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A Study to Determine the Nitroglycerin Ointment Dose and Dosing Interval That Best Promote the Healing of Chronic Anal Fissures

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Diseases of the Colon & Rectum

Abstract

PURPOSE: The aim of this study was to determine the optimal dose and dosing interval of nitroglycerin ointment to heal chronic anal fissures. METHOD: A randomized, double-blind study of intra-anally applied nitroglycerin ointment (Anogesic™) was conducted in 17 centers in 304 patients with chronic anal fissures. The patients were randomly assigned to one of eight treatment regimens (0.0, 0.1, 0.2, 0.4 percent nitroglycerin ointment applied twice or three times per day), for up to eight weeks. A dose-measuring device standardized the delivery of 374 mg ointment. Healing of fissures (complete reepithelialization) was assessed by physical examination using an observer unaware of treatment allocation. The subjects assessed pain intensity daily by completing a diary containing a visual analog scale for average pain intensity for the day, the worst pain intensity for the day, and pain intensity at the last defecation. RESULTS: There were no significant differences in fissure healing among any of the treatment groups; all groups, including placebo had a healing rate of approximately 50 percent. This rate of placebo response was inexplicably higher than previously reported in the literature. Treatment with 0.4 percent (1.5 mg) nitroglycerin ointment was associated with a significant (P < 0.0002) decrease in average pain intensity compared with vehicle as assessed by patients with a visual analog scale. The decreases were observed by Day 4 of treatment. At 8 weeks the magnitude of the difference between 0.4 percent nitroglycerin and control was a 21 percent reduction in average pain. Treatment was well tolerated, with only 3.29 percent of patients discontinuing treatment because of headache. Headaches were the primary adverse event and were dose related. CONCLUSION: Nitroglycerin ointment did not alter healing but significantly and rapidly reduced the pain associated with chronic anal fissures.

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References

  1. R Farouk GS Duthie AB MacGregor DC Bartolo (1994) ArticleTitleSustained internal sphincter hypertonia in patients with chronic anal fissure Dis Colon Rectum 37 424–429 Occurrence Handle1:STN:280:ByuB3sjgsl0%3D Occurrence Handle8181401

    CAS  PubMed  Google Scholar 

  2. Y Arabi J Alexender-Williams MR Keighley (1977) ArticleTitleAnal pressure in hemorrhoids and anal fissure Am J Surg 134 608–610 Occurrence Handle1:STN:280:CSeD3sfhslw%3D Occurrence Handle920890

    CAS  PubMed  Google Scholar 

  3. N Williams NA Scott MH Irving (1995) ArticleTitleEffect of lateral sphincterotomy on internal anal sphincter function Dis Colon Rectum 38 700–704 Occurrence Handle1:STN:280:ByqA3s7gslM%3D Occurrence Handle7607028

    CAS  PubMed  Google Scholar 

  4. JK Lin (1989) ArticleTitleAnal Manometric studies in hemorrhoids and anal fissures Dis Colon Rectum 32 839–842 Occurrence Handle1:STN:280:By%2BD3cvntlU%3D Occurrence Handle2791768

    CAS  PubMed  Google Scholar 

  5. BD Hancock (1977) ArticleTitleThe internal sphincter and anal fissure Br J Surg 64 92–95 Occurrence Handle1:STN:280:CSiB2czitFE%3D Occurrence Handle890253

    CAS  PubMed  Google Scholar 

  6. WJ Schouten JW Briel JJ Auwerda (1994) ArticleTitleRelationship between anal pressure and anodermal blood flow Dis Colon Rectum 37 664–669 Occurrence Handle1:STN:280:ByuB1MfktFE%3D Occurrence Handle8026232

    CAS  PubMed  Google Scholar 

  7. T O’Kelly A Brading N Mortensen (1993) ArticleTitleNerve mediated relaxation of the human internal anal sphincter Gut 34 689–693 Occurrence Handle1:CAS:528:DyaK3sXlslyhu74%3D Occurrence Handle7684992

    CAS  PubMed  Google Scholar 

  8. DR Cox (1972) ArticleTitleRegression models and life tables J R Statistics Soc 34 187–220

    Google Scholar 

  9. EL Kaplan P Meier (1958) ArticleTitleNon-parametric estimation from incomplete observations J Am Stat Assoc 53 457–481

    Google Scholar 

  10. N Mantel (1966) ArticleTitleEvaluation or survival data and two new rank order statistics arising in consideration Cancer Chemother Rep 50 163–481 Occurrence Handle1:STN:280:CCmC3M3htlw%3D Occurrence Handle5910392

    CAS  PubMed  Google Scholar 

  11. R Peto J Peto (1972) ArticleTitleAsymptotically efficient rank invariant test procedures J R Statistics Soc 135 185–206

    Google Scholar 

  12. NM Laird JH Ware (1982) ArticleTitleRandom effects models for longitudinal data Biometrics 38 963–974 Occurrence Handle1:STN:280:BiyC2sbhs1Q%3D Occurrence Handle7168798

    CAS  PubMed  Google Scholar 

  13. JN Lund JH Scholefield (1997) ArticleTitleA randomised, prospective, double-blind, placebo-controlled trial of glyceryl trinitrate ointment in the treatment of anal fissure Lancet 349 11–14 Occurrence Handle10.1016/S0140-6736(96)06090-4 Occurrence Handle1:CAS:528:DyaK2sXltVaqug%3D%3D Occurrence Handle8988115

    Article  CAS  PubMed  Google Scholar 

  14. LS Freedman (1982) ArticleTitleTables of the number of patients required in clinical trials using the logrank test Stat Med 1 121–129 Occurrence Handle1:STN:280:BiuD2cvgt1c%3D Occurrence Handle7187087

    CAS  PubMed  Google Scholar 

  16. HA Shub EP Salvati RJ Rubin (1978) ArticleTitleConservative treatment of anal fissure Dis Colon Rectum 21 582–583 Occurrence Handle1:STN:280:CSaC3cnmvVw%3D Occurrence Handle738173

    CAS  PubMed  Google Scholar 

  18. SL Jensen (1986) ArticleTitleTreatment of the first episodes of acute anal fissure BMJ 292 1167–1169 Occurrence Handle1:STN:280:BimB3MnpvVE%3D Occurrence Handle3011180

    CAS  PubMed  Google Scholar 

  19. L Rosen ME Abel PH Gordon et al. (1992) ArticleTitlePractice parameters for the management of anal fissure. The Standards Task Force American Society of Colon and Rectal Surgeons Dis Colon Rectum 35 206–208 Occurrence Handle1:STN:280:By2C3snpslU%3D Occurrence Handle1735328

    CAS  PubMed  Google Scholar 

  20. JB Kortbeek JM Lanqevin RE Khoo JA Heine (1992) ArticleTitleChronic fissure-in-ano Dis Colon Rectum 35 835–837 Occurrence Handle1:STN:280:By2A1c%2FhtFw%3D Occurrence Handle1511641

    CAS  PubMed  Google Scholar 

  21. MJ McNamara JP Percy IR Felding (1990) ArticleTitleA manometric study of anal fissure treated by subcutaneous lateral internal sphincterotomy Ann Surg 211 235–238 Occurrence Handle1:STN:280:By%2BC2cnltFw%3D Occurrence Handle2302000

    CAS  PubMed  Google Scholar 

  22. NL Chowcat JG Araujo PB Boulos (1986) ArticleTitleInternal sphincterotomy for chronic anal fissure Br J Surg 73 915–916 Occurrence Handle1:STN:280:BiiD2sjjtFI%3D Occurrence Handle3790924

    CAS  PubMed  Google Scholar 

  23. FR Sharp (1996) ArticleTitlePatient selection and treatment modalities for chronic anal fissure Am J Surg 171 512–515 Occurrence Handle1:STN:280:BymB2crhtFI%3D Occurrence Handle8651398

    CAS  PubMed  Google Scholar 

  24. S Chakder S Rattan (1993) ArticleTitleRelease of nitric oxide by activation of nonadrenergic noncholinergic neurons of internal anal sphincter Am J Physiol 26411 7–12

    Google Scholar 

  25. S Rattan A Sarkar S Chakder (1992) ArticleTitleNitric oxide pathway in rectoanal inhibitory reflex of opossum internal anal sphincter Gastroenterology 103 43–45 Occurrence Handle1:CAS:528:DyaK38XkvVOntLc%3D Occurrence Handle1612356

    CAS  PubMed  Google Scholar 

  26. M Bogaert (1987) ArticleTitleClinical pharmacokinetics of glyceryl trinitrate following the use of systemic and topical preparations Clin Pharmacokinet 12 1–11 Occurrence Handle1:STN:280:BiiC3s7pvFM%3D Occurrence Handle3102143

    CAS  PubMed  Google Scholar 

  27. U Thadani T Whitselt (1988) ArticleTitleRelationship of pharmacokinetic and pharmacodynamic properties of the organic nitrates Clin Pharmacokinet 15 32–43 Occurrence Handle1:CAS:528:DyaL1cXlt1Wrt7w%3D Occurrence Handle3135973

    CAS  PubMed  Google Scholar 

  28. PB Loder MA Kamm RL Nicholls et al. (1994) ArticleTitle“Reversible chemical sphincterotomy” by local application of glyceryl trinitrate Br J Surg 81 1386–1389 Occurrence Handle1:STN:280:ByqD2c7it1Y%3D Occurrence Handle7953427

    CAS  PubMed  Google Scholar 

  29. F Guillemot H Leroi YC Lone CG Rousseau MD Lamblin A Cortot (1993) ArticleTitleAction of in situ nitroglycerin on upper anal canal pressure of patients with terminal constipation Dis Colon Rectum 36 372–376 Occurrence Handle1:STN:280:ByyB3cbgvFY%3D Occurrence Handle8458265

    CAS  PubMed  Google Scholar 

  30. SR Gorfine (1995) ArticleTitleTreatment of benign anal disease with topical nitroglycerin Dis Colon Rectum 38 453–457 Occurrence Handle1:STN:280:ByqB2Mvps1E%3D Occurrence Handle7736873

    CAS  PubMed  Google Scholar 

  31. J Lund N Armitage J Scholefield (1996) ArticleTitleUse of glyceryl trinitrate ointment in the treatment of anal fissure Br J Surg 83 776–777 Occurrence Handle1:STN:280:BymA3svotlQ%3D Occurrence Handle8696737

    CAS  PubMed  Google Scholar 

  32. WR Schouten JW Briel MO Boerman et al. (1996) ArticleTitlePathophysiological aspects and clinical outcome of intra-anal application of isosorbide dinitrate in patients with chronic anal fissure Gut 39 465–469 Occurrence Handle1:STN:280:ByiC3cnptVM%3D Occurrence Handle8949655

    CAS  PubMed  Google Scholar 

  33. H Bacher HJ Mischinger G Werkgartner et al. (1997) ArticleTitleLocal nitroglycerin for treatment of anal fissures Dis Colon Rectum 40 840–845 Occurrence Handle1:STN:280:ByiA28vptFE%3D Occurrence Handle9221864

    CAS  PubMed  Google Scholar 

  34. GJ Oettle (1997) ArticleTitleGlyceryl trinitrite vs. sphincterotomy for treatment of chronic fissure-in-ano Dis Colon Rectum 40 1318–1320 Occurrence Handle1:STN:280:DyaK1c%2FjsVSguw%3D%3D Occurrence Handle9369106

    CAS  PubMed  Google Scholar 

  35. ML Kennedy S Sowter H Nguyen DZ Lubowski (1999) ArticleTitleGlyceryl trinitrite ointment for the treatment of chronic anal fissure Dis Colon Rectum 42 1000–1006 Occurrence Handle1:STN:280:DyaK1MzosFejsQ%3D%3D Occurrence Handle10458121

    CAS  PubMed  Google Scholar 

  36. EA Carapeti MA Kamm PJ McDonald et al. (1999) ArticleTitleRandomized controlled trial shows that glyceryl trinitrite heals anal fissure, higher doses are not more effective, and there is a high recurrence rate Gut 44 727–730 Occurrence Handle1:CAS:528:DyaK1MXjtF2kt74%3D Occurrence Handle10205213

    CAS  PubMed  Google Scholar 

  37. G Brisinda G Maria AR Bentivoglio et al. (1999) ArticleTitleA comparison of injections of botulinum toxin and topical nitroglycerin ointment for the treatment of chronic anal fissure N Engl J Med 341 65–69 Occurrence Handle10.1056/NEJM199907083410201 Occurrence Handle1:CAS:528:DyaK1MXks1GlsLc%3D Occurrence Handle10395629

    Article  CAS  PubMed  Google Scholar 

  38. B Tander A Guven S Demirbag Y Ozkan H Ozturk S Cetinkursun (1999) ArticleTitleA prospective, randomized, double-blind, placebo-controlled trial of glyceryl-trinitrate ointment in the treatment of children with anal fissure J Pediatr Surg 34 1810–1812 Occurrence Handle1:STN:280:DC%2BD3c%2FptVartA%3D%3D Occurrence Handle10626860

    CAS  PubMed  Google Scholar 

  39. DF Altomore M Rindali G Milito et al. (2000) ArticleTitleGlyceryl trinitrate for chronic anal fissure-healing or headache? Results of a multicenter, randomized, placebo-controlled, double-blind trial Dis Colon Rectum 43 174–181 Occurrence Handle1:STN:280:DC%2BD3c7lvF2lsQ%3D%3D Occurrence Handle10696890

    CAS  PubMed  Google Scholar 

  40. SJ Watson MA Kamm R Nichols RK Phillips (1996) ArticleTitleTopical glyceryl trinitrite in the treatment of chronic anal fissure Br J Surg 83 771–775 Occurrence Handle1:STN:280:BymA3svot10%3D Occurrence Handle8696736

    CAS  PubMed  Google Scholar 

  41. CM Manookian P Fleshner B Moore et al. (1998) ArticleTitleTopical nitroglycerin in the treatment of anal fissure Am Surg 64 962–964 Occurrence Handle1:STN:280:DyaK1cvjsFOgsw%3D%3D Occurrence Handle9764702

    CAS  PubMed  Google Scholar 

  42. NH Hyman PA Cataldo (1999) ArticleTitleNitroglycerin ointment for anal fissures Dis Colon Rectum 42 383–385 Occurrence Handle1:STN:280:DyaK1M3jvVaktQ%3D%3D Occurrence Handle10223761

    CAS  PubMed  Google Scholar 

  43. G Dorfman M Levitt C Platell (1999) ArticleTitleTreatment of chronic anal fissure with topical glyceryl trinitrate Dis Colon Rectum 42 1007–1010 Occurrence Handle1:STN:280:DyaK1MzosFejtg%3D%3D Occurrence Handle10458122

    CAS  PubMed  Google Scholar 

  44. WR Schouten JW Briel MO Boerma JJ Auwerda EB Wilms BH Graatsma (1996) ArticleTitlePathophysiological aspects and clinical outcome of intra-anal application of isosorbide dinitrate in patients with chronic anal fissure Gut 39 465–469 Occurrence Handle1:STN:280:ByiC3cnptVM%3D Occurrence Handle8949655

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. University of Texas, Houston, Texas, Ochsner Clinic Foundation, New Orleans, Louisiana, Northwest Colon and Rectal Clinic, Seattle, Washington, Atlanta, Georgia, New York, New York, Cleveland Clinic Foundation, Cleveland, Ohio, Orlando, Florida, Henry Ford Hospital, Detroit, Michigan, Weil Cornell Medical College, New York, New York, Providence, Rhode Island, University of Cincinnati, Cincinnati, Ohio, Anaheim, California, University of Miami, Miami, Florida, Cleveland Clinic Foundation, Cleveland, Ohio, University of California at Los Angeles, Torrance, California, San Francisco, California, Mayo Clinic, Rochester, Minnesota, Chicago, Illinois, USA

    H. Randolph Bailey M.D., David E. Beck M.D., Richard P. Billingham M.D., Sander R. Binderow M.D., Lester Gottesman M.D., Tracy L. Hull M.D., Sergio W. Larach M.D., David A. Margolin M.D., Jeffrey W. Milsom M.D., Fabio M. Potenti M.D., Janice F. Rafferty M.D., Dennis S. Riff M.D., Lawrence R. Sands M.D., Anthony Senagore M.D., Michael J. Stamos M.D., Laurence F. Yee M.D., Tonia M. Young-Fadok M.D. & Robert D. Gibbons Ph.D.

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  1. H. Randolph Bailey M.D.
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  2. David E. Beck M.D.
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  5. Lester Gottesman M.D.
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  6. Tracy L. Hull M.D.
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  7. Sergio W. Larach M.D.
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  8. David A. Margolin M.D.
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  9. Jeffrey W. Milsom M.D.
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  10. Fabio M. Potenti M.D.
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  11. Janice F. Rafferty M.D.
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Bailey, H.R., Beck, D.E., Billingham, R.P. et al. A Study to Determine the Nitroglycerin Ointment Dose and Dosing Interval That Best Promote the Healing of Chronic Anal Fissures. Dis Colon Rectum 45, 1192–1199 (2002). https://doi.org/10.1007/s10350-004-6392-9

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