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Oral therapies via the PDE5i sildenafil, vardenafil, and tadalafil have been proven to be generally safe and effective in select NED populations. The majority of the treatment effectiveness data has been generated in the SCI population.

Data regarding the use of PDE5i outside of the SCI population is lacking (58).

Furthermore, the ED that exists in the population with neurologic disorders is often multifactorial and may be caused by psychogenic, psychosocial, hormonal, medication-related and disability-related factors.

A careful evaluation of each patient must be performed to isolate these factors prior to initiating vasoactive therapy. Spinal cord injury (SCI) Oral PDE5i remains the first line treatment for NED from SCI.

Three of the four PDE5i currently available in the U.S., avanafil excluded, have been investigated in the SCI, and all of the more recent studies have shown improvements in erectile function based on IIEF score compared to placebo when included (59-63).

Other studies have also shown significant improvements in the IIEF score when compared to baseline (64-69). Furthermore, treatment efficacy when compared to placebo occurs despite LOI or American Spinal Injury Association (ASIA) score characterizing impairment related to the injury (59,61).

compared the effectiveness and satisfaction associated with use of several ED therapies including sildenafil alone, intracavernosal injections (ICI) followed by sildenafil after ICI discontinuation and vacuum erections devices (VED) followed by sildenafil therapy after VED discontinuation (60). Seventy percent of men receiving vasoactive medications preferred sildenafil to ICI, even lybrido price though rigidity was superior in the ICI group. All men using VEDs were dissatisfied with that form of therapy. The duration of erections is also improved by sildenafil in men with SCI. showed that sildenafil use increased the duration of erections from 8.4 to 10 minutes when compared to baseline.

Men using sildenafil were also more confident that they could maintain their erection compared to prior therapies such as VEDs (65).

compared sildenafil to vardenafil and tadalafil (69).

Sildenafil was effective in 85% of SCI patients, 74% of the patients on vardenafil and 72% of the patients on tadalafil. Sildenafil was associated with more rigid and longer lasting erections. Additionally, 50 mg of sildenafil was effective in 55% of patients compared to more than 70% of the patients on vardenafil and tadalafil requiring 20 mg for a similar response. Men who used tadalafil were able to achieve erections 24 hours after administration, improving overall satisfaction related to

the

Del Popolo also evaluated the time/duration effectiveness of PDE5i sildenafil 50 mg versus tadalafil 10 mg (64).

Tadalafil 10 mg significantly increased the percentage of successful intercourse attempts at 12–24 hours compared with sildenafil. One can suspect that vardenafil, which has a longer half-life than sildenafil, could offer a similar benefit but a study investigating this occurrence has yet to be performed. Sildenafil use has led to increased patient satisfaction and partner satisfaction after initiating therapy (67).

showed that 88.2% of patients, and 85% of partners reported significantly improved sexual satisfaction and overall satisfaction regardless of pretreatment degree of ED or LOI.

Several pre-treatment factors have been described that may indicate success with PDE5i therapy.

The presence of an upper motor neuron lesion up to T12 suggests a successful response, as well as requirement for a viagra online overnight shipping lower dosage of medication (62,68-71). Additionally, the presence of residual erections after injury or an incomplete SCI (ASI-A vs. ASIB-D) also improve the chance of PDE5i treatment success (59,67,68,71).

Adverse effects related to PDE5i use with mild-moderate and transient (58).

Furthermore, side effects usually attenuate if use is not discontinued. Autonomic dysreflexia, a life-threatening phenomenon characterized by bradycardia, hypertension, facial flushing and headaches associated with SCI lesions above T6, has not been reported with use.

However, hypotension leading to dizziness in individuals treated with sildenafil has been noted with high thoracic and cervical levels of injury (72).

No adverse events were noted within the study; however, the dizziness was reported by use of sildenafil 50 mg in the cervical LOI and 100 mg in the thoracic LOI patients.

Headache is the most reported side effect of all PDE5i, followed by dyspepsia and flushing.

Priapism, and death have not been reported after use of PDE5i by SCI patients.

Ultimately, PDE5i have had a significant impact on the treatment of ED in men with SCI. The ease of use and tolerability of the medication has also led to improved satisfaction and quality of life that had been previously affected by SD. Head to head trials evaluating specific PDE5i within the SCI population are required to further elucidate drug preference. PDE5i should be considered first line therapy, however men with high thoracic and cervical lesions should be warned about an increased chance of dizziness with sildenafil and possibly other PDE5i use.

Parkinson’s disease (PD) PDE5i use in PD has not been well studied; however its benefits have been shown.

Raffaele performed an open label, prospective study evaluating the efficacy of sildenafil 50 mg on demand and depressive symptoms experienced by the PD patient (73). Erections were improved in approximately 85% of men and 75% noted improvements in their depressive symptoms as well. Sildenafil was well tolerated without significant side effects. , performed a shorter study showing improvements in erectile function but no change in depression and parkinsonisms after ED treatment (74).

Iatrogenic hypotension can occur in men in neurodegenerative disease using

sildenafil

placed men with PD and MSA on sildenafil and recorded blood pressure before and after.

Half of the 12 MSA patients developed postural hypotension, while none of the twelve PD patients did. Since MSA can be difficult to distinguished diagnostically from PD, baseline blood pressure measurements prior to prescribing the medication and seeking medical assistance if symptomatic hypotension occurred was recommended for all patients with PD, and MSA.

Of note, none of the men with MSA who developed hypotension discontinued sildenafil use due to its effectiveness at improving their erections. Multiple sclerosis (MS) PDE5i for ED in patients with MS can be considered as reasonably effective and safe. performed a randomized, multicenter, double-blind, flexible dose trial with open label extensions comparing sildenafil to placebo (75).

A nearly 4-fold increase in effective erections was noted in the treatment arm, 96% vs.

Sexual satisfaction and overall satisfaction were also improved in the treatment group based on IIEF scores, and quality of life assessments. Seventy eight percent of the men responded with improved erections, better quality of life with regards to sexual function, partner relationship and family life.

Just less than half the men who responded to the tadalafil did so at the lower dosage of 10 mg. Subjects in either studies did not have any significant adverse side effects beyond flushing, and headache with PDE5i use. Spina bifida (SB) One study by Palmer and colleagues evaluated sildenafil use in SB males with thoracic lesions (76). A prospective, blinded, randomized, placebo-controlled, dose-escalation, crossover study in 17 patients with SB and ED was performed.

All study participates took sets of tablet in groups, two sets of placebo, one of 25 mg, and the last 50 mg. Overall response to the tablet sets was measured by IIEF response and self-report of erectile rigidity.

Patients reported that taking 50 mg of sildenafil led to improved erections, duration of erections, frequency of erections and level of confidence compared to sildenafil 25 mg and more significantly compared to placebo.

Of the five patients who reported side effects, two experienced mild hematological changes that reverted to baseline after study completion. Sildenafil has been previously suggested as a treatment option for ED in men with epilepsy (77,78). warned that PDE5i are potentially pro-convulsant and should be

used

Animal studies in rat and mice overwhelmingly suggest PDE5i can reduce seizure threshold.

PDE5i exerted their proconvulsive effect by lower seizure threshold possibly by worsening sleep or obstructive sleep apnea, causing cardiovascular changes, or leading to EEG changes specifically with tadalafil use. Apomorphine is a non-selective D1/D2 receptor agonist with moderate efficacy and good tolerability in the treatment of mild ED (80). Apomorphine can be administered via subcutaneous injection or sublingually. However, studies have shows a lower efficacy for apomorphine compared to oral sildenafil (81,82). Apomorphine has a set role in the management of PD for non-motor symptoms, and has been reported to cause spontaneous erections and possible hypersexuality in PD men (83,84).

Its role in the management of ED has been postulated for men with PD but should be considered as an alternative to sildenafil.

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 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). 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

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 blocks post synaptic adrenergic ?1 receptors preventing smooth muscle contraction. However, it also may interfere with prejunctional ?2 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.

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. 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 ?g 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. (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. 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.

performed penile implant surgery in 245 men with neurolgic impairment caused by spinal cord injury, CNS neoplasm, CNS infection, MS and SB (110).