Phosphodiesterase Type 5 Inhibitors (PDE5i) and Other Oral Agents
Phosphodiesterase Type 5 Inhibitors (PDE5i) are a class of vasodilating medications that relax smooth muscle cells and improve blood flow by inhibiting the PDE5 enzyme. They are primarily used to treat erectile dysfunction (ED) and pulmonary hypertension by enhancing the signaling molecule cyclic GMP (cGMP).
Erection is initiated by smooth muscle relaxation of the corpora cavernosa (erectile bodies) of the penis and depends on the nitric oxide-cyclic guanosine monophosphate [NO- cGMP] pathway. PDE5i are recommended for individuals with SCI because of its safety, effectiveness, and ease of oral usage (Tienforti et al. 2024). It is imperative that either neuronal or endothelial NO release occur for the PDE5i to work (this equates to mental sexual arousal and healthy endothelium).
The PDE5i are selective inhibitors of type 5 (cGMP specific) phosphodiesterase, which decreases the rate of cGMP breakdown in the cavernous tissue. Thus, the availability of cGMP prolongs and enhances the erectile response (Tienforti et al. 2024). Apomorphine is a dopamine-receptor agonist important in the control of sexual functioning. Fampridines, or 4–aminopyridine, is a K+ channel-blocking agent noted for increasing neurotransmitter release at neuronal sites and enhancing conductivity in demyelinated axons. Most clinicians recommend that men with SCI, regardless of their level of injury, be offered a trial of PDE‐5 inhibitors (Rizio et al. 2012).
Discussion
The evidence supports the use of PDE5i as the first line of treatment for men with erectile dysfunction (ED) after SCI (Tienforti et al. 2024). PDE5i are now widely accessible such as the generic compound, commercial labs, and internet availability. Caution to internet drugs should be exercised, since the mixture of content is not always PDE5i and unidentified which can cross-react and cause side effects with other medications. In terms of dosing, 50-100mg of Viagra® has similar therapeutic effects to 10-20mg prn of Cialis® and Levitra®. Viagra® is available in 25, 50, and 100mg tablets, whereas Cialis® offered as 10 and 20 mg as needed or 2.5 and 5 mg for daily use. Levitra® is available in 10 and 20 mg. (for the reader, Viagra® 50 and 100 mg is the same dose as Cialis and Levitra 10 and 20 mg, Elliott, personal communication, 2026).
Meta-analysis of case-series reports estimates sildenafil efficacy at 79% for improving erectile function for sexual intercourse at home (DeForge et al. 2006). Ergin et al. (2008) found that sildenafil was effective regardless of completeness of injury; however, the treatment showed more significant impacts among individuals with incomplete injuries (p<0.05). Khorrami et al. (2010) found that sildenafil was more effective in upper motor neuron (UMN) (82% responsive) versus lower motor neuron (LMN) (28.5%) injuries. Soler et al. (2007) reported a significant improvement in ejaculation and orgasm only in the group taking sildenafil, while others (Giuliano et al. 2006) have reported overall improvement in ejaculatory function with vardenafil (19% compared to 10% in placebo), particularly in those with incomplete lesions (29% compared to 15%). In addition, sildenafil has been identified as the most cost-effective and high utility PDE5i (Martin et al. 2013). The annual estimated cost for sildenafil (in 2005) was CAN $1,534 and had a cost-effective ratio of less than CAN $20,000 per quality-adjusted life year (QALY) (Mittman et al. 2005).
In a systematic review and meta-analysis of 1,492 men with TSCI, Taladafil (Cialis®) (81%) was identified to be the best PDE5i for ED after SCI (Tienforti et al. 2024). The effectiveness of PDE5i depends on if the injury is UMN or LMN and the completeness of injury (Ergin et al. 2008; Khorrami et al. 2010). In general, a lesion above the sacral spinal tract and a reflexive erection are favorable predictors for a positive response to all PDE5i (Lombardi 2009a; Soler 2007; Schmid et al. 2000; Sanchez Ramos 2001). For patients with extensive ischemic damage involving both the thoraco-lumbar and sacral cord segments, PDE5i are not as effective (Schmid et al. 2000). It appears that efficacy is maintained with the use of PDE5i over time, and tachyphylaxis (a decrease in the response to a drug after repeated doses over a short time period) is rare (Lombardi et al 2009b).
Results from 3 large RCTs (Giuliano et al. 2006; 2007; 2008) have shown similar efficacy for vardenafil and tadalafil compared to placebo, with reported improvements in erectile function (~10 points gain in IIEF/EF scores), success in penetration (~75%), maintenance and duration of erection (25-30 mins), and successful attempts at intercourse (~50-60%). Sildenafil, tadalafil, and vardenafil were all statistically significant in improving erectile functioning and were observed to be equally effective (Lombardi et al. 2012; Rizio et al. 2012). However, a current systematic review and meta-analysis (Tienforti et al. 2024) found that tadalafil was 5.4 times more effective than the placebo, vardenafil by 4.7 times, and sildenafil by 4 times.
Lombardi et al. (2009a) found that tadalafil did not significantly improve in ejaculatory and orgasmic parameters, however, the increase in IIEF scores to > 26 (normal) was apparent in most of the men with SCI in the study. Studies show that tadalafil allows 80% of participants taking 10mg or 20 mg of tadalafil to achieve successful intercourse within 24 hours of taking the drug, and approximately 65% were still able to have successful intercourse after 24 hours had passed (Del Popolo et al. 2004; Lombardi et al. 2009a). This long-acting duration allows for more spontaneous sexual activity compared to “on demand” sexual activity (Giuliano et al. 2007; Rizio et al. 2012). However, Soler et al. (2007) and Del Popolo et al. (2004) found that the mean erection duration of tadalafil (26 min) was shorter than both sildenafil (34 min) and vardenafil (28 min). Most studies in this review directed participants to be taking PDE5i within 1-4 hours of initiating sexual activity, while others prescribed ongoing daily administration. Long-term research on daily vs. on-demand administration is not available, but daily use may require more medical monitoring and possibility of drug interactions than on-demand use.
The importance of correct dose titration has been emphasized by various studies. Some patients only require low doses (25mg) of sildenafil (Tuzgen et al. 2006), while over 50% of patients respond to a 50mg dose (Soler et al. 2007a). Whereas other 50-70% of patients need a higher dose of 20mg of vardenafil or tadalafil (Giuliano et al. 2006; 2007; Soler et al. 2007a; Lombardi et al. 2009a). Kimoto et al. (2006) reported a 5-point increase in IIEF/EF score following an upward titration of Vardenafil from 10mg to 20mg.
Common side effects of using PDE5i in SCI populations include headache (8-15%) and flushing (3-14%), and UTIs followed by dyspepsia, nasal congestion, dizziness, visual disturbances, and infrequently, back pain (Ergin et al. 2008; Khorrami et al. 2010; Schmid et al. 2000). Priapism (prolonged erection) and symptoms of dysreflexia are not reported in the SCI population after PDE5i use (Giuliano 1999). Instances of symptomatic hypotension that require withdrawal of PDE5i have rarely been reported (Giuliano et al. 2006; Lombardi et al 2009a). Garcia-Bravo et al. (2006) noted that patients with injuries above T6 have often been systematically excluded from earlier studies due to potential risks of autonomic dysreflexia and, more particularly, concern about inducing hypotension. A small study demonstrated significant reductions in blood pressure in individuals with a higher SCI lesion (n=12) compared to patients with neurologic levels below T5 (n=10) up to 4 hours after taking sildenafil (50mg dose). None of the patients with high-level SCI reported hypotensive symptoms. Although not a primary question in their study, Sheel et al. (2005) also noted a significant hypotensive effect of sildenafil being present in a group of 8 participants with tetraplegia. Data supports an adequate tolerance of sildenafil in men with high-thoracic level paraplegia. However, despite a general absence of clinical reports of symptomatic postural hypotension associated with other PDE5i use, these studies suggest that men with tetraplegia may be at risk of significant hypotension during orthostatic challenges and some caution should be exercised in this group after taking PDE5i.
Three studies (2 RCTs and 1 case series) have tried oral medications other than PDE5i for men with SCI. Cardenas et al. (2007) assessed the safety and efficacy of fampridine-SR in patients with incomplete injuries. Strong trends were observed between fampridine-SR and increased IIEF scores, levels of sexual desire, and erection frequency and firmness compared to placebo groups. However, adverse events were frequently reported, including pain, dizziness, insomnia, nervousness, paresthesia and one seizure, with 24% of patients discontinuing this trial, particularly those taking higher dose (40mg b.i.d.) of fampridine-SR. This study used considerably higher doses of fampridine-SR than an earlier exploratory trial (Potter et al. 1998) in 26 men with incomplete SCI, and reported statistical improvement in Global Assessment of Patient Satisfaction, but only five patients (19%) reported stronger, more frequent and better sustained erections. Apomorphine, a relatively successful medication in men without SCI, was used for 22 men with SCI and noted to have an overall low rate of response for erectile dysfunction, with 41% experiencing side effects (headache, nausea, tiredness) (Strebel et al. 2004).
Conclusion
There is one meta-analysis (Tienforti et al. 2024) PDE5i were four times more effective than placebo in improving erectile function, with Tadalafil, Sildenafil, and Vardenafil all effective in the 70-80% range.
There is level 1 evidence from multiple RCTs Derry et al. 1998; Giuliano et al. 1999; Del Popolo et al. 2004; Giuliano et al. 2006; Giuliano et al. 2007; Ergin et al. 2008; Khorrami et al. 2010; Ohl et al. 2017; Soler et al. 2007) that supports the use of PDE5i as a safe and effective treatment for erectile dysfunction in men with SCI.
