Pharmaceutical products alleviate suffering in patients by presenting therapeutic benefits to them. There is risk in the use of these products, but by consenting to use the drug, the patient has deemed it fit that the benefits of the drug far outweigh the potential danger they may pose. There are two types of reactions that may be exhibited by the patient; adverse drug reaction and adverse drug event . Adverse drug reaction is the typical way in which the body responds to a drug that is toxic, and whose use was unintended. This usually occurs at normal doses for disease treatment. Adverse drug event on the other hand is a sudden response by the body after the use of a particular drug; the difference lies in the fact that this response does not bear a causal relationship with the therapeutic action of the drug. ADE does not guarantee a sure causality relationship to link the drug to the event, but relies on probability.
This is where Pharmacovigilance comes in; pharmacovigilance refers to the science that studies the detection, assessment and monitoring of adverse effects related to drug administration. This ensures patient safety in regard to the use of pharmaceutical products and is necessitated by the fact that most adverse drug reactions can be prevented, giving rise to causality assessment . Causality assessment is an integral component of the health system as it provides the health practitioner with a basis to ascertain that the adverse reactions seen are as a result of the drug administered. This is important because many external factors may lead to an adverse drug reaction, and it is necessary to distinguish between drug-related reactions and those arising from other factors .
2. Description of the case
In 1988, a male patient, 30 years old, was admitted to hospital due to bloody diarrhea and severe abdominal pain. Upon investigating his medical history, it was discovered he had no underlying medical conditions. The thyroid supplementation he took was necessitated following the removal of a part of his thyroid gland due to a follicular adenoma that was present. He also did not use any drugs or alcohol. Hematological and biochemical blood tests were carried out. The results obtained indicated a slight elevation in the ESR levels at 30 mm/hour and haptoglobin at 360 mg/dl. Erythrocyte sedimentation rate (ESR) is a blood test that is used to detect inflammation in the body. It entails measuring the rate at which the red blood cells sediment following blood extraction from the patient. This rate is taken in millimeters per hour; high levels indicate inflammation in the body. The results from the patient also showed mild sideropenic anemia, a group of anemia characterized by decreased levels of plasma iron. Other tests carried out, including serum amylase and lipase, cholesterol and liver function test provided normal results.
Examination of the colon indicated ulcerative colitis of the rectum and colon. The patient was put on 5-ASA treatment on an initial dose of 400mg/ day to determine drug tolerance. After four days, the daily dosage was doubled. Twenty four hours after administering this dosage, the patient started complaining of excruciating epigastric pain. Tests that were done revealed a sharp increase in the levels of amylase, lipase and blood glucose with no indication of any other biochemical deviations. The patient had an abdominal CT scan and ultrasound examination, both of which showed no pancreatic abnormalities. The use of 5-ASA was withdrawn and the epigastric pain vanished after two days. In addition, the amylase and lipase levels reverted to normal after 10 days and 5 days respectively. Colitis was controlled using localized steroidal treatment.
Global introspection is an assessment method where each factor is studied to see whether a causal relationship can be established between the drugs given and the resultant adverse effects . In this case, it’s evident that the patient developed epigastric pain after the administration of 5-ASA was doubled. It is important to note that the patient did not use alcohol, nor use any stimulants. This creates the basis to determine whether the drug caused this severe reaction. Information that is crucial to make this decision includes the patient’s age and gender, the dosage of drugs administered as well as the indications for which the drug is given. The onset of these effects is then studied bearing in mind the medical history of the patient. Using this information, it becomes possible to know the duration after the patient exhibited these effects, their severity and the results of dechallenge and rechallenge.
In the case of this 30 year old male patient, 5-ASA was administered for the treatment of ulcerative colitis, and the dosage doubled after four days. The sudden turn of events recorded just twenty four hours after this point to the likelihood of adverse drug reactions. This is because withdrawal of the 5-ASA registered a big improvement in the patient, with the pain disappearing after just two days. There are various categories for the use of this method, including certain, probable, possible and unlikely. For this particular case, it is probable that these reactions were the result of 5-ASA treatment. The reason behind this is that dechallenge indicated marked improvement when the use of 5-ASA was eliminated.
The shortcomings of this method however, include the disparity in the assessors’ views. One assessors ‘probable’ may be a ‘possible’ for another. This divergence in opinions is largely due to the fact that global introspection is an uncalibrated tool of causality assessment. In trying to address these shortcomings, there have been numerous algorithmic developments. One of the algorithmic methods is the Naranjo method used to determine whether these adverse reactions were due to the drug or not .
Also known as the Naranjo Scale, this method makes use of a questionnaire to assess the adverse drug reaction and decide, based on scores, what the results are. It is a basic method whose questionnaire is shown in the table below, with the scores alongside it.
The results are obtained by tallying the figures on the extreme right column. In this case, the total is 6, qualifying it in the category of probable Adverse Drug Reaction. The interpretation of the score at 6 simply means that the reaction occurred after a reasonable sequence following the administration of 5-ASA. Secondly, the reaction recorded was a known response of the suspected medication the patient received, and this was ascertained, not by exposure to the 5-ASA, but by its withdrawal. In addition, bearing in mind that the patient did not take any drugs or alcohol, the reaction observed could not be sufficiently tied to the patient’s medical state.
The criteria used to determine the results from the Naranjo algorithms mean that it is highly unlikely that the reaction can be linked to any other underlying disease or drugs. The response to withdrawal in this case is also clinically reasonable and does not require a recalling. To make a complete assessment, it is important to find a reasonable time relationship which includes the drug’s pharmacokinetics as well as the type and site of reaction. The mode of action of the drug(s) is also important as this will give clues as to the active ingredients available for the reaction to take place. The importance of both the algorithms and the global introspection method lies in their differences; algorithms are excellent tools in identifying ADRs, but exhibit poor specificity. Global introspection on the other hand, presents a setup that allows a panel of assessors to agree on the probable cause of the ADR by weighing their options and determining the best way forward .
Both methods used in the causality case are devoid of the ability to be reproduced, making it hard to validate any results thereof. This is because varying causality groups are used and both methods are assessed using different criteria, thus lowering the inter-rater reliability. In conclusion, both tools are used to date as there is no single method validated for causality assessment. As a result, the two methods serve the purpose of complementing one another and hence give authenticity to causality assessment.
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