A systematic literature review of observational studies
A systematic literature review of observational studies
Paracetamol is the most widely used over-the-counter and prescription analgesic worldwide.1 It is the first step on the WHO pain ladder and is currently recommended as first-line pharmacological therapy by a variety of international guidelines for a multitude of acute and chronic painful conditions.2
The mechanism of paracetamol's analgesic action remains largely unknown, but recent studies demonstrate that paracetamol inhibits prostaglandin production within the central nervous system and within peripheral tissues.3 Irrespective of its efficacy, it is generally considered to be safer than other commonly used analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) or opiates.
We searched Medline and Embase for English-language studies published from database inception to 7 May 2013. The full search strategy was limited to only identify observational studies and can be found in the online supplementary material. All relevant references were checked for additional citations. Randomised controlled trial (RCT)-level evidence was not considered a meaningful way of capturing AE data because of the short-term follow-up of RCT trial participants as well as strict eligibility for trial entry, meaning that the general population would not be represented. If cohort-level evidence was found for an AE outcome, case–control evidence was not considered.
Studies were eligible for inclusion if they met the predefined protocol: the study population was adults aged >18 years and the study investigated one or more of the AEs of interest when people were taking oral paracetamol at a standard therapeutic dose of 0.5–1 g every 4–6 h to a maximum of 4 g/day compared with non-use.
The main outcomes investigated were all-cause mortality, cardiovascular AEs (specifically incidence of myocardial infarction, cerebrovascular accidents and hypertension), gastrointestinal (GI) AEs (specifically incidence of GI bleeding) and renal AEs (specifically reductions in estimated glomerular filtration rate (eGFR), increases in serum creatinine concentration and the need for renal replacement therapy).
We first screened titles and abstracts, and one reviewer (SB) screened relevant full-text articles. The second reviewer (VDN) reviewed 10% of the full-text articles screened, which were selected at random. One reviewer (SB) extracted study characteristics and adjusted summary statistics with 95% CIs and recorded the data in a standard form. Two authors (SB and ER) independently assessed the study quality using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Each outcome is given a quality rating of high, moderate, low or very low based upon risk of bias, inconsistency, indirectness and imprecision. Risk of bias for each outcome was assessed using checklists for observational studies, which are based on the Strengthening the Reporting of Observational Studies in Epidemiology statement.7 GRADE clinical evidence profiles for each outcome can be found in the online supplementary material.
Studies that met the inclusion criteria and reported summary statistics with 95% CIs, or presented sufficient data for the calculation of summary statistics and 95% CIs, were considered for inclusion in meta-analysis. Where data were able to be pooled, heterogeneity was assessed using the χ2 and I2 statistics. Heterogeneity was predefined as χ2 p<0.1 or I2 >50%, and where heterogeneity was unable to be removed by predefined subgroups a random effects model was assumed and outcomes were downgraded in quality. In instances where data were unable to be pooled, due to difference in outcome or Paracetamol dosage reporting, individual adjusted summary statistics were presented for each outcome per study. We produced forest plots to visually assess the summary statistics and 95% CIs of each study; analyses were done with Review Manager Version Five.
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