What is the difference between an Adverse Drug Reaction (ADR) and an adverse drug event?

Differences Between Adverse Drug Reactions (ADRs) and Adverse Drug Events

An adverse drug reaction (ADR) is specifically a noxious, unintended response to a medicinal product occurring at doses normally used in humans, while an adverse drug event is any untoward medical occurrence in a patient administered a pharmaceutical product, regardless of causal relationship to the treatment. 1, 2

Definitions and Key Distinctions

Adverse Drug Reaction (ADR)

• Defined by the World Health Organization (WHO) as "a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease, or the modification of physiological function" 1, 2
• FDA definition: "any undesirable experience associated with the use of a medical product in a patient" 1
• EMA definition: "a response to a medicinal product which is noxious and unintended and which occurs at doses normally used in humans for the prophylaxis, diagnosis or therapy of disease or for the restoration, correction or modification of physiological function" 1
• Implies a causal relationship between the drug and the adverse effect 3

Adverse Drug Event (ADE)

• Broader term that encompasses "any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment" 1
• Includes ADRs but also medication errors, therapeutic failures, and other drug-related problems 2
• Does not require proof of causality between the drug and the event 1

Classification of Adverse Drug Reactions

ADRs are commonly classified into several types using the mnemonic system 1, 2, 3, 4:

1. Type A (Augmented): Dose-related, predictable from known pharmacology

   • High morbidity, low mortality
   • Example: Bleeding with anticoagulants

2. Type B (Bizarre): Non-dose related, unpredictable, idiosyncratic

   • Low morbidity, high mortality
   • Example: Anaphylaxis, immune-mediated reactions

3. Type C (Chronic): Dose and time-related, cumulative effects

   • Example: Hypothalamic-pituitary-adrenal axis suppression with corticosteroids

4. Type D (Delayed): Time-related, appear after drug use

   • Example: Teratogenicity, carcinogenicity

5. Type E (End of use): Withdrawal reactions

   • Example: Rebound hypertension after clonidine discontinuation

6. Type F (Failure): Unexpected failure of therapy

   • Example: Inadequate dosage of oral contraceptives

7. Type G (Genetic): Genetically determined reactions

   • Example: Glucose-6-phosphate dehydrogenase deficiency causing hemolysis with certain drugs

Clinical Relevance and Reporting

Significance

• ADRs account for significant morbidity and mortality, with serious ADRs occurring in approximately 6.7% of hospitalized patients and fatal ADRs in 0.32% 5
• More than 80% of serious ADRs are Type A reactions, which are potentially avoidable 2

Reporting

• Healthcare professionals should report suspected ADRs through established reporting systems like the Yellow Card Scheme 4
• Low-certainty evidence suggests that educational interventions combined with reminder cards and ADR report forms can substantially improve reporting rates 6
• Standardized discharge forms with ADR items may also improve reporting 6

Practical Approach to Distinguishing Between ADRs and ADEs

When evaluating a patient with a potential drug-related problem:

1. For Adverse Drug Events:

   • Document any untoward medical occurrence temporally associated with drug administration
   • No need to establish causality initially
   • Include medication errors, overdoses, and therapeutic failures

2. For Adverse Drug Reactions:

   • Evaluate for causal relationship between drug and adverse effect
   • Consider timing, pattern of illness, results of investigations
   • Drug rechallenge (when ethically appropriate) can help confirm causality 3

3. Management Considerations:

   • For confirmed ADRs, consider drug withdrawal if possible
   • Provide specific treatment for effects
   • Consider allergist/immunologist consultation for suspected anaphylactic reactions 1
   • Implement observation periods after anaphylactic reactions due to risk of biphasic reactions 1

Understanding the distinction between ADRs and ADEs is crucial for proper pharmacovigilance, patient safety monitoring, and clinical management of drug-related problems.