Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.
The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support.
Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.
When a patient takes a medication and subsequently develops an adverse event (AE), establishing causality between the drug exposure and the AE is a difficult and complex process (Hutchinson & Lane, 1989). If a causal relationship can be confirmed, an AE is referred to as an adverse drug reaction (ADR). Most ADRs are mild to moderate in severity, but some can be serious and even fatal. The incidence of fatal ADRs is as high as 3% (Lazarou, Pomeranz, & Corey, 1998; Wester, Jönsson, Spigset, Druid, & Hägg, 2008). Nurses can play a key role in the detection of ADRs (Bäckström, Mjörndal, & Dahlqvist, 2003; Morrison-Griffiths, Walley, Park, Breckenridge, & Pirmohamed, 2003) but should be aware of the complexity of assessing causality and understand how this can be done.
For a patient taking one or more drugs, are the reported signs or symptoms of the “reaction” due to the drug(s), the underlying disorder, or other unrelated or concurrent factors? Just because a patient taking a drug reports an AE does not mean that the drug and the effect are definitely or plausibly linked.
Patients taking a placebo in placebo-controlled drug treatment studies can report AEs that are similar to the drug under study. Expectancy and conditioning theories have been used to explain the placebo effect (Howland, 2008a, 2008b). Expectancy theory proposes that the expectations or beliefs that patients have about treatment will influence how they respond to treatment. Such expectations may be conscious or unconscious. Patients who have positive expectations that treatment will be beneficial demonstrate a significantly higher level of response to an active medication compared with patients who have less positive expectations taking the same medication. Therefore, patients with positive expectations may get better even if they are only taking a placebo.
By contrast, negative expectations about taking medication may have a deleterious effect. For this reason, some patients may develop noxious effects even though they are taking placebo, referred to as the nocebo effect. Positive or negative expectations harbored by treatment providers also might affect what patients believe will happen with medication treatment, and this may contribute to placebo and nocebo effects. Conditioning theory proposes that past experiences may lead to unconscious learning (conditioning) that contributes to symptom changes or AEs. Conditioning might be somewhat more relevant for explaining the development of nocebo effects in people, through negative past experiences and aversive learning.
Establishing a valid link between a drug exposure and an AE depends in part on using accepted criteria for an unambiguous diagnosis of the AE (Wilke et al., 2007). Many AEs are fairly simple to describe, such as diarrhea, headache, or skin rash. Other types of AEs are likely to be complex and to have multifactorial etiologies. Examples include weight gain, metabolic syndrome, tardive dyskinesia, suicidality, hepatic dysfunction, or cardiac abnormalities. These conditions are clinically significant and often linked to drug therapies but cannot be easily or solely attributed to drug exposure.
From a clinical perspective, ADRs can be generally classified into one of two subtypes (Pirmohamed & Park, 2001). Type A ADRs are related to a drug’s known pharmacological effect, and genetic factors might be important. They occur more frequently than Type B ADRs and constitute the majority of all ADRs of a drug. Type A ADRs are often dose related, predictable, and potentially preventable. They typically can be demonstrated in animals and are usually first detected in the early clinical trials. Severity can vary, but mortality risk is low. For nurses in clinical practice, a working knowledge of the pharmacology of various psychotropic drugs can be helpful for recognizing or identifying Type A ADRs.
Type B ADRs are idiosyncratic and unpredictable. They occur less frequently than Type A ADRs and may not be first detected until the drug is used more extensively after its clinical trial development. They are not clearly related to the drug’s pharmacological effect, are not necessarily dose related, and are less readily preventable. Unknown or uncharacterized susceptibility factors in particular patients are likely to underlie Type B ADRs. Severity can vary, but the mortality risk is disproportionately higher. Deaths and allergic reactions would fall into the category of Type B ADRs. During routine clinical monitoring, including telephone calls, nurses should always be vigilant about unusual or unexpected physical signs or symptoms that might be a Type B ADR. Both types of ADRs are clinically important, and each may be serious or severe, but Type B reactions often carry a proportionately greater risk of significant morbidity or even mortality.
Establishing the Probability of ADRs
The conventional approach to defining ADRs is based on a clinical judgment that the link between drug exposure and AE is definite, probable, possible, or doubtful. The validity and reliability of this assessment varies according to the knowledge, background, and experience of the clinician making the assessment. Such an assessment is also likely to be influenced by positive or negative bias. A systematic method for estimating the probability of an ADR has been described by Naranjo et al. (1981). This method solicits answers to 10 questions (Sidebar); based on the total score, the suspected ADR is assigned a probability: ≥9 (definite ADR), 5 to 8 (probable ADR), 1 to 4 (possible ADR), and ≤0 (doubtful ADR). Naranjo et al. (1981) and others have found that this method is a valid and reliable way to assess ADRs. This approach has been frequently adopted for use in assessing ADRs in clinical studies. It also is applicable for clinical use and can be a helpful guide for nurses in assessing suspected ADRs. The Naranjo method is a good way of assessing a suspected ADR in preparing a case report for publication or for submitting a report to MedWatch, which is the U.S. Food and Drug Administration’s (FDA) safety information and adverse event reporting program ( http://www.fda.gov/Safety/MedWatch/default.htm).
Detecting ADRs is obviously important for patient care, where nurses have a frontline role, but doing so accurately is especially important. The misdiagnosis of ADRs has potentially negative consequences for individual patients and for public health. Underdiagnosing ADRs can result in needlessly exposing patients to uncomfortable or potentially serious AEs, whereas overdiagnosing ADRs can result in unnecessarily discontinuing a drug therapy. Accurate ADR reports to the FDA are important for assessing the safety of marketed drugs in the general population, complementing and extending the safety assessments conducted in clinical trials.
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