Drug Safety

, Volume 36, Issue 3, pp 147–153 | Cite as

Distinguishing Hazards and Harms, Adverse Drug Effects and Adverse Drug Reactions

Implications for Drug Development, Clinical Trials, Pharmacovigilance, Biomarkers, and Monitoring
Special Article


The terms ‘adverse drug effects’ and ‘adverse drug reactions’ are commonly used interchangeably, but they have different implications. Adverse drug reactions arise when a compound (e.g. a drug or metabolite, a contaminant or adulterant) is distributed in the same place as a body tissue (e.g. a receptor, enzyme, or ion channel), and the encounter results in an adverse effect (a physiological or pathological change), which results in a clinically appreciable adverse reaction. Both the adverse effect and the adverse reaction have manifestations by which they can be recognized: adverse effects are usually detected by laboratory tests (e.g. biochemical, haematological, immunological, radiological, pathological) or by clinical investigations (e.g. endoscopy, cardiac catheterization), and adverse reactions by their clinical manifestations (symptoms and/or signs). This distinction suggests five scenarios: (i) adverse reactions can result directly from adverse effects; (ii) adverse effects may not lead to appreciable adverse reactions; (iii) adverse reactions can occur without preceding adverse effects; (iv) adverse effects and reactions may be dissociated; and (v) adverse effects and reactions can together constitute syndromes. Defining an adverse drug reaction as “an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product” suggests a definition of an adverse drug effect: “a potentially harmful effect resulting from an intervention related to the use of a medicinal product, which constitutes a hazard and may or may not be associated with a clinically appreciable adverse reaction and/or an abnormal laboratory test or clinical investigation, as a marker of an adverse reaction.”


  1. 1.
    Ferner RE, Aronson JK. EIDOS: a mechanistic classification of adverse drug effects. Drug Saf. 2010;33(1):13–23.CrossRefGoogle Scholar
  2. 2.
    Yu KH, Nation RL, Dooley MJ. Multiplicity of medication safety terms, definitions and functional meanings: when is enough enough? Qual Saf Health Care. 2005;14(5):358–63.PubMedCrossRefGoogle Scholar
  3. 3.
    Garnero P. Biomarkers for osteoporosis management: utility in diagnosis, fracture risk prediction and therapy monitoring. Mol Diagn Ther. 2008;12(3):157–70.PubMedCrossRefGoogle Scholar
  4. 4.
    Carbone LD, Johnson KC, Robbins J, Larson JC, Curb JD, Watson K, et al. Antiepileptic drug use, falls, fractures, and BMD in postmenopausal women: findings from the Women’s Health Initiative (WHI). J Bone Miner Res. 2010;25(4):873–81.PubMedGoogle Scholar
  5. 5.
    Wittes J, Lakatos E, Probstfield J. Surrogate endpoints in clinical trials: cardiovascular diseases. Stat Med. 1989;8:415–25.PubMedCrossRefGoogle Scholar
  6. 6.
    NIH Definitions Working Group. Biomarkers and surrogate endpoints in clinical research: definitions and conceptual model. In: Downing GJ, editor. Biomarkers and surrogate endpoints. Amsterdam: Elsevier; 2000. p. 1–9.Google Scholar
  7. 7.
    Inman WH. Postmarketing surveillance of adverse drug reactions in general practice. I: Search for new methods. Br Med J (Clin Res Ed). 1981;282(6270):1131–2.CrossRefGoogle Scholar
  8. 8.
    Taira CA, Opezzo JA, Mayer MA, Höcht C. Cardiovascular drugs inducing QT prolongation: facts and evidence. Curr Drug Saf. 2010;5(1):65–72.PubMedCrossRefGoogle Scholar
  9. 9.
    Ferner RE. Hazards, risks and reality. Br J Clin Pharmacol. 1992;33(2):125–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Herxheimer A. Benefit, risk and harm. Aust Prescr. 2001;24(1):18.Google Scholar
  11. 11.
    Youngster I, Arcavi L, Schechmaster R, Akayzen Y, Popliski H, Shimonov J, et al. Medications and glucose-6-phosphate dehydrogenase deficiency: an evidence-based review. Drug Saf. 2010;33(9):713–26.PubMedCrossRefGoogle Scholar
  12. 12.
    Hauben M, Aronson JK. Paradoxical reactions: under-recognized adverse effects of drugs. Drug Saf. 2006;29(10):970.Google Scholar
  13. 13.
    Smith SW, Hauben M, Aronson JK. Paradoxical and bidirectional drug effects. Drug Saf. 2012;35(3):173–89.PubMedGoogle Scholar
  14. 14.
    Assmann I, Fiehring H, Oltmanns G, Dittrich P, Basche S, Strauss HJ. Hämodynamische Untersuchungen zur Herzglykosidwirkung bei hypertrophischer obstruktiver Kardiomyopathie. Z Kardiol. 1982;71(7):473–9.PubMedGoogle Scholar
  15. 15.
    Rubinstein E. Comparative safety of the different macrolides. Int J Antimicrob Agents. 2001;18(Suppl 1):S71–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Sabers A. Pharmacokinetic interactions between contraceptives and antiepileptic drugs. Seizure. 2008;17(2):141–4.PubMedCrossRefGoogle Scholar
  17. 17.
    Cacoub P, Musette P, Descamps V, Meyer O, Speirs C, Finzi L, et al. The DRESS syndrome: a literature review. Am J Med. 2011;124(7):588–97.PubMedCrossRefGoogle Scholar
  18. 18.
    Aronson JK, Ferner RE. Clarification of terminology in drug safety. Drug Saf. 2005;28(10):851–70.PubMedCrossRefGoogle Scholar
  19. 19.
    Cragg ST, Clarke EA, Daly IW, Miller RR, Terrill JB, Ouellette RE. Subchronic inhalation toxicity of ethylbenzene in mice, rats, and rabbits. Fundam Appl Toxicol. 1989;13(3):399–408.PubMedCrossRefGoogle Scholar
  20. 20.
    Department of Health. Expert Group on Phase One Clinical Trials: final report. http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_063117. Accessed 16 Jan 2013.
  21. 21.
    Ioannidis JP, Evans SJ, Gøtzsche PC, O’Neill RT, Altman DG, Schulz K, et al. Better reporting of harms in randomized trials: an extension of the CONSORT statement. CONSORT Group. Ann Intern Med. 2004;141(10):781–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Glueck CJ, Rawal B, Khan NA, Yeramaneni S, Goldenberg N, Wang P. Should high creatine kinase discourage the initiation or continuance of statins for the treatment of hypercholesterolemia? Metabolism. 2009;58(2):233–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Carstairs KC, Breckenridge A, Dollery CT, Worlledge SM. Incidence of a positive direct Coombs test in patients on α-methyldopa. Lancet. 1966;2(7455):133–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Worlledge SM, Carstairs KC, Dacie JV. Autoimmune haemolytic anaemia associated with α-methyldopa. Lancet. 1966;2(7455):135–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Aronson JK. Biomarkers and surrogate endpoints in monitoring therapeutic interventions. In: Glasziou P, Irwig L, Aronson JK, editors. Evidence-based medical monitoring: from principles to practice. Oxford: Blackwell Publishing/BMJ Books; 2008. p. 48–62.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Department of Primary Care Health SciencesNew Radcliffe House, Radcliffe Observatory QuarterOxfordUK

Personalised recommendations