Acta Med Scand 205: 449-450. 1979
EDITORIAL
Adverse Drug Reactions-A Adverse drug reactions a r e - o r should be-the concern of all physicians, in surgical as well as in medical specialities. The lay public-and to some extent also physicians-seem to believe that drugs entirely free from adverse reactions can be obtained. This is a dream, and will remain so, although, to talk with Hamlet, “a dream devoutly to be wished”. No drug is completely free from riskand never will be! A few years ago J . G. Waldenstrom stated in an editorial (6) that the Acta would like to collaborate in disseminating knowledge about toxic effects of drugs and the methods of recognizing them. The response has not been impressive. A perusal of the contents of the last ten volumes (1974-78) shows that out of close on 1000 articles only 30, i.e. 3 76, dealt directly with adverse drug reactions-and that no visible increase occurred as a result of the appeal of the Editor. The attitude towards adverse drug reactions differs widely-from that of the enthusiastic physician-therapist, who believes that modern drugs do so much good that an occasional adverse reaction does not count, to that of the deadly scared and tormented patient with a severe adverse reaction. The American Medical Association had to abandon its registry on adverse drug reactions, and recently lngelfinger (4) said that “the total number of adverse reactions per given population per year may be a figure for the record books, but in itself is of hardly any pragmatic importance”. It is important to realize that we have to live with adverse drug reactions-as we have learnt to live with complications to surgery. The important thing is to minimize the number of such reactions as well as their negative effects when they do occur. And this can be achieved by learning more about drugs, about their benefits and disadvantages. And knowledge in the latter aspect can be obtained only by collecting and analyzing such adverse drug reactions as have occurred and by returning such knowledge to the prescribing physicians-and also to the patients and the public at large. The problem with adverse drug reactions is to a large extent a problem of information. It is as such 29-792986
Plea for a Realistic Attitude both a difficult and a delicate problem, that must be handled with great care. Advantages must be balanced against disadvantages, positive drug effects against risks of adverse reactions. The press handles all reports .on adverse drug reactions in the same way-the negative sides are grossly exaggerated and the positive effects are not mentioned at all. Such negative over-dramatization is harmful to our patients, who get scared and do not take the drugs that are necessary for their recovery and health. Even physicians get scared and refrain from using valuable drugs. This type of negative and one-sided information prevents a realistic and balanced attitude towards the drugs that we need in modern medicine. In Sweden all physicians have to report adverse drug reactions to a central Adverse Drug Reaction Committee, which has been active since 1965. During 13 years of operation (1966-78) a total of 18000 reports have been received-the annual number has gone up from 600 to over 2 200 in 1978. All incoming reports have been carefully analyzed as to the cause-and-effect relation between the intake of the drug and the ensuing negative reaction. The material has formed the basis for a large number of studies ( ~ 7 0that ) have been published-two examples are to be found in this issue. Analysis of a nation-wide material of adverse drug reactions as large as that of the Swedish Committee will permit us to identify p a t i m t s ut special risk, as well as tell what adverse reactions especially to look for with specific drugs and what driigs are likely to be involved when a certain negative reaction is encountered. Also, Swedish experiences clearly demonstrate that the results of the work with adverse drug reactions can be used to influence the drug market in the country. The number of adverse reactions rises very markedly with increasing age of the patient. This is true for all occurring reactions and still more for those with a fatal outcome (cf. p. 452). This puts a special emphasis on the many difficulties involved in geriatric pharrnucotherupy which, although at the opposite end of the life span, has at least as many special aspects and problems as neonatal and
450
Editoricil
pediatric pharmacotherapy. To mention only a few, elderly and old people have many simultaneous diseases and ailments, they take many drugs-but they also may have decreased drug metabolic capacity, they definitely have impaired renal function and there are indications that they have increased sensitivity at the receptor level, e.g. for dicumarol, all of which changes may lead to accumulation of drugs-and adverse reactions! Rapid changes occur in the spectrum of adverse reactions, especially due to shifts among the drugs commonly prescribed. This is well illustrated by Table 1V in the article “Drug-induced Blood Dyscrasias” in this issue. Out of 12 drugs-or groups of drugs-responsible for drug-induced cytopenias, only one (methyldopa) remained in the same position on the list during two consecutive S-year periods. All others had appeared, disappeared or changed position on the list. Another example is the oral contraceptives that 10 years ago accounted for 40% of the reports to the Swedish Committee-to-day the figure is 5 96. Antibiotics and sulfonamides have increased from 9% in the late 1960s to 30-35% at the present time. Especially the large number of sulfonamide-induced deaths is disturbing. The sulfonamides have, although under constant development, been on the market for more than 40 years. This in itself is reason enough to re-evaluate them and their position in modern pharmacotherapy, a task that becomes even more imperative when they are found to cause a considerable number of adverse reactions and even deaths. Sulfonamides today are used mainly on two indications, urinary tract infections-ften in combination with trimetoprim-and ulcerative colitis. Interesting studies in progress indicate that it may be possible in both conditions to proceed without the sulfonamide component. Danish studies have indicated that trimetoprim alone might be as effective as the trimetoprin-sulfonamide combination in treatment of urinary tract infections (9,and studies in Oxford that the active moiety of sulphasalazine (Salazopyrin)may well be 5-aminosalicylic acid ( 1). Perhaps it is time for the sulfonamides to retire from the scene? The results from the Swedish Adverse Drug Reaction Committee also bear witness to the usefulness of the work-definite changes on the Swedish drug market have been brought about! The Committee warned against the indiscriminate use of
chloramphenicol-sales figures dropped and no case of chloramphenicol-induced aplastic anemia has been seen in Sweden during the last 8 years. Repeated warnings against dipyrone (noramidopyrine) first led to a marked and abrupt decrease in sales figures, later to its disappearance from the market. The Committee has been active in banning oral contraceptives with high estrogen content and lately brought about the disappearance of thenalidin and phenformin. International cooperation is of great importance also in the field of adverse drug reactions. One example of such efforts is the WHO International Drug Monitoring Centre, since 1978 located in Uppsala, Sweden, that now receives data on adverse drug reactions from 23 countries all over the world. It will be interesting to see what the Centre can accomplish in its new location. International differences may be expected because of variations between systems of medical care, medical education and drug usage. Such differences have, for example, explained a large part of the greatly varied occurrence of drug-induced aplastic anemia between the Far East and the western world (3)-such aplasia is at least 4-5 times as common in the east. Also, pharmacogenetics are of importance-the proportion of people with, e.g., low content of hepatic acetyl transferase or red cell glucose-6phosphate dehydrogenase differs widely between populations. Let this suffice to demonstrate that work with adverse drug reactions is of importance and that we may learn much from it. And we do need more knowledge about the drugs we use, about their positive as well as negative effects, to increase the standards of our pharmacotherapy.
L . E . Bottiger, Stockholm, Sweden REFERENCES 1 . Azad Khan, A. K., Piris, J . & Truelove, S. C.: An experiment to determine the active therapeutic moiety of Sulphasalazine.Lancet 2: 892, 1977. 2. Bergman, U., Boman, G . & Wiholm, B.-E.: Ep3.
4.
5. 6.
idemiology of adverse drug reactions to phenformin and metformin. Br Med J 2: 464, 1978. BBttiger, L. E.: Epidemiology and etiology of aplastic anemia. International Symposium on Aplastic Anemia, Schloss Reisenburg, 1978. In press 1979. Ingelfinger, F. J.: Counting adverse drug reactions that count. N Engl J Med 294: 1003, 1976. Vejlsgaard, R.: Personal communication, 1979. Waldenstrom, J. G.: Toxicology in clinical medicine (editorial).Acta Med Scand 199: 378, 1976.
EDITORIAL
Adverse Drug Reactions-A Adverse drug reactions a r e - o r should be-the concern of all physicians, in surgical as well as in medical specialities. The lay public-and to some extent also physicians-seem to believe that drugs entirely free from adverse reactions can be obtained. This is a dream, and will remain so, although, to talk with Hamlet, “a dream devoutly to be wished”. No drug is completely free from riskand never will be! A few years ago J . G. Waldenstrom stated in an editorial (6) that the Acta would like to collaborate in disseminating knowledge about toxic effects of drugs and the methods of recognizing them. The response has not been impressive. A perusal of the contents of the last ten volumes (1974-78) shows that out of close on 1000 articles only 30, i.e. 3 76, dealt directly with adverse drug reactions-and that no visible increase occurred as a result of the appeal of the Editor. The attitude towards adverse drug reactions differs widely-from that of the enthusiastic physician-therapist, who believes that modern drugs do so much good that an occasional adverse reaction does not count, to that of the deadly scared and tormented patient with a severe adverse reaction. The American Medical Association had to abandon its registry on adverse drug reactions, and recently lngelfinger (4) said that “the total number of adverse reactions per given population per year may be a figure for the record books, but in itself is of hardly any pragmatic importance”. It is important to realize that we have to live with adverse drug reactions-as we have learnt to live with complications to surgery. The important thing is to minimize the number of such reactions as well as their negative effects when they do occur. And this can be achieved by learning more about drugs, about their benefits and disadvantages. And knowledge in the latter aspect can be obtained only by collecting and analyzing such adverse drug reactions as have occurred and by returning such knowledge to the prescribing physicians-and also to the patients and the public at large. The problem with adverse drug reactions is to a large extent a problem of information. It is as such 29-792986
Plea for a Realistic Attitude both a difficult and a delicate problem, that must be handled with great care. Advantages must be balanced against disadvantages, positive drug effects against risks of adverse reactions. The press handles all reports .on adverse drug reactions in the same way-the negative sides are grossly exaggerated and the positive effects are not mentioned at all. Such negative over-dramatization is harmful to our patients, who get scared and do not take the drugs that are necessary for their recovery and health. Even physicians get scared and refrain from using valuable drugs. This type of negative and one-sided information prevents a realistic and balanced attitude towards the drugs that we need in modern medicine. In Sweden all physicians have to report adverse drug reactions to a central Adverse Drug Reaction Committee, which has been active since 1965. During 13 years of operation (1966-78) a total of 18000 reports have been received-the annual number has gone up from 600 to over 2 200 in 1978. All incoming reports have been carefully analyzed as to the cause-and-effect relation between the intake of the drug and the ensuing negative reaction. The material has formed the basis for a large number of studies ( ~ 7 0that ) have been published-two examples are to be found in this issue. Analysis of a nation-wide material of adverse drug reactions as large as that of the Swedish Committee will permit us to identify p a t i m t s ut special risk, as well as tell what adverse reactions especially to look for with specific drugs and what driigs are likely to be involved when a certain negative reaction is encountered. Also, Swedish experiences clearly demonstrate that the results of the work with adverse drug reactions can be used to influence the drug market in the country. The number of adverse reactions rises very markedly with increasing age of the patient. This is true for all occurring reactions and still more for those with a fatal outcome (cf. p. 452). This puts a special emphasis on the many difficulties involved in geriatric pharrnucotherupy which, although at the opposite end of the life span, has at least as many special aspects and problems as neonatal and
450
Editoricil
pediatric pharmacotherapy. To mention only a few, elderly and old people have many simultaneous diseases and ailments, they take many drugs-but they also may have decreased drug metabolic capacity, they definitely have impaired renal function and there are indications that they have increased sensitivity at the receptor level, e.g. for dicumarol, all of which changes may lead to accumulation of drugs-and adverse reactions! Rapid changes occur in the spectrum of adverse reactions, especially due to shifts among the drugs commonly prescribed. This is well illustrated by Table 1V in the article “Drug-induced Blood Dyscrasias” in this issue. Out of 12 drugs-or groups of drugs-responsible for drug-induced cytopenias, only one (methyldopa) remained in the same position on the list during two consecutive S-year periods. All others had appeared, disappeared or changed position on the list. Another example is the oral contraceptives that 10 years ago accounted for 40% of the reports to the Swedish Committee-to-day the figure is 5 96. Antibiotics and sulfonamides have increased from 9% in the late 1960s to 30-35% at the present time. Especially the large number of sulfonamide-induced deaths is disturbing. The sulfonamides have, although under constant development, been on the market for more than 40 years. This in itself is reason enough to re-evaluate them and their position in modern pharmacotherapy, a task that becomes even more imperative when they are found to cause a considerable number of adverse reactions and even deaths. Sulfonamides today are used mainly on two indications, urinary tract infections-ften in combination with trimetoprim-and ulcerative colitis. Interesting studies in progress indicate that it may be possible in both conditions to proceed without the sulfonamide component. Danish studies have indicated that trimetoprim alone might be as effective as the trimetoprin-sulfonamide combination in treatment of urinary tract infections (9,and studies in Oxford that the active moiety of sulphasalazine (Salazopyrin)may well be 5-aminosalicylic acid ( 1). Perhaps it is time for the sulfonamides to retire from the scene? The results from the Swedish Adverse Drug Reaction Committee also bear witness to the usefulness of the work-definite changes on the Swedish drug market have been brought about! The Committee warned against the indiscriminate use of
chloramphenicol-sales figures dropped and no case of chloramphenicol-induced aplastic anemia has been seen in Sweden during the last 8 years. Repeated warnings against dipyrone (noramidopyrine) first led to a marked and abrupt decrease in sales figures, later to its disappearance from the market. The Committee has been active in banning oral contraceptives with high estrogen content and lately brought about the disappearance of thenalidin and phenformin. International cooperation is of great importance also in the field of adverse drug reactions. One example of such efforts is the WHO International Drug Monitoring Centre, since 1978 located in Uppsala, Sweden, that now receives data on adverse drug reactions from 23 countries all over the world. It will be interesting to see what the Centre can accomplish in its new location. International differences may be expected because of variations between systems of medical care, medical education and drug usage. Such differences have, for example, explained a large part of the greatly varied occurrence of drug-induced aplastic anemia between the Far East and the western world (3)-such aplasia is at least 4-5 times as common in the east. Also, pharmacogenetics are of importance-the proportion of people with, e.g., low content of hepatic acetyl transferase or red cell glucose-6phosphate dehydrogenase differs widely between populations. Let this suffice to demonstrate that work with adverse drug reactions is of importance and that we may learn much from it. And we do need more knowledge about the drugs we use, about their positive as well as negative effects, to increase the standards of our pharmacotherapy.
L . E . Bottiger, Stockholm, Sweden REFERENCES 1 . Azad Khan, A. K., Piris, J . & Truelove, S. C.: An experiment to determine the active therapeutic moiety of Sulphasalazine.Lancet 2: 892, 1977. 2. Bergman, U., Boman, G . & Wiholm, B.-E.: Ep3.
4.
5. 6.
idemiology of adverse drug reactions to phenformin and metformin. Br Med J 2: 464, 1978. BBttiger, L. E.: Epidemiology and etiology of aplastic anemia. International Symposium on Aplastic Anemia, Schloss Reisenburg, 1978. In press 1979. Ingelfinger, F. J.: Counting adverse drug reactions that count. N Engl J Med 294: 1003, 1976. Vejlsgaard, R.: Personal communication, 1979. Waldenstrom, J. G.: Toxicology in clinical medicine (editorial).Acta Med Scand 199: 378, 1976.
