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

Management of Neurogenic Erectile Dysfunction (ED)

PDE5 Inhibitors (PDE5i)

The American Urological Association Guideline on the Management of ED states oral PDE5i are considered first line therapy for the treatment of ED, unless contraindicated.[57] Sildenafil, the first oral PDE5i, was introduced in 1998 and has revolutionized ED therapy due to its broad applicability, effectiveness and safety profile. PDE5i work by preventing hydrolysis of cGMP by the PDE5 enzyme in the smooth muscle of the corpora cavernosa. cGMP degradation typically leads to smooth muscle contraction and detumescence prevented by PDE5i administration. Two other PDE5i, vardenafil and tadalafil are other PDE5i with different pharmacokinetics, PDE receptor selectivity and side effect profiles.

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]

Moemen et al. 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 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. Gans et al. 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]

Soler et al. 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 possible spontaneity of sexual encounters. 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] Sánchez Ramos et al. 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 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. Zesiewicz et al., 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.[49] Hussain et al. 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. Fowler et al. 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. 24%. Sexual satisfaction and overall satisfaction were also improved in the treatment group based on IIEF scores, and quality of life assessments. Lombardi et al. evaluated tadalafil use in men with MS.[71] 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.

Epilepsy

Sildenafil has been previously suggested as a treatment option for ED in men with epilepsy.[77,78] However, Matos et al. warned that PDE5i are potentially pro-convulsant and should be used with great caution in men with epilepsy.[79] Animal studies in rat and mice overwhelmingly suggest PDE5i can reduce seizure threshold. In human trials, seizures were rare but reported. 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

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.

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