Background: Proton pump inhibitors (PPIs) are one of the most prescribed drugs in the world. Frequent use and long-term maintenance of these drugs drew the attention of researchers for sporadic adverse effects reports. Objective: The purpose of this narrative review is to discuss appropriate data and causality related to these adverse events and PPIs. Methods: A narrative review was conducted by systematizing information about safety and adverse events on PPIs from 2015 to 2020. A structured search on Pubmed was performed to identify systematic reviews and meta-analysis investigating the following situations: a) gastric cancer; b) micronutrients deficiency; c) acid rebound; d) infections; e) fractures; f) dementia; g) kidney disease; and h) sudden death and cardiovascular changes. Results: Recent studies have potentially associated PPIs with some adverse events as osteoporosis-related fractures. There are also reports of intestinal infections, including Clostridium difficile, besides poor vitamins absorption and minerals such as vitamin B12, magnesium, and iron. Furthermore, there are some dementia, pneumonia, kidney disease, myocardial infarction, and stroke reports. For kidney diseases, studies consistently suggest that the use of PPI may be associated with an increased risk of adverse kidney events, especially in the elderly, with long-term PPI use and pre-existing kidney disease. Another additional question is whether chronic PPI use would also lead to the onset of gastric cancer. The abrupt discontinuation of PPIs is also related to increased gastric acid production above pre-PPI treatment levels; this phenomenon is called acid rebound. Conclusion: The key to mitigate adverse effects is the rational use of PPIs at the lowest effective dose and in the shortest possible duration. Although these adverse effects have a potential clinical impact, their causal association is still subject to validation.

Objectives: The present study aims to evaluate the efficacy, tolerability and compliance of a fixed combination of dipyrone, isometheptene and caffeine versus paracetamol and placebo for the treatment of acute primary headache disorders. Method: A phase IV, multicentric, double-blind, placebo-controlled, randomized, crossover, prospective study was conducted. Approximately equal number of patients received dipyrone 300 mg, isometheptene 50 mg and caffeine 30 mg (combination therapy), paracetamol 200 mg/ml or placebo (oral drops). The primary efficacy endpoint was sustained pain-free (SPF) rate, defined as being headache-free at 120 minutes, without recurrences of any intensity or the use of rescue medication within 24 hours of treatment. Results: Among 99 subjects, most of them classified as having mild to moderate headache (96.0%), primary endpoint was achieved by 61.8%, 48.7% and 28.9% treated with combined therapy, paracetamol and placebo, respectively. A significative improvement in pain severity was observed with combined therapy at 30 and 90 minutes and in headache-related interference on daily activities after 30 minutes versus paracetamol. Both active treatments showed grater satisfaction levels versus placebo after 24 hours. No serious adverse events were registered. Conclusions: Substantial therapeutic gain was obtained with combined therapy on patients with mild to moderate acute primary headache episodes versus paracetamol and placebo. A favorable and tolerable safety profile was reported.Keywords: Headache disorders, primary; Dipyrone; Isometheptene; Caffeine; Acetaminophen; Clinical trialResumoFundamento: A associação de dipirona, isometepteno e cafeína tem sido utilizada no Brasil para o tratamento de cefaleias primárias agudas. Objetivo: O estudo teve como objetivo avaliar a eficácia, tolerabilidade e adesão de uma combinação fixa de dipirona, isometepteno e cafeína, em comparação com paracetamol e placebo, para o tratamento de cefaleias primárias agudas. Métodos: Foi realizado um estudo prospectivo, multicêntrico, randomizado, duplo-cego, cruzado, controlado por placebo e de fase IV. Um número aproximadamente igual de pacientes recebeu a combinação de dipirona 300 mg, isometepteno 50 mg e cafeína 30 mg (terapia combinada), paracetamol 200 mg/ml ou placebo (solução oral). O desfecho primário de eficácia consistiu na proporção de pacientes com ausência total da dor após 120 minutos, sem reincidências ou uso de medicamento de resgate por 24 horas. Resultados: Entre 99 pacientes, o desfecho primário foi alcançado por 61,8%, 48,7% e 28,9% dos pacientes tratados com terapia combinada, paracetamol e placebo, respectivamente. Melhora significativa foi observada na gravidade da dor com a terapia combinada em 30 e 90 minutos e na interferência da cefaleia nas atividades diárias após 30 minutos versus paracetamol. Ambos os tratamentos ativos apresentaram maiores níveis de satisfação versus placebo, após 24 horas. Nenhum evento adverso grave foi relatado. Conclusão: Obteve-se um ganho terapêutico substancial com a terapia combinada, em pacientes com episódios de cefaleia primária aguda leve a moderada versus paracetamol e placebo. Um perfil de segurança favorável e tolerável foi reportado.Descritores: Transtornos da cefaleia primários, Dipirona, Isometepteno, Cafeína, Acetaminofen, Ensaio clínico