Nitroglycerin 0.4% ointment vs placebo in the treatment of pain resulting from chronic anal fissure: a randomized, double-blind, placebo-controlled study

BMC Gastroenterology

Ann Yellowlees⁵  Michael Safdi²  Dennis S Riff⁶  John E Pappas⁷  Julian Howell⁹  Gregory V Collins⁸  Gemma Clark⁹  Raj Bhandari³  Charles F Barish⁴  Scott M Berry¹ 

[1] CRC of Jackson, 501 Marshall Street #500, Jackson, MS 39202, USA;Consultants for Clinical Research/GCGA Physicians, 2925 Vernon Place, Suite 200, Cincinnati, OH, USA;Delta Research Partners, LLC, 608 Grammant Street, Monroe, LA 71201, USA;Wake Research Associates, LLC, 3100 Blue Ridge Road, Suite 300, Raleigh, NC 27612, USA;Quantics Consulting, Roslin BioCentre, Edinburgh, Scotland, UK;Advanced Clinical Research Institute, 1211 West La Palma Ave. Suite 303, Anaheim, CA 92801, USA;Kentucky Medical Research Center, 354 Waller Avenue, Suite 110, Lexington, KY 40504, USA;Charlotte Clinical Research, 330 Billingsley Road, Charlotte, NC 28211, USA;ProStrakan Pharmaceuticals Ltd, Galabank Business Park, Galashiels TD1 1QH, UK

关键词: Pain;    Nitroglycerin;    Fissure In Ano;    Clinical Trial;   

Others  :  857860
DOI  :  10.1186/1471-230X-13-106

 received in 2012-07-25, accepted in 2013-06-05,  发布年份 2013

【 摘 要 】

Background

Complications of chronic anal fissure (CAF) treatments are prompting interest in lower-risk therapies. This study was conducted to compare nitroglycerin (NTG) 0.4% ointment with placebo for pain associated with CAF.

Methods

In this randomized, double-blind, placebo-controlled trial, patients with one CAF and moderate-to-severe pain (≥50 mm on a 100 mm visual analog scale [VAS]) received 375 mg NTG 0.4% (1.5 mg active ingredient) or 375 mg placebo ointment applied anally every 12 hours for 21 days. The primary end point was change from baseline VAS score in 24-hour pain averaged over days 14–18. Review of data from patients who withdrew early was blinded to treatment. To control for the confounding effects of analgesics, all patients received 650 mg acetaminophen for headache prophylaxis before each application.

Results

A total of 247 patients were enrolled (NTG, n = 123; placebo, n = 124). The prespecified baseline observation carried forward (BOCF) analysis found no significant difference between groups; however, a last observation carried forward (LOCF) analysis showed a significant advantage for NTG. A post hoc analysis (LOCF/BOCF hybrid) demonstrated a significant adjusted mean difference of −7.0 mm in favor of NTG 0.4% (95% CI −13.6, –0.4; P = .038). Headache was the most common adverse event in the NTG (69.9%) and placebo (47.6%) groups.

Conclusions

This was the first placebo-controlled study that also controlled for the confounding effects of analgesics used to treat NTG-induced headache. In patients with moderate-to-severe CAF pain, NTG 0.4% ointment effectively reduced CAF pain compared with placebo.

Trial registration

ClinicalTrials.gov, NCT00522041

【 授权许可】

   
2013 Berry et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Azarnoff DL, Lee JC, Lee C, Chandler J, Karlin D: Quality of extemporaneously compounded nitroglycerin ointment. Dis Colon Rectum 2007, 50:509-516.
• [2]Bailey HR, Beck DE, Billingham RP, Binderow SR, Gottesman L, Hull TL, Larach SW, Margolin DA, Milsom JW, Potenti FM, Rafferty JF, Riff DS, Sands LR, Senagore A, Stamos MJ, Yee LF, Young-Fadok TM, Gibbons RD: A study to determine the nitroglycerin ointment dose and dosing interval that best promote the healing of chronic anal fissures. Dis Colon Rectum 2002, 45:1192-1199.
• [3]International Conference on Harmonisation Working Group: ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 (R1). International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Washington, DC; 1996. Available at: [http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf webcite]. Accessed: March 1, 2013
• [4]World Medical Association: Declaration of Helsinki: ethical principles for medical research involving human subjects. 2008. Available at: [http://www.wma.net/en/30publications/10policies/b3/17c.pdf webcite]. Accessed: March 4, 2013
• [5]Bijur PE, Silver W, Gallagher EJ: Reliability of the visual analog scale for measurement of acute pain. Acad Emerg Med 2001, 8:1153-1157.
• [6]Gallagher EJ, Liebman M, Bijur PE: Prospective validation of clinically important changes in pain severity measured on a visual analog scale. Ann Emerg Med 2001, 38:633-638.
• [7]RECTIV (nitroglycerin): Ointment 0.4%, for intra-anal use [package insert]. Bedminster, NJ: ProStrakan, Inc; 2011.
• [8]Carapeti EA, Kamm MA, McDonald PJ, Chadwick SJ, Melville D, Phillips RK: Randomised controlled trial shows that glyceryl trinitrate heals anal fissures, higher doses are not more effective, and there is a high recurrence rate. Gut 1999, 44:727-730.
• [9]Kennedy ML, Sowter S, Nguyen H, Lubowski DZ: Glyceryl trinitrate ointment for the treatment of chronic anal fissure: results of a placebo-controlled trial and long-term follow-up. Dis Colon Rectum 1999, 42:1000-1006.
• [10]Altomare DF, Rinaldi M, Milito G, Arcana F, Spinelli F, Nardelli N, Scardigno D, Pulvirenti-D’Urso A, Bottini C, Pescatori M, et al.: Glyceryl trinitrate for chronic anal fissure–healing or headache? Results of a multicenter, randomized, placebo-controled, double-blind trial. Dis Colon Rectum 2000, 43:174-179.
• [11]Nelson RL: Non surgical therapy for anal fissure. Cochrane Database Syst Rev 2006, 18(4):CD003431.
• [12]Ahmad J, Andrabi SI, Rathore MA: Comparison of topical glyceryl trinitrate with lignocaine ointment for treatment of anal fissure: a randomised controlled trial. Int J Surg 2007, 5:429-432.
• [13]Brisinda G, Cadeddu F, Brandara F, Marniga G, Maria G: Randomized clinical trial comparing botulinum toxin injections with 0.2 per cent nitroglycerin ointment for chronic anal fissure. Br J Surg 2007, 94:162-167.
• [14]Fruehauf H, Fried M, Wegmueller B, Bauerfeind P, Thumshirn M: Efficacy and safety of botulinum toxin a injection compared with topical nitroglycerin ointment for the treatment of chronic anal fissure: a prospective randomized study. Am J Gastroenterol 2006, 101:2107-2112.
• [15]Shrivastava UK, Jain BK, Kumar P, Saifee Y: A comparison of the effects of diltiazem and glyceryl trinitrate ointment in the treatment of chronic anal fissure: a randomized clinical trial. Surg Today 2007, 37:482-485.
• [16]Collins EE, Lund JN: A review of chronic anal fissure management. Tech Coloproctol 2007, 11:209-223.