Nitric Oxide and the Pathophysiology of Pain Associated With Chronic Anal Fissure

  • Chronic anal fissure (CAF) is characterized by hypertonicity of the internal anal sphincter (IAS) and breakdown of the anoderm due to decreased blood flow1-3
    • The resulting ischemic environment is thought to contribute to the pain of CAF4,5
  • Nitric oxide (NO), the main inhibitory neurotransmitter that mediates relaxation of the IAS, may have a role in relieving the pain of CAF1
  • Research suggests that patients with CAF may have a low presence of the enzyme nitric oxide synthase (NOS), which produces NO, in blood vessels of the IAS6
    • This reduced presence of NO may lead to the decreased blood flow in the IAS and high sphincter tone reported in patients with CAF6

Nitric oxide donors can address the pain associated with CAF

  • NO donors, such as nitroglycerin, have been shown to improve blood flow and reduce pressure in the IAS1,9
    • It is believed that these actions contribute to relieving the pain associated with CAF4,10

References: 1. Madoff RD, Fleshman JW; for American Gastroenterological Association Clinical Practice Committee. AGA technical review on the diagnosis and care of patients with anal fissure. Gastroenterology. 2003;124(1):235-245. 2. Schouten WR, Briel JW, Auwerda JJA, De Graaf EJR. Ischaemic nature of anal fissure. Br J Surg. 1996;83(1):63-65. 3. Schouten WR, Briel JW, Auwerda JJA. Relationship between anal pressure and anodermal blood flow: the vascular pathogenesis of anal fissures. Dis Colon Rectum. 1994;37(7):664-669. 4. Villalba H, Villalba S, Abbas MA. Anal fissure: a common cause of anal pain. Perm J. 2007;11(4):62-65. 5. Gibbons CP, Read NW. Anal hypertonia in fissures: cause or effect? Br J Surg. 1986;73(6):443-445. 6. Lund JN. Nitric oxide deficiency in the internal anal sphincter of patients with chronic anal fissure. Int J Colorectal Dis. 2006;21:673-675. 7. Kua KB, Kocher HM, Kelkar A, Patel AG. Effect of topical glyceryl trinitrate on anodermal blood flow in patients with chronic anal fissures. ANZ J Surg. 2001;71(9):548-550. 8. Evgenov OV, Pacher P, Schmidt PM, et al. NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov. 2006;5(9):755-768. 9. RECTIV [package insert]. Bridgewater, NJ: Aptalis Pharma US, Inc.; July 2013. 10. Berry SM, Barish CF, Bhandari R, et al. 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. 2013;13:106.

IMPORTANT SAFETY INFORMATION

Contraindications

  • Use of phosphodiesterase type 5 (PDE5) inhibitors (eg, sildenafil, vardenafil, and tadalafil), as these are shown to potentiate the hypotensive effects of organic nitrates.
  • Severe anemia
  • Increased intracranial pressure
  • Known hypersensitivity to nitroglycerin, other nitrates and nitrites, or any components of the ointment.

Warnings and Precautions

  • Cardiovascular Disorders: Venous and arterial dilatation as a consequence of nitroglycerin treatment can result in hypotension. Exercise caution in patients with any of the following conditions: blood volume depletion, existing hypotension, cardiomyopathies, congestive heart failure, acute myocardial infarction, or poor cardiac function for other reasons. If patients with any of these conditions are treated with RECTIV, monitor cardiovascular status and clinical condition. The adverse reactions of RECTIV are likely to be more pronounced in the elderly.
  • Headache: RECTIV produces dose-related headaches, which may be severe. Tolerance to headaches occurs.

Drug Interactions

The following drug interactions may occur in patients taking RECTIV:
  • PDE5 inhibitors: potentiation of hypotensive effects of organic nitrates; concomitant use is contraindicated
  • Antihypertensives: possible additive hypotensive effects
  • Aspirin: increased nitroglycerin levels
  • Tissue-type Plasminogen Activator (t-PA): decreased thrombolytic effect
  • Heparin: anticoagulant effect of heparin may be reduced. Monitor activated partial thromboplastin time (APTT).
  • Ergotamine: increased bioavailability of ergotamine
  • Alcohol: additive vasodilatory effects to nitroglycerin. Consumption of alcohol should be avoided.

Adverse Reactions

  • The most common adverse reactions in RECTIV-treated patients (incidence ≥2% and greater than placebo) were headache (64% vs 41%) and dizziness (5% vs 0%).

Indications and Usage

  • RECTIV® (nitroglycerin) Ointment 0.4% is indicated for the treatment of moderate to severe pain associated with chronic anal fissure.

Please see full Prescribing Information.

The information provided in this site is intended for U.S. healthcare professionals only. The products described on this site may have different product labeling in countries outside of the United States. For additional information about RECTIV, call Allergan Medical Information toll-free at 1.800.678.1605.


Allergan

Allergan® and its design are trademarks of Allergan, Inc.

RECTIV® is a registered trademark of Aptalis Pharma US, Inc., an Allergan affiliate.

© 2017 Allergan. All rights reserved.REC52946_v307/17

IMPORTANT SAFETY INFORMATION

Contraindications

  • Use of phosphodiesterase type 5 (PDE5) inhibitors (eg, sildenafil, vardenafil, and tadalafil), as these are shown to potentiate the hypotensive effects of organic nitrates.
  • Severe anemia
  • Increased intracranial pressure
  • Known hypersensitivity to nitroglycerin, other nitrates and nitrites, or any components of the ointment.

Warnings and Precautions

  • Cardiovascular Disorders: Venous and arterial dilatation as a consequence of nitroglycerin treatment can result in hypotension. Exercise caution in patients with any of the following conditions: blood volume depletion, existing hypotension, cardiomyopathies, congestive heart failure, acute myocardial infarction, or poor cardiac function for other reasons. If patients with any of these conditions are treated with RECTIV, monitor cardiovascular status and clinical condition. The adverse reactions of RECTIV are likely to be more pronounced in the elderly.
  • Headache: RECTIV produces dose-related headaches, which may be severe. Tolerance to headaches occurs.

Drug Interactions

The following drug interactions may occur in patients taking RECTIV:
  • PDE5 inhibitors: potentiation of hypotensive effects of organic nitrates; concomitant use is contraindicated
  • Antihypertensives: possible additive hypotensive effects
  • Aspirin: increased nitroglycerin levels
  • Tissue-type Plasminogen Activator (t-PA): decreased thrombolytic effect
  • Heparin: anticoagulant effect of heparin may be reduced. Monitor activated partial thromboplastin time (APTT).
  • Ergotamine: increased bioavailability of ergotamine
  • Alcohol: additive vasodilatory effects to nitroglycerin. Consumption of alcohol should be avoided.

Adverse Reactions

  • The most common adverse reactions in RECTIV-treated patients (incidence ≥2% and greater than placebo) were headache (64% vs 41%) and dizziness (5% vs 0%).

Indications and Usage

  • RECTIV® (nitroglycerin) Ointment 0.4% is indicated for the treatment of moderate to severe pain associated with chronic anal fissure.

Please see full Prescribing Information.

The information provided in this site is intended for U.S. healthcare professionals only. The products described on this site may have different product labeling in countries outside of the United States. For additional information about RECTIV, call Allergan Medical Information toll-free at 1.800.678.1605.


Allergan

Allergan® and its design are trademarks of Allergan, Inc.

RECTIV® is a registered trademark of Aptalis Pharma US, Inc., an Allergan affiliate.

© 2017 Allergan. All rights reserved.REC52946_v307/17