Phosphodiesterase Type 5 Inhibitors (PDE5i) and Other Oral Agents

Erection is initiated by smooth muscle relaxation of the corpora cavernosa (erectile bodies) of the penis and depends on the nitric oxide-cyclic guanosine monophoshpate [cGMP] pathway. The PDE5i are selective inhibitors of type 5 (cGMP specific) phosphodiesterase, which in turn delay breakdown of cGMP, prolonging and enhancing the erectile response. Apomorphine is a dopamine-receptor agonist important in the control of sexual functioning, whereas 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

Over 2000 men with SCI have been investigated in 14 RCTs and 9 prospective case series (pre-post) studies using oral agents for ED. The evidence supports the use of PDE5i as the first-line of treatment in men with ED secondary to SCI. Sildenafil (Viagra®) being the first available PDE5i has been more frequently studied to date than either vardenafil (Levitra®) or tadalafil (Cialis®). Meta-analysis of case-series reports of sildenafil efficacy have shown a random effects pooled estimate of 79% success (with 95% CI from 68-90%) improving erectile function (EF) sufficient for intercourse at home (DeForge et al. 2006). Ergin et al. (2008) found that sildenafil was effective for improving erective function regardless of completeness of injury however the treatment showed wider impacts among individuals with incomplete injuries. Khorrami et al. (2010) found that sildenafil was more effective in upper motor neuron (UMN) versus lower motor neuron (LMN) injuries, with the latter being no more effective than that found with placebo.

In addition, in a cost-utility study of ED treatments in men with SCI (Mittmann et al. 2005), sildenafil has been shown to be preferred to non-oral treatments, as well as a cost-effective option with a calculated total annual cost of CAN $1,530 and incremental cost-utility ratio less than CAN $20,000 per QALY. Results from 3 large RCTs (Giuliano et al. 2006; 2007; 2008), as well as several case-series studies (Kimoto et al. 2006; Morgentaler et al. 2006; Soler et al. 2007), 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%).

Only one small RCT (n=28) has directly compared the efficacy of different oral treatments in men with SCI (Del Popolo et al. 2004), comparing sildenafil (50mg) and tadalafil (10mg) in a randomized, blinded, cross-over design with washout. In this study, tadalafil significantly increased the percentage of successful intercourse attempts at 24 hours post dosing (68%), compared to sildenafil (18%). The increased duration of action of tadalafil, providing for more spontaneous rather than planned “on-demand” sexual activity, has also been noted as a benefit by other authors (Giuliano et al. 2007; Soler et al. 2007). Of interest, in the study by Del Popolo et al. (2004), two out of 5 patients not responding to sildenafil did respond to tadalafil, both having LMN incomplete lumbar lesions. Two newer studies with higher subject numbers (Khorrami et al. 2010; Ergin et al 2008) have expanded on the effectiveness of PDE5i depending on completeness of injury and whether it is UMN or LMN. There is also lack of effectiveness of PDE5i where there is extensive ischemic damage involving both thoraco-lumbar and sacral cord segments (Schmid et al. 2000). In general though, a lesion above the sacral spinal tract and a higher reflexive erection are predicable favorable parameters for a positive response to all PDE5i (Lombardi et al. 2009a; Soler et al. 2007; Schmid et al. 2000; Sanchez Ramos et al. 2001). It appears that efficacy is maintained with the use of PDE5i over time, and tachphylaxis (a decrease in the response to a drug after repeated doses over a short time period) is rare (Lombardi et al. 2009b).

The importance of correct dose titration has been emphasized by various studies, with over 50% of patients responding to sildenafil at a dose of 50 mg (Soler et al. 2007) and even as low as 25mg in some (Tuzgen et al. 2006), whereas around 50-70% of patients will require the higher dose (20mg instead of 10mg) of vardenafil and tadalafil (Giuliano et al. 2006; 2007; Soler et al. 2007; Lombardi et al. 2009a). Kimoto et al. (2006) reported a 5-point increase in IIEF/EF score following up-titration of Vardenafil from 10 to 20mg. 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%). A recent study (Lombardi et al. 2009a) on tadalfil failed to show a significant improvement in the ejaculatory and orgasmic parameter, however, the improvement in IIEF to > 26 (normal) was apparent in the majority of the men with SCI in the study. With the long acting tadalafil, over 80% of subjects on either 10 or 20 mg of tadalafil were able 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 (however the percentage of men attempting intercourse within versus after 24 hours were approximately 67% versus 33% respectively).

Headache (8-15%) and flushing (3-14%) were noted to be the most common side effects for men with SCI using PDE5i, followed by dyspepsia, nasal congestion, dizziness, visual disturbances and infrequently back pain. Urinary tract infection was also found to be a common adverse event, along with headache, in one sildenafil study (Ergin et al. 2008). Priapism and symptoms of dysreflexia are not reported in the SCI population after PDE5i use (Maytom et al. 1999, Giuliano et al. 1999, Gans et al. 2001). Despite some concerns, cases of symptomatic hypotension requiring withdrawal of medication have rarely been reported with PDE5i (Gans et al. 2001; Giuliano et al. 2006; Lombardi et al. 2009a). Garcia-Bravo et al. (2006) noted that patients with neurological impairment above T6 level had often been systematically excluded from earlier studies due to potential risks of autonomic dysreflexia and, more particularly, concern about inducing hypotension. This 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). Although a maximum drop of 26mmHg (mean change of 17.5mmHg) in systolic and 17mmHg (mean 11mmHg) in diastolic BP was observed, none of these 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 subjects 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 trialed oral medications other than PDE5i for men with SCI. In a RCT assessing safety and efficacy of fampridine-SR in persons with established incomplete SCI (AIS grades C or D), Cardenas et al. (2007) reported strong trends for improved IIEF scores and increased erection frequency and firmness, ability to maintain erections and levels of sexual desire for fampridine-SR 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 level 1a evidence (from 9 RCTs, excluding 2 reporting outcomes of a previous trial: Derry et al. 1998; Giuliano et al. 1999; Hultling et al. 2000; Del Popolo et al. 2004; Giuliano et al. 2006; Tuzgen et al. 2006; Giuliano et al. 2007; Ergin et al. 2008; Khorrami et al. 2010) that supports the use of PDE5i as a safe and effective treatment for erectile dysfunction in men with SCI.