Adverse drug reactionsBMJ 2018; 363 doi: https://doi.org/10.1136/bmj.k4051 (Published 06 November 2018) Cite this as: BMJ 2018;363:k4051
All rapid responses
I read with interest the ‘practice’ update on adverse drug reactions (ADRs) by Ferner and Gettigan (1). As pointed out by the authors, the nature of the drug development paradigm is such that it may be impossible to detect relatively rare adverse events within the confines of patient population and duration of pivotal trials targeted to assess efficacy primarily. Consequently, it becomes essential for both healthcare professionals as well as consumers to suspect and detect adverse drug events that can further strengthen the evidence base for the risk-benefit profile of the candidate drug.
With regulatory agencies worldwide being forced to strike a balance between maximizing access to novel therapeutics and safeguarding population from potential health risks, some laxity in adherence to traditional rigorous standards for drug safety and efficacy is expected and evident (2). Thus, the need for prescribers to remain ‘pharmacovigilant’ at all times cannot be overemphasized. Spontaneous reporting is considered to be the backbone of post marketing safety surveillance activities and requires an alert healthcare professional linking an adverse reaction to the use of a suspected drug and reporting it to the ADR monitoring agency. Despite its well-recognized importance, the rates of spontaneous reporting of ADRs remain universally low with lack of suspicion and uncertainty of causality – initially described as ‘diffidence’ by Inman, being cited as principal reasons by healthcare professionals (3–5). Therefore, prescribers need to be familiar with some of the structured tools devised specifically for causality assessment of suspected ADRs.
These algorithms are based on Bradford Hill criteria for establishing causality and allow for a structured and harmonized ADR assessment. The Naranjo algorithm and World Health Organization – Uppsala Monitoring Centre (WHO-UMC) scale are the two widely accepted methods with latter offering a simpler approach based on temporal relationship, adverse event being definitive pharmacologically or phenomenologically, ruling out other drugs or disease, dechallenge and rechallenge criteria (6). The WHO-UMC system enables classification of ADRs into one of six categories -- namely, certain, probable, possible, unlikely, conditional/ unclassified, or unassessable / unclassifiable -- with decreasing likelihood of relationship and has been shown to be the most consistent algorithm for ADR assessment in hospitals (7). Expert judgement and probabilistic approaches, the other two methods available to assess causal relationship are limited in their clinical utility due to marked disagreement between assessors and complexity respectively (8). Even though, as authors mention none of the available algorithms are universally acceptable, familiarity with the common principles of causality determination is expected to allow objective assessment of the available evidence and lend support to clinical suspicion enabling confident decision making.
Another area of concern is the quality of ADR reports submitted by prescribers that form the bedrock of signal generation and ultimately regulatory interventions. Multiple studies across diverse settings have found the quality of information communicated through ADR reports to be an area of concern with reports often missing critical data (9–11). The prescribers need to be diligent while reporting suspected adverse events to prevent loss of signal and optimize evaluation of drug-reaction relatedness.
1. Ferner RE, McGettigan P. Adverse drug reactions. BMJ. 2018 Nov 6;363:k4051.
2. Califf RM. Balancing the Need for Access With the Imperative for Empirical Evidence of Benefit and Risk. JAMA. 2017 Aug 15;318(7):614–6.
3. Inman WH. Attitudes to adverse drug reaction reporting. Br J Clin Pharmacol. 1996;41:434–5.
4. Vallano A, Cereza G, Pedròs C, Agustí A, Danés I, Aguilera C, et al. Obstacles and solutions for spontaneous reporting of adverse drug reactions in the hospital. Br J Clin Pharmacol. 2005 Dec;60(6):653–8.
5. Kiguba R, Karamagi C, Waako P, Ndagije HB, Bird SM. Recognition and reporting of suspected adverse drug reactions by surveyed healthcare professionals in Uganda: key determinants. BMJ Open. 2014 Nov 1;4(11):e005869.
6. Uppsala Monitoring Centre. The use of the WHO-UMC system for standardized case causality assessment. Available: http://www.who.int/medicines/areas/quality_safety/safety_efficacy/WHOcau....
7. Varallo FR, Planeta CS, Herdeiro MT, Mastroianni P de C. Imputation of adverse drug reactions: Causality assessment in hospitals. PLOS ONE. 2017 Feb 6;12(2):e0171470.
8. Arimone Y, Bégaud B, Miremont-Salamé G, Fourrier-Réglat A, Moore N, Molimard M, et al. Agreement of expert judgment in causality assessment of adverse drug reactions. Eur J Clin Pharmacol. 2005 May;61(3):169–73.
9. Bergvall T, Noren GN, Lindquist M. vigiGrade: a tool to identify well-documented individual case reports and highlight systematic data quality issues. Drug Saf. 2014;37:65–77.
10. Sanchez-Sanchez B, Altagracia-Martinez M, Kravzov-Jinich J, Moreno-Bonett C, Vazquez-Moreno E, Martinez-Nunez JM. Evaluation of completeness of suspected adverse drug reaction reports submitted to the Mexican National Pharmacovigilance Centre: a cross-sectional period-prevalence study. Drug Saf. 2012;35:837–44.
11. Durrieu G, Jacquot J, Mège M, Bondon-Guitton E, Rousseau V, Montastruc F, et al. Completeness of Spontaneous Adverse Drug Reaction Reports Sent by General Practitioners to a Regional Pharmacovigilance Centre: A Descriptive Study. Drug Saf. 2016;39(12):1189–95.
Competing interests: No competing interests
In clinical practice we are required to inform patients of medication response rates and adverse drug reactions.1 Providing information about treatment for patients if not done properly could yield adverse consequences, even if it is entirely out of well meaning to improve the outcome of treatment. This phenomenon is namely the “nocebo effect”2 which is not rare in psychiatry. It even has a negative impact on the relationship between doctors and patients.
In a randomized, double-blind controlled study, 39 drug-naïve depressed patients were given education or control intervention before drug treatment. Patients in the education group were exposed to a 10-min, individualized, face-to-face, interactively educational session on the nature of depression, antidepressant treatment, benefits and hazards of the drug and its management plan. Control patients received treatment as usual. At the 6-week study endpoint, the educational intervention (relative to control) was found to have no effect on knowledge about and attitudes toward treatment. The groups did not differ in treatment adherence, either. However, patients in the intervention group were shown to have experienced a doubled adverse events burden relative to patients in the control group.3
For ethical reasons, patients need to be educated about their illness and its treatment. However, such education may be a two-edged sword, with an increased nocebo effect as the most salient consequence. Educating patients about medications may increase their experience of adverse effects.4 It is well known in clinical practice that favorable beliefs about a treatment can contribute to its efficacy; unfavorable beliefs about a treatment can diminish treatment efficacy. Information provided to patients can shape patient beliefs. For example, since there are many generics in developing China, information that a treatment is inexpensive may carry the connotation that the treatment is less effective, resulting in decreased compliance and treatment efficacy.5,6
What should we say to the patients about adverse drug reactions?
First, present drug efficacy and adverse effects in a balanced manner; second, teach and train patients about strategies to cope with adverse effects; and lastly, provide evidence-based information. We may communicate in a truthful, ethical, and yet reassuring way about adverse events. For example, we may say “About 10% patients who receive this drug experience nausea or vomiting. This means that there is a 90% chance that you will not have nausea or vomiting", or “The common adverse effect of nausea or vomiting is mostly minor.”
It is the ethical duty of a physician to provide information about the efficacy and adverse events of the medicines that are to be prescribed; but how much information should a patient receive? It is clearly impractical and unnecessary to list every possible adverse event, because listing all adverse effects may cause some patients to worry about them, and worry can affect the way the mind and body function, resulting in the adverse effects occurring. Remember: never induce adverse drug reactions due to inappropriate information, and inform patients about drug effects using positive suggestion.7,8
1 Steinert T. Chance of response to an antidepressant: what should we say to the patient? World Psychiatr 2018;17(1):114–115.
2 Zhou Z, Curtis A, Breslin M, et al. Concerns related to the nocebo effect. Lancet
3 John AP, Singh NM, Nagarajaiah, et al. Impact of an educational module in antidepressant-naive patients prescribed antidepressants for depression: pilot, proof-of concept, randomized controlled trial. Indian J Psychiatr 2016;58(4):425–431.
4 Andrade C. Patient education in psychopharmacology and the risk of nocebo-related treatment inefficacy and harm. J Clin Psychiatr 2017;78(9):e1310–e1312.
5 Cai J, Ye M, Fei C, et al. Impact of brand-name drug worship and expectation psychology on antidepressant efficacy. Int J Clin Exp Med 2013;6(8):724–726.
6 Li M, Cai J, Zhang P, et al. Drug brand response and its impact on compliance and efficacy in depression patients. Front Pharmacol 2016;7:540.
7 Xu F. Caution in prescribing antidepressants for patients with cancer. Am J Health Syst Pharm 2008;65(8):700.
8 Xu F. Informing patients about drug effects using positive suggestion. J Manag Care Pharm 2008;14(4):395–396.
Competing interests: No competing interests