Efficacy and safety of modified-release paracetamol for acute and chronic pain: a systematic review protocol.

Introduction: Paracetamol (acetaminophen) is widely used for management of mild-to-moderate pain and reduction of fever. It is available as immediate release (IR) and modified-release (MR) formulation. In 2017, European Medicines Agency recommended a suspension of marketing of MR paracetamol in the European Union. Benefit-risk balance of these products has been assessed as negative as data showed that existing procedures for overdose management may not be efficient. Since MR paracetamol is still available in other countries (Australia and USA) and there is no available systematic review (SR) of efficacy and safety of MR paracetamol in the literature, we have decided to perform one to evaluate available data from randomised clinical trials (RCTs).

Methods And Analysis: Using predefined search criteria, we will search EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform to identify RCTs evaluating efficacy and safety of MR paracetamol alone in any dose or duration for any pain. Participants are defined as adults and adolescents (over 12 years). Primary efficacy outcomes will be pain intensity, pain relief and sleep. Primary safety outcomes will be the number of patients experiencing any (serious) adverse event, the number of patients withdrawn due to adverse events and the number of patients with gastrointestinal and hepatic adverse events. Data analysis will be subdivided based on different clinical syndromes. Meta-analysis will be conducted if possible. Cochrane risk of bias (RoB) tool with seven dimensions will be used to assess RoB of individual studies.

Ethics And Dissemination: This SR will include only data collected from trial reports; therefore, an ethical approval will not be sought. We will publish the protocol and our findings in peer-reviewed journals.

Prospero Registration Number: CRD42018115769.