α-Blockers

The European Association of Urology current clinical guidelines state the use of α-blockers should be restricted to men with moderate to severe LUTS. Furthermore, these pharmacologic agents are often considered the first line of pharmacotherapy for BPH-LUTS. α-Blockers are known for their ability to rapidly relieve LUTS by interrupting the stimulation of α-adrenoceptors located on the smooth muscle in either the neck of the bladder, the prostate, or the prostatic urethra. Currently, there are several different α-blockers commercially available, which are silodosin, alfuzosin, doxazosin, terazosin, and tamsulosin.

RCTs with direct comparisons between different α-blockers are minimal. However, Chapple and colleagues compared the effectiveness of silodosin 8 mg, tamsulosin 0.4 mg, and a placebo among 1228 men in an RCT. Researchers evaluated the patient’s International Prostate Symptom Score (IPSS) and maximum urinary flow rate (Qmax). Those patients in both pharmacotherapy groups demonstrated statistical improvements in both IPSS scores and Qmax when compared with those in the placebo group. Comparably, both silodosin and tamsulosin were equally effective in relieving the patient of LUTS; however, follow-up in those taking silodosin showed marked improvements in nocturia. Furthermore, silodosin in comparison to other α-blockers is highly selective for α-1A andrenoceptor subtype over subtype 1B. The high affinity of silodosin is thought to have a minimal prevalence for cardiovascular adverse events, but higher incidence of ejaculatory dysfunction.

5-α-Reductase Inhibitors

In normal development, the growth of the prostate is regulated by the conversion of testosterone to dihydrotestosterone (DHT) by 5-α-reductase (5-AR) existing as type 1 and type 2. Those with BPH tend to have an overabundance of DHT leading to BPH. In order to combat this accumulation, the use of 5-AR inhibitors has been effective, and unlike α-blockers, has a direct effect on reducing the prostatic tissue. The 2 main 5-AR inhibitors used for treating BPH/LUTS currently available are dutasteride and finasteride. The difference between the 2 is that dutasteride is capable of inhibiting both subtypes 1 and 2, whereas finasteride inhibits only subtype 2. Nickel and colleagues evaluated the effectiveness of dutasteride and finasteride in a head-to-had trial. This study, known as the Enlarged Prostate International Comparator Study (EPICS), was a multicenter randomized double-blind study of 1630 men older than the age of 50. Researchers found that both therapies were comparably effective in improving Qmax, reducing prostatic volume, and reducing other urinary symptoms in men with BPH when administered over a 12-month period.

Kaplan and colleagues retrospectively evaluated the safety, efficacy, and prostate volume (PV) over a 5-year period in BPH patients who were either treated with dutasteride or finasteride. Efficacy was evaluated using the following measures: peak urinary flow rate (Qmax), PV, postvoid residual urine volume (PVR), prostate-specific antigen (PSA), and IPSS. From baseline to the 5-year mark, there were no significant differences in Qmax, PV, PVR, PSA, or IPSS for those in the finasteride group compared with those taking dutasteride. Furthermore, those taking dutaseride had a higher incidence of sexual side effects, such as erectile dysfunction (ED) and ejaculatory dysfunction ( P <.01) compared with those on finasteride. In sum, men presenting with LUTS secondary to BPH on finasteride had less adverse events.

Anticholinergics Therapy

As LUTS secondary to BPH treatment has developed, a new class of drug therapies has emerged known as anticholinergics, once thought to be contraindicated in men suffering from BPH. The use of this pharmacotherapy has been effective in treating detrusor overactivity as well as storage symptoms. Drug therapies currently available are MRAs, also known as anticholinergics. There have been limited RCTs assessing direct head-to-head trials evaluating the efficacy of different anticholinergics. In 2008, Kaplan and colleagues evaluated the efficacy of tolterodine, solifenacin, or darifenacin in 107 men with LUTS secondary to BPH currently taking α-blockers with overactive bladder (OAB). The study criteria were defined as men over the age of 45 years, those who had documented micturition frequency more than 8 voids per day, urgency more than 3 times per day, and an IPSS score greater than 12. Kaplan and colleagues evaluated efficacy through evaluating micturitions over a 24-hour period and urgency as well as IPSS scores. Tolterodine, solifenacin, and darifenacin were all effective in reducing frequency over 24 hours and total IPSS scores ( P <.05). Furthermore, those taking tolterodine ( P <.01) and solifenacin ( P <.05) showed significant reductions in micturition frequency and IPSS storage symptoms ( P <.01). Darifenacin showed a significant increase in overall PVR (≥50 mL). Five individuals taking darifenacin went into urinary retention and required a catheter to alleviate the adverse event. In conclusion, daridenacin was not recommended as an effective line of therapy to improve symptoms of LUTS secondary to BPH due to the profile of increased side effects.

β-3-Andrenoceptor Agonists

In the bladder, β-3-andrenoceptor agonists are known to be the principal subtype among all β-adrenoceptors. In multiple studies, it has been shown that stimulation of these types of receptors may feasibly increase a patient’s bladder capacity without compromising other important urinary factors. β-3-Adrenoceptor agonists are recommended for men with LUTS secondary to BPH with OAB. Globally, there have been several clinical trials evaluating the safety, efficacy, and tolerance among men with LUTS using the β3-agonist mirabegron. Mirabegron targets receptors located on the smooth muscle to decrease detrusor overactivity while promoting relaxation of urothelial functions. Using mirabegron, Nitti and colleagues assessed different urodynamic parameters of men with bladder outlet obstruction and LUTS. In total, 200 men were enrolled in the study with 3 groups: mirabegron 50 mg, mirabegron 100 mg, and a placebo. After a 3-month follow-up, the researchers discovered a significant decrease in urinary frequency versus those taking the placebo, whereas those in the mirabegron 50-mg group showed the most significant decrease in urine urgency. Although results are promising, further studies are needed that evaluate direct head-to-head comparisons to assess this new therapy.

In a systematic literature review, Maman and colleagues compared the efficacy and safety of various medical treatments used to manage symptoms of OAB. In their analysis, they used changes in symptoms such as micturition frequency and incontinence and the incidence of adverse effects that are associated with various OAB medications. They discovered mirabegron was as effective as anticholinergics in reducing frequency of micturition incontinence along with a lower incidence of adverse events.

Phosphodiesterase Type 5 Inhibitors

Despite the main objective to alleviate symptoms of LUTS and BPH, many treatments can cause adverse events, which can be detrimental on the patient’s sexual function during and beyond treatment. Because of these adverse effects, the introduction of PDE5-Is has been evaluated and identified as a viable form of treatment to combat LUTS/BPH and comorbidities such as ED. The most commonly used PDE5-Is are sildenafil, tadalafil, and vardenafil. Patients with BPH-LUTS and who have a history of ED are viable candidates for this line of drug treatment. These agents work to increase intracellular levels of cGMP, which in turn reduce detrusor, prostate, and urethra smooth muscle tone. The only significant difference among these drugs is their duration of action with tadalafil lasting up to 32 hours longer than the others. Clinical studies have demonstrated that the use of either of these PDE5-Is can have significant improvements in LUTS in men with BPH. Despite this, clinical trials have not showed any meaningful changes in outlet obstruction such as PVR volume.

Unfortunately, there are no clinical trials assessing the effectiveness of PDE5-Is using direct comparison; however, Yuan and colleagues in their meta-analysis of medical treatments used for LUTS secondary to BPH evaluated the efficacy within the different formulations. The measures evaluated for efficacy were IPSS scores and peak urinary flow rate. Similarly, they found IPSS scores and peak urinary flow were improved comparably across all groups: vardenafil, sildenafil, and tadalafil.