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Glyceryl trinitrate ointment for chronic anal fissure
T H E LANCET
and its representatives on earth-the purchasers. He who pays the piper calls the tune.
Glyceryl trinitrate ointment for chronic anal fissure
SIR-In the excellent trial of glyceryl trinitrate (GTN) ointment in the treatment of chronic anal fissure, York Y O 1 5DD, UK (Lund and Scholefield, Jan 4, p ll)’, 58% of patients using G T N had 1 Sackett DL, Rosenberg WM, Gray JA, headache at some time, which is a Haynes RB, Richardson WS. Evidence remarkably high proportion. Headache based medicine; what it is and what it isn’t. was presumably caused by the high B M J 1996; 312: 71-72. 2 Sacket DL. The doctor’s (ethical and dose of G T N in each application of economic) dilemma. London: Office of ointment. Standard sublingual tablets Health Economics, 1996. of G T N contain 300 or 500 p,g, whereas 0.5 g of a 0.2% ointment contains 1 mg, much of which will have been absorbed through the mucosa. At Tetanus toxoid for adults what times in the 24 hours did SIR-Bowman and colleagues (Dec 14, headache occur, and was it commoner p 1664)’ rightly argue in favour of during the first week of treatment? tetanus immunisation for adults. They Perhaps those people who get headache report a patient who, despite adequate could usefully try a 0.1% ointment antibodies (0.13 IUlmL), developed applied three or four times a day, at tetanus after a minor graze. Generally, least during the first week or two, with even lower antibody concentrations are a long interval at night to keep regarded as protective (0.01 IU/mL), development of tolerance to a but tetanus has been reported in minimum. patients with titres as high as 0.16 The investigators do not mention IU/mL.Z In addition, tetanus antitoxin whether any of the patients were on concentrations decline over time, and other medication, and whether any had the immune response to tetanus toxoid cardiovascular disease. Did any have also declines after 50 years of age, previous experience of GTN, or have probably because of a reduced angina pectoris? And since constipation response of helper-T cells to the would tend to worsen pain on toxoid.? Elderly patients may fail to defaecation and to slow healing of the seroconvert within 14 days of b o o ~ t e r . ~ fissure, one would like to know howHence, giving a booster of tetanus and how successfully-the patients in toxoid to the elderly is good practice. the two treatment groups prevented Boosting at 10-year intervals is even constipation. more commendable and this would tend to keep antibody titres higher than Andrew Herxheimer protective levels; this would be more 9 Park Crescent, London N3 ZNL, U K essential in developed countries in which natural exposure to tetanus may 1 Lund JN, Scholefield JH. A randomised, be low. Natural boosting is quite prospective, double-blind placebocontrolled trial of glyceryl trinitrate common in developing countries where ointment in treatment of anal fissure. Lancet such an exposure may provide the 1997; 349: 11-14. necessary boosting effect even in the absence of a ~ a c c i n e . ~ Authors ’ reply Alan Maynard
Department of Heath Sciences and Clinical Evaluation, Alcuin College, Heslington,
R Sehgal Department of Microbiology, BP Koirala Institute of Health Sciences. Dharan, Nepal 1 Bowman C, Hearing S , Bewley J. Tetanus toxoid in adults. Lancet 1996; 348: 1664. 2 Passen EL, Andersen BR. Clinical tetanus despite a protective level of toxin neutralizing antibody. J A M 1986; 255: 1 17 1-73. 3 Peel MM, Edsall G, White WG, Barnes GM. Relationship between lymphocyte responses to tetanus toxoid and age of lymphocyte donor. J H y g (Lond) 1978; 80: 259. 4 Gareau AB, Eby RJ, Mclellan BA, Williams DR. Tetanus immunization status and immunologic response to a booster in an emergency department geriatric population. Ann Emerg Med 1990; 19: 1377-82. 5 Dastur FD, Awatramani VP, Dixit SIC, et al. Response to single dose of tetanus vaccine in subjects with naturally-acquired tetanus antitoxin. Lancet 1981; 11: 219.
Vo1349 * February 22, 1997
SIR-Although the dose of GTN used seems high it is uncertain how much of the ointment adheres to the anal canal long enough to be absorbed, and indeed how much of the drug is absorbed locally or systemically. Because the GTN is prepared as an ointment the amount of drug applied necessarily varies between patients applying it to themselves at home. Patients were advised to use a lump of ointment the size of half a pea at each application and we estimated that the 1st
2wk
4wk 6wk 8wk
application ----GTN (n=38) 4 Placebo (n=40) 0
19 5
13 4
8
2
4 1
Incidence of headaches reported after 1st application and at 2 weekly review of patients receiving GTN or placebo
maximum anyone who followed this advice would apply was 0.5 g. The concentration of 0.2% was the maximum that could be tolerated without unpleasant side-effects in a small study in healthy volunteers.’ It may be that a lower concentration could be used, and we are investigating the optimum dose. Headaches occurred within 10-1 5 min of application (morning and early evening with 12 h separating doses) and lasted no more than 30 min in most patients. Headache was commonest not after the first application but in the first 2 weeks of treatment (table). It is noteworthy how many in the placebo group also reported headaches after application of ointment, having been warned that it may be a side-effect of treatment. No patients received any other local medication during the trial, nor was any use made of stool softeners or laxatives, nor was any dietary advice given. One patient in the trial was being treated with oral slow-release nitrates for angina and did not experience headache. *Jonathan N Lund, John H Scholefield Department of Surgery, University Hospital, Queen’sMedical Centre, Nottingham N G 7 2UH. UK 1 Lund JN, Armitage NC, Scholefield JH. Use of glyceryl trinitrate ointment in the treatment of anal fissure. Br J Surg 1996; 83: 776-77.
Science from the patient’s point of view SIR-Simini’s Christmas review (Dec 21/28, suppl 11, p 1)’ of the year’s progress in anaesthesia made my heart both leap and contract with pain. It was so refreshing to read about the science assessed from the patient’s point of view, and the science itself questioned. Writing about the increased rather than decreased aspiration of gastric contents caused by unnecessary nasogastric tubes in “patients without risk factors for gastro-oesophageal reflux”, Simini goes on to ask, “will this inspire critical reappraisal of other procedures, ubiquitous in medical practice, of unproven benefit yet blindly continued.. . which cause needless discomfort, increase workloads, and usurp limited resources which could be put to better use?” Although I do not share his faith in evidenced-based medicine, I do think that the effort put into randomised controlled trials is almost always far more informative than the often negative statistical results, and needs to be encouraged whenever possible. But what really cheered me and gave
573
and its representatives on earth-the purchasers. He who pays the piper calls the tune.
Glyceryl trinitrate ointment for chronic anal fissure
SIR-In the excellent trial of glyceryl trinitrate (GTN) ointment in the treatment of chronic anal fissure, York Y O 1 5DD, UK (Lund and Scholefield, Jan 4, p ll)’, 58% of patients using G T N had 1 Sackett DL, Rosenberg WM, Gray JA, headache at some time, which is a Haynes RB, Richardson WS. Evidence remarkably high proportion. Headache based medicine; what it is and what it isn’t. was presumably caused by the high B M J 1996; 312: 71-72. 2 Sacket DL. The doctor’s (ethical and dose of G T N in each application of economic) dilemma. London: Office of ointment. Standard sublingual tablets Health Economics, 1996. of G T N contain 300 or 500 p,g, whereas 0.5 g of a 0.2% ointment contains 1 mg, much of which will have been absorbed through the mucosa. At Tetanus toxoid for adults what times in the 24 hours did SIR-Bowman and colleagues (Dec 14, headache occur, and was it commoner p 1664)’ rightly argue in favour of during the first week of treatment? tetanus immunisation for adults. They Perhaps those people who get headache report a patient who, despite adequate could usefully try a 0.1% ointment antibodies (0.13 IUlmL), developed applied three or four times a day, at tetanus after a minor graze. Generally, least during the first week or two, with even lower antibody concentrations are a long interval at night to keep regarded as protective (0.01 IU/mL), development of tolerance to a but tetanus has been reported in minimum. patients with titres as high as 0.16 The investigators do not mention IU/mL.Z In addition, tetanus antitoxin whether any of the patients were on concentrations decline over time, and other medication, and whether any had the immune response to tetanus toxoid cardiovascular disease. Did any have also declines after 50 years of age, previous experience of GTN, or have probably because of a reduced angina pectoris? And since constipation response of helper-T cells to the would tend to worsen pain on toxoid.? Elderly patients may fail to defaecation and to slow healing of the seroconvert within 14 days of b o o ~ t e r . ~ fissure, one would like to know howHence, giving a booster of tetanus and how successfully-the patients in toxoid to the elderly is good practice. the two treatment groups prevented Boosting at 10-year intervals is even constipation. more commendable and this would tend to keep antibody titres higher than Andrew Herxheimer protective levels; this would be more 9 Park Crescent, London N3 ZNL, U K essential in developed countries in which natural exposure to tetanus may 1 Lund JN, Scholefield JH. A randomised, be low. Natural boosting is quite prospective, double-blind placebocontrolled trial of glyceryl trinitrate common in developing countries where ointment in treatment of anal fissure. Lancet such an exposure may provide the 1997; 349: 11-14. necessary boosting effect even in the absence of a ~ a c c i n e . ~ Authors ’ reply Alan Maynard
Department of Heath Sciences and Clinical Evaluation, Alcuin College, Heslington,
R Sehgal Department of Microbiology, BP Koirala Institute of Health Sciences. Dharan, Nepal 1 Bowman C, Hearing S , Bewley J. Tetanus toxoid in adults. Lancet 1996; 348: 1664. 2 Passen EL, Andersen BR. Clinical tetanus despite a protective level of toxin neutralizing antibody. J A M 1986; 255: 1 17 1-73. 3 Peel MM, Edsall G, White WG, Barnes GM. Relationship between lymphocyte responses to tetanus toxoid and age of lymphocyte donor. J H y g (Lond) 1978; 80: 259. 4 Gareau AB, Eby RJ, Mclellan BA, Williams DR. Tetanus immunization status and immunologic response to a booster in an emergency department geriatric population. Ann Emerg Med 1990; 19: 1377-82. 5 Dastur FD, Awatramani VP, Dixit SIC, et al. Response to single dose of tetanus vaccine in subjects with naturally-acquired tetanus antitoxin. Lancet 1981; 11: 219.
Vo1349 * February 22, 1997
SIR-Although the dose of GTN used seems high it is uncertain how much of the ointment adheres to the anal canal long enough to be absorbed, and indeed how much of the drug is absorbed locally or systemically. Because the GTN is prepared as an ointment the amount of drug applied necessarily varies between patients applying it to themselves at home. Patients were advised to use a lump of ointment the size of half a pea at each application and we estimated that the 1st
2wk
4wk 6wk 8wk
application ----GTN (n=38) 4 Placebo (n=40) 0
19 5
13 4
8
2
4 1
Incidence of headaches reported after 1st application and at 2 weekly review of patients receiving GTN or placebo
maximum anyone who followed this advice would apply was 0.5 g. The concentration of 0.2% was the maximum that could be tolerated without unpleasant side-effects in a small study in healthy volunteers.’ It may be that a lower concentration could be used, and we are investigating the optimum dose. Headaches occurred within 10-1 5 min of application (morning and early evening with 12 h separating doses) and lasted no more than 30 min in most patients. Headache was commonest not after the first application but in the first 2 weeks of treatment (table). It is noteworthy how many in the placebo group also reported headaches after application of ointment, having been warned that it may be a side-effect of treatment. No patients received any other local medication during the trial, nor was any use made of stool softeners or laxatives, nor was any dietary advice given. One patient in the trial was being treated with oral slow-release nitrates for angina and did not experience headache. *Jonathan N Lund, John H Scholefield Department of Surgery, University Hospital, Queen’sMedical Centre, Nottingham N G 7 2UH. UK 1 Lund JN, Armitage NC, Scholefield JH. Use of glyceryl trinitrate ointment in the treatment of anal fissure. Br J Surg 1996; 83: 776-77.
Science from the patient’s point of view SIR-Simini’s Christmas review (Dec 21/28, suppl 11, p 1)’ of the year’s progress in anaesthesia made my heart both leap and contract with pain. It was so refreshing to read about the science assessed from the patient’s point of view, and the science itself questioned. Writing about the increased rather than decreased aspiration of gastric contents caused by unnecessary nasogastric tubes in “patients without risk factors for gastro-oesophageal reflux”, Simini goes on to ask, “will this inspire critical reappraisal of other procedures, ubiquitous in medical practice, of unproven benefit yet blindly continued.. . which cause needless discomfort, increase workloads, and usurp limited resources which could be put to better use?” Although I do not share his faith in evidenced-based medicine, I do think that the effort put into randomised controlled trials is almost always far more informative than the often negative statistical results, and needs to be encouraged whenever possible. But what really cheered me and gave
573