• No results found

OAB: WHEN DRUGS DON T WORK

N/A
N/A
Protected

Academic year: 2021

Share "OAB: WHEN DRUGS DON T WORK"

Copied!
9
0
0

Loading.... (view fulltext now)

Full text

(1)

OAB:

W

HEN

D

RUGS

D

ON

T

W

ORK

……

DUDLEY ROBINSON MDFRCOG,

CONSULTANT UROGYNAECOLOGIST,DEPARTMENT OF UROGYNAECOLOGY,KINGS COLLEGE HOSPITAL

WHAT IS OVERACTIVE BLADDER?

Overactive Bladder (OAB) is the term used to describe the symptom complex of urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence, in the absence of urinary tract infection or other obvious pathology.1

Epidemiological studies in North America have reported a prevalence of OAB in women of 16.9%, the prevalence increases with age, being 4.8% in women under 25 years and rising to 30.9% in those over the age of 65 years2. This is supported by prevalence data from Europe3 showing the overall prevalence in men and women 40 years and older was 16.6%. Frequency was the most commonly reported symptom (85%) whilst 54% complained of urgency and 36% urgency incontinence.

The symptoms of OAB are due to involuntary contractions of the detrusor muscle during the filling phase of the micturition cycle. These involuntary contractions are termed detrusor overactivity1 and are mediated by acetylcholine-induced stimulation of bladder muscarinic receptors under the control of the parasympathetic nervous system. Consequently OAB is a symptom based diagnosis and detrusor overactivity is a diagnosis that can only be made after urodynamic investigation. Equally the two terms are not synonymous; 64% of women with OAB have urodynamically proven detrusor overactivity whilst 83% of women with detrusor overactivity have symptoms suggestive of OAB4

(2)

HOW WELL DO ANTIMUSCARINIC DRUGS WORK?

There are now a number of different licensed antimuscarinic drugs available on the market within the UK. These have all been recently reviewed by the International Consultation on Incontinence5

[Box 1] and all have Level 1 evidence6 and a Grade A recommendation7.

BOX 1:ANTIMUSCARINIC DRUGS USED IN THE TREATMENT OF OVERACTIVE BLADDER

Antimuscarinic drugs Darifenacin Fesoterodine Oxybutynin Propiverine Solifenacin Tolterodine Trospium

The clinical effectiveness of antimuscarinic agents was first questioned in a systematic review of 32 trials including 6800 participants.8 Following treatment cure or improvement (RR 1.41, 95%CI: 1.29-1.54) were all significantly in favour of antimuscarinic therapy (p<0.0001) although the differences from placebo were small and of questionable clinical significance. A subsequent Cochrane review of 61 trials including 11 956 patients was supportive of these findings with a significantly greater cure or improvement rate in the antimuscarinic group when compared to placebo (RR1.39, 95%CI: 1.28-1.51). Importantly there was also a significant improvement in QoL implying clinical, as well as statistical significance.9 Overall the additional benefit of active treatment was about 15% more improved or cured which translates into a Number Needed to Treat (NNT) of seven.

(3)

The most recent systematic review and meta-analysis of 83 studies, including 30 699 patients and six different drugs (fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine and trospium), also supports the efficacy of antimuscarinic therapy in the treatment of OAB. Overall there was a significantly higher return to continence favouring active treatment over placebo; the pooled RR across different studies and different drugs being 1.3 – 3.5 (p<0.01). Antimuscarinic therapy was also shown to be statistically significantly more effective in reduction of incontinence episodes per day (pooled differences in mean change 0.4-1.1) , reduction in number of micturitions per day (pooled differences in mean change 0.5-1.3) and reduction of urgency episodes per day (pooled differences in mean change 0.64 -1.56).10

Whilst these data confirm the efficacy of antimuscarinic drugs clinically the evidence comparing drugs with one another is less robust. The available evidence would suggest that extended release oxybutynin and tolterodine have superior efficacy to the immediate release preparations11. In addition solifenacin has been shown to be non inferior to12, and fesoterodine superior to13 tolterodine extended release.

HOW COST EFFECTIVE ARE ANTIMUSCARINIC DRUGS?

The cost effectiveness of all antimuscarinic therapies has recently been assessed within the UK National Health Service (NHS). Overall solifenacin was associated with the highest Quality Adjusted Life Year (QALY) gain in terms of urinary urgency, frequency and incontinence. Solifenacin was found to be dominant to fesoterodine, tolterodine and propiverine in terms of cost effectiveness although not to oxybutynin for frequency and incontinence.14 Furthermore a cost utility analysis comparing solifenacin and tolterodine has found that solifenacin was less expensive and more effective than tolterodine; one year costs being £509 with solifenacin as compared to £526 for tolterodine.15

(4)

WHAT ARE THE TREATMENT STRATEGIES AFTER PRIMARY DRUG THERAPY FAILURE?

After conservative therapy antimuscarinic agents are the most commonly used agents in the management of OAB although compliance and persistence rates continue to be poor. Lack of efficacy has been shown to be the primary reason why patients stop therapy with intolerable side effects being the second most common. Should efficacy be the main reason for stopping therapy then it would seem appropriate to try an alternative drug whilst if adverse effects are the main reason for discontinuation then an alternative route of administration may be useful.

Before resorting to more invasive treatment options in the management of OAB there are several different treatment approaches that should be considered.

A]MAKE AN ACCURATE DIAGNOSIS

OAB is a symptom complex rather than a urodynamic diagnosis and there are many different causes of frequency and urgency. Consequently those patients who fail on primary therapy may benefit from further investigation with urodynamic studies in addition to excluding other gynaecological, urological and medical causes of lower urinary tract symptoms

The symptoms of OAB are due to involuntary contractions of the detrusor muscle during the filling phase of the micturition cycle. These involuntary contractions are termed detrusor overactivity1 and are mediated by acetylcholine-induced stimulation of bladder muscarinic receptors16. However OAB is not synonymous with detrusor overactivity as the former is a symptom based diagnosis whilst the latter is a urodynamic diagnosis. It has been estimated that 64% of patients with OAB have urodynamically proven detrusor overactivity and that 83% of patients with detrusor overactivity have symptoms suggestive of OAB17. Hence the terms are not synonymous.

(5)

B]USE A HOLISTIC APPROACH

There is considerable evidence to show that combination therapy with medication and conservative measures lead to a greater improvement in patient symptoms. Equally improving patient awareness and education should lead to an improvement in compliance with medication.

Antimuscarinic therapy may be a useful addition to non drug therapy in the management of patients with OAB. In a Cochrane review of 13 trials including 1770 patients symptomatic improvement was more common amongst those on antimuscarinic therapy compared to bladder retraining (RR 0.73; 95%CI 0.59-0.90) and combination treatment was also associated with more improvement than bladder training alone (RR 0.55; 95% CI: 0.32-0.93). Similarly there was a trend towards greater improvement with a combination of antimuscarinic therapy with bladder retraining compared to antimuscarinic therapy alone (RR 0.81; 95%CI: 0.61-1.06) although this was not statistically significant.18

C]ARE THERE ANY ALTERNATIVES TO ANTIMUSCARINIC DRUGS?

Many other drugs are used in the treatment of patients with OAB although the levels of evidence supporting their usage varies5 [Box 2]. Using an alternative treatment approach may be helpful to groups of patients with troublesome OAB symptoms that have not responded to conventional antimuscarinic therapy.

Desmopressin, a synthetic vasopressin analogue has been used primarily in the treatment of nocturia and nocturnal enuresis in children 19 and adults20 although has also been reported for the treatment of daytime urinary incontinence.21

In addition newer agents remain under evaluation. Although the use of calcium blocking agents and potassium channel opening drugs showed initial promise neither have proved to be useful in the clinical setting22,23. Consequently the search for novel agents to treat OAB continues and has

(6)

recently focused on the use of neurokinin antagonists24, vitamin D analogues25 and β adrenoceptor agonists26.

BOX 2:DRUGS USED IN THE TREATMENT OF OVERACTIVE BLADDER

Level of

evidence Grade of recommendation Drugs acting on membrane

channels

Calcium channel antagonists

Potassium channel openers 2 2 D D

Drugs with mixed actions

Flavoxate 2 D Alpha-antagonists Alfuzosin Doxazosin Prazosin Terazosin Tamsulosin 3 3 3 3 3 C C C C C Beta agonists Terbutaline Salbutamol 3 3 C C Antidepressants Imipramine Duloxetine 3 2 C C Prostaglandin synthesis inhibitors Indomethacin Flurbiprofen 2 2 C C Vasopressin analogues Desmopressin 1 A

D]IS THERE A ROLE FOR VAGINAL OESTROGENS IN POST MENOPAUSAL WOMEN?

The available evidence would suggest that local oestrogen therapy may be beneficial in managing the symptoms associated with OAB although whether this is due to a true effect on the bladder or by simply reversing local atrophic changes remains unclear.

More recently there has been some evidence regarding the synergistic use of vaginal oestrogen therapy with antimuscarinic therapy in the management of postmenopausal women with OAB

(7)

although the results are contradictory.27,28 There is also some evidence to suggest that local oestrogen therapy may be as beneficial as an oral antimuscarinic.29

CONCLUSION

Overactive bladder remains a bothersome condition, known to affect Quality of Life (QoL). Whilst antimuscarinic drug therapy remains integral in the management of these patients many will discontinue medication due to problems with efficacy and adverse effects. However there are a number of different management options available for those patients with failed primary therapy before resorting to more invasive treatments which may be associated with higher morbidity and cost.

REFERENCES

1Haylen BT, de Ridder D, Freeman RM, Swift SE, Berghmans B, Lee J, Monga A, Petri P, Rizk DE, Sand PK, Schaer

GN. An International Urogynaecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Int Urogynecol J 2010; 21: 5-26.

2 Stewart WF, Corey R, Herzog AR et al. Prevalence of overactive bladder in women: results from the NOBLE program.

Int Urogynaecol. J. 2001; 12 (3): S66.

3 Milsom I, Abrams P, Cardozo L, Roberts RG, Thuroff J, Wein AJ. How widespread are the symptoms of overactive

bladder and how are they managed? A population-based prevalence study. BJU Int 2001; 87(9): 760-766.

4 Hashim H, Abrams P. Do symptoms of overactive bladder predict urodynamic detrusor overactivity? Neurorol

Urodyn 2004; 23: 484.

5 Andersson KE, Chapple CR, Cardozo L, Cruz F, Hashim H, Michel MC, Tannenbaum C, Wein AJ. Pharmacological

treatment of urinary incontinence. In Incontinence, 4th Edition. 2009. Eds Abrams P, Cardozo L, Khoury S, Wein A.

Health Publication Ltd, Editions 21, Paris, France. 631-700.

6 Hadorn DC, Baker D, Hodges JS, Hicks N.Rating the quality of evidence for clinical practice guidelines. J Clin

Epidemiol 1996; 49(7):749-54

7 Harbour R, Miller J. A new system for grading recommendations in evidence based guidelines. BMJ 2001; 323:334-336

8 Herbison P, Hay-Smith J, Ellis G, Moore K. Effectiveness of anticholinergic drugs compared to placebo in the

treatment of overactive bladder: systematic review. BMJ 2003; 326(7394): 841-844.

9 Nabi G, cody JD, Ellis G, Hay-Smith J, Herbison GP. Anticholinergic drugs versus placebo for overactive bladder

syndrome in adults. Cochrane Database of Systematic Reviews 2006, Issue . Art No: CD003781. DOI: 10.1002/14651858.pub2

(8)

10 Chapple CR, Khullar V, Gabriel Z, Muston D, Bitoun CE, Weinstein D. The effects of antimuscarinic treatments in

overactive bladder: an update of a systematic review and meta-analysis. Eur Urol 2008; 54(3): 543-562.

11 Diokno AC, Appell RA, Sand PK, Dmochowski RR, GburekBM, Klimberg IW, Kell SH; OPERA Stuy Group.

Prospective, randomised, double blind study of the efficacy and tolerability of the extended-release formulations of oxybutynin and tolterodine for overactive bladder: results of the OPERA trial. Mayo Clin Proc. 2003; 78(6): 687-695.

12 Chapple CR, Martinez-Garcia R, Selvaggi L, Toozs-Hobson P, Warnack W, Drogendijk T, Wright DM, Bolodeoku J;

for the STAR study group. A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at treating overactive bladder syndrome: results of the STAR trial. Eur Urol 2005; 48: 464-70.

13 Herschorn S, Swift S, Guan Z, Carlsson M, Morrow J, Brodsky M, Gong J. Comparison of fesoterodine and

tolterodine extended release for the treatment of overactive bladder: a head to head placebo controlled trial. BJU Int 2009; 105: 58-66.

14 Cardozo L, Thorpe A, Warner J, Sidhu M. The cost effectiveness of solifenacin vs fesoterodine, oxybutynin immediate

release, propiverine, tolterodine extended release and tolterodine immediate release in the treatment of patients with overactive bladder in the UK National Health Service. BJU Int 2010; 106: 506-514.

15 Speakman M, Khullar V, Mundy A, Odeyemi I, Bolodeoku J. A cost-utility analysis of once daily solifenacin compared

to tolterodine in the treatment of overactive bladder syndrome. Curr Med Res Opin 2008; 24(8): 2173-2179.

16 Anderson KE. The overactive bladder: pharmacologic basis of drug treatment. Urology 1997; 50:74-89

17 Hashim H, Abrams P. Is the bladder a reliable witness for predicting detrusor overactivity? J Urol 2006; 175: 191-195

18 Alhasso AA, McKinlay J, Patrick K, Stewart L. Anticholinergic drugs versus non drug active therapies for overactive

bladder syndrome in adults. Cochrane Database of Systematic Reviews 2006; Issue 4. Art No: CD003193. DOI: 10.1002/14651858.CD003193.pub3.

19 Norgaard JP, Rillig S, Djurhuus JC, Nocturnal enuresis: an approach to treatment based on pathogenesis.J Pediatrics

1989;114:705-9.

20 Mattiasson A, Abrams P, Van Kerrebroeck P, Walter S, Weiss J. Efficacy of Desmopressin in the treatment of

nocturia: a double blind placebo controlled studying men. BJU Int. 2002; 89: 855-862.

21 Robinson D, Cardozo L, Akeson M, Hvistendahl G, Riis A, Norgaard J. Women take control; Desmopressin – A drug

for daytime urinary incontinence. Neurourol Urodyn 2002 21(4): 385- 386.

22 Laval KU, Lutzeyer W. Spontaneous phasic activity of the detrusor: a cause of uninhibited contractions in unstable

bladder. Urol. Int. 1980; 35: 182-187.

23 Chapple C, Patroneva A, Raines S. Effect of an ATP-sensitive potassium channel opener in subjects with overactive

bladder: A randomized double-blind placebo controlled study (ZD0947IL/0004). Eur Urol 2006; 879-886.

24 Green SA, Alon A, Ianus J. Mc Naughton, Tozzi CA, Reiss TF. Efficacy and safety of a neurokinin-1 receptor

antagonist in postmenopausal women with overactive bladder with urge urinary incontinence. J Urol 2006; 176: 2535-2540.

25 Colli E, Digesu GA, Olivieri L. Overactive bladder treatments in early phase clinical trials. Expert Opin Investig

Drugs 2007; 16: 999-1007.

26 Chapple CR, Yamaguchi O, Ridder A. Clinical proof of concept study (Blossom) shows novel β3 adrenoceptor

agonist YM178 is effective and well tolerated in the treatment of symptoms of overactive bladder. Eur Urol Suppl 2008; 7: 239.

(9)

27Tseng LH, Wang AC, Chang YL, Soong YK, Lloyd LK, Ko YJ. Randomized comparison of tolterodine with vaginal

estrogen cream versus tolterodine alone for the treatment of postmenopausal women with overactive bladder syndrome. Neurourol Urodyn. 2009;28(1):47-51.

28 Serati M, Salvatore S, Uccella S, Cardozo L, Bolis P. Is there a synergistic effect of topical oestrogens when

administered with antimuscarinics in the treatment of symptomatic detrusor overactivity? Eur Urol. 2009 Mar;55(3):713-9.

29 Nelken RS, Ozel BZ, Leegant AR, Felix JC, Mishell DR. radomised trial of oestradiol vaginal ring versus oral

References

Related documents

The result of this study revealed that personal photographs could help the students to develop ideas, organize their sentences into good order, improve their vocabulary, accuracy

In situations where military capacity and assets are used to support the implementation of humanitarian action, ensure that such use is in conformity with international

While viewing ownership and control arrangements are still a part of a society’s core characteristics and will remain to a considerable degree idiosyncratic, Nestor

Also an increase in Bax/Bcl-2 ratio in rat hippocampus cells .Memantine pretreatment could not change the levels of Bax, Bcl-2, Caspase-3 significantly in rat’s hippocampus

In the context of Iran, Vaezi (2009) attempted to describe and examine Iranian undergraduate students’ integrative and instrumental motivation toward learning

We also compare improved IPPP with government provision, PPP and original IPPP and conclude that improved IPPP has advantages in achieving potential Pareto-improvement, relief of

Production function analysis, including five variables, showed significant effect of human labour, fingerlings and fuel cum energy cost but feed and manure cum fertilizers cost