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Title: Safety use of non-opioid analgesic medications


Introduction Non-opioid analgesics are a large and diverse group of substances with an analgesic effect without a psychotropic effect. This is a category of drugs that is among the most commonly used and purchased in Poland. They are also a serious cause of side effects, both type A and type B. The most characteristic of this group of drugs is hepatotoxicity associated with paracetamol overdose and hypersensitivity reactions to nonsteroidal anti-inflammatory drugs. Materials and methods In the study of side effects of selected non-opioid analgesics, we used the pan-European database of reports on drug-related adverse events and clinical data of patients from the Department of Toxicology and Allergology Unit in the Department of Toxicology and Environmental Diseases of the Jagiellonian University Medical College. In the first publication of the series, reports from a period of 10 years were collected from the EudraVigilance database supervised by the European Medicines Agency regarding suspected serious adverse events of the hypersensitivity type after the use of paracetamol. The second publication analyzed clinical and laboratory risk factors for hepatotoxicity in patients hospitalized in the toxicology ward due to paracetamol poisoning. In the next publication, the study population consisted of patients who, as part of the diagnostic work-up of drug-induced hypersensitivity ; reactions, were subjected to an oral challenge test with a non-opioid analgesic and obtained a negative result. After the assumed period of time, information about possible subsequent exposures to a given drug and its tolerance was collected. After data collection and database creation, all statistical analyzes were performed using Statistica 13 software (TIBCO Software Inc., USA). For continuous variables, nonparametric U-Mann Whitney tests were used, and Pearson's correlation coefficient r was calculated for particular variables. Differences in proportions between groups were compared using the Chi-square test. For the assessment of paracetamol-related hepatotoxicity risk, logistic regression models were built and odds ratios were calculated. A p-value less than 0.05 was considered statistically significant. Summary of results and conclusions In the first study, We identified in EudraVigilance 4,589 reports on serious adverse events related to hypersensitivity symptoms, of which 58 were fatal. Reports containing information on hypersensitivity symptoms accounted for 27.3% of all reports of serious adverse events. In the analyzed reports, symptoms of hypersensitivity were recorded 9,489 times. The most common symptoms reported were 'angioedema', 'exanthema' and 'urticaria'. The most serious symptoms included Stevens-Johnson syndrome, toxic epidermal necrolysis and anaphyla ; xis. Prodromal symptoms of Stevens-Johnson syndrome appeared in 286 reports, which accounted for 6.2% of all reports. The results of the study confirm that paracetamol, in addition to its hepatotoxic properties, can cause life-threatening symptoms of hypersensitivity. Awareness among medical staff of the occurrence of prodromal symptoms of these severe reactions allows to increase the safety of using this drug and to enable earlier treatment. The second publication describes a retrospective study on a group of 185 patients hospitalized due to paracetamol overdose. The study identified the most important variable associated with the risk of hepatotoxicity, which is the time period between drug intake and hospitalization. The dose of paracetamol was also a significant risk factor, however, in the logistic regression model, the time from taking the drug to hospitalization turned out to be the only statistically significant independent variable. This result of our study has a direct impact on daily clinical practice as it points to the fact that admission to the hospital and the initiation of appropriate therapy should be prioritized over other procedures. Incorporating the above conclusions into the management strategy of patients with paracetamol overdose may improve the effectiveness of treatment and prevention of this important cause of acute liver failure. In the third publi ; cation, a group of 164 patients was analysed, in whom no symptoms of hypersensitivity to the tested drug were found in the oral challenge test (OCT). In follow-up, 9.2% of those who were re-exposed experienced symptoms of drug hypersensitivity (negative predictive value OCT 90.8%). Hypersensitivity symptoms that occurred after re-exposure were mild. The analysis of excipients present in generic drugs that caused symptoms after re-exposure (acetylsalicylic acid, paracetamol, meloxicam, and diclofenac) showed that they may be one of the potential causes of false-negative OCT. 33 patients in the study group avoided re-exposure to the drug, despite the negative results of the challenge tests. Our results showed that oral challenges with non-opioid analgesics have high diagnostic value. Patients should be advised to use exactly the same medicinal product that was used for their negative OCT in their daily lives due to variability in the formulation of excipients in generics containing the same active substance. Since many patients avoid re-exposure to a given drug, despite the negative test result, another very important conclusion is the need to properly educate patients about the goals and results of the diagnostics. The chapter of the monograph constituting the final part of the series of publications summarizes key information on the mechanisms, symptoms and management of para ; cetamol-induced hepatotoxicity and hypersensitivity reactions.

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2 - studia doktoranckie

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Rada Dyscypliny Nauki medyczne


Porębski, Grzegorz ; Hydzik, Piotr

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pol; eng

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tylko w bibliotece

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Jul 4, 2024

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Apr 26, 2024

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ZB-140089 Jul 4, 2024


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