufficient erection produced. Since then multiple reports on the efficacy of intracavernosal therapy have been published using, phentolamine, papaverine, prostaglandin, vasoactive intestinal peptide (VIP), and these medications in combination.[86–90] These medications have been found to be extremely effective for neurogenic ED due to their ability act locally and essentially bypassing neuronal pathways. Local therapies are usually considered second-line after PDE5i fail to elicit a desired response which can occur in about 25–30% of men with ED, in general.[91] Furthermore, the locally delivered medications can be quite dangerous if not used appropriately as priapism and significant pain with injections can occur. These specific occurrences have been suggested as a reason for high discontinuation rates with intracavernosal therapy.[92]

Papaverine

Papaverine is an opium alkaloid that acts as a non-specific PDEi that increases intracellular cAMP and cGMP leading corporal smooth muscle relaxation.[93] Intracavernosal papaverine injection was the first clinically effective pharmacological therapy for ED and led to a full erection in at least half of the patient in early studies.[94,95]

Alprostodil/Prostoglandin E1

Alprostadil is a potent vasodilator and smooth muscle relaxant identical to the naturally occurring PGE1. PGE1 binds with specific receptors on smooth muscle cells and activates intracellular adenylate cyclase to produce cAMP, which in turn induces tissue relaxation through a second messenger system.[96] PGE1 is the only FDA approved form of intracavernosal therapy and is available commercailly as EDEX, or Caverject. Its efficacy was demonstrated in several clinical trials where the rate of responders ranged from 40% to 80%.[97,98] The most common adverse event is penile pain, which is not related to the injection of the medication itself. In men with prolonged use the pain is usually self-limited.[99]

Vasoactive Intestinal Peptide (VIP)

VIP is a neurotransmitter with regulatory actions on blood flow, secretion and muscle tone with intracorporal adenylate cyclase activation and smooth muscle relaxation. VIP has been shown to elevate cAMP intracellular concentrations without affecting cGMP levels. However, when VIP is given alone it may not induce erection and requires combination with phentolamine or papaverine for it to be effective.[88] Common associated adverse effects were facial flushing and headache. VIP in combination with phentolamine is currently being used in the UK and Europe and is seeking regulatory approval for use in the United States.

Phentolamine

Phentolamine blocks post synaptic adrenergic α1 receptors preventing smooth muscle contraction. However, it also may interfere with prejunctional α2 receptors, which may counteract the process.[100] Consequently, this may be a reason phentolamine is not prescribed as monotherapy, and frequently is combined with papaverine, alprostadil or VIP.

Combination Therapy

Multiple combinations of intracavernosal therapy exist and the effectiveness of them varies based on patient characteristics and varying dosing strength (Table 1). Combination therapy have been extremely effective in the SCI population, and have several advantages including a reduction in cost per dose and side effects base on the lowered dose of each component.[101,102] Effectiveness of combination therapy in the spinal cord population is well established, but no specific dose recommendations can be made based on the data.[103–106] The use of combination therapy on other forms of neurogenic ED have not been well studied, but there use can be trialed as second-line therapy, or for populations were the side effects of PDE5i may preclude use such as in MSA due to hypotension.

Intraurethral Alprostadil

Alprostadil may be delivered via the urethra in the form of a pellet (MUSE).[107] This form of therapy has been trialed in SCI men with intermediate success.[108] Bodner trialed MUSE dose escalation in SCI men and found 1,000 μg to be the most effective dose. Several men had hypotension when a constriction ring was not used in conjunction with the MUSE therapy.

Vacuum Erection Devices (VED)

VED involved placing the penis in a clear plastic tube where negative pressure created by the vacuum pump leads to penile engorgement and tumescence. Usually a constriction ring can be placed on the base of penis following penile engorgement. Some men complain of bruising, a "cold" penis and pain associated with the constriction ring; however, in some men with NED sensation may not be intact mitigating the side effects of VEDs. VEDs have reported effectiveness up to 90% in certain ED populations and it remains a non-invasive means to achieve and erection.

Chancellor et al.[109] compared VEDs with papaverine injections in 18 males with SCI. The injections and pumps were equally effective in inducing erections and no adverse effects from the treatments were reported. Treatment arms were crossed over, subsequently seven men chose the VED and seven men chose the papavarine highlighting equal efficacy in this population. In another treatment arm topical minoxidil was applied without any effective erections achieved by the study subjects.

VEDs in general have great success in the neurogenic population. Limitations that may affect use are limited manual dexterity, cost due to non-insurance coverage, lack of spontaneity, artificiality of erection, obesity/buried penis, and anticoagulant use.

Penile Implant Surgery

Prior to the introduction of PDE5i in 1998, intracavernosal vasoactive medications and penile implant surgery were the mainstays of treatment. Penile implant surgery involves placement of inflatable or malleable rods within the corpora cavernosa to provide rigidity for intercourse. Choice of which implant to place usually depends upon manual dexterity and function of the patient, patient anatomy, physician preference and surgical approach.

Zerman et al. performed penile implant surgery in 245 men with neurolgic impairment caused by spinal cord injury, CNS neoplasm, CNS infection, MS and SB.[110] Mean follow-up time of 7.2 years was achieved in 195 patients, 50 patients were excluded for lost to follow-up or death from nonurological causes. Interestingly, 135 patients underwent penile implantation to assist with management of urinary incontinence and improve ability for condom/intermittent catheterization. Ninety-two patients patient underwent implantation for ED. Eighty two percent of patients were satisfied with implantation for ED, and 67% of partners were satisfied. Complications included infection (5%), perforation (0–18%), and technical dysfunction (7–33%). Perforation rates were high with the malleable device when it was placed through a subcoronal incision. After adopting an infrapubic approach the perforation rates dropped substantially.

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