A method for estimating the probability of adverse drug reactions
Abstract
The estimation of the probability that a drug caused an adverse clinical event is usually based on clinical judgment. Lack of a method for establishing causality generates large between-raters and within-raters variability in assessment. Using the conventional categories and definitions of definite, probable, possible, and doubtful adverse drug reactions (ADRs), the between-raters agreement of two physicians and four pharmacists who independently assessed 63 randomly selected alleged ADRs was 38% to 63%, kappa (k, a chance-corrected index of agreement) varied from 0.21 to 0.40, and the intraclass correlation coefficient of reliability (R[est]) was 0.49. Six (testing) and 22 wk (retesting) later the same observers independently reanalyzed the 63 cases by assigning a weighted score (ADR probability scale) to each of the components that must be considered in establishing causal associations between drug(s) and adverse events (e.g., temporal sequence). The cases were randomized to minimize the influence of learning. The event was assigned a probability category from the total score. The between-raters reliability (range: percent agreement = 83% to 92%; κ = 0.69 to 0.86; r = 0.91 to 0.95; R(est) = 0.92) and within-raters reliability (range: percent agreement = 80% to 97%; κ = 0.64 to 0.95; r = 0.91 to 0.98) improved (p < 0.001). The between-raters reliability was maintained on retesting (range: r = 0.84 to 0.94; R(est) = 0.87). The between-raters reliability of three attending physicians who independently assessed 28 other prospectively collected cases of alleged ADRs was very high (range: r = 0.76 to 0.87; R(est) = 0.80). It was also shown that the ADR probability scale has consensual, content, and concurrent validity. This systematic method offers a sensitive way to monitor ADRs and may be applicable to postmarketing drug surveillance. Clinical Pharmacology and Therapeutics (1981) 30, 239–245; doi:10.1038/clpt.1981.154
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In cases of drug-induced palpitations, palpitations may be linked to sinus tachycardia; drugs involved include sympathomimetics, anticholinergics, vasodilators, and hydralazine.
“In such cases, palpitations may be linked to sinus tachycardia; drugs involved include sympathomimetics, anticholinergics, vasodilators, and hydralazine.40”
From Management of patients with palpitations: a position paper from the European Heart Rhythm Association (2011) · cites this paper as [40]
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“The Naranjo Scale preceded its development as a tool for evaluating adverse drug reactions in clinical trials, but it was not specific or valid for liver reactions [170, 171].”
MethodHypertension and incident cardiovascular events following ibrutinib initiation
Dickerson, T., Wiczer, T. E., Waller, A., Philippon, J., Porter, K. M., Haddad, D. A., Guha, A., Rogers, K. A., Bhat, S. A., Byrd, J. C., et al. (2019) · Blood · doi:10.1182/blood.2019000840 · Cited by 261 · see citing works
Génin, E., Chen, D.-P., Chung, W., et al. (2013) · The Pharmacogenomics Journal · doi:10.1038/tpj.2013.40 · Cited by 257 · see citing works
Drug-Related Deaths in a Department of Internal Medicine
Ebbesen, J., Buajordet, I., Erikssen, J., Brørs, O., Hilberg, T., Svaar, H., & Sandvik, L. (2001) · Archives of Internal Medicine · doi:10.1001/archinte.161.19.2317 · Cited by 254 · see citing works
Senior, J. R. (2012) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2012.108 · Cited by 248 · see citing works
Pont, L., Alhawassi, T. M., Bajorek, B. V., & Krass, I. (2014) · Clinical Interventions in Aging · doi:10.2147/cia.s71178 · Cited by 288 · see citing works
“Only two studies used custom predefined definitions.(20,21) Half (n=7) of the studies included in this review described an explicit causality assessment.”
Women encounter ADRs more often than do men
Zopf, Y., Rabe, C., Neubert, A. C., Gaßmann, K., Rascher, W., Hahn, E. G., Brune, K., & Dormann, H. (2008) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-008-0494-6 · Cited by 246 · see citing works
“Doubtful ADRs were excluded from statistical consideration [21].”
BackgroundLiverTox: A website on drug-induced liver injury
Hoofnagle, J. H., Serrano, J., Knoben, J. E., & Navarro, V. J. (2012) · Hepatology · doi:10.1002/hep.26175 · Cited by 255 · see citing works
Meyboom, R. H. B., Hekster, Y. A., Egberts, T. C. G., Gribnau, F. W. J., & Edwards, I. R. (1997) · Drug Safety · doi:10.2165/00002018-199717060-00004 · Cited by 241 · see citing works
Causality assessment in pharmacovigilance: The French method and its successive updates
Miremont‐Salamé, G., Théophile, H., Haramburu, F., et al. (2016) · Therapies · doi:10.1016/j.therap.2016.02.010 · Cited by 235 · see citing works
A Case Series of Proton Pump Inhibitor–Induced Hypomagnesemia
Hoorn, E. J., van der Hoek, J., de Man, R. A., et al. (2010) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2009.11.019 · Cited by 232 · see citing works
Schultz, B. G., Patten, D. K., & Berlau, D. J. (2018) · Translational Neurodegeneration · doi:10.1186/s40035-018-0110-3 · Cited by 230 · see citing works
“The Naranjo adverse drug reaction probability scale [18] was used to describe the relationship between statins and cognitive impairment.”
BackgroundMethodComparative Safety of Tetracycline, Minocycline, and Doxycycline
Shapiro, L. E. (1997) · Archives of Dermatology · doi:10.1001/archderm.1997.03890460044005 · Cited by 226 · see citing works
Inappropriate prescribing and adverse drug events in older people
Hamilton, H. J., Gallagher, P., & O’Mahony, D. (2009) · BMC Geriatrics · doi:10.1186/1471-2318-9-5 · Cited by 225 · see citing works
“The Naranjo criteria are often used to assess ADE causality (see additional file 2), with interrater agreement scores superior to subjective clinical judgement [21].”
Effect of Nitrous Oxide on Excitatory and Inhibitory Synaptic Transmission in Hippocampal Cultures
Mennerick, S. J., Jevtović‐Todorović, V., Todorovic, S. M., Shen, W., Olney, J. W., & Zorumski, C. F. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-23-09716.1998 · Cited by 225 · see citing works
Prevalence of Unplanned Hospitalizations Caused by Adverse Drug Reactions in Older Veterans
Marcum, Z. A., Amuan, M. E., Hanlon, J. T., Aspinall, S. L., Handler, S. M., Ruby, C. M., & Pugh, M. J. (2011) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2011.03772.x · Cited by 221 · see citing works
“For chart abstracts that screened positive for a potential ADR, two trained clinical pharmacists (ZM, JH) separately evaluated whether the hospitalization was causally related to an ADR using the reliable and valid standardized Naranjo ADR algorithm.(23) Each confirmed ADR was also evaluated for preventability, define…”
MethodHanlon, J. T., Pieper, C. F., Hajjar, E. R., Sloane, R. J., Lindblad, C. I., Ruby, C. M., & Schmader, K. E. (2006) · The Journals of Gerontology Series A · doi:10.1093/gerona/61.5.511 · Cited by 223 · see citing works
“Outcome Measures Blinded geriatrician and geropharmacist pairs evaluated ADR causality using the narrative and the reliable and valid algorithm by Naranjo and colleagues (11).”
MethodFranceschi, M., Scarcelli, C., Niro, V., Seripa, D., Pazienza, A. M., Pepe, G., Colusso, A. M., Pacilli, L., & Pilotto, A. (2008) · Drug Safety · doi:10.2165/00002018-200831060-00009 · Cited by 221 · see citing works
Nightmares: from anxiety symptom to sleep disorder
Spoormaker, V. I., Schredl, M., & van den Bout, J. (2005) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2005.06.001 · Cited by 220 · see citing works
- Authors
- Naranjo, C. A., Busto, U., Sellers, E. M., Sandor, P., Ruiz, I., Roberts, E. A., Janecek, E., Domecq, C., & Greenblatt, D. J.
- Affiliations
- University of Toronto (CA)
- Corresponding author
- Naranjo, C A
- Venue
- Clinical Pharmacology and Therapeutics
- Publisher
- Wiley
- Published
- 1981-08
- Volume
- 30
- Issue
- 2
- Pages
- 239-245
- ISSN
- 0009-9236 (ISSN-L)
- 1532-6535
- OpenAlex
- W2067978628
- Cited by
- 11,914
- References
- 0
- Citations by year
- 2026: 650 · 2025: 601 · 2024: 583 · 2023: 592 · 2022: 750 · 2021: 699 · 2020: 645 · 2019: 564 · 2018: 577 · 2017: 591 · 2016: 516 · 2015: 509 · 2014: 485 · 2013: 473 · 2012: 430
- FWCI
- 11.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Reliability and Agreement in Measurement
- Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
- Keywords
- adverse drug reactions, drug causality assessment, probability of causation, inter-rater reliability, temporal sequence, post-marketing surveillance, pharmacovigilance, content validity, concurrent validity
- MeSH terms
- Evaluation Studies as Topic, Humans, Methods, Pharmacists, Physicians, Probability, Random Allocation, Drug-Related Side Effects and Adverse Reactions
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