Naranjo algorithm
The Naranjo algorithm, also known as the Naranjo Adverse Drug Reaction Probability Scale, is a clinical assessment tool consisting of a 10-question questionnaire designed to evaluate the causal relationship between a suspected drug and an adverse event by assigning a probability score.[1] Developed in 1981 by Claudio A. Naranjo and colleagues at the University of Toronto, the scale standardizes the determination of drug-induced adverse reactions through objective criteria, improving inter-rater reliability compared to unstructured clinical judgment alone.[1][2] The algorithm's purpose is to provide a systematic method for causality assessment in pharmacovigilance, particularly useful in clinical trials, postmarketing surveillance, and case reports of suspected adverse drug reactions (ADRs).[1] It was validated in a study of 63 alleged ADRs, where it demonstrated high reliability (kappa values of 0.69–0.86 for inter-rater agreement and 0.64–0.95 for intra-rater consistency) and applicability across physicians and pharmacists.[1] Originally created for general ADR evaluation, it has been widely adopted in various medical contexts despite not being tailored to specific conditions like drug-induced liver injury.[2] Each of the 10 questions addresses key elements of causality, such as previous reports of the reaction with the drug, temporal association, dechallenge (resolution upon drug withdrawal), rechallenge (recurrence upon re-administration), and alternative causes, with scores ranging from -1 (no) to +2 (yes or definitive).[2] The total score, ranging from -4 to +13, categorizes the likelihood as definite (≥9), probable (5–8), possible (1–4), or doubtful (≤0).[2] This scoring system facilitates consistent documentation and reporting of ADRs in medical literature and regulatory submissions.[2] While the Naranjo algorithm remains one of the most commonly used tools for ADR causality assessment due to its simplicity and brevity, it has limitations, including subjectivity in some questions, lack of specificity for certain organ systems, and lower performance in complex cases without rechallenge data.[2] Alternative scales, such as the Roussel Uclaf Causality Assessment Method (RUCAM) for liver injury, have been developed to address these gaps, but the Naranjo scale continues to influence global pharmacovigilance practices.[2]Background
Development
The Naranjo algorithm, formally known as the Adverse Drug Reaction Probability Scale, was originally developed and published in 1981 by Claudio A. Naranjo and a team of collaborators in the journal Clinical Pharmacology & Therapeutics. The paper, titled "A method for estimating the probability of adverse drug reactions," introduced a structured scoring system to quantify the likelihood of drug-induced adverse events. This development arose from the recognized need for a more objective and standardized approach to causality assessment in adverse drug reactions (ADRs), which previously relied on subjective clinical judgment often leading to inconsistent inter-rater agreements of only 38%–63%. By building on these earlier limitations, the algorithm aimed to enhance reliability in pharmacovigilance practices. The project was a collaborative effort involving pharmacologists and clinicians affiliated with the Clinical Pharmacology Program at the Addiction Research Foundation Clinical Institute, as well as the Departments of Medicine and Pharmacology at the University of Toronto. Key contributors included Ursula Busto, Edward M. Sellers, Pedro Sandor, Isabel Ruiz, Eve A. Roberts, Eva Janecek, Carlos Domecq, and David J. Greenblatt, all working within this interdisciplinary environment. Initial validation of the scale was conducted retrospectively on 63 cases of suspected ADRs, where it achieved inter-rater agreements of 83%–92% and demonstrated strong within-rater reliability, confirming its utility for consistent causality evaluation.Purpose
The Naranjo algorithm was developed to provide a quantitative probability score for determining whether a drug caused an observed adverse event, thereby offering a structured approach to causality assessment in clinical settings.[1] This tool assigns a score based on key factors influencing causal relationships, categorizing the likelihood as definite, probable, possible, or doubtful, which helps clinicians move beyond qualitative evaluations.[1] By introducing this method in 1981, it aimed to enhance the precision and reproducibility of ADR evaluations.[1] A primary rationale for the algorithm is to mitigate the inconsistencies inherent in subjective clinical judgments, where inter-rater agreement can be as low as 38% without standardization.[1] The structured questionnaire format reduces variability among healthcare professionals, achieving higher reliability in assessments, with inter-rater agreement improving to 83–92%.[1] This standardization is particularly valuable in diverse healthcare environments, ensuring more uniform decision-making.[2] The algorithm is designed for broad applicability across all types of adverse drug reactions (ADRs), without restriction to specific drug classes or reaction severities, making it a versatile tool for general pharmacotherapy monitoring.[2] It supports comprehensive evaluation regardless of the clinical context, from inpatient care to outpatient settings.[2] Furthermore, by fostering consistent causality determinations, the Naranjo algorithm promotes reliable reporting to pharmacovigilance databases, such as those maintained by the FDA and WHO, facilitating effective postmarketing surveillance of drug safety.[1] This contributes to global efforts in identifying and mitigating drug-related risks on a larger scale.[1]The Algorithm
Questionnaire
The Naranjo algorithm employs a structured questionnaire consisting of 10 specific questions designed to evaluate the likelihood of an adverse drug reaction (ADR) being caused by a suspected drug. Each question is answered with one of three options—Yes, No, or Do not know—and assigned corresponding point values ranging from -1 to +2, which collectively contribute to an overall causality assessment. This ternary response format helps minimize subjective bias by standardizing evaluations while allowing for uncertainty in cases with incomplete data.[3] The questions systematically probe key elements of causality, including temporal associations between drug administration and the ADR, the role of alternative causes, effects of drug withdrawal (dechallenge) and re-administration (rechallenge), dose-response relationships, and supporting objective evidence. For instance, questions on timing and rechallenge emphasize the importance of chronological links and reproducibility, while those addressing alternative causes and placebo responses help rule out confounding factors. Objective evidence, such as toxic drug levels or confirmatory tests, adds weight to the assessment when available. This approach ensures a balanced evaluation grounded in clinical pharmacology principles.[3][2] Below is the complete list of the 10 questions, along with their response options and assigned scores, as originally formulated:| Question | Yes | No | Do not know or not done |
|---|---|---|---|
| 1. Are there previous conclusive reports on this reaction? | +1 | 0 | 0 |
| 2. Did the adverse event appear after the suspected drug was administered? | +2 | -1 | 0 |
| 3. Did the adverse event improve when the drug was discontinued or a specific antagonist was administered? | +1 | 0 | 0 |
| 4. Did the adverse reaction reappear when the drug was readministered? | +2 | -1 | 0 |
| 5. Are there alternative causes (other than the drug) that could on their own have caused the reaction? | -1 | +2 | 0 |
| 6. Did the reaction reappear when a placebo was given? | -1 | +1 | 0 |
| 7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? | +1 | 0 | 0 |
| 8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? | +1 | 0 | 0 |
| 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? | +1 | 0 | 0 |
| 10. Was the adverse event confirmed by any objective evidence? | +1 | 0 | 0 |