OAB in male patients – bladder outlet or both

Introduction

Lower urinary tract symptoms (LUTS), overactive bladder (OAB), and benign prostatic hyperplasia (BPH) are very commonly experienced in men.¹Chung DE, Sandhu JS. Curr Urol Rep. 2011 Feb;12(1):77-85.   OAB is a highly prevalent condition affecting 17% of the general population, with a significant negative effect on quality of life (QOL), impairing several areas with physical, social, emotional and sexual limitations; the prevalence increases with age in both men and women.²Colli E, Digesu GA, Olivieri L. Expert Opin Investig Drugs. 2007 Jul;16(7):999-1007.  

Based on their temporal relationship to the micturition cycle, LUTS are divided into three categories (Table 1). 3 OAB is synonymous with the storage subcategory of LUTS; the International Continence Society (ICS) defines the condition as ‘urgency, with or without urge incontinence, usually with frequency and nocturia’.³Abrams P, Cardozo L, Fall M, et al. Urology 61: 37-49.  

The symptom combinations are suggestive of urodynamically demonstrable detrusor overactivity.⁴Abrams P, Andersson KE. BJU Int. 2007 Nov;100(5):987-1006.   Bladder outlet obstruction can be a contributing factor in detrusor overactivity, possibly through cholinergic denervation of the detrusor and supersensitivity of cholinergic receptors to acetylcholine.4 All definitions rely on the interplay between bladder and outlet.

Even though the OAB symptoms have considerable prevalence in both men and women, with equally substantial impact on QOL, ironically, OAB symptoms in men are not frequently treated, and medical therapies often aim at bladder outlet obstruction. In fact, OAB symptoms in men are frequently attributed to a bladder outlet obstruction due to BPH and treated accordingly. In contrast, women with similar symptom often receive treatment that is aimed at presumed detrusor overactivity.⁵Rosenberg MT, Staskin DR, Kaplan SA, et al. Int J Clin Pract 61: 1535-1546.   Yet, in men pathophysiology of OAB may have special consideration in the context of BPH and concomitant bladder outlet obstruction.⁶Yamaguchi O, Aikawa K, Shishido K, et al. World J Urol. 2009 Dec;27(6):723-8.   The recent ‘paradigm shift’ in the treatment of male patients with OAB (with or without concomitant outlet obstruction) appear consistent with limitation of prostatespecific treatments in a considerable number of men with OAB symptoms, and the proven safety and benefit of pharmacological treatment of detrusor overactivity in this patient population.⁷Chapple CR, Roehrborn CG. Eur Urol 2006; 49: 651-659.  

Epidemiology

LUTS, OAB, urinary incontinence and LUTS suggestive of bladder outlet obstruction (LUTS/ bladder outlet obstruction) are highly prevalent conditions worldwide. Numbers of affected individuals are projected to increase with time.

An estimated 45.2%, 10.7%, 8.2% and 21.5% of the 2008 worldwide population (4.3 billion) was affected by at least one LUTS, OAB, urinary incontinence and LUTS/ bladder outlet obstruction, respectively, and it is speculated that by 2018, an estimated 2.3 billion individuals will be affected by at least one LUTS (18.4% increase), 546 million by OAB (20.1%), 423 million by urinary incontinence (21.6%) and 1.1 billion by LUTS/ bladder outlet obstruction (18.5%) (Figure 1).⁸Irwin DE, Kopp ZS, Agatep B, et al. BJU Int. 2011;108(7):1132-8.  

The regional burden of these conditions is estimated to be greatest in Asia; the number of affected individuals is expected to increase most in the developing regions of Africa (30.1-31.1% increase across conditions, 2008-2018), South America (20.5-24.7%) and Asia (19.7-24.4%).

Pathophysiology of OA B symptoms

The pathophysiology of OAB is multifactorial and not yet fully understood. In men, the pathophysiology of LUTS and OAB may be from a number of causes including bladder outlet obstruction, detrusor overactivity, or both.⁹MacDiarmid S, Rogers A. Curr Urol Rep. 2007 Jan;8(1):66-73.  ^,10Ouslander JG. N Engl J Med 2004;350: 786-799.  

Though symptoms such as urgency and urge urinary incontinence are outcomes of detrusor overactivity, there are many factors which can influence its development; hormonal changes, aging, bladder outlet obstruction, ischemia, and concomitant neurologic and non-neurologic conditions are factors that may impact bladder function.¹¹Andersson KE. Urology 2003; 62(Suppl 5B): 3-10.  

The mechanisms proposed contributing to OAB symptoms may be sensory or motor, and may be myogenic, neurogenic, mixed, or idiopathic in origin.¹⁰Ouslander JG. N Engl J Med 2004;350: 786-799.  ^,12Andersson KE. Lancet Neurol 2004;3: 46-53.   In addition, various receptors and neurotransmitters associated with the urothelium may also have a role in generation of the symptoms of OAB.

Detrusor overactivity was traditionally thought to result from a decreased capacity to handle increased afferent information or from a loss/decrease of the tonic inhibition of afferent impulses.¹²Andersson KE. Lancet Neurol 2004;3: 46-53.   Consequently, involuntary detrusor contractions may generate from low intensity afferent input and at lower bladder volumes. Andersson proposed a cascade of further peripheral events that may result in detrusor overactivity.¹²Andersson KE. Lancet Neurol 2004;3: 46-53.   There is increased afferent signaling during bladder filling because of an enhanced reaction to heightened wall tension and stretching of the detrusor smooth muscle. Furthermore, increased urothelial signaling to suburothelial nerves may result in increased afferent activity, as may be seen in bladder outlet obstruction and normal aging.

Another theory relates to an increased amount of acetylcholine (ACh) released from the urothelium during bladder filling, above and beyond the typical basal ACh release. As a result, there is increased sensitivity of the detrusor to neurotransmitters attributable to increase in ACh release from neuronal and non-neuronal (urothelial) sources. The resultant detrusor micromotion increases afferent signaling in the sub-urothelium and detrusor, and there is sensation of urgency. ACh is released from the urothelium and the detrusor. The feedback mechanism to the central nervous system (CNS) generates sensation of urgency.

According to the ‘myogenic theory’, morphologic changes in the detrusor, brought on by conditions such as bladder outlet obstruction, normal aging, and neurogenic insults, may be associated with OAB.¹³Brading AF. Urology 1997;50(6A Suppl): 57-67.   Multiple changes associated with these conditions lead to potentially increased excitability between detrusor myocytes.^14-1614) Turner WH, Brading AF. Pharmacol Ther 1997;75: 77-110.
15) Charlton RG, Morley AR, Chambers P et al. BJU Int 1999;84: 953-960.
16) Mills IW, Greenland JE, McMurray G, et al. J Urol 2000;163: 646-651.     Furthermore, the denervation areas may correspond to individual muscle ‘modules’ developing an increased sensitivity to neurotransmitters for instance Ach.¹⁷Drake MJ, Mills IW, Gillespie JI. Lancet 200;358: 401-403.   Similar to denervation supersensitivity, the heightened muscular excitability results in an increased ability for activity to spread among cells. Then, local uncoordinated detrusor contractions cause an increase in afferent signaling. The pathway appears to connect the neurogenic and myogenic theories of OAB.

Symptoms of OAB may also be attributed to bladder outlet obstruction, through changes in intracellular communication between myocytes. An involvement of gap junctions has been implicated considering the belief that detrusor cells are electrically coupled.^18-2018) Daniel EE, Cowan W, et al. Can J Physiol Pharmacol 1983;61: 1247-1273.
19) Andersson KE. Pharmacol Rev 1993;45: 253-308.
20) Neuhaus J,Weimann A, et al. World J Urol 2002;20: 250-254.       Though the expression of connexin 43 has not only been localized in human detrusor smooth muscle, its upregulation in bladder outlet obstruction has been demonstrated.²¹Christ GJ, Day NS, Day M et al. Am J Physiol Regul Integr Comp Physiol 2003;284:R1241-R1248.  ^,22Haferkamp A, Mundhenk J, et al. Eur Urol 2004;46: 799-805.   Moreover, bladders of patients with detrusor activity appear to have abnormal inter-cellular gap junctions.^23-2723) Elbadawi A, Yalla SV, Resnick NM. J Urol 1993;150: 1650-1656.
24) Elbadawi A, Yalla SV, Resnick NM. J Urol 1993;150: 1657-1667.
25) Elbadawi A, Hailemariam S, Yalla SV, et al. J Urol 1997;157: 1802-1813.
26) Elbadawi A, Hailemariam S, Yalla SV, et al. J Urol 1997;157: 1814-1822.
27) Tse V, Wills E, Szonyi G, et al. J Urol 2000;163: 535-539.     As a result, coordinated myogenic contraction of the entire bladder and detrusor overactivity may result due to increased receptormediated muscle contractility and interaction between smooth muscle cells.²⁸Yoshimura N, Kaiho Y, Miyazato M, et al. Naunyn Schmiedebergs Arch Pharmacol 2008;377: 437-448.  

Evaluation of OA B in Men

OAB symptom severity progress dynamically and is also sustained over time.²⁹Irwin DE, Milsom I, et al. Eur Urol. 2010 Oct;58(4):532-43.   The American Urological Association (AUA) Guideline Panel on the Management of BPH has made recommendations regarding the initial evaluation of LUTS in men.³⁰http://www.auanet.org/content/clinical-practice-guidelines/clinicalguidelines/archived-guidelines/chapt_1_appendix.pdf.   Accordingly, a medical history, focusing on the urinary tract, previous surgical procedures, and medical conditions and symptoms that lead to bladder dysfunction or polyuria, is necessary in all men presenting with LUTS suggestive of BPH in order to identify and exclude other causes of voiding dysfunction or comorbidities, which may complicate treatment. A family history of BPH and prostate cancer should be elicited. The presence of locally advanced prostate cancer should be excluded as it can also produce LUTS. The neurologic examination should assess lower extremity neuromuscular function and anal sphincter tone besides the patient’s general mental status and ambulatory status. A urinalysis should be performed to screen for hematuria and urinary tract infection.

A symptom assessment instrument – International Prostate Symptom Score (IPSS) – in the initial assessment of each patient presenting with BPH is recommended; it has been found to be superior to an unstructured interview in quantifying symptom severity and frequency.³¹Barry MJ, Fowler Jr FJ, O’Leary MP, et al. J Urol 148: 1549-1557.   The scale uses 7 questions related to associated symptoms, and classify symptoms in the ranges from mild (0-7) to moderate (8-19) or severe (20-35).

Other validated assessment instruments which address the severity and frequency of LUTS in men with BPH, bother due to symptoms, interfering with daily activities, urinary continence, sexual functioning and health-related quality of life are deemed optional. Urinary flow rate recording and measurement of postvoid residual urine are other optional tests which may follow initial evaluation.

The sixth International Consultation on New Developments in Prostate Cancer and Prostate Disease also published its recommendations relating to initial evaluation of LUTS in men.³²Abrams P, Chapple C, Khoury S, et al. J Urol 2008;181: 1779-1787.   Besides, the recommended tests (history, physical examination, assessment of symptom bother, and urinalysis) being same as those recommended by AUA BPH Guidelines, the panel also recommended a serum prostate specific antigen (PSA) in men with a life expectancy > 10 years or when a diagnosis of prostate cancer can impact the management, in addition to a frequency-volume chart in men with nocturia as a predominant symptom. Furthermore, it recommended validated questionnaires, urinary flow rate recording, frequency-volume charting, and postvoidal residual urine, for men with persistent bothersome LUTS after basic management. In addition, it recommended pressure-flow studies before invasive therapy, unless the maximum flow rate on noninvasive flow recording is less than 10 cc/sec.

Imaging of the prostate with ultrasound (trans-abdominal or transrectal), upper urinary tract imaging with ultrasound or intravenous (IV) urography, and endoscopy of the lower urinary tract are other optional tests which can be included in the diagnosis protocol of men with LUTS.

Treatment

Both pharmacological and non-pharmacological options are included as treatment options for the OAB symptoms. Lifestyle interventions, for example modifying excessive fluid intake, regular exercise, and smoking cessation, may be helpful in overall management. Likewise, wise limitation of caffeine and increasing dietary intake of vegetables, β-carotene, lutein, and vitamin C may also help in lowering the BPH risk.³³Suzuki S, Platz EA, Kawachi I, et al. Am J Clin Nutr 2002;75: 689-697.  ^,34Rohrmann S, Giovannucci E, Willett WC, et al et al. Am J Clin Nutr 2007;85: 523-529.   Also, seeing that the incidence of OAB is high in men with obstructive sleep apnea, additional symptom relief may be offered by addressing this comorbidity.³⁵Kemmer H, Mathes AM, Dilk O, et al. Sleep 2009;32: 271-275.  

Pharmacologic therapy

Though available options include pharmacotherapy, biofeedback, electrical stimulation, bladder training, or a combination of these options, nevertheless, pharmacotherapy is the treatment of choice for OAB symptoms.²Colli E, Digesu GA, Olivieri L. Expert Opin Investig Drugs. 2007 Jul;16(7):999-1007.  ^,36Burgio KL, Locher JL, Goode PS. J Am Geriatr Soc 2000;48: 370-374.   In fact, drug therapy for OAB is associated with improvements in symptoms and QOL.³⁷Basra RK, Wagg A, Chapple C, et al. BJU Int. 2008 Sep;102(7):774-9.   Typically, more invasive non-pharmacologic options, for example intravesical botulinum toxin injection and neuromodulation, are reserved for refractory cases.

The pharmacologic management of male LUTS focuses on two main approaches i.e. ‘prostate-centered’ and ‘symptom-centered’, and is generally directed towards the central or the peripheral neural control pathways or the detrusor muscle.

The ‘prostate-centered’ approach to treating LUTS in men is reliant on the postulation that urinary urgency and frequency result only because of incomplete emptying owing to partial bladder outlet obstruction. However, the assumption has its limitations as it fails to consider the bladder’s role, and overlooking it may leave a proportion of men undertreated – while male LUTS are often attributed to BPH, however, coexisting OAB may be responsible for storage symptoms in a substantial proportion.

Anticholinergic agents: Position in OA B therapy

ACh is the primary contractile neurotransmitter in the human detrusor, and anticholinergics exert their effects on OAB/detrusor overactivity by inhibiting the binding of ACh at cholinergic receptors M(2) and M(3) on detrusor smooth muscle cells and other structures within the bladder wall.⁴Abrams P, Andersson KE. BJU Int. 2007 Nov;100(5):987-1006.  ^,5Rosenberg MT, Staskin DR, Kaplan SA, et al. Int J Clin Pract 61: 1535-1546.  ^,38Abrams P, Andersson KE. Cholinergic receptor antagonists for overactive bladder. BJU Int. 2007 Nov;100(5):987-1006.   Dependent on their antagonistic action at cholinergic receptors on the detrusor muscle, anticholinergic medications inhibit detrusor overactivity, thus, preventing unwanted muscle contraction resulting from the parasympathetic ACh release. Although these are commonly used options, side effects limit their long term compliance. The concern regarding acute urinary retention (AUR) development in men with bladder outlet obstruction likely attributes to reluctance to initiate OAB treatment with an anticholinergic agent. Nevertheless, the warning specifies neither the postvoidal residual urine nor degree of bladder outlet obstruction that would place a man at risk of developing a clinically significant risk of deterioration of his bladder emptying.

Flavoxate

Treatment of OAB with anticholinergic drugs has been considered hazardous in BPH because of concerns that they may predispose to AUR.³⁹Armitage J, Emberton M. Curr Opin Urol. 2008;18(1):11-5.   The presence of phosphodiestrase enzymes in the prostate and the detrusor muscle of the bladder implies that phosphodiestrase inhibitors like Flavoxate may be appropriate candidate therapies for BPH related LUTS. Flavoxate is commonly used in OAB patients who do not achieve symptom relief and QOL improvement with conservative management⁴⁰Novara G, Galfano A, Secco S, et al. Eur Urol. 2008;54(4):740-63.   as it was found to increase bladder capacity significantly, without increasing the residual urine in such patients.⁴¹Pedersen E. Studies on the effect and mode of action of Flavoxate in human urinary bladder and sphincter. Urol Int. 1977;32(2-3):202-8.  

In fact, Flavoxate is the first antispasmodic agent approved by the Food and Drug Administration (FDA) to treat symptoms of OAB.⁴²Hesch K. Proc (Bayl Univ Med Cent). 2007;20(3):307-14.   The drug was found to completely cure the symptoms of urgency/incontinence in 67% patients with urgency/incontinence of various types. Patients were given 200 mg drug three times daily, orally, for 2 weeks.⁴³Gu FL, Reng ZY, Shang GZ, et al. J Int Med Res. 1987;15(5):312-8.   The cure rate increased with the rising dose of the drug, and amongst those receiving a daily dosage of 1200 mg, 82% of patients were completely cured of urgency/incontinence symptoms, and the remaining 18% improved with no sideeffects. Additionally, Flavoxate was also effective in 77.4% of patients refractory to previous anticholinergic treatment.

Treatment did not increase the end-residual volume. The experience, thus, clearly showed Flavoxate as an effective and well tolerated treatment for urgency/incontinence of various causes.

Clinical studies performed in over 2500 patients clearly indicate that Flavoxate has good efficacy and an excellent tolerance, and in controlled clinical trials has shown a therapeutic advantage over other drugs.⁴⁴R. Milani, S. Scalambrino, R. Milia, et al. International urogynecology journal 1993;4(1):3-8.  

Also, in a double blind crossover comparison of Flavoxate with Oxybutynin, even though they had comparable efficacy, only 26.8% patients experienced adverse reactions with Flavoxate compared to 90.2 % with Oxybutynin.⁴⁴R. Milani, S. Scalambrino, R. Milia, et al. International urogynecology journal 1993;4(1):3-8.  

Conclusion

OAB is an important lower urinary tract syndrome that negatively affects the quality of life of millions of people worldwide, and is now recognized as a chronic debilitating condition with huge economic costs. With an ageing population these costs will increase, and, therefore, it is necessary that healthcare systems around the world recognize this impact.⁴⁵Hashim H, Abrams P. Curr Opin Urol. 2007 Jul;17(4):231-6.  

Nevertheless, many symptomatic men remain untreated, and physicians more likely use agents directed at BPH to improve emptying rather than using OAB agents as a firstline therapy. Many of these men treated with α-blockers or 5-alpha-reductase inhibitors will have persistent storage symptoms. Concurrently, there is early evidence suggesting that anticholinergics/Flavoxate are efficacious for male OAB. Further, additional data supports the combination of anticholinergics/Flavoxate and α-blockers in men with concomitant OAB and bladder outlet obstruction. The concern regarding an increased incidence of urinary retention with antimuscarinic use appears to be speculative; so, use of Flavoxate appears to be a more appropriate choice for urgency/incontinence of various causes.

References

1. Chung DE, Sandhu JS. Curr Urol Rep. 2011 Feb;12(1):77-85.
2. Colli E, Digesu GA, Olivieri L. Expert Opin Investig Drugs. 2007 Jul;16(7):999-1007.
3. Abrams P, Cardozo L, Fall M, et al. Urology 61: 37-49.
4. Abrams P, Andersson KE. BJU Int. 2007 Nov;100(5):987-1006.
5. Rosenberg MT, Staskin DR, Kaplan SA, et al. Int J Clin Pract 61: 1535-1546.
6. Yamaguchi O, Aikawa K, Shishido K, et al. World J Urol. 2009 Dec;27(6):723-8.
7. Chapple CR, Roehrborn CG. Eur Urol 2006; 49: 651-659.
8. Irwin DE, Kopp ZS, Agatep B, et al. BJU Int. 2011;108(7):1132-8.
9. MacDiarmid S, Rogers A. Curr Urol Rep. 2007 Jan;8(1):66-73.
10. Ouslander JG. N Engl J Med 2004;350: 786-799.
11. Andersson KE. Urology 2003; 62(Suppl 5B): 3-10.
12. Andersson KE. Lancet Neurol 2004;3: 46-53.
13. Brading AF. Urology 1997;50(6A Suppl): 57-67.
14. Turner WH, Brading AF. Pharmacol Ther 1997;75: 77-110.
15. Charlton RG, Morley AR, Chambers P et al. BJU Int 1999;84: 953-960.
16. Mills IW, Greenland JE, McMurray G, et al. J Urol 2000;163: 646-651.
17. Drake MJ, Mills IW, Gillespie JI. Lancet 200;358: 401-403.
18. Daniel EE, Cowan W, et al. Can J Physiol Pharmacol 1983;61: 1247-1273.
19. Andersson KE. Pharmacol Rev 1993;45: 253-308.
20. Neuhaus J,Weimann A, et al. World J Urol 2002;20: 250-254.
21. Christ GJ, Day NS, Day M et al. Am J Physiol Regul Integr Comp Physiol 2003;284:R1241-R1248.
22. Haferkamp A, Mundhenk J, et al. Eur Urol 2004;46: 799-805.
23. Elbadawi A, Yalla SV, Resnick NM. J Urol 1993;150: 1650-1656.
24. Elbadawi A, Yalla SV, Resnick NM. J Urol 1993;150: 1657-1667.
25. Elbadawi A, Hailemariam S, Yalla SV, et al. J Urol 1997;157: 1802-1813.
26. Elbadawi A, Hailemariam S, Yalla SV, et al. J Urol 1997;157: 1814-1822.
27. Tse V, Wills E, Szonyi G, et al. J Urol 2000;163: 535-539.
28. Yoshimura N, Kaiho Y, Miyazato M, et al. Naunyn Schmiedebergs Arch Pharmacol 2008;377: 437-448.
29. Irwin DE, Milsom I, et al. Eur Urol. 2010 Oct;58(4):532-43.
30. http://www.auanet.org/content/clinical-practice-guidelines/clinicalguidelines/archived-guidelines/chapt_1_appendix.pdf.
31. Barry MJ, Fowler Jr FJ, O’Leary MP, et al. J Urol 148: 1549-1557.
32. Abrams P, Chapple C, Khoury S, et al. J Urol 2008;181: 1779-1787.
33. Suzuki S, Platz EA, Kawachi I, et al. Am J Clin Nutr 2002;75: 689-697.
34. Rohrmann S, Giovannucci E, Willett WC, et al et al. Am J Clin Nutr 2007;85: 523-529.
35. Kemmer H, Mathes AM, Dilk O, et al. Sleep 2009;32: 271-275.
36. Burgio KL, Locher JL, Goode PS. J Am Geriatr Soc 2000;48: 370-374.
37. Basra RK, Wagg A, Chapple C, et al. BJU Int. 2008 Sep;102(7):774-9.
38. Abrams P, Andersson KE. Cholinergic receptor antagonists for overactive bladder. BJU Int. 2007 Nov;100(5):987-1006.
39. Armitage J, Emberton M. Curr Opin Urol. 2008;18(1):11-5.
40. Novara G, Galfano A, Secco S, et al. Eur Urol. 2008;54(4):740-63.
41. Pedersen E. Studies on the effect and mode of action of Flavoxate in human urinary bladder and sphincter. Urol Int. 1977;32(2-3):202-8.
42. Hesch K. Proc (Bayl Univ Med Cent). 2007;20(3):307-14.
43. Gu FL, Reng ZY, Shang GZ, et al. J Int Med Res. 1987;15(5):312-8.
44. R. Milani, S. Scalambrino, R. Milia, et al. International urogynecology journal 1993;4(1):3-8.
45. Hashim H, Abrams P. Curr Opin Urol. 2007 Jul;17(4):231-6.