Adverse Drug Reaction: Recognition, Assessment, and Causality

An adverse drug reaction is an unintended and noxious response to a medicine that occurs at doses normally used in humans. Recognising one in practice means noticing that a clinical change may be drug-related, characterising its nature and severity, and then judging how likely it is that the suspected medicine actually caused it, a judgement formalised through causality assessment.

Definition

An adverse drug reaction is a response to a medicinal product that is noxious and unintended and that occurs at doses normally used in humans for prophylaxis, diagnosis, or therapy, distinguished from an adverse drug event, which is any harm temporally associated with use regardless of whether the drug caused it.

Scope

This entry covers the definition of an adverse drug reaction and how it differs from an adverse event, the classic classification of reactions, and the logic of causality assessment including structured instruments. It is a reference description of how reactions are recognised and attributed; it gives no dosing or treatment advice for any specific medicine or patient.

Key concepts

• Adverse drug reaction versus adverse drug event
• Type A (augmented, dose-related, predictable) reactions
• Type B (bizarre, idiosyncratic, not dose-related) reactions
• Dechallenge and rechallenge
• Temporal relationship and plausibility
• Causality assessment
• Naranjo probability scale
• Severity and seriousness grading

Mechanisms

Recognition begins with a clinical change that might be attributable to a medicine, after which the reaction is characterised and its causal relationship to the suspected drug is assessed. The traditional framework distinguishes Type A reactions, which are augmented extensions of the drug's known pharmacology and are dose-related and largely predictable, from Type B reactions, which are bizarre, idiosyncratic, not dose-related, and harder to anticipate. Causality assessment weighs the temporal relationship between exposure and event, the response to stopping the drug (dechallenge) and to restarting it (rechallenge), the existence of alternative explanations, and biological plausibility. Structured instruments such as the Naranjo probability scale convert these considerations into a reproducible score that categorises a reaction as doubtful, possible, probable, or definite.

Clinical relevance

Distinguishing a probable reaction from a coincidental event and grading its severity are central to medication review and to deciding whether a suspected reaction warrants reporting. This entry describes the reasoning and instruments used to recognise and attribute reactions as a matter of reference understanding; it does not provide management instructions for individual patients.

Epidemiology

Adverse drug reactions are common in hospital populations. A meta-analysis of prospective studies estimated that serious reactions occur in a notable fraction of hospitalised patients, and a large prospective study found that reactions accounted for a meaningful share of admissions, a majority of which were judged potentially avoidable. These estimates depend heavily on how reactions are defined and ascertained.

History

Systematic attention to adverse reactions grew after mid-twentieth-century drug disasters exposed the limits of pre-marketing testing. The need to compare and aggregate suspected reactions drove the development of standardised causality-assessment methods, of which the Naranjo scale, published in 1981, became one of the most widely used, while later reviews refined the definitions and the distinction between reactions and events.

Debates

How reliable is causality assessment?

Structured scales improve reproducibility over unaided clinical judgement but still show limited agreement between assessors, because attributing a single event to a single drug is intrinsically uncertain when alternative explanations and polypharmacy are present.

Key figures

• I. Ralph Edwards
• Jeffrey K. Aronson
• Carlos A. Naranjo
• Munir Pirmohamed

Seminal works

• edwards-aronson-2000
• naranjo-1981
• lazarou-1998

Frequently asked questions

What is the difference between a Type A and a Type B reaction?

Type A reactions are dose-related, predictable extensions of the drug's known pharmacology, while Type B reactions are idiosyncratic and not dose-related, making them harder to anticipate from the drug's expected effects.

What does causality assessment try to establish?

It estimates how likely it is that a particular medicine, rather than the underlying illness or another factor, caused an observed harmful event, using clues such as timing, dechallenge and rechallenge, plausibility, and alternative explanations.