An anal fissure is a linear crack or tear in the distal anoderm. Patients with anal fissures usually present with minor anal bleeding and severe anal pain. The etiology of anal fissures is not known with certainty, however, a considerable body of evidence now suggests an association between abnormal internal anal sphincter (IAS) function and anal fissures. Many studies have documented elevated resting anal pressures in fissure patients.(1,2) It is probable that an abnormal pressure response of the IAS plays a role in the causation of these lesions.
Many acute fissures resolve with conservative treatment, however, fissures which become chronic usually require surgical therapy. The Standards Task Force of the American Society of Colon and Rectal Surgeons recommends management of chronic anal fissures by "subcutaneous or open lateral internal sphincterotomy, posterior internal sphincterotomy with advancement flap, or manual dilatation".(3) Healing will occur following sphincterotomy in 95 percent of cases.(4) Successful sphincterotomy (or anal dilatation) is associated with a significant decrease in intra-anal pressure.(5,6) Although sphicterotomy is quite effective in promoting healing of anal fissures, it is not without risk. Many studies have demonstrated complications, most notably, temporary or permanent incontinence to gas, liquid and solid stool following sphincterotomy or anal dilatation.(7,8)
Recent evidence suggests that nitric oxide (NO) is the neurotransmitter released by inhibitory enteric neurons innervating the IAS.(9) Endogenous and exogenous nitric oxide (NO) in contact with the IAS causes relaxation of that muscle.(9,10) Organic nitrates, such as nitroglycerin, are degraded by cellular metabolism, liberating NO.(11) Nitroglycerin (NTG) applied topically to the anus has been shown to cause a lowering of IAS pressure in normal human subjects.(12,13)
To test the hypothesis that local delivery of NO to the anoderm reduces pain and promotes healing of anal fissures, studies of topical anal NTG ointment were initiated.(14,15) Fifty-four fissure patients were recruited to particiapte. Forty-one patients completed the requested follow-up schedule. Ninety percent of patients experienced significant pain relief after the first dose of topically applied NTG. Pain levels were reduced on average 78 percent within five minutes of NTG application. Fissures healed within 2 weeks or less in 11 patients (27 percent), within four weeks or less in 24 patients (58 percent) and within eight weeks or less in 29 patients (71 percent). None of the patients became incontinent during treatment. Side effects were limited to mild transient headaches in 12 patients (29 percent).
Lund and colleagues(16) performed a similar study of 21 chronic fissure patients. Patients were treated with NTG 0.2 percent ointment applied to the distal anal canal twice daily. Manometric assessment of maximal resting anal pressure (MRAP) was obtained before and 20 minutes after application of the test medication. Mean (s.d.) MRAP fell 41 percent from 118.7 (45.0) cm H2O to 70.3 (34.1) cm H2O (p<0.001, Student's paired t-test). Fissures healed in 11 patients (52 percent) at four weeks and in 18 patients (86 percent) at six weeks. All patients whose fissures subsequently healed reported that pain on defecation had disappeared within two weeks. Four patients (19 percent) experienced headaches while on therapy. None of the patients experienced incontinence. Four patients experienced recurrent fissures during the study period, and three of these responded to a second course of NTG therapy.
The same group has completed a prospective, blinded, randomized trial of NTG versus placebo in promoting healing of chronic anal fissures.(17) Patients were randomized to groups using NTG 0.2 percent or placebo twice daily for eight weeks. Fissures healed in 26 (68 percent) of 38 cases treated with NTG compared to three (eight percent) of 39 cases treated with placebo (p<0.0001, chi square). Application of NTG reduced MRAP from a mean of 115.9 (31.6) cm H2O to 75.9 (30.1) cm H2O (p<0.0001, Student's paired t-test) while placebo caused no significant fall in MRAP. Laser Doppler measurements of bloodflow improved in the NTG group from 32.4(27.5) units to 42.8(27.6) units (p<0.05, Student's t-test) whereas there was no improvement in the placebo group. Pain scores were significantly reduced after two weeks of treatment with NTG while there was no reduction in pain experienced by those treated with placebo. Fifty-eight percent of the NTG group experienced at least one episode of headache during therapy compared to 18 percent of those using placebo. Three fissures recurred after successful NTG therapy during four months of follow-up. All were successfully retreated by NTG.
Schouten and colleagues(18) used a one percent isosorbide dinitrate (ISDN) ointment in the treatment of 34 patients with chronic anal fissures. ISDN is an organic nitrate also metabolized to yield NO. Patients applied ISDN to the anoderm every three hours while awake. MRAP measurements in 11 patients showed a mean pressure reduction of 49 percent within five minutes of application. MRAP and bloodflow were measured after three and six weeks of therapy. Compared with baseline measurements, a significant reduction in MRAP and a significant increase in anodermal bloodflow were noted at both intervals. Healing occurred at six weeks or less in 14 patients (41 percent), nine weeks or less in 22 patients (65 percent) and 12 weeks or less in 30 patients (88 percent). All patients experienced headaches. During a follow-up period of 11 months there were two recurrences (seven percent) among the 30 patients who had healed.
The Saint Mark's group treated nineteen chronic fissure patients with NTG at concentrations shown manometrically to reduce MRAP at least 25 percent.(19) NTG was applied to the anal margin rather than within the anal canal. Fissures healed in nine of 13 patients (69 percent) completing treatment. As six patients withdrew, were lost to follow-up, or were referred for sphincterotomy, only 47 percent of those who began the study healed while on NTG therapy (nine of 19).
Topical NTG ointment was well tolerated by most patients. Headache was the most common side effect, occurring in 19 to 100 percent of patients. Headaches were generally self-limited, and abated after about 15 minutes. None of the patients in any of these studies developed incontinence. Surgical treatment of fissures and ulcers by lateral internal anal sphincterotomy (LAS) has a cure rate approaching 100 percent, but will result in long-term incontinence in up to seven percent of cases.
These studies indicate that therapy for chronic anal fissure is about to undergo a revolutionary change. The literature has already produced calls for NTG therapy as the standard of initial care.(20) More cautious optimism has been offered by others.(21) Controlled trials with special attention to dose ranging and dose scheduling are required. It is possible that a lowered intra-anal dose may effect reduction in MRAP without causing significant side effects. However, there can be little doubt that NTG is effective in promoting healing and relieving the pain of anal fissures. Optimum NO delivery may achieve cure rates approaching those attained by sphincterotomy, with faster onset of pain relief and without the attendant risk of incontinence. The body of evidence accumulated to date strongly suggests that topical, intra-anal NO therapy represents a significant advance in the management of anal fissures.
Last modified: 12 Jan 97, back to home page.