Male Lower Urinary Tract Symptoms in Primary Care Setting

Lower urinary tract symptoms in men:An overview

Lower urinary tract symptoms (LUTS) are described as a cluster of urinary symptoms that are classified into three general categories: voiding, storage, and postmicturation symptoms (Table1). Males show an increased propensity to develop LUTS with varied presentation as their age advances. The global increase in the ageing population has contributed linearly to the prevalence of LUTS in older men. It is estimated that 90% of men between 45 and 80 years of age have LUTS. The cause of LUTS in males is mutlifactorial.¹Dimitropoulos K, Gravas S. New therapeutic strategies for the treatment of male lower urinary tract symptoms. Research and Reports in Urology. 2016;8:51-59.   ²Lower urinary tract symptoms in men: management. https://www.nice.org.uk/guidance/cg97/chapter/Introduction. Accessed on: 27/6/2016.   ³National Clinical Guideline Centre (UK). The Management of Lower Urinary Tract Symptoms in Men [Internet]. London: Royal College of Physicians (UK); 2010. (NICE Clinical Guidelines, No. 97.) Appendix A, Scope. Available from: http://www.ncbi.nlm.nih.gov/books/NBK65067/  Unlike the widely held view that regarded benign prostate hypertrophy (BPH) as the hallmark of the LUTS in males, it is now increasingly recognized that the differential diagnosis of LUTS comprises both urological and non-urological conditions.⁴Lepor H. Pathophysiology of Lower Urinary Tract Symptoms in the Aging Male Population. Reviews in Urology. 2005;7(Suppl 7):S3-S11.   LUTS can significantly deter men’s quality of life and can progress towards a serious pathology of the urogenital tract.⁵Kirby M, Chapple C, Jackson G, et al. Erectile dysfunction and lower urinary tract symptoms: a consensus on the importance of co-diagnosis. International Journal of Clinical Practice.2013;67(7):606-618.   In addition to the impairment of the quality of life parameters, an increased risk of fall and hindrance in day-to-day activity, males with LUTS experience elevated levels of psychosocial distress,depression and anxiety. This underlines the overall impact of LUTS on the mental, social and physical well being of the affected individuals.⁶Matthew A, Elterman D. Men’s mental health: Connection to urologic health. Canadian Urological Association Journal. 2014;8(7- 8 Suppl 5):S153-S155.  

Risk factors and etiology of LUTS

The combination of symptoms in LUTS establishes a complex interaction between the bladder and the outflow tract of urine.⁷   An array of risk factors affecting the functioning of the bladder, prostate and urethra of ten contribute to LUTS. These factors include age,hormones, inflammatory processes, lifestyle, metabolic diseases, congenital factors. Socioeconomic factors and nocturnal enuresis have also been investigated as the cause of LUTS with varying results (Box 1).⁸Parsons JK. Benign Prostatic Hyperplasia and Male Lower Urinary Tract Symptoms: Epidemiology and Risk Factors. Current Bladder Dysfunction Reports. 2010;5(4):212-218.   ⁹Haidinger G, Temml C, Schatzl G, Brössner C, Roehlich M,Schmidbauer CP, Madersbacher S. Risk factors for lower urinary tract symptoms in elderly men. For the Prostate Study Group of the Austrian Society of Urology. Eur Urol. 2000 Apr;37(4):413-20.  

Table 2 comprehensively depicts urological and non-urological causes of LUTS in males.¹⁰Homma Y, Araki I, Igawa Y, Ozono S, Gotoh M, Yamanishi T,Yokoyama O, Yoshida M; Japanese Society of Neurogenic Bladder.Clinical guideline for male lower urinary tract symptoms. Int J Urol.2009 Oct;16(10):775-90.  

A paradigm shift from prostate to bladder functioning in LUTS

In men, LUTS is often concurrent with BPH. The progression of BPH can lead to benign prostatic enlargement (BPE) resulting in an enlarged prostate, or the voiding dysfunction along with bladder outlet obstruction (BOO). Approximately 90% of men tend to develop histologic evidence of BPH by 80 years of age with varying degree of prostatic enlargement.¹¹Lepor H. Pathophysiology of Benign Prostatic Hyperplasia in the Aging Male Population. Reviews in Urology. 2005;7(Suppl 4):S3-S12.   However,the current clinical understanding and the management LUTS has drifted from the prostate to the bladder. An increasing number of incidences are suggestive of bladder as the central organ in the pathogenesis of LUTS. Evidences have shown that bladder dysfunction is directly involved in the development of symptoms, and as such managing bladder disorder could control LUTS.The contribution of bladder dysfunction to male LUTS is directly linked to overactive bladder (OAB) symptoms.¹²Roosen A, Chapple CR, Dmochowski RR, et al. A refocus on the bladder as the originator of storage lower urinary tract symptoms: a systematic review of the latest literature. Eur Urol.2009;56(5):810-819.    ¹³Chapple CR, Roehrborn CG. A shifted paradigm for the further understanding, evaluation, and treatment of lower urinary tract symptoms in men: focus on the bladder. Eur Urol. 2006;49(4):651-658.   The storage subcategory of LUTS is synonymous with OAB, defined by the International Continence Society (ICS) as ‘urgency, with or without urge incontinence,usually with frequency and nocturia. OAB is often associated with detrusor overactivity (DO), a urodynamic observation characterized by involuntary detrusor contractions during bladder filling. DO is an outcome of the impact of many factors such as hormonal changes,BOO, aging, ischemia, and concomitant neurologic and non-neurologic conditions that may ultimately impact bladder function and lead to LUTS.¹⁴Dmochowski RR, Gomelsky A. Overactive bladder in males.Therapeutic Advances in Urology. 2009;1(4):209-221.  

Evaluation and clinical assessment of male urinary tract symptoms

Examination is an integral part of evaluating both subjective (symptoms and quality of life issues) and objective aspects (physiological function of lower urinary tract) of patients presenting with LUTS.¹⁰Homma Y, Araki I, Igawa Y, Ozono S, Gotoh M, Yamanishi T,Yokoyama O, Yoshida M; Japanese Society of Neurogenic Bladder.Clinical guideline for male lower urinary tract symptoms. Int J Urol.2009 Oct;16(10):775-90.  

• Clinical examination: It comprises a detailed medical history that focuses on the nature and duration of the symptoms, prior surgical procedures, general health issues, sexual function or dysfunction, medications currently taken, and the patient’s fitness for possible surgical intervention as needed.It includes all the factors that hamper the qualityof-life of the patients.¹⁵Warren GJ, Erickson BA. The role of noninvasive testing and questionnaires in urethroplasty follow-up. Translational Andrology and Urology. 2014;3(2):221-226.  
• Physical examination comprising digital rectal examination (DRE): The lower abdomen, pelvis,and external genitalia should be inspected for any abnormalities including neurological ones. Lower abdominal distension suggests urinary retention.DRE should be performed to assess anal sphincter tone in addition to prostate gland size, and shape.The prostate is palpable anteriorly and consistency is judged accordingly.¹⁶Roehrborn CG. Focus on Lower Urinary Tract Symptoms:Nomenclature, Diagnosis, and Treatment Options: Highlights from the 5th International Consultation on Benign Prostatic Hyperplasia June 25-27, 2000, Paris, France. Reviews in Urology.2001;3(3):139-145.   ¹⁷National Clinical Guideline Centre (UK). The Management of Lower Urinary Tract Symptoms in Men [Internet]. London: Royal College of Physicians (UK); 2010. (NICE Clinical Guidelines, No. 97.) 4,Diagnosis. Available from: http://www.ncbi.nlm.nih.gov/books/NBK65072/.  
• Symptom and QOL questionnaires: Males with LUTS often report varied symptoms and thus, diagnosis of the underlying condition using the symptoms alone becomes difficult. Symptoms are often usually assessed using questionnaires. An array of questionnaires is used to assess the diseases that manifest LUTS in males as depicted in box 2. Some questionnaires are not disease-specific, and thus can be used for patients with no definite diagnosis or multiple conditions. The International Consultation on Incontinence Modular Lower Urinary Tract Symptoms Questionnaire (ICIQ-MLUTS) and the Core Lower Urinary Tract Symptoms Score (CLSS)are often used for the general assessment.¹⁰Homma Y, Araki I, Igawa Y, Ozono S, Gotoh M, Yamanishi T,Yokoyama O, Yoshida M; Japanese Society of Neurogenic Bladder.Clinical guideline for male lower urinary tract symptoms. Int J Urol.2009 Oct;16(10):775-90.   ¹⁸Okamura K, Nojiri Y, Yamamoto M, Kobayashi M, Okamoto Y, Yasui T. [Questionnaire survey on lower urinary tract symptoms (LUTS) for patients attending general practice clinics]. Nihon Ronen Igakkai Zasshi. 2006 Jul;43(4):498-504.  

• Frequency volume charts (voiding diaries, bladder diaries / charts): Voiding diaries form a part of the initial diagnosis strategy in patients complaining of LUTS. These are simple, non-invasive tools,particularly advised for those who have storage symptoms such as increased urinary frequency and incontinence. These diaries are indicative of the voiding pattern, the severity of symptoms and add objectivity to the history. They also reflect the impact on the patient’s life and may show ‘coping strategies’ that the patient has devised in order to manage his symptoms. They are also useful in identifying abnormalities of renal origin such as abnormal production of urine related to the circadian rhythm. A number of different diaries have been defined by the International Continence Society (ICS) (Box 3). These diaries are used to record the possible time of the event such as void and episodes of incontinence, measuring the volume of void using a graduated container and time of awake and sleep. The patient are directed to continue the daily activity and diaries maintained for at least 24 hours although in practice a period of 3-7 days is usually chosen.¹⁹National Clinical Guideline Centre (UK). The Management of Lower Urinary Tract Symptoms in Men [Internet]. London: Royal College of Physicians (UK); 2010. (NICE Clinical Guidelines, No. 97.) 4,Diagnosis. Available from: http://www.ncbi.nlm.nih.gov/books/NBK65072/  
• Blood and urine tests: Urine analysis forms the first-line of investigation and is recommended for exclusion of hematuria, proteinuria, pyuria,or other pathological findings. This can be done either by a dipstick test or by urinary sediment after centrifugation. A mid-stream urine (MSU) sterile sample is the usual method of collecting urine from adults. However, in cases of infection of prostate and urethra the initial voided and terminal urine samples are preferred. Serum creatinine measurement is recommended as a screening test for renal dysfunction. Prostate-specific antigen(PSA) is highly sensitive to prostate cancer,and is recommended for all men complaining of LUTS. PSA testing can be offered at the physician’s discretion if LUTS are suggestive of benign prostate enlargement (BPE), the prostate feels abnormal on DRE, or the patient is concerned about prostate cancer.¹⁰Homma Y, Araki I, Igawa Y, Ozono S, Gotoh M, Yamanishi T,Yokoyama O, Yoshida M; Japanese Society of Neurogenic Bladder.Clinical guideline for male lower urinary tract symptoms. Int J Urol.2009 Oct;16(10):775-90.   ¹⁶Roehrborn CG. Focus on Lower Urinary Tract Symptoms:Nomenclature, Diagnosis, and Treatment Options: Highlights from the 5th International Consultation on Benign Prostatic Hyperplasia June 25-27, 2000, Paris, France. Reviews in Urology.2001;3(3):139-145.   ²⁰Lower urinary tract symptoms in men management.Available at: https://www.nice.org.uk/guidance/cg97/chapter/1-Recommendations. Accessed on: 28/6/2016.  

• Urinary flow measurement > Uroflowmetry: It is a non invasive and inexpensive test that gives useful information regarding voiding function by measuring the rate of flow of voided urine. It measures urine voided per unit time, which is usually expressed as milliliters per second. It includes assessment of the flow pattern, voided volume,maximum flow rate (Q_max), voiding time, and time to maximum flow. It is used to suggest the presence of bladder outlet obstruction (BOO) or a poorly functioning detrusor. However, the final confirmation is based on further urodynamic studies.
• Ultrasound post-void residual (PVR): It is a noninvasive screening test and used to measure postvoid residual urine volume (PVR), the amount of residual urine in the bladder after a voluntary void in order to evaluate the voiding dysfunction. Most urologists suggest volumes of 50 mL to 100 mL constitute the lower threshold defining abnormal residual urine volume. Large PVRs are associated with UTIs, spinal cord injury or diabetes. Very large PVRs (>300 mL) may be associated with an increased risk of upper urinary tract dilation, renal insufficiency, BOO or bladder hypocontractility or acontractility.Portable ultrasound devices can be used to scan and calculate the volume of urine in the bladder (whether in retention or post-void residual).More accurate assessment of post void residuals can be obtained by catheterisation, but this is invasive and patients generally dislike this means of assessing residual urine.¹⁰Homma Y, Araki I, Igawa Y, Ozono S, Gotoh M, Yamanishi T,Yokoyama O, Yoshida M; Japanese Society of Neurogenic Bladder.Clinical guideline for male lower urinary tract symptoms. Int J Urol.2009 Oct;16(10):775-90.   ²¹Kelly CE. Evaluation of Voiding Dysfunction and Measurement of Bladder Volume. Reviews in Urology. 2004;6(Suppl 1):S32-S37.  

Interventional strategies for LUTS

An array of therapeutic modalities is available according to individual patients’ preference and physicians’discretion. These are:²²Arianayagam M1, Arianayagam R, Rashid P. Lower urinary tract symptoms -current management in older men. Aust Fam Physician. 2011 Oct;40(10):758-67.  

• Watchful waiting (including reassurance and/or behavioural modification)
• Pharmacological therapy
• Surgery

Figure 1 depicts the step-wise approach towards treatment of LUTS in males.

Anticholinergics/antimuscarinics in management of LUTS

Anticholinergics (antimuscarinics) have been used for the treatment for urgency, frequency and urge incontinence and are associated with improvement in bladder contractions, bladder capacity and reducing involuntary detrusor contractions. Their anticholinergic effects are mediated through actions over the M2 and M3 receptors,which are prevalent in the bladder. However, since muscarinic receptors are also located in other organ systems throughout the body, and since antimuscarinic drugs are frequently non-selective, numerous other effects or rather adverse effects may result from their use and seriously impairing a patient’s physical as well as mental well being.²³Jayarajan J, Radomski SB. Pharmacotherapy of overactive bladder in adults: a review of efficacy, tolerability, and quality of life. Research and Reports in Urology. 2014;6:1-16.   ²⁴Andersson KE. Antimuscarinics for treatment of overactive bladder.Lancet Neurol. 2004 Jan;3(1):46-53.  

Elderly patients are vulnerable to the anticholinergic action of drugs owing to the ongoing aging process and constant fear of drug interactions. The classic anticholinergic problems of decreased secretions,slowed gastrointestinal motility, blurred vision, increased heart rate, heat intolerance, sedation and possibly mild confusion can further deteriorate the health of older patients.²⁵Feinberg M. The problems of anticholinergic adverse effects in older patients. Drugs Aging. 1993 Jul-Aug;3(4):335-48.   The use of anticholinergic/antimuscarinic drugs results in both peripheral and central adverse reactions and have been shown in table 3.²⁶Lieberman JA. Managing Anticholinergic Side Effects. Primary Care Companion to The Journal of Clinical Psychiatry. 2004;6(suppl 2):20-23.  

Role of flavoxate in LUTS

Antispasmopdic drugs have long been used in treating various symptoms of LUTs associated with OAB. Among,the various antispasmodics, flavoxate is the first drug that was approved by FDA for the treatment of urinary complaints. The drug is a flavone derivative with smooth muscle relaxing activity. It has a broad range of indications and is primarily used in the treatment of urogenital disorders with minimal side effects and high tolerability.²⁷Hsieh K, Taylor JA, Albertsen PC Lower urinary tract symptoms in the older male. Conn Med. 2003 Sep;67(8):487-90.   ²⁷Hesch K. Agents for treatment of overactive bladder: a therapeutic class review. Proceedings (Baylor University Medical Center). 2007;20(3):307-314.   ²⁹Zor M1, Aydur E, Dmochowski RR. Flavoxate in urogynecology: an old drug revisited. Int Urogynecol J. 2015 Jul;26(7):959-66.   Its primary action is mediated through its selective and direct muscle relaxant activity mediated through superimposition of myotropic, calcium antagonistic and local anaesthetic activity (figure 2).³⁰Cazzulani P, Panzarasa R, Luca C, Oliva D, Graziani G. Pharmacological studies on the mode of action of flavoxate. Arch Int Pharmacodyn Ther. 1984 Apr;268(2):301-12.  

Clinical evidence on the efficacy and tolerability of flavoxate in LUTS

Various studies have documented the efficacy of flavoxate in LUTs. A study³¹Gu FL, Reng ZY, Shang GZ, Shao HX, Wang B, Cheng ZD, Jiang Y,Zhao WP, Zheng JF, Qu CT, et al. Treatment of urgency and urge incontinence with flavoxate in the People’s Republic of China. J Int Med Res. 1987 Sep-Oct;15(5):312-8.   was conducted involving 366 patients with urgency/incontinence of various types. The patients were divided into 2 groups: 336 patients were administered flavoxate 200 mg three times daily, orally,for 2 weeks and 33 patients received a daily dosage of 1200 mg. It was reported that 228 (67%) were completely cured of urgency/incontinence symptoms, 66 (20%) were improved and 42 (13%) patients were unchanged.Flavoxate was found to be effective in 77.4% of patient’s refractory to previous anti-cholinergic treatment.Hence, flavoxate has been deemed an effective and well tolerated treatment for urgency/incontinence due to various causes. These findings were further coroborrated by another study³²Fehrmann-Zumpe P, Karbe K, Blessman G. Using flavoxate as primary medication for patients suffering from urge symptomatology. Int Urogynecol J Pelvic Floor Dysfunct. 1999;10(2):91-5.   that used flavoxate for urge incontinence. The study comprised 1800 patients in a sub group. The study results showed a reduction of dysuria (37%), nocturia (53%), and both daytime (61%) and nighttime urge (69%) in a sub group (618 patients).Bladder volume at first urge sensation increased by 55.1±58.8 ml (36%), which was comparable to data from the entire group (1800 patients).

Patients suffering from LUTS arising from inflammation and/or infection or from spasm following diagnostic or therapeutic procedures, use of flavoxate afford to confer significant improvement in frequency, suprapubic pain,dysuria, hesitancy and burning.³³Baert L. Controlled double-blind trail of flavoxate in painful conditions of the lower urinary tract. Curr Med Res Opin. 1974-1975;2(10):631-5.   The effects of flavoxate on hyperactive detrusor contraction are also found to be satisfactory. The urodynamic data showed diminishing of the mean pressure during uninhibited detrusor contraction by almost 50% and the delay of the onset by 80% of bladder capacity. The primary effect of flavoxate was documented in motoric urge patients.³⁴Jonas U, Petri E, Kissel J. Effect of flavoxate on hyperactive detrusor muscle. Eur Urol. 1979;5(2):106-9.   Hence, the above instances showed flavoxate to be effective and well tolerated (box 4).

Tolerability profile of flavoxate

Flavoxate acts as a spasmolytic agent with no antimuscarinic activity and has least risk of antimuscarinic/anticholinergic side effects.²⁷Hesch K. Agents for treatment of overactive bladder: a therapeutic class review. Proceedings (Baylor University Medical Center). 2007;20(3):307-314.   A Cochrance meta-analysis compared anticholinergic drugs with other drugs for the treatment of OAB. Flavoxate was compared with anticholinergics in 10 trials. The study reported no difference in cure rates between anticholinergics and flavoxate but adverse effects were more frequent in anticholinergic groups versus flavoxate groups.³⁵Roxburgh C, Cook J, Dublin N. Anticholinergic drugs versus other medications for overactive bladder syndrome in adults. Cochrane Database Syst Rev. 2007;(3):CD003190.   Flavoxate also significantly increased bladder volume capacity (BVC), with better results when compared to other drugs such as emepronium bromide and propantheline.³⁶Arcaniolo D, Conquy S, Tarcan T. Flavoxate: present and future. Eur Rev Med Pharmacol Sci. 2015;19(5):719-31.   Extensive researches and considerable clinical experience with flavoxate are suggestive of its clinical efficacy, safety and tolerability profile with least risk of anticholinergic side effects.

These above instances provide a strong case for the use of flavoxate in patients presenting with OAB and LUTS.

Conclusion

Lower urinary tract symptoms in men refer to a combination of urinary symptoms. Majority of men experience LUTS. It’s prevalence and severity increases with age. Men with LUTS often experience urinary incontinence or OAB symptoms which are an outcome of complex interplay of pathophysiology, including bladder and bladder outlet dysfunction.LUTS in men have significant detrimental effects on physical and mental functioning. The medical management of LUTS is aimed at addressing bothersome symtomatology in patients. The pharmacologic options used in combination of behavior modification are the first line treatment strategy. The time-tested and clinically proven antispasmodic flavoxate is extensively used in patients with urinary incontinence owing to its favorable tolerability and efficacy. The drug has least anticholinergic side effects and can be used in elderly and vulnerable patient population with LUTS.

References

1. Dimitropoulos K, Gravas S. New therapeutic strategies for the treatment of male lower urinary tract symptoms. Research and Reports in Urology. 2016;8:51-59.
2. Lower urinary tract symptoms in men: management. https://www.nice.org.uk/guidance/cg97/chapter/Introduction. Accessed on: 27/6/2016.
3. National Clinical Guideline Centre (UK). The Management of Lower Urinary Tract Symptoms in Men [Internet]. London: Royal College of Physicians (UK); 2010. (NICE Clinical Guidelines, No. 97.) Appendix A, Scope. Available from: http://www.ncbi.nlm.nih.gov/books/NBK65067/
4. Lepor H. Pathophysiology of Lower Urinary Tract Symptoms in the Aging Male Population. Reviews in Urology. 2005;7(Suppl 7):S3-S11.
5. Kirby M, Chapple C, Jackson G, et al. Erectile dysfunction and lower urinary tract symptoms: a consensus on the importance of co-diagnosis. International Journal of Clinical Practice.2013;67(7):606-618.
6. Matthew A, Elterman D. Men’s mental health: Connection to urologic health. Canadian Urological Association Journal. 2014;8(7- 8 Suppl 5):S153-S155.
7. Speakman MJ, Cheng X. Management of the complications of BPH/BOO. Indian Journal of Urology: IJU: Journal of the Urological Society of India. 2014;30(2):208-213.
8. Parsons JK. Benign Prostatic Hyperplasia and Male Lower Urinary Tract Symptoms: Epidemiology and Risk Factors. Current Bladder Dysfunction Reports. 2010;5(4):212-218.
9. Haidinger G, Temml C, Schatzl G, Brössner C, Roehlich M,Schmidbauer CP, Madersbacher S. Risk factors for lower urinary tract symptoms in elderly men. For the Prostate Study Group of the Austrian Society of Urology. Eur Urol. 2000 Apr;37(4):413-20.
10. Homma Y, Araki I, Igawa Y, Ozono S, Gotoh M, Yamanishi T,Yokoyama O, Yoshida M; Japanese Society of Neurogenic Bladder.Clinical guideline for male lower urinary tract symptoms. Int J Urol.2009 Oct;16(10):775-90.
11. Lepor H. Pathophysiology of Benign Prostatic Hyperplasia in the Aging Male Population. Reviews in Urology. 2005;7(Suppl 4):S3-S12.
12. Roosen A, Chapple CR, Dmochowski RR, et al. A refocus on the bladder as the originator of storage lower urinary tract symptoms: a systematic review of the latest literature. Eur Urol.2009;56(5):810-819.
13. Chapple CR, Roehrborn CG. A shifted paradigm for the further understanding, evaluation, and treatment of lower urinary tract symptoms in men: focus on the bladder. Eur Urol. 2006;49(4):651-658.
14. Dmochowski RR, Gomelsky A. Overactive bladder in males.Therapeutic Advances in Urology. 2009;1(4):209-221.
15. Warren GJ, Erickson BA. The role of noninvasive testing and questionnaires in urethroplasty follow-up. Translational Andrology and Urology. 2014;3(2):221-226.
16. Roehrborn CG. Focus on Lower Urinary Tract Symptoms:Nomenclature, Diagnosis, and Treatment Options: Highlights from the 5th International Consultation on Benign Prostatic Hyperplasia June 25-27, 2000, Paris, France. Reviews in Urology.2001;3(3):139-145.
17. National Clinical Guideline Centre (UK). The Management of Lower Urinary Tract Symptoms in Men [Internet]. London: Royal College of Physicians (UK); 2010. (NICE Clinical Guidelines, No. 97.) 4,Diagnosis. Available from: http://www.ncbi.nlm.nih.gov/books/NBK65072/.
18. Okamura K, Nojiri Y, Yamamoto M, Kobayashi M, Okamoto Y, Yasui T. [Questionnaire survey on lower urinary tract symptoms (LUTS) for patients attending general practice clinics]. Nihon Ronen Igakkai Zasshi. 2006 Jul;43(4):498-504.
19. National Clinical Guideline Centre (UK). The Management of Lower Urinary Tract Symptoms in Men [Internet]. London: Royal College of Physicians (UK); 2010. (NICE Clinical Guidelines, No. 97.) 4,Diagnosis. Available from: http://www.ncbi.nlm.nih.gov/books/NBK65072/
20. Lower urinary tract symptoms in men management.Available at: https://www.nice.org.uk/guidance/cg97/chapter/1-Recommendations. Accessed on: 28/6/2016.
21. Kelly CE. Evaluation of Voiding Dysfunction and Measurement of Bladder Volume. Reviews in Urology. 2004;6(Suppl 1):S32-S37.
22. Arianayagam M1, Arianayagam R, Rashid P. Lower urinary tract symptoms -current management in older men. Aust Fam Physician. 2011 Oct;40(10):758-67.
23. Jayarajan J, Radomski SB. Pharmacotherapy of overactive bladder in adults: a review of efficacy, tolerability, and quality of life. Research and Reports in Urology. 2014;6:1-16.
24. Andersson KE. Antimuscarinics for treatment of overactive bladder.Lancet Neurol. 2004 Jan;3(1):46-53.
25. Feinberg M. The problems of anticholinergic adverse effects in older patients. Drugs Aging. 1993 Jul-Aug;3(4):335-48.
26. Lieberman JA. Managing Anticholinergic Side Effects. Primary Care Companion to The Journal of Clinical Psychiatry. 2004;6(suppl 2):20-23.
27. Hsieh K, Taylor JA, Albertsen PC Lower urinary tract symptoms in the older male. Conn Med. 2003 Sep;67(8):487-90.
28. Hesch K. Agents for treatment of overactive bladder: a therapeutic class review. Proceedings (Baylor University Medical Center). 2007;20(3):307-314.
29. Zor M1, Aydur E, Dmochowski RR. Flavoxate in urogynecology: an old drug revisited. Int Urogynecol J. 2015 Jul;26(7):959-66.
30. Cazzulani P, Panzarasa R, Luca C, Oliva D, Graziani G. Pharmacological studies on the mode of action of flavoxate. Arch Int Pharmacodyn Ther. 1984 Apr;268(2):301-12.
31. Gu FL, Reng ZY, Shang GZ, Shao HX, Wang B, Cheng ZD, Jiang Y,Zhao WP, Zheng JF, Qu CT, et al. Treatment of urgency and urge incontinence with flavoxate in the People’s Republic of China. J Int Med Res. 1987 Sep-Oct;15(5):312-8.
32. Fehrmann-Zumpe P, Karbe K, Blessman G. Using flavoxate as primary medication for patients suffering from urge symptomatology. Int Urogynecol J Pelvic Floor Dysfunct. 1999;10(2):91-5.
33. Baert L. Controlled double-blind trail of flavoxate in painful conditions of the lower urinary tract. Curr Med Res Opin. 1974-1975;2(10):631-5.
34. Jonas U, Petri E, Kissel J. Effect of flavoxate on hyperactive detrusor muscle. Eur Urol. 1979;5(2):106-9.
35. Roxburgh C, Cook J, Dublin N. Anticholinergic drugs versus other medications for overactive bladder syndrome in adults. Cochrane Database Syst Rev. 2007;(3):CD003190.
36. Arcaniolo D, Conquy S, Tarcan T. Flavoxate: present and future. Eur Rev Med Pharmacol Sci. 2015;19(5):719-31.