The discovery of drug-induced illness can be analysed thus:3
• Drug commonly induces an otherwise rare illness: this effect is likely to be discovered by clinical observation in the licensing (premarketing) formal therapeutic trials and the drug will almost always be abandoned; but some patients are normally excluded from such trials, e.g. pregnant women, and detection will then occur later.
• Drug rarely induces an otherwise common illness: this effect is likely to remain undiscovered.
• Drug rarely induces an otherwise rare illness:
3 After: Jick H 1977 New England Journal of Medicine 296: 481-485.
this effect is likely to remain undiscovered before the drug is released for general prescribing; the effect should be detected by informal clinical observation or during any special postregistration surveillance and confirmed by a case-control study (see p. 68), e.g. chloramphenicol and aplastic anaemia; practolol and oculomucocutaneous syndrome.
• Drug commonly induces an otherwise common illness: this effect will not be discovered by informal clinical observation. If very common, it may be discovered in formal therapeutic trials and in case-control studies, but if only moderately common it may require observational cohort studies, e.g. proarrhythmic effects of antiarrhythmic drugs.
• Drug adverse effects and illness incidence in intermediate range: both case-control and cohort studies may be needed.
Some impression of the features of drug-induced illness can be gained from the following statistics:
• Adverse reactions cause 2-3% of consultations in general practice.
• Adverse reactions account for 5% of all hospital admissions.
• Overall incidence in hospital inpatients is 10-20%, with possible prolongation of hospital stay in 2-10% of patients in acute medical wards.
• A review of records of a Coroner's Inquests for a district with a population of 1.19 million (UK) during the period 1986-91 found that of 3277 inquests on deaths, 10 were due to errors of prescribing and 36 were caused by adverse drug reactions.4 Nevertheless, 17 doctors in the UK were charged with manslaughter in the 1990s compared with two in each of the preceding decades, a reflection of 'a greater readiness to call the police or to prosecute'.5
• Predisposing factors: age over 60 years or under one month, female, previous history of adverse reaction, hepatic or renal disease.
4 Ferner R E, Whittington R M 1994 Journal of the Royal Society of Medicine 87:145-148.
5 Ferner R E 2000 Medication errors that have led to manslaughter charges. British Medical Journal 321: 1212-1216.
• Adverse reactions most commonly occur early in therapy (days 1-10).
It is important to avoid alarmist or defeatist extremes of attitude. Many treatments are dangerous, e.g. surgery, electroshock, drugs, and it is irrational to accept the risks of surgery for biliary stones or hernia and refuse to accept any risk at all from drugs for conditions of comparable seriousness.
Many patients whose death is deemed to be partly or wholly caused by drugs are dangerously ill already; justified risks may be taken in the hope of helping them; ill-informed criticism in such cases can act against the interest of the sick. On the other hand there is no doubt that some of these accidents are avoidable. Avoidability is often more obvious when reviewing the conduct of treatment after death, i.e. with hindsight, than it was at the time.
Sir Anthony Carlisle,6 in the first half of the 19th century, said that 'medicine is an art founded on conjecture and improved by murder'. Although medicine has advanced rapidly, there is still a ring of truth in that statement to anyone who follows the introduction of new drugs and observes how, after the early enthusiasm, the reports of serious toxic effects appear. The challenge is to find and avoid these, and indeed, the present systems for detecting adverse reactions came into being largely in the wake of the thalidomide, practolol and benoxaprofen disasters (see Ch. 5); they are now an increasingly sophisticated and effective part of medicines development.
Another cryptic remark of this therapeutic nihilist was 'digitalis kills people' and this is true. William Withering in 1785 laid down rules for the use of digitalis that would serve today. Neglect of these rules resulted in needless suffering for patients with heart failure for more than a century until the therapeutic criteria were rediscovered. Any drug that is really worth using can do harm.
Effective therapy depends not only on the correct choice of drugs but also on their correct use.
6 Noted for his advocacy of the use of 'the simple carpenter's saw' in surgery.
This latter is sometimes forgotten and a drug is condemned as useless when it has been used in a dose or way which absolutely precluded a successful result; this can be regarded as a negative adverse effect.
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