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Drugs for Lower Urinary Tract Symptoms—Anything New?
Editorials
Drugs for Lower Urinary Tract Symptoms—Anything New? EFFECTIVE treatment for lower urinary tract symptoms (LUTS) continues to be a problem, since available drugs either have insufficent efficacy or unacceptable adverse effects in many patients. Lower urinary tract symptoms include storage, voiding and post-micturition symptoms. Overactive bladder (OAB) is a syndrome defined as urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia.1 Thus OAB, a syndrome of storage symptoms, is a subset of LUTS. In contrast to these symptom-based terms, detrusor overactivty (DO) refers to the urodynamic finding of involuntary detrusor contrctions during bladder filling. Traditionally LUTS has been used mostly to describe male symptoms but this category is no longer tenable because women also experience storage and voiding symptoms, and urodynamioc DO may occur in both genders. From a treatment point of view, it has become clear that even if several drugs can be used as monotherapy for all of these conditions, individualized treatment, sometimes combination therapy, is necessary to obtain an optimal effect. At the 5th International Consultation on Incontinence in February this year drugs used to treat LUTS were discussed and an update of previous recommendations for their use was provided. Focus was given to the many drugs intended for the treatment of OAB. Antimuscarinics are still considered as first line drugs, and the only new addition to the existing sortiment is imidafenacin, currently available in Japan and Korea but not in Western countries. The drug seems to have similar efficacy and adverse effect profiles as other alternatives. However, it should be emphasized that none of the antimuscarinic drugs evaluated (darifenacin, fesoterodine, imidafenacin, oxybutynin, propantheline, propiverine, solifenacin, tolterodine or trospium) is ideal as a first line drug for all patients with OAB. Optimal treatment must be individualized, taking into consideration patient comorbidities and concomitant
0022-5347/12/1882-0349/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
medications, and the pharmacological profiles and costs of the different drugs. Alternatives to antimuscarinics have been desired for a long time, and great hopes have been attached to the 3-adrenoceptor agonists. Mirabegron seems to have an efficacy similar to, but not better than, that of antimuscarinics with a somewhat different adverse effect profile. The drug was approved in Japan in 2011 with a warning not to administer to patients of reproductive age, and currently it must be regarded as a second line alternative. A panel at the Food and Drug Administration recently recommended approval of the drug in the U.S. and it is currently under evaluation in Europe. For treatment of LUTS in men, including storage symptoms, phosphodiesterase type 5 inhibitors may be an alternative but long-term effects have not been studied. To my knowledge, there is no published information that these drugs are effective on OAB symptoms in women. Botulinum toxin (onabotulinumtoxin A) was recently approved by the Food and Drug Administration for neurogenic DO. However, it also has documented efficacy in patients with idiopathic (ie nonneurogenic) DO.2– 4 Drugs with a main site of action in the central nervous system may have good rationale and great potential but to date no really useful alternatives have emerged. Even if some advances have been made in the development of drugs for the treatment of LUTS, progress is slow and few drugs with well documented efficacy and acceptable adverse effects profile are available. Since the pathophysiology of these disorders is multifactorial and treatment is mainly based on fairly nonspecific symptoms, it cannot be expected that a single drug can be effective in all cases. This conclusion calls for new approaches to diagnostic subdivision of these cases and further research, including studies on cost-effectiveness. Karl-Erik Andersson Section Editor
http://dx.doi.org/10.1016/j.juro.2012.05.024 Vol. 188, 349-350, August 2012 Printed in U.S.A.
www.jurology.com
349
350
DRUGS FOR LOWER URINARY TRACT SYMPTOMS
REFERENCES
APPENDIX Drugs used to treat LUTS, OAB syndrome and DO Level of Evidence
Grade of Recommendation
3 1 1 1 2 1 1 1
C A A B B A A A
1 1 2
A A D
2 2
D D
3 2
C C
3 3 3 3 3 3 3
C C C C C C C
3 3 1
C C B
1
B
2 2
C C
1 1 2 2
A B C C
3
C
2 1
C A
Antimuscarinic with “specific” action: Atropine, hyoscyamine Darifenacin Fesoterodine Imidafenacin Propantheline Solifenacin Tolterodine Trospium Antimuscarinics with “mixed” actions: Oxybutynin Propiverine Flavoxate Drugs acting on membrane channels: Calcium antagonists K-channel openers Antidepressants: Imipramine Duloxetine ␣-Adrenergic receptor antagonists: Alfuzosin Doxazosin Naftopidil Prazosin Silodosin Tamsulosin Terazosin -adrenergic receptor antagonists: Terbutaline (2) Salbutamol (2) Mirabegron (3) Phosphodiesterase type 5 inhibitors: Sildenafil, taladafil, vardenafil (male LUTS/OAB) COX-inhibitors: Indomethacin Flurbiprofen Toxins: Botulinum toxin (neurogenic, bladder wall) Botulinum toxin (idiopathic, bladder wall) Capsaicin (neurogenic, intravesical) Resiniferatoxin (neurogenic, intravesical) Other drugs: Baclofen (intrathecal) Hormones: Estrogen Desmopressin (nocturia, nocturnal polyuria)* Assessments according to the Oxford system (modified). * Caution hyponatremia especially in the elderly.
1. Abrams P, Artibani W, Cardozo L et al: Reviewing the ICS 2002 terminology report: the ongoing debate. Neurourol Urodyn 2009; 28: 287. 2. Sahai A, Khan MS and Dasgupta P: Efficacy of botulinum toxin-A for treating idiopathic detrusor overactivity: results from a single center, randomized, double-blind, placebo controlled trial. J Urol 2007; 177: 2231. 3. Brubaker L, Richter HE, Visco A et al: Refractory idiopathic urge urinary incontinence and botulinum A injection. J Urol 2008; 180: 217. 4. Tincello DG, Kenyon S, Abrams KR et al: Botulinum toxin A versus placebo for refractory detrusor overactivity in women: a randomised blinded placebocontrolled trial of 240 women (the RELAX study). Eur Urol, Epub ahead of print January 5, 2012.
Drugs for Lower Urinary Tract Symptoms—Anything New? EFFECTIVE treatment for lower urinary tract symptoms (LUTS) continues to be a problem, since available drugs either have insufficent efficacy or unacceptable adverse effects in many patients. Lower urinary tract symptoms include storage, voiding and post-micturition symptoms. Overactive bladder (OAB) is a syndrome defined as urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia.1 Thus OAB, a syndrome of storage symptoms, is a subset of LUTS. In contrast to these symptom-based terms, detrusor overactivty (DO) refers to the urodynamic finding of involuntary detrusor contrctions during bladder filling. Traditionally LUTS has been used mostly to describe male symptoms but this category is no longer tenable because women also experience storage and voiding symptoms, and urodynamioc DO may occur in both genders. From a treatment point of view, it has become clear that even if several drugs can be used as monotherapy for all of these conditions, individualized treatment, sometimes combination therapy, is necessary to obtain an optimal effect. At the 5th International Consultation on Incontinence in February this year drugs used to treat LUTS were discussed and an update of previous recommendations for their use was provided. Focus was given to the many drugs intended for the treatment of OAB. Antimuscarinics are still considered as first line drugs, and the only new addition to the existing sortiment is imidafenacin, currently available in Japan and Korea but not in Western countries. The drug seems to have similar efficacy and adverse effect profiles as other alternatives. However, it should be emphasized that none of the antimuscarinic drugs evaluated (darifenacin, fesoterodine, imidafenacin, oxybutynin, propantheline, propiverine, solifenacin, tolterodine or trospium) is ideal as a first line drug for all patients with OAB. Optimal treatment must be individualized, taking into consideration patient comorbidities and concomitant
0022-5347/12/1882-0349/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
medications, and the pharmacological profiles and costs of the different drugs. Alternatives to antimuscarinics have been desired for a long time, and great hopes have been attached to the 3-adrenoceptor agonists. Mirabegron seems to have an efficacy similar to, but not better than, that of antimuscarinics with a somewhat different adverse effect profile. The drug was approved in Japan in 2011 with a warning not to administer to patients of reproductive age, and currently it must be regarded as a second line alternative. A panel at the Food and Drug Administration recently recommended approval of the drug in the U.S. and it is currently under evaluation in Europe. For treatment of LUTS in men, including storage symptoms, phosphodiesterase type 5 inhibitors may be an alternative but long-term effects have not been studied. To my knowledge, there is no published information that these drugs are effective on OAB symptoms in women. Botulinum toxin (onabotulinumtoxin A) was recently approved by the Food and Drug Administration for neurogenic DO. However, it also has documented efficacy in patients with idiopathic (ie nonneurogenic) DO.2– 4 Drugs with a main site of action in the central nervous system may have good rationale and great potential but to date no really useful alternatives have emerged. Even if some advances have been made in the development of drugs for the treatment of LUTS, progress is slow and few drugs with well documented efficacy and acceptable adverse effects profile are available. Since the pathophysiology of these disorders is multifactorial and treatment is mainly based on fairly nonspecific symptoms, it cannot be expected that a single drug can be effective in all cases. This conclusion calls for new approaches to diagnostic subdivision of these cases and further research, including studies on cost-effectiveness. Karl-Erik Andersson Section Editor
http://dx.doi.org/10.1016/j.juro.2012.05.024 Vol. 188, 349-350, August 2012 Printed in U.S.A.
www.jurology.com
349
350
DRUGS FOR LOWER URINARY TRACT SYMPTOMS
REFERENCES
APPENDIX Drugs used to treat LUTS, OAB syndrome and DO Level of Evidence
Grade of Recommendation
3 1 1 1 2 1 1 1
C A A B B A A A
1 1 2
A A D
2 2
D D
3 2
C C
3 3 3 3 3 3 3
C C C C C C C
3 3 1
C C B
1
B
2 2
C C
1 1 2 2
A B C C
3
C
2 1
C A
Antimuscarinic with “specific” action: Atropine, hyoscyamine Darifenacin Fesoterodine Imidafenacin Propantheline Solifenacin Tolterodine Trospium Antimuscarinics with “mixed” actions: Oxybutynin Propiverine Flavoxate Drugs acting on membrane channels: Calcium antagonists K-channel openers Antidepressants: Imipramine Duloxetine ␣-Adrenergic receptor antagonists: Alfuzosin Doxazosin Naftopidil Prazosin Silodosin Tamsulosin Terazosin -adrenergic receptor antagonists: Terbutaline (2) Salbutamol (2) Mirabegron (3) Phosphodiesterase type 5 inhibitors: Sildenafil, taladafil, vardenafil (male LUTS/OAB) COX-inhibitors: Indomethacin Flurbiprofen Toxins: Botulinum toxin (neurogenic, bladder wall) Botulinum toxin (idiopathic, bladder wall) Capsaicin (neurogenic, intravesical) Resiniferatoxin (neurogenic, intravesical) Other drugs: Baclofen (intrathecal) Hormones: Estrogen Desmopressin (nocturia, nocturnal polyuria)* Assessments according to the Oxford system (modified). * Caution hyponatremia especially in the elderly.
1. Abrams P, Artibani W, Cardozo L et al: Reviewing the ICS 2002 terminology report: the ongoing debate. Neurourol Urodyn 2009; 28: 287. 2. Sahai A, Khan MS and Dasgupta P: Efficacy of botulinum toxin-A for treating idiopathic detrusor overactivity: results from a single center, randomized, double-blind, placebo controlled trial. J Urol 2007; 177: 2231. 3. Brubaker L, Richter HE, Visco A et al: Refractory idiopathic urge urinary incontinence and botulinum A injection. J Urol 2008; 180: 217. 4. Tincello DG, Kenyon S, Abrams KR et al: Botulinum toxin A versus placebo for refractory detrusor overactivity in women: a randomised blinded placebocontrolled trial of 240 women (the RELAX study). Eur Urol, Epub ahead of print January 5, 2012.