the incidence of adverse reactions to drugs

J. clin. Path., 28, Suppl. (Roy. Coll. Path.), 9, 7-13

The incidence of adverse reactions to drugs0. L. WADE

From the Department of Clinical Pharmacology, University ofBirmingham

Concern about adverse reactions to drugs is notnew. In 1887 at a meeting in Manchester the BritishMedical Association set up a small committee toexamine the sudden and unexpected deaths whichsometimes occurred during chloroform anaesthesia.This was the first collaborative investigation of anadverse reaction of a drug in human subjects.Professor McKendrick, Professor of Physiology inGlasgow, and Dr Coats, pathologist, and DrNewman, pathological chemist, at the WesternInfirmary, Glasgow (1880) reported that chloroformwas hazardous in man not only because excessivedoses depressed respiration but because small doseshad a deleterious effect on the heart and might causecardiac arrest. This report was contrary to theexperience of many who had used chloroform exten-sively. Its findings were repudiated by SurgeonMajor Lawrie, Residency Surgeon at Hyderabad inthe Deccan, with such heat that it is surprising thatthe now yellowing pages of the Lancet of 1889 and1890 are not a little charred. Major Lawrie appointedtwo Hyderabad Chloroform Commissions, on bothof which he sat as President. Following the extensiveadministration of chloroform to dogs that Commis-sion in its final report stated, in the words of acontemporary Anglo-Indian, that chloroform givenin doses which did not cause respiratory depressionwas 'as safe as whisky and water' (Lawrie, Brunton,Bomford, and Hakin, 1890). But the report receivedlittle attention in Britain for here it was alreadyindisputable that in human beings sudden death didsometimes occur in the early stages of chloroformanaesthesia.

This ancient controversy is worth recalling. It notonly showed for the first time the enormous emotionthat mayAbe aroused in doctors when a drug whichthey value is found to cause serious adverse reactions,but it also demonstrated, although the lesson has yetto be fully appreciated, that the administration of adrug to animals may fail to reveal its hazards inman.Towards the end of the first World War another

collaborative investigation concerning an adversereaction to a drug was instituted. The MedicalResearch Committee, later to become the present

Medical Research Council, appointed a 'SpecialCommittee on the Manufacture, Biological Testingand Clinical Administration of Salvarsan and itsSubstitutes'. Its enquiries followed an outbreak ofacute yellow atrophy due to neoarsphenaminebenzoate at Cherry Hinton Hospital near Cambridgein 1917 and 1918. The Committee reported (MedicalResearch Council, 1922) that the most probablecause of the outbreak was the toxicity of organo-arsenical compounds. But Professor StuartMcDonald, Professor of Pathology at Newcastle,suspected that there was an additional factor causingthe epidemic of jaundice which was probablymicrobial infection (McDonald, 1918). The aetiologyof this jaundice was in retrospect probably serumhepatitis. By a strange coincidence the Committeealso made a report of a peculiar outbreak of malariaamong patients treated with neoarsphenamine '606'at Portobello Hospital, Dublin. Eight soldiers haddied, and Professor A. C. O'Sullivan, Professor ofPathology at Trinity, found their organs full ofmalaria parasites, although only one of them wasknown to have served in a tropical country. TheCommittee found no reason to dissent fromProfessor O'Sullivan's opinion that the infectionhad been conveyed from one or more carriers ofthe disease to others through the apparatus forinjecting '606', the blood of the carrier regurgitatinginto the last segment of the rubber tubing remainingin the crevices there and being washed into the veinsof the next patient. If the hazard of crossinfectionhad been considered as a cause of the epidemic ofjaundice at Cherry Hinton Hospital identificationof an infectious cause of jaundice might have beenmade 20 years earlier than was the case.The introduction of the sulphonamides in the late

1930s brought familiarity with adverse reactions toall physicians. But these drugs, and later penicillin,streptomycin, and the adrenocorticosteroids, led tosuch advances in medical treatment that adversereactions, although recognized, caused no greatanxiety. This complacency was shattered in 1961. Ata congress of gynaecologists at Kiel on 19-20October 1961, von Massenbach from Lubeck, Lenzfrom Hamburg, and Wiedemann from Kiel drew

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0. L. Wade

attention to the large number of children who hadrecently been born in Germany with hypoplastic oraplastic limb deformities.Amonth later,at apaediatricsmeeting in Dusseldorf, Lenz first suggested that thehypnotic drug thalidomide might be the responsibleagent (Taussig, 1962). Thalidomide was marketed inGermany under a number of proprietary names andoften was compounded with analgesics for thetreatment of pain, cough, and insomnia. Not onlywere these preparations widely prescribed bydoctors but they were purchased over the counterby the public. The profusion of preparations andnames made retrospective inquiries about themedicines women had used in pregnancy difficult butLenz's suspicions were soon confirmed. It is nowbelieved that more than 6000 deformed babies wereborn in West Germany and some 500 in Britain asa result of the use of thalidomide. Many of thesechildren still live, and remain a grim reminder of atragedy that shocked the world.One result of the public outcry after the thalido-

mide tragedy was that governments in manycountries established organizations to ensure thatadequate and appropriate toxicity tests were carriedout before new drugs were used in human beings.However, as it became recognized that the resultsof tests in animals cannot be directly extrapolated toman, an urgent need developed for monitoring theuse of drugs, especially newly introduced drugs, toidentify adverse reactions as soon as possible. InBritain a report on the assessment of drug toxicitywhich was prepared for the Medical ResearchCouncil (1963) not only gave advice about the wayin which a system of notification of adverse reactionsby doctors using drugs should be established butstated: 'Early recognition alone is not always enough.The purpose of determining the toxic effects (of adrug) in man will usually be to obtain intelligentrestriction of its further use. To make such adecision possible it is necessary not only to recognizethe toxic effect but also to estimate its incidence andto compare that with the danger of the diseasesfor which the drug is being used.'These wise words bear repetition for hasty and

unnecessary decisions to ban the use of a drug havebeen a feature of recent years and are often theresult of undue, unbalanced, and sometimes pre-mature publicity by the press which lead to over-reaction of the public or politicians. It is, however,now widely recognized that there is a need not onlyto identify the adverse reactions to a drug but todetermine their incidence in relation to the use of thedrug. The data available to answer such questionshave come from sources each of which has had itslimitations.

Medical Literature

Although there was increasing awareness of theserious nature of adverse reactions to certain drugsfollowing the introduction of the sulphonamides in1935, it was considered sufficient throughout the1950s to leave the duty of reporting the toxic effectsof drugs to individual physicians or pharmacolo-gists who usually reported them in articles or lettersin medical journals. It is, however, usually difficultfor a physician to establish the relationship betweenan unexpected toxic effect and a drug. The patientmay be receiving many drugs and a single physicianmay seldom see the same adverse reaction to a drugmore than once or twice in his professional life.Nevertheless since 1957 Dr L. Meyler and hiscolleagues have published a number of mostvaluable surveys of reports of adverse reactions todrugs occurring in the world literature (Meyler,1957; Meyler and Herxheimer, 1968). These surveysare of great value as works of reference, for thereader can. rapidly ascertain what reactions havebeen reported with any given drug. However, theyseldom provide reliable information about theincidence of reactions and indeed may give a falseimpression of the incidence, for many reports mayappear about certain reactions of special interest tophysicians or pharmacologists.

The Registries Reports of Adverse Reactions

In 1951 two American haematologists, Wintrobe andSturgeon, found by accident that each had seen twoor three cases of aplastic anaemia in patientswho had been treated with chloramphenicol. It wasDr Wintrobe's idea to establish a Registry of BloodDyscrasias and between 1955 and 1962 reports of1195 patients with blood dyscrasias suspected asdue to drugs were received. The number of reportsreceived was small: this was due to poor publicity,the novelty of the scheme, and the dauntingly detailedform which had to be filled in. There was also anxiety,which persists in the United States, that by reportingan illness as due to a drug he has prescribed, aphysician might expose himself to a charge ofnegligence by his patient. The establishment of thisregistry by Dr Wintrobe marks the beginning ofsystemic monitoring of adverse reactions to drugs(Erslev and Wintrobe, 1962).

After the thalidomide catastrophe registries ofadverse reactions were established in a number ofcountries. Their main purpose is to provide an earlywarning that a drug causes an adverse reaction. Itis clear, however, that only a small proportion ofadverse reactions that occur are reported. In theUnited Kingdom in 1966 when the relationship

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between the oral contraceptive pill and thrombosiswas of wide public interest, it was found that in a

sample of 53 women who had died of thromboticillnesses and who were known by their familydoctor to be on oral contraceptives only eight hadbeen reported to the Committee on Safety of Drugs(Inman and Vessey, 1968). It is known, too, thatmany deaths of asthmatic patients using isoprenalineaerosols were never reported, but this was becausethe relationship between these aerosols and suddendeath was unsuspected (Inman and Adelstein,1969).Yet despite serious defects these registries still

constitute one of our most valuable sources ofinformation about adverse reactions. The Com-mittee on Safety of Medicines (the name was changedwhen the Medicines Act was passed in 1968) receivesabout 350 reports a month. It is now possible tocharacterize a profile of the reactions of a given drugor group of drugs. When a new but related drugis marketed suspicions may be aroused if reports ofan unexpected reaction such as jaundice begin toarrive (Wade, 1970).The Committee's policy has always been to ask

for a simple report from doctors and a supply ofprepaid yellow postcards is sent to every medicalpractitioner. They are asked to report all unexpectedand all serious adverse reactions to drugs, especiallythose suspected to be due to new drugs. It has beena disappointment that so few reports of adversereactions to drugs have come to the Committee fromhospitals. Reporting from a hospital can be greatlyincreased if a physician on the staff takes a majorinterest in the problem and if junior doctors, nurses,or pharmacists can be employed as 'drug safetyofficers'. In the West Midlands Region a MidlandsAdverse Reactions Study Group has been formedand reporting from a number of the hospitals hasincreased greatly. It may be possible to stimulate theinterest of family doctors working in the community,and this is desirable because the use of drugs by themis very different from the use in hospitals.

Intensive Monitoring

The seriousness of an adverse reaction depends notonly on its nature but also on its frequency inrelation to the use of a drug. In the US ArmyCuster (1946) determined the incidence of aplasticanaemia due to the antimalarial drug mepacrinewith a precision which will seldom be equalled. Heshowed that the incidence was 2-84 per 100 000men taking mepacrine compared with 0-1 per100 000 men not taking mepacrine. In spite of thislow incidence, Custer's evidence that mepacrine can

cause aplastic anaemia is accepted because he

surveyed millions of troops with excellent medicalrecords.

Intensive monitoring has been developed inhospitals. Patients are kept under surveillance, alldrugs administered are recorded, and any event

which might be an adverse reaction to a drug isnoted. In a survey carried out at the Belfast CityHospital, Hurwitz and Wade (1969) showed thatabout 10% of patients in our wards had adversereactions to drugs (table I), that these tended to becommoner in women than men (table II), and were

more frequent in the aged than in the young (tableIII). It was interesting to find that patients who on

admission had a history of previous drug reactionsor of allergic illness were at greater risk than thosewho had no such history (table IV) and it was

possible to identify certain drugs (table V) whichcaused a high incidence of reactions and certaincombinations of drugs (table VI). Similar findingshave been reported by others.

No. Adverse Reaction Rate (%)to Drugs

Patients admitted 1268 118 9-3No. given drugs 1160 118 10-2

Table I Adverse reactions to drugs in hospitals

Sex No. ofPatients Rate (%)

Given WithDrugs Reactions

Males 682 50 7-3Females 478 68 14-2

Total 1160 118 10-2

Table II Sex and drug reaction0-01 > P > 0-001

Age of No. Given No. with Rate (Patients Drugs Reactions(years)

10-19 64 2 3-120-29 100 3 3-030-39 122 7 5-740-49 159 12 7-550-59 222 18 8-160-69 252 27 10 770-79 178 38 21-380-89 59 11 18-690-99 4 0 0

Total 1160 118 10 2

Table III Age and drug reactionsRank correlation coefficient c + 0-86

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Previous Reactions Allergic Disease Jaundice

1042 patients with no drug reactions 70 (6-7 %) 48 (4-6 %) 46 (44 Y.)118 patients with drug reactions 27 (229 Y.) 19 (16-1 %) 4 (3 4%)p <0-001 <0-001 0-70 > p > 0 50

Table IV Adverse reactions and a history ofprevious reactions, allergic disease, andjaundice

Drug No. ofPatients Rate (Y.)

Given Drugs With Reactions

Ampicillin 103 8 7-8Other penicillins 167 0 0Orciprenaline 74 6 8-1Choline theophyllinate 100 5 5-0Methoxyphenamine 133 1 0-8Morphine 90 5 5 6Methadone 78 2 2-6Opium 57 1 1-8Pethidine 200 1 0 5Dihydrocodeine 76 0 0Paracetamol 128 0 0

Table V Drugs and adverse reactions

Patients Reactions ReactionGiven to RateDrugs Digitalis ( Y,)

Digitalis alone 53 5 9Digitalis and frusemide 79 16 20Digitalis and hydroflumethazide 23 8 35Digitalis, frusemide and

hydroflumethazide 18 6 33Digitalis and other diuretics 24 4 17Digitalis and all diuretics 144 34 24

Table VI Reactions to digitalis and diuretics

The Therapeutic Audit

The thoughtful doctor will realize that it is notenough to establish and improve the monitoring ofadverse reactions to drugs. If sensible decisions areto be made much needs to be known about theuse of the drug. How widely is it used? Whoprescribes it? Which patients receive it? For whatillnesses? What good does it do? What other drugsare available?

Studies on the use of drugs in the community arevery much in their infancy. Dr Helen Hood and Ihad the fortunate opportunity to have access todetails of all prescriptions written by family doctorsin Northern Ireland from 1966 onwards (Wade,1970). All the data are recorded on computer tapeto allow payments to be made to pharmacists andwe have been able to follow the change of prescribingof individual drugs over time. Figure 1 shows thechanges in the prescribing of hypnotic drugs between1966 and 1970 (Wade and Hood, 1972a). The greatincrease in the prescribing of Mandrax was probablyrelated to intense and skilful advertising of thispreparation; its use decreased after 1969 andnitrazepam (Mogodon) is now the group leader. Ofspecial interest, in view of the deaths caused by

Oc tober 1966 133.218)MANDRAX CYCLOBARBITONE

MllOGADN _ | XPHENOBA R TON E

*EL.DORM

SONERYL

AMYTAL SECONAL

TRICLORY NEMBUTAL.

October 1967 (37 526) Oczobcr 1968 (40.050)

October 1969 (42,638)

0. L. Wade

Fig 1 The prescribing ofhypnotic drugs in NorthernIreland 1966-1970.

Oct ober i1970 (41.241)

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October 1967 (4024 prescriptions) October 1969 (6101 prescriptions)

Fig 2 The prescribing ofbronchodilatoraerosols in Northern Ireland 1967-1973.

October 1973 (9544 prescriptions)

OT

NTAL

t..\

V.-EDHALER 50-FORTE

MEDHALER- EPI

_\ B

BROVON

ALUPENT

WYENTOLIN

excessive use of isoprenaline aerosols, is a study ofthe use of bronchodilator aerosols. This shows(fig 2) a considerable increase in the use of chromo-glycate (Intal) and salbutamol (Ventolin) while theuse of the isoprenaline aerosols decreased (Wade andHood, 1972b).

It has also been possible to study the geographyof drug use. One of our first studies was of the use

of insulin and oral hypoglycaemic drugs (Wade,Hadden, and Hood, 1972). The prescribing ofinsulin was remarkably evenly distributed through-out the province. But there were great variations inthe prescribing of oral hypoglycaemic drugs (fig 3).At the time of the survey (1966) the drugs beingmainly used were tolbutamide and chlorpropamide.A detailed survey was made of the use of thesedrugs in Londonderry and Newry, low- and high-useareas respectively (table VII). It was found that ineach city almost exactly the same proportion ofpersons were receiving oral hypoglycaemic drugs.The difference in overall use was due to the lowdaily doses prescribed for each patient in London-derry and the high doses in Newry. I suspect that themain reason for this difference was that in London-derry the diabetic clinic had a dietician who gaveadvice and detailed supervision of patients. In Newrythere was no dietician. These observations may beimportant in relation to the anxiety raised by theUniversity Diabetic Group Project (1970) in theUSA. The incidence of cardiovascular complica-tions found in that survey was higher in patients on

the oral antidiabetic drugs than in those on insulin.This might be investigated in areas where the use

of the oral drugs differs greatly.

0~~~~~ ~~~1-9

0~ ~

0 00 A.0

0~~~

UNITS/1000 PATIENTS~400+

200399

Fig 3 The prescribing of oral hypoglycaemic drugs inNorthern Ireland 1966.

The circles indicate the population in different townsand rural areas. The prescribing density is representedby the shading and hatching.

Newry Derry

Diabetic patients 39 101Diabetics per 1000 patients 1-21 1-33Units of antidiabetic drugs/1000

patients/month 411 132Units of antidiabetic drugs/month/per

doctor 837 263

Table VII Prescribing of oral antidiabetic drugsin two towns

October 1971 (8177 pr-escriptions)

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ORAL ANTIDIAETIC AMIT 1970

IEIABITATS

10000 -

r -

I .15000

PATIENTS

ME

> 25% APOVE THE MEAI

MEAN + 25%

< 25% BELOW THE MEAN

Fig 4 The prescribing oforal hypoglycaemic drugs inNorway (top left), Sweden (top right) and NorthernIreland (bottom left) in 1972.

Recently it has been possible to carry out a studyof the prescribing of the oral hypoglycaemic drugsin Northern Ireland, Norway, and Sweden (Crooks,Elmes, Friebel, Halse et al, 1974). The analysis isnot yet complete but it is clear that the differencesin prescribing found within Northern Ireland arevery much smaller than the differences which existbetween these three countries (fig 4). It seems tome that if large differences in the prescribing ofdrugs are occurring it may be possible not only tolearn more about the incidence of adverse reactionsto the drug but also to assess what value its use is,by comparing the morbidity, span of life, andmortality of communities in which the drug is usedwith those where it is not used. It has been particu-larly interesting to find that in one area of Sweden,the county of Jamtland, it is possible not only to

Fig 5 Prescribing of oral antidiabetic drugs inJamtland, 1970.

The age and sex of the community is shown in openhistograms and superimposed is the hatched and shadedhistogram ofpatients receiving oral antidiabetic drugs.

enumerate all the citizens by age and sex but also toidentify who in the community gets a particulardrug. Cardiac glycosides, antihypertensive drugs,and oral hypoglycaemic drugs are found to beprescribed predominantly to the over 60s (fig 5).

It is likely that studies in other countries wouldshow other important differences in the use of drugs.Some eight years ago a study of the sales of anti-biotics in six European countries showed that atthat time a quarter of all antibiotics used in Germanywas chloramphenicol (table VIII) (Engels andSiderius, 1968).

Death and Drugs

It has always seemed to me that the most importantadverse reactions of drugs are those which cause orcontribute to death. With Dr Tesh and with thecooperation of Professor Curran and his colleagues,I have recently arranged an investigation of thepart that drugs may have played in the death of100 patients coming to necropsy at the Queen

France UK West Germany Belgium Sweden Holland

Penicillins 20 35 45 11 55 30Ampicillins 1 15 5 13 15 30Tetracyclines 40 35 20 20 25 30Macrolides 8 5 1 30 2 2Combined tetracyclines and macrolides 8 2 1 15 0 1Chloramphenicol 5 1 25 1 1 1Others 18 7 3 10 2 6

Table VIII Sales ofantibiotics in Europe. As percentage of total sales within each country

O. L. Wade

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Important Factors Contributing to Death No. of Patients

After operation 12Diagnostic procedures 4Drugs 20Cessation of therapy 4Bed rest 3None of above 57

Table IX Analysis of 100 necropsies

Elizabeth Hospital, Birmingham (table IX).Although the assessment is rather subjective andthe analysis incomplete, it would appear that theuse of drugs, or the cessation of drug therapy, hasplayed a part in the death of at least a quarter ofthe patients. To me this suggests that a comprehen-sive multicentre survey carried out by pathologistsmight be of considerable value. It might lead to amore cautious use of drugs by physicians and itmight identify drug hazards which are not yetrecognized.

References

Crooks, J., Elmes, P. C., Friebel, H., Halse, M., Halvorsen, T.,Hood, H., Lunde, P. K., Moe, M., Sjoquist, F., Wade, O. L.,and Westerholm, B. (1975). Preliminary findings of WHOworking party. (In press.)

Custer, R. P. (1946) Aplastic anaemia in soldiers treated with atebrine(quinacrine). Amer. J. med Sci. 212, 211.

Engels, A., and Siderius, P. (1968). The consumption of drugs.Report of a study, 1966-67. Unpublished WHO WorkingDocument, EURO 1301, Copenhagen.

Erslev, A. J., and Wintrobe, M. M. (1962). Detection and preventionof drug induced blood dyscrasias. J. Amer. med. Ass., 181,114-119.

Hurwitz, N., and Wade, O.'L. (1969). Intensive hospital monitoring ofadverse reactions to drugs. Brit. med J., 1, 531.

Inman, W. H. W., and Adelstein, A. M. (1969). Rise and fall ofasthmamortality in England and Wales in relation to use of pres-surised aerosols. Lancet, 2, 279-285.

Inman, W. H. W., and Vessey, M. P. (1968). Investigation of deathsfrom pulmonary, coronary and cerebral thrombosis andembolism in women of child bearing age. Brit. med. J., 2,193-199.

Lawrie, E., Brunton, T. L., Bomford, G., and Hakim, R. D. (1890).Report of the Second Hyderabad Chloroform Commission.Lancet, 1, 149-159.

McDonald, S. (1918). Acute yellow atrophy in syphilis. Brit. med. J.,1, 76-78.

McKendrick, J. G., Coats, J., and Newman, D. (1880). Report onthe action of anaesthetics. Brit. med. J., 2, 957-972.

Medical Research Council (1922). Toxic effects following the employ-ment of arsenobenzenol preparations. Spec. Rep. Ser. med.Res. Coun. (Lond.), 66.

Medical Research Council (1963). Assessment of drug toxicity.Internal paper, 63/658.

Meyler, L. (1957). Side Effects of Drugs. Excerpta Medica Foundation,Amsterdam.

Meyler, L., and Herxheimer, A. (1968). Side Effects of Drugs, Vol. VI.Excerpta Medica Foundation, Amsterdam.

Taussig, H. B. A. (1962). A Study of the German outbreak of phoco-melia. J. Amer. med. Ass., 180, 1106-1114.

University Diabetic Group Project (1970). A study of the effects ofhypoglycaemic agents on vascular complications in patientswith adult onset diabetes. Diabetes, 19, 747-830.

Wade, 0. L. (1968). The computer and drug prescribing. In Computersin the Service of Medicine, edited by G. McLachlan and R. A.Shegog, vol. 1, pp.153-161. Oxford University Press, London.

Wade, 0. L. (1970). Pattern of drug-induced disease in the community:an unsolved enigma. Brit. med. Bull., 26, 240-244.

Wade, 0. L., Hadden, D. R., and Hood, H. (1973). The prescribingof drugs used in the treatment of diabetes. Brit. J. prev. soc.Med., 27, 44-48.

Wade, 0. L., and Hood, H. (1972a). An analysis of prescribing of anhypnotic in the community. Brit. J. prev. soc. Med., 26,121-128.

Wade, 0. L., and Hood, H. (1972b). Prescribing of drugs reportedto cause adverse reactions. Brit. J. prev. soc. Med.. 26, 205-21 1

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