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Digestive Diseases and Sciences

, Volume 56, Issue 1, pp 7–18 | Cite as

Overactive Bladder Drugs and Constipation: A Meta-Analysis of Randomized, Placebo-Controlled Trials

  • Patrick D. Meek
  • Samuel D. Evang
  • Mina Tadrous
  • Dianne Roux-Lirange
  • Darren M. Triller
  • Bora Gumustop
Review

Abstract

Background

Anticholinergic drugs are commonly prescribed for symptomatic treatment of overactive bladder (OAB). While recent meta-analyses have characterized the prevalence of dry mouth among patients utilizing OAB medications, prevalence of constipation has not been systematically reviewed.

Aims

To provide an effect measure for constipation associated with anticholinergic OAB drugs versus placebo.

Methods

A meta-analysis of trials with darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, and trospium was conducted. All randomized, placebo-controlled studies of anticholinergic OAB drugs published in English language and identified in Medline and Cochrane databases were considered for inclusion in this meta-analysis. Those meeting predetermined design characteristics and having sufficient duration (≥2 weeks) were included. Constipation-related data from all included studies were abstracted.

Results

One hundred two English-language, randomized, placebo-controlled trials were originally identified. Thirty-seven studies were ultimately included in the analysis, involving 19,434 total subjects (12,368 treatment + 7,066 placebo patients). The odds ratios for constipation compared with placebo were as follows: overall [odds ratio (OR) 2.18, 95% confidence interval (CI) = 1.82–2.60], tolterodine (OR 1.36, 95% CI = 1.01–1.85), darifenacin (OR 1.93, 95% CI = 1.40–2.66), fesoterodine (OR 2.07, 95% CI = 1.28–3.35), oxybutynin (OR 2.34, 95% CI = 1.31–4.16), trospium (OR 2.93, 95% CI = 2.00–4.28), and solifenacin (OR 3.02, 95% CI = 2.37–3.84).

Conclusions

Our results demonstrate that patients prescribed anticholinergic OAB drugs are significantly more likely to experience constipation. Differences in muscarinic receptor affinities among individual agents may possibly account for the modest variation in constipation rates observed; however, such a determination warrants additional research.

Keywords

Meta-analysis Adverse effects Constipation Cholinergic antagonists 

Notes

Acknowledgments

This work was performed without financial support. The authors of this paper have no financial interests to declare.

Supplementary material

10620_2010_1313_MOESM1_ESM.doc (180 kb)
Supplementary material 1 (DOC 179 kb)
10620_2010_1313_MOESM2_ESM.eps (1 mb)
Fig. S3. Meta-analysis of studies of anticholinergic drugs versus placebo for overactive bladder in the analysis of constipation events (subgroup analyses by treatment duration and trial quality). (EPS 1,043 kb)

References

  1. 1.
    Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003;20(6):327–336.PubMedGoogle Scholar
  2. 2.
    Rudd KM, Raehl CL, Bond CA, Abbruscato TJ, Stenhouse AC. Methods for assessing drug-related anticholinergic activity. Pharmacotherapy. 2005;25(11):1592–1601.CrossRefPubMedGoogle Scholar
  3. 3.
    Sink KM, Thomas J 3rd, Xu H, Craig B, Kritchevsky S, Sands LP. Dual use of bladder anticholinergics and cholinesterase inhibitors: long-term functional and cognitive outcomes. J Am Geriatr Soc. 2008;56(5):847–853.CrossRefPubMedGoogle Scholar
  4. 4.
    Tune LE. Anticholinergic effects of medication in elderly patients. J Clin Psychiatry. 2001;62(Suppl 21):11–14.PubMedGoogle Scholar
  5. 5.
    D’Souza AO, Smith MJ, Miller LA, Doyle J, Ariely R. Persistence, adherence, and switch rates among extended-release and immediate-release overactive bladder medications in a regional managed care plan. J Manag Care Pharm. 2008;14(3):291–301.PubMedGoogle Scholar
  6. 6.
    Yu YF, Nichol MB, Yu AP, Ahn J. Persistence and adherence of medications for chronic overactive bladder/urinary incontinence in the California medicaid program. Value Health. 2005;8(4):495–505.CrossRefPubMedGoogle Scholar
  7. 7.
    Brubaker L, Fanning K, Goldberg EL, et al. Predictors of discontinuing overactive bladder medications. BJU Int. 2009.Google Scholar
  8. 8.
    Hay-Smith J, Herbison P, Ellis G, Morris A. Which anticholinergic drug for overactive bladder symptoms in adults. Cochrane Database Syst Rev. 2005;(3):CD005429.Google Scholar
  9. 9.
    Abrams P, Andersson KE, Buccafusco JJ, et al. Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol. 2006;148(5):565–578.CrossRefPubMedGoogle Scholar
  10. 10.
    Kay GG, Abou-Donia MB, Messer WS Jr, Murphy DG, Tsao JW, Ouslander JG. Antimuscarinic drugs for overactive bladder and their potential effects on cognitive function in older patients. J Am Geriatr Soc. 2005;53(12):2195–2201.CrossRefPubMedGoogle Scholar
  11. 11.
    Kay G, Crook T, Rekeda L, et al. Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. Eur Urol. 2006;50(2):317–326.CrossRefPubMedGoogle Scholar
  12. 12.
    Nabi G, Cody JD, Ellis G, Herbison P, Hay-Smith J. Anticholinergic drugs versus placebo for overactive bladder syndrome in adults. Cochrane Database Syst Rev. 2006;(4):CD003781.Google Scholar
  13. 13.
    Choung RS, Locke GR 3rd, Schleck CD, Zinsmeister AR, Talley NJ. Cumulative incidence of chronic constipation: a population-based study 1988–2003. Aliment Pharmacol Ther. 2007;26(11–12):1521–1528.CrossRefPubMedGoogle Scholar
  14. 14.
    Shah ND, Chitkara DK, Locke GR, Meek PD, Talley NJ. Ambulatory care for constipation in the United States, 1993–2004. Am J Gastroenterol. 2008;103(7):1746–1753.CrossRefPubMedGoogle Scholar
  15. 15.
    Crane SJ, Talley NJ. Chronic gastrointestinal symptoms in the elderly. Clin Geriatr Med. 2007;23(4):721–734.CrossRefPubMedGoogle Scholar
  16. 16.
    Spinzi GC. Bowel care in the elderly. Dig Dis. 2007;25(2):160–165.CrossRefPubMedGoogle Scholar
  17. 17.
    Singh G, Lingala V, Wang H, et al. Use of health care resources and cost of care for adults with constipation. Clin Gastroenterol Hepatol. 2007;5(9):1053–1058.CrossRefPubMedGoogle Scholar
  18. 18.
    Dmochowski RR, Appell RA. Advancements in pharmacologic management of the overactive bladder. Urology. 2000;56(6 Suppl 1):41–49.CrossRefPubMedGoogle Scholar
  19. 19.
    Roxburgh C, Cook J, Dublin N. Anticholinergic drugs versus other medications for overactive bladder syndrome in adults. Cochrane Database Syst Rev. 2007;(4):CD003190.Google Scholar
  20. 20.
    Wein AJ. Pharmacologic options for the overactive bladder. Urology. 1998;51(2A Suppl):43–47.CrossRefPubMedGoogle Scholar
  21. 21.
    Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1–12.CrossRefPubMedGoogle Scholar
  22. 22.
    Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719–748.PubMedGoogle Scholar
  23. 23.
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188.CrossRefPubMedGoogle Scholar
  24. 24.
    Higgins JP, Thompson SG. Controlling the risk of spurious findings from meta-regression. Stat Med. 2004;23(11):1663–1682.CrossRefPubMedGoogle Scholar
  25. 25.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–560.CrossRefPubMedGoogle Scholar
  26. 26.
    Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–634.PubMedGoogle Scholar
  27. 27.
    Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088–1101.CrossRefPubMedGoogle Scholar
  28. 28.
    Lipton RB, Kolodner K, Wesnes K. Assessment of cognitive function of the elderly population: effects of darifenacin. J Urol. 2005;173(2):493–498.CrossRefPubMedGoogle Scholar
  29. 29.
    Staskin DR, Dmochowski RR, Sand PK, et al. Efficacy and safety of oxybutynin chloride topical gel for overactive bladder: a randomized, double-blind, placebo controlled, multicenter study. J Urol. 2009;181(4):1764–1772.CrossRefPubMedGoogle Scholar
  30. 30.
    Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57(3):414–421.CrossRefPubMedGoogle Scholar
  31. 31.
    The CONSORT Group: CONSORT Statement Website [online]. URL: http://www.consort-statement.org/home; 2010 Accessed 04.03.10.
  32. 32.
    Ioannidis JP, Evans SJ, Gotzsche PC, et al. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med. 2004;141(10):781–788.PubMedGoogle Scholar
  33. 33.
    Alhasso AA, McKinlay J, Patrick K, Stewart L. Anticholinergic drugs versus non-drug active therapies for overactive bladder syndrome in adults. Cochrane Database Syst Rev. 2006;(4):CD003193.Google Scholar
  34. 34.
    Jonas U, Hofner K, Madersbacher H, Holmdahl TH. Efficacy and safety of two doses of tolterodine versus placebo in patients with detrusor overactivity and symptoms of frequency, urge incontinence, and urgency: urodynamic evaluation. The International Study Group. World J Urol. 1997;15:144–151.CrossRefPubMedGoogle Scholar
  35. 35.
    Malone-Lee JG, Walsh JB, Maugourd MF. Tolterodine: a safe and effective treatment for older patients with overactive bladder. J Am Geriatr Soc. 2001;49(6):700–705.CrossRefPubMedGoogle Scholar
  36. 36.
    Jacquetin B, Wyndaele J. Tolterodine reduces the number of urge incontinence episodes in patients with an overactive bladder. Eur J Obstet Gynecol Reprod Biol. 2001;98(1):97–102.CrossRefPubMedGoogle Scholar
  37. 37.
    Chapple CR, Rechberger T, Al-Shukri S, et al. Randomized, double-blind placebo- and tolterodine-controlled trial of the once-daily antimuscarinic agent solifenacin in patients with symptomatic overactive bladder. BJU Int. 2004;93(3):303–310.CrossRefPubMedGoogle Scholar
  38. 38.
    Pfizer, Canada: product monograph—Detrol (tolterodine tablets) [online]. URL: http://www.pfizer.ca/english/our%20products/prescription%20pharmaceuticals/default.asp?s=1&id=8&doc=enmonograph; Accessed 04.03.10.
  39. 39.
    Appell RA. Clinical efficacy and safety of tolterodine in the treatment of overactive bladder: a pooled analysis. Urology. 1997;50(6A Suppl):90–96; discussion 97–9.Google Scholar
  40. 40.
    Homma Y, Paick JS, Lee JG, Kawabe K. Clinical efficacy and tolerability of extended-release tolterodine and immediate-release oxybutynin in Japanese and Korean patients with an overactive bladder: a randomized, placebo-controlled trial. BJU Int. 2003;92(7):741–747.CrossRefPubMedGoogle Scholar
  41. 41.
    Kaplan SA, Roehrborn CG, Rovner ES, Carlsson M, Bavendam T, Guan Z. Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial. JAMA. 2006;296(19):2319–2328.CrossRefPubMedGoogle Scholar
  42. 42.
    Khullar V, Hill S, Laval KU, Schiotz HA, Jonas U, Versi E. Treatment of urge-predominant mixed urinary incontinence with tolterodine extended release: a randomized, placebo-controlled trial. Urology. 2004;64(2):269–274; discussion 274–5.Google Scholar
  43. 43.
    Rackley R, Weiss JP, Rovner ES, Wang JT, Guan Z. Nighttime dosing with tolterodine reduces overactive bladder-related nocturnal micturitions in patients with overactive bladder and nocturia. Urology. 2006;67(4):731–736; discussion 736.Google Scholar
  44. 44.
    Novartis Pharmaceutical Corp. Center for Drug Evaluation and Research—application number 21-513; medical review: Enablex (darifenacin) extended release tablets [online]. URL: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-513_Enablex.cfm; Accessed 04.03.10.
  45. 45.
    Haab F, Stewart L, Dwyer P. Darifenacin, an M3 selective receptor antagonist, is an effective and well-tolerated once-daily treatment for overactive bladder. Eur Urol. 2004;45(4):420–429; discussion 429.Google Scholar
  46. 46.
    Hill S, Khullar V, Wyndaele JJ, Lheritier K. Dose response with darifenacin, a novel once-daily M3 selective receptor antagonist for the treatment of overactive bladder: results of a fixed dose study. Int Urogynecol J Pelvic Floor Dysfunct. 2006;17(3):239–247.CrossRefPubMedGoogle Scholar
  47. 47.
    Steers W, Corcos J, Foote J, Kralidis G. An investigation of dose titration with darifenacin, an M3-selective receptor antagonist. BJU Int. 2005;95(4):580–586.CrossRefPubMedGoogle Scholar
  48. 48.
    Chapple C, DuBeau C, Ebinger U, Rekeda L, Viegas A. Darifenacin treatment of patients ≥65 years with overactive bladder: results of a randomized, controlled, 12-week trial. Curr Med Res Opin. 2007;23(10):2347–2358.CrossRefPubMedGoogle Scholar
  49. 49.
    Pfizer, Inc. Center for Drug Evaluation and Research—application number 22-030; drug approval package: Toviaz (Fesoterodine Fumarate) tablets [online]. URL: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022030s000TOC.cfm; Accessed 04.03.10.
  50. 50.
    Chapple C, Van Kerrebroeck P, Tubaro A, et al. Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder. Eur Urol. 2007;52(4):1204–1212.CrossRefPubMedGoogle Scholar
  51. 51.
    Nitti VW, Dmochowski R, Sand PK, et al. Efficacy, safety and tolerability of fesoterodine for overactive bladder syndrome. J Urol. 2007;178(6):2488–2494.CrossRefPubMedGoogle Scholar
  52. 52.
    Herschorn S, Swift S, Guan Z, et al. Comparison of fesoterodine and tolterodine extended release for the treatment of overactive bladder: a head-to-head placebo-controlled trial. BJU Int. 2010;105(1):58–66.CrossRefPubMedGoogle Scholar
  53. 53.
    Szonyi G, Collas DM, Ding YY, Malone-Lee JG. Oxybutynin with bladder retraining for detrusor instability in elderly people: a randomized controlled trial. Age Ageing. 1995;24(4):287–291.CrossRefPubMedGoogle Scholar
  54. 54.
    Watson Pharma, Inc. Center for Drug Evaluation and Research—application number 21-351; package label: Oxytrol (oxybutynin transdermal system) [online]. URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/021351lbl.pdf; Accessed 04.03.10.
  55. 55.
    Watson Pharma, Inc. Center for Drug Evaluation and Research—application number 21-351; medical review: Oxytrol (oxybutynin transdermal system) [online]. URL: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-351_Oxytrol.cfm; Accessed 04.03.10.
  56. 56.
    Dmochowski RR, Sand PK, Zinner NR, Gittelman MC, Davila GW, Sanders SW. Comparative efficacy and safety of transdermal oxybutynin and oral tolterodine versus placebo in previously treated patients with urge and mixed urinary incontinence. Urology. 2003;62(2):237–242.CrossRefPubMedGoogle Scholar
  57. 57.
    Lackner TE, Wyman JF, McCarthy TC, Monigold M, Davey C. Randomized, placebo-controlled trial of the cognitive effect, safety, and tolerability of oral extended-release oxybutynin in cognitively impaired nursing home residents with urge urinary incontinence. J Am Geriatr Soc. 2008;56(5):862–870.CrossRefPubMedGoogle Scholar
  58. 58.
    Thuroff JW, Bunke B, Ebner A, et al. Randomized, double-blind, multicenter trial on treatment of frequency, urgency and incontinence related to detrusor hyperactivity: oxybutynin versus propantheline versus placebo. J Urol. 1991;145(4):813–816; discussion 816–7.Google Scholar
  59. 59.
    Tapp AJ, Cardozo LD, Versi E, Cooper D. The treatment of detrusor instability in post-menopausal women with oxybutynin chloride: a double blind placebo controlled study. Br J Obstet Gynaecol. 1990;97(6):521–526.CrossRefPubMedGoogle Scholar
  60. 60.
    Zinner N, Tuttle J, Marks L. Efficacy and tolerability of darifenacin, a muscarinic M3 selective receptor antagonist (M3 SRA), compared with oxybutynin in the treatment of patients with overactive bladder. World J Urol. 2005;23(4):248–252.CrossRefPubMedGoogle Scholar
  61. 61.
    Zinner N, Gittelman M, Harris R, Susset J, Kanelos A, Auerbach S. Trospium chloride improves overactive bladder symptoms: a multicenter phase III trial. J Urol. 2004;171(6 Pt 1):2311–2315. (quiz 2435).CrossRefPubMedGoogle Scholar
  62. 62.
    Indevus Pharmaceutical, Inc. Center for Drug Evaluation and Research—application number 21-595; drug approval package: Sanctura (Trospium Chloride) extended release capsules [online]. URL: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-595_Sanctura.cfm; Accessed 04.03.10.
  63. 63.
    Rudy D, Cline K, Harris R, Goldberg K, Dmochowski R. Multicenter phase III trial studying trospium chloride in patients with overactive bladder. Urology. 2006;67(2):275–280.CrossRefPubMedGoogle Scholar
  64. 64.
    Staskin D, Sand P, Zinner N, Dmochowski R. Once daily trospium chloride is effective and well tolerated for the treatment of overactive bladder: results from a multicenter phase III trial. J Urol. 2007;178(3 Pt 1):978–983; discussion 983–4.Google Scholar
  65. 65.
    Indevus Pharmaceutical, Inc. Center for Drug Evaluation and Research—application number 22-103; drug approval package: Sanctura XR (Trospium Chloride) extended release capsules [online]. URL: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022103s000TOC.cfm; Accessed 04.03.10.
  66. 66.
    Dmochowski RR, Sand PK, Zinner NR, Staskin DR. Trospium 60 mg once daily (QD) for overactive bladder syndrome: results from a placebo-controlled interventional study. Urology. 2008;71(3):449–454.CrossRefPubMedGoogle Scholar
  67. 67.
    Yamanouchi Pharma America, Inc. Center for Drug Evaluation and Research—application number 21-518; drug approval package: VesiCare (Solifenacin Succinate) tablets [online]. URL: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-518_VesiCare.cfm; Accessed 04.03.10.
  68. 68.
    Cardozo L, Lisec M, Millard R, et al. Randomized, double-blind placebo controlled trial of the once daily antimuscarinic agent solifenacin succinate in patients with overactive bladder. J Urol. 2004;172(5 Pt 1):1919–1924.CrossRefPubMedGoogle Scholar
  69. 69.
    Yamaguchi O, Marui E, Kakizaki H, et al. Randomized, double-blind, placebo- and propiverine-controlled trial of the once-daily antimuscarinic agent solifenacin in Japanese patients with overactive bladder. BJU Int. 2007;100(3):579–587.CrossRefPubMedGoogle Scholar
  70. 70.
    Cardozo L, Hessdorfer E, Milani R, et al. Solifenacin in the treatment of urgency and other symptoms of overactive bladder: results from a randomized, double-blind, placebo-controlled, rising-dose trial. BJU Int. 2008;102(9):1120–1127.CrossRefPubMedGoogle Scholar
  71. 71.
    Karram MM, Toglia MR, Serels SR, Andoh M, Fakhoury A, Forero-Schwanhaeuser S. Treatment with solifenacin increases warning time and improves symptoms of overactive bladder: results from VENUS, a randomized, double-blind, placebo-controlled trial. Urology. 2009;73(1):14–18.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Patrick D. Meek
    • 1
  • Samuel D. Evang
    • 2
  • Mina Tadrous
    • 3
  • Dianne Roux-Lirange
    • 4
  • Darren M. Triller
    • 4
  • Bora Gumustop
    • 5
  1. 1.Research Institute for Health Outcomes, Department of Pharmacy PracticeAlbany College of Pharmacy and Health SciencesAlbanyUSA
  2. 2.School of Pharmacy at DallasTexas Tech UniversityDallasUSA
  3. 3.College of PharmacyUniversity of Tennessee Health Science CenterMemphisUSA
  4. 4.Pharmacy Services, IPROAlbanyUSA
  5. 5.Albany Gastroenterology ConsultantsAlbanyUSA

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