1194 4Fantus, B, J3ournal of the American Medical Association, 1937, 109, 128. 5 Marriott, H L, and Kekwick, A, Lancet, 1935, 1, 977. 6 Rowbotham, E S, and Magill, I W, Proceedings of the Royal Society of Medicine, 1921, 14, 17. 7Weese, H, and Scharpff, W, Deutsche medizinische Wochenschrift, 1932, 58, 1205. 8 Lundy, J S, Northwest Medicine, 1934, 33, 308. 9 Waters, R M, and Schmidt, E R, Jrournal of the American Medical Association, 1934, 103, 925.
BRITISH MEDICAL JOURNAL
10 NOVEMBER 1979
10
Guedel, A E, Anesthesiology, 1940, 1, 13. " Nosworthy, M D, Proceedings of the Royal Society of Medicine, 1941, 34, 479. 12 Hewer, C L, and Hadfield, C F, British Medical,Journal, 1941, 1, 924. 13 Griffith, H R, and Johnson, E, Anesthesiology, 1942, 3, 418. 14 Bourne, J G, British Medical_Journal, 1947, 2, 694. 5 Gray, T C, and Halton, J A, Proceedings of the Royal Society of Medicine, 1946, 39, 400. 16 Johnstone, M, British journal of Anaesthesia, 1956, 28, 392.
General Practice Observed Adverse reactions to drugs in general practice CEDRICK R MARTYS British Medical3Journal, 1979, 2, 1194-1197
Summary and conclusions Of 817 patients in a general-practice survey of adverse reactions to drugs, 41% were thought to have "certainly" or "probably" had a reaction to the drug prescribed. Adverse effects on the gastrointestinal and central nervous systems were the most frequently reported, and 90% of reactions had occurred by the fourth day of treatment. More patients given drugs acting on the central nervous system and antihistamines reported reactions than those in other categories. A higher incidence of adverse drug effects is shown in this general-practice survey than in other, mainly hospital-based, surveys. Further intensive surveillance for adverse effects of drugs is recommended to provide additional information on the burden of drug-induced disease in the community.
Introduction An adverse reaction to a drug has been defined as "any unintended or undesired consequence of drug therapy,"' or alternatively as any effect of a drug that is "noxious and unintended and occurs at doses used in man for prophylaxis, investigation, or therapy."2 Since the thalidomide disaster several intensive hospital monitoring systems have been set up to measure the incidence of drug-induced disease during inpatient treatment.1 3-8 Adverse reactions to drugs present at the time of admission or occurring while the patient was in hospital have been investigated and recorded in a systematic manner. The Boston Collaborative Drug Surveillance Programme has for over 10 years run a multicentre survey of hospital patients using specially trained monitors stationed on wards to record adverse effects of drugs. Reports are issued at regular intervals,9 10 and a comprehensive
Stonecroft, Whitworth Road, Darley Dale, Derbyshire CEDRICK R MARTYS, MD, MRCGP, general practitioner
picture is now emerging of the incidence and severity of drug. induced disease in hospital patients. Although the frequency of adverse effects reported from hospital-based surveys varies between 1%fll and 28%',12 most of the work cited earlier gives a rate of detection of adverse drug effects of 10-20%/. The burden of drug-induced disease in the community is not known,'3-15 but reaction rates can vary from 3%0 to 68%.16-18 This wide variation in incidence rate probably reflects different methods of data collection. As there are no intensive monitoring systems in the community comparable to those established in some hospitals for measuring the incidence of adverse effects of drugs the incidence of reporting in a voluntary system is likely to be low.19 20 The present survey was undertaken to obtain a more accurate measure of the incidence of drug-induced disease in the community.
Methods To measure the incidence of adverse drug reactions in the community a two-year prospective study was undertaken in general practice. The practice of about 3300 patients is part urban, part rural in Darley Dale at the edge of the Derbyshire Peak District. All patients who had been given a drug for the first time were asked to complete a questionnaire. The usual details of name, date of birth, and sex were recorded, followed by treatment, dose administered, and diagnosis. Patients were asked to state in their own words whether any symptoms occurring since starting treatment might have been a side effect of the drug prescribed. They were then questioned about specific symptoms that could be drug-related (table I) and asked whether the severity of the reaction had led to discontinuation of treatment, and also questioned about self-medication. After a pilot survey had been completed, all patients entering the main survey were asked at the end of their consultation to make an appointment for one week later (except those given oral contraceptives, who were seen after one month), when they would be asked about any unwanted effects or side effects of the drug prescribed. Details of the pilot survey and the questionnaire are given elsewhere.2' Except for some patients in the pilot survey who were seen by the health visitor, all patients in the survey had to see the doctor to complete their questionnaires. Since these additional interviews had to be conducted within the existing appointments system of the practice, reactions could not be investigated at the same time for all drugs. In the first year the two major drug groups (antibiotics and analgesics) were investigated concurrently, and all other groups of drugs in the second year. Nevertheless, a considerable strain was thrown on the efficient working of the appointments system at times.
BRITISH MEDICAL JOURNAL TABLE
1195
10 NOVEMBER 1979
i-Frequency of specific reactions No
Type of reaction
reported
%, incidence in total no of reapondenta
Gastrointestinal system Nausea.94 Vomiting..19
Diarrhoea.68 Glossitis/stomatitis.14 Dyspepsia/flatulence.38 Dry mouth.44 Melaena.1 Central nervous system Excesaive wakefulness.10 Excessive sleepineass.98 Confusion.17 Hallucinations.7 Tremors.6 Convulsions.0 Headache.46 Dizziness.75 Cardiorespiratory system Fainting.10 Palpitations.3 Respiratory obstruction.3 Asthma . Chest pain.1 Skin
11-5 2-3 8-3
1-7
4-6
5.4
0.1
1-2 12-0 2-1 0.9 0-7 0.0 5-6 9-2
Rash.24
.7
Dry eyes . Tinnitus.1
1
No replying
No in
to
405
366 Drugs acting on central nervous system. Drugs acting on cardiorespiratory system 68 Drugs acting on gastrointestinal system. 43 .. Antihistamines 39 77 Nutritional, hormonal, metabolic, and misc Total
998
Table III shows the time interval between onset to
of adverse reactions. The
three
days after starting
peak
872 mean = 87
onset
of
occurred
and
treatment
incidence of reactions
treatment; 9000
Response
questionnaire rate (%) 348 86 323 88 63 93 36 84 33 85 69 89
group
..
Antibiotics
0.1 0-5 0-2 0-6 1-5 0.9 0-5 0.1 0.1 0-7 0.1 0.1
Paraesthesia.4 Haematemesis.2
of drugs prescribed
Drug group
2-9 2-7
Itching.22 Vaginal discharge (thrush).1
Other systems
Sweating.5 Constipation.12 Depression Hot flushes.4 Impotence.1 Double vision.1 Blurred vision.6
TABLE II-Number and type
1-2 0-4 0-4 0.1 0.1
1
for stopping treatment. Three per cent of patients complained of confusion or hallucination, reactions that caused immediate cessation of treatment. Pentazocine and dihydrocodeine were most often associated with these symptoms. Rash occurred in 30o of patients, half of whom were receiving or had just completed a course of ampicillin. None of these patients had been suspected of suffering from glandular fever before treatment began. Other reactions, not on the check list but volunteered by the patient, are also listed. Probably the most serious of these was depression, mentioned by seven patients, but no case of attempted suicide due to side effects of drug treatment occurred.
was
one
by the fourth
day.
The survey
was
restricted
for the first time in
to
all
patients given single-drug
given (1) Most patients in general practice present with relatively
ment
year for several
a
treat-
of reaction
TABLE iii-Time to onset
reasons.
problems, for which treatment with a single drug is entirely appropriate. (2) Those patients needing two or more drugs at the start of treatment of a particular condition are often the more-severely ill. They may be removed suddenly to hospital, and the opportunity for follow-up of possible adverse drug reactions is lost. Although the likelihood of a reaction is increased the more drugs the patient is given, the actual measure of morbidity in the practice is not likely to be greatly affected by omitting patients on multiple treatment, as they constitute only a small minority of the total undergoing treatment at any one time. (3) In a relatively small survey such as this, particular adverse reactions can be shown to occur with a given drug only if this is the
patient is receiving. If
patient is on combined unequivocally that a reaction he suffers is due to one and not another of the drugs he is taking. Often in this case only large surveys of many thousands of patients will make the picture clear and show unambiguously which drug is causing the reaction. Patients on long-term treatment-for instance, digoxin, diureticswho during the two years were given a new drug were included in the survely so long as drug interaction between old and new treatment We could then reasonably conclude that any adverse was unlikely. reaction developing was probably due to the drug they had been given. only drug
that the
treatment
it is much
more
difficult
to
Time to onset of reaction (days) 1-3 4-6 >--7
st.raight
BRITISH MEDICAL JOURNAL
10 NOVEMBER 1979
10
Guedel, A E, Anesthesiology, 1940, 1, 13. " Nosworthy, M D, Proceedings of the Royal Society of Medicine, 1941, 34, 479. 12 Hewer, C L, and Hadfield, C F, British Medical,Journal, 1941, 1, 924. 13 Griffith, H R, and Johnson, E, Anesthesiology, 1942, 3, 418. 14 Bourne, J G, British Medical_Journal, 1947, 2, 694. 5 Gray, T C, and Halton, J A, Proceedings of the Royal Society of Medicine, 1946, 39, 400. 16 Johnstone, M, British journal of Anaesthesia, 1956, 28, 392.
General Practice Observed Adverse reactions to drugs in general practice CEDRICK R MARTYS British Medical3Journal, 1979, 2, 1194-1197
Summary and conclusions Of 817 patients in a general-practice survey of adverse reactions to drugs, 41% were thought to have "certainly" or "probably" had a reaction to the drug prescribed. Adverse effects on the gastrointestinal and central nervous systems were the most frequently reported, and 90% of reactions had occurred by the fourth day of treatment. More patients given drugs acting on the central nervous system and antihistamines reported reactions than those in other categories. A higher incidence of adverse drug effects is shown in this general-practice survey than in other, mainly hospital-based, surveys. Further intensive surveillance for adverse effects of drugs is recommended to provide additional information on the burden of drug-induced disease in the community.
Introduction An adverse reaction to a drug has been defined as "any unintended or undesired consequence of drug therapy,"' or alternatively as any effect of a drug that is "noxious and unintended and occurs at doses used in man for prophylaxis, investigation, or therapy."2 Since the thalidomide disaster several intensive hospital monitoring systems have been set up to measure the incidence of drug-induced disease during inpatient treatment.1 3-8 Adverse reactions to drugs present at the time of admission or occurring while the patient was in hospital have been investigated and recorded in a systematic manner. The Boston Collaborative Drug Surveillance Programme has for over 10 years run a multicentre survey of hospital patients using specially trained monitors stationed on wards to record adverse effects of drugs. Reports are issued at regular intervals,9 10 and a comprehensive
Stonecroft, Whitworth Road, Darley Dale, Derbyshire CEDRICK R MARTYS, MD, MRCGP, general practitioner
picture is now emerging of the incidence and severity of drug. induced disease in hospital patients. Although the frequency of adverse effects reported from hospital-based surveys varies between 1%fll and 28%',12 most of the work cited earlier gives a rate of detection of adverse drug effects of 10-20%/. The burden of drug-induced disease in the community is not known,'3-15 but reaction rates can vary from 3%0 to 68%.16-18 This wide variation in incidence rate probably reflects different methods of data collection. As there are no intensive monitoring systems in the community comparable to those established in some hospitals for measuring the incidence of adverse effects of drugs the incidence of reporting in a voluntary system is likely to be low.19 20 The present survey was undertaken to obtain a more accurate measure of the incidence of drug-induced disease in the community.
Methods To measure the incidence of adverse drug reactions in the community a two-year prospective study was undertaken in general practice. The practice of about 3300 patients is part urban, part rural in Darley Dale at the edge of the Derbyshire Peak District. All patients who had been given a drug for the first time were asked to complete a questionnaire. The usual details of name, date of birth, and sex were recorded, followed by treatment, dose administered, and diagnosis. Patients were asked to state in their own words whether any symptoms occurring since starting treatment might have been a side effect of the drug prescribed. They were then questioned about specific symptoms that could be drug-related (table I) and asked whether the severity of the reaction had led to discontinuation of treatment, and also questioned about self-medication. After a pilot survey had been completed, all patients entering the main survey were asked at the end of their consultation to make an appointment for one week later (except those given oral contraceptives, who were seen after one month), when they would be asked about any unwanted effects or side effects of the drug prescribed. Details of the pilot survey and the questionnaire are given elsewhere.2' Except for some patients in the pilot survey who were seen by the health visitor, all patients in the survey had to see the doctor to complete their questionnaires. Since these additional interviews had to be conducted within the existing appointments system of the practice, reactions could not be investigated at the same time for all drugs. In the first year the two major drug groups (antibiotics and analgesics) were investigated concurrently, and all other groups of drugs in the second year. Nevertheless, a considerable strain was thrown on the efficient working of the appointments system at times.
BRITISH MEDICAL JOURNAL TABLE
1195
10 NOVEMBER 1979
i-Frequency of specific reactions No
Type of reaction
reported
%, incidence in total no of reapondenta
Gastrointestinal system Nausea.94 Vomiting..19
Diarrhoea.68 Glossitis/stomatitis.14 Dyspepsia/flatulence.38 Dry mouth.44 Melaena.1 Central nervous system Excesaive wakefulness.10 Excessive sleepineass.98 Confusion.17 Hallucinations.7 Tremors.6 Convulsions.0 Headache.46 Dizziness.75 Cardiorespiratory system Fainting.10 Palpitations.3 Respiratory obstruction.3 Asthma . Chest pain.1 Skin
11-5 2-3 8-3
1-7
4-6
5.4
0.1
1-2 12-0 2-1 0.9 0-7 0.0 5-6 9-2
Rash.24
.7
Dry eyes . Tinnitus.1
1
No replying
No in
to
405
366 Drugs acting on central nervous system. Drugs acting on cardiorespiratory system 68 Drugs acting on gastrointestinal system. 43 .. Antihistamines 39 77 Nutritional, hormonal, metabolic, and misc Total
998
Table III shows the time interval between onset to
of adverse reactions. The
three
days after starting
peak
872 mean = 87
onset
of
occurred
and
treatment
incidence of reactions
treatment; 9000
Response
questionnaire rate (%) 348 86 323 88 63 93 36 84 33 85 69 89
group
..
Antibiotics
0.1 0-5 0-2 0-6 1-5 0.9 0-5 0.1 0.1 0-7 0.1 0.1
Paraesthesia.4 Haematemesis.2
of drugs prescribed
Drug group
2-9 2-7
Itching.22 Vaginal discharge (thrush).1
Other systems
Sweating.5 Constipation.12 Depression Hot flushes.4 Impotence.1 Double vision.1 Blurred vision.6
TABLE II-Number and type
1-2 0-4 0-4 0.1 0.1
1
for stopping treatment. Three per cent of patients complained of confusion or hallucination, reactions that caused immediate cessation of treatment. Pentazocine and dihydrocodeine were most often associated with these symptoms. Rash occurred in 30o of patients, half of whom were receiving or had just completed a course of ampicillin. None of these patients had been suspected of suffering from glandular fever before treatment began. Other reactions, not on the check list but volunteered by the patient, are also listed. Probably the most serious of these was depression, mentioned by seven patients, but no case of attempted suicide due to side effects of drug treatment occurred.
was
one
by the fourth
day.
The survey
was
restricted
for the first time in
to
all
patients given single-drug
given (1) Most patients in general practice present with relatively
ment
year for several
a
treat-
of reaction
TABLE iii-Time to onset
reasons.
problems, for which treatment with a single drug is entirely appropriate. (2) Those patients needing two or more drugs at the start of treatment of a particular condition are often the more-severely ill. They may be removed suddenly to hospital, and the opportunity for follow-up of possible adverse drug reactions is lost. Although the likelihood of a reaction is increased the more drugs the patient is given, the actual measure of morbidity in the practice is not likely to be greatly affected by omitting patients on multiple treatment, as they constitute only a small minority of the total undergoing treatment at any one time. (3) In a relatively small survey such as this, particular adverse reactions can be shown to occur with a given drug only if this is the
patient is receiving. If
patient is on combined unequivocally that a reaction he suffers is due to one and not another of the drugs he is taking. Often in this case only large surveys of many thousands of patients will make the picture clear and show unambiguously which drug is causing the reaction. Patients on long-term treatment-for instance, digoxin, diureticswho during the two years were given a new drug were included in the survely so long as drug interaction between old and new treatment We could then reasonably conclude that any adverse was unlikely. reaction developing was probably due to the drug they had been given. only drug
that the
treatment
it is much
more
difficult
to
Time to onset of reaction (days) 1-3 4-6 >--7
st.raight
