Metamizole versus ibuprofen at home after day surgery: study protocol for a randomised controlled trial

This is an investigator-initiated, double-blind, randomised controlled, non-inferiority trial. The study is being performed in accordance with the Declaration of Helsinki and has been approved by the ethics committee of the JESSA Hospital Hasselt (registration number 15.105/pijn15.02) and by the European Union Drug Regulating Authorities Clinical Trials (EudraCT Number 2015-003987-35). Informed consent will be obtained from all participants. The final report will follow the CONSORT 2010 guidelines as well as the extension to non-inferiority trials.

Consecutive adult patients undergoing elective haemorrhoid surgery, arthroscopic shoulder or knee surgery, or inguinal hernia repair in a day care setting will be informed about the study on their preoperative visit by the surgeon and they will be provided with a patient information sheet.

Patients will be assessed for eligibility on arrival at the outpatient clinic. Detailed eligibility criteria are listed in Table 1. The purpose, procedures, and potential risks and benefits of the study will be explained thoroughly to all participants who meet the eligibility criteria by a trained resident physician or study nurse. If interested, a written informed consent will be obtained from each participant prior to randomisation. The participants will be able to withdraw from the study at any time without consequences for therapy. This trial will be performed at a high-volume institution (JESSA Hospital, Hasselt, Belgium). Based on the number of selected procedures performed annually in the JESSA hospital, it is estimated that the trial will be executed from 28 January 2016 to January 2017, including enrollment and follow-up.

After obtaining written informed consent, patients will be randomised in a 1:1 ratio to either of the two study groups: a combination of metamizole and paracetamol (MP) or a combination of ibuprofen and paracetamol (IP) group. Patients in the MP group (experimental arm) will be instructed to take metamizole 1 g orally three times a day for 4 days and patients in the IP group (control arm) will be instructed to take ibuprofen 600 mg orally three times a day for 4 days. All patients will also be treated with paracetamol 1 g orally four times a day during the entire study period. The first dose of study medication (metamizole and paracetamol (MP) or ibuprofen and paracetamol (IP) will be given 30 minutes before surgery. Rescue medication consists of tramadol 50 mg orally and will be taken up to three times a day only if pain relief was not satisfactory with the study medication. Patients will be instructed to take their trial medication as prescribed and will be provided with a detailed medication schedule. Furthermore, they will be called by telephone daily and asked if they took their trial medication as prescribed.

All patients scheduled for an arthroscopic shoulder procedure will receive an interscalene block preoperatively.

In addition, general anaesthesia will be induced with intravenous (IV) alfentanil 10 mcg/kg IV sufentanil 0.15 mcg/kg and IV propofol 2 mg/kg. Patients undergoing arthroscopic shoulder surgery or laparoscopic inguinal hernia repair will also receive rocuronium 20–40 mg before endotracheal intubation. A laryngeal mask airway will be inserted in all other patients. Anaesthesia will be maintained with sevoflurane in a mixture of 50:50 air/oxygen. Before the end of surgery, all patients will receive ondansetron 4 mg IV. Furthermore, wound infiltration with local anaesthesia (bupivacaine 0.5 %) will be performed in all patients except those receiving an interscalene block. Duration of surgery will be recorded.

Postoperatively, all patients will be treated with subsequent bolus injections of piritramide 2 mg intravenously until a Numeric Rating Scale (NRS) ≤3 is reached/achieved in the Post-Anaesthesia Care Unit (PACU). Before hospital discharge, patients will receive the study medication and instructions for use. Dropout criteria are surgical complications leading to either resurgery or unanticipated hospital admission.

Outcome measures will be assessed at baseline and by telephone call at day 0, 1, 2, 3, 4, 7, 14 and 28 postoperatively. Several attempts at different times will be repeated in case of an initial unsuccessful call attempt. Outcomes in the domains of pain, QOR, compliance with study medication and patient satisfaction will be assessed (Fig. 1).

Primary endpoints are:

The following outcomes will also be assessed (see also Fig. 1):

In addition to the primary and secondary outcome measures, the researcher will also record participants’: age, gender, body mass index (BMI), ASA classification, work status, highest level of education, fear of the surgical procedure (using an 8-item surgical fear questionnaire) [3, 35], preoperative pain (the baseline NRS score), expected pain (NRS score), baseline GSR, FRI and EQ-5D, and the history of (related) surgery.

All possible adverse effects (AEs) of study medication will be explained thoroughly to all patients who meet the eligibility criteria. All participants will be questioned about adverse events at each telephone call (day 1, 2, 3, 4, 7, 14 and 28 postoperatively). Patients will be specifically asked whether they experienced postoperative nausea and vomiting, pyrosis or stomach ache, obstipation, anaphylaxis, fever, chills, mouth ulcers, a sore throat or signs of infection, petechiae and bleeding diathesis. Furthermore, patients are instructed to contact a research assistant immediately by phone if they experience moderate to severe signs of infection and/or bleeding diathesis. A complete blood count will then be performed to exclude leukopenia, anaemia and thrombocytopenia and trial medication will be withdrawn from the patient. Such an event will be reported as a serious adverse event (SAE).

Participants will be randomly assigned to the MP or the IP group using a computer-generated random allocation sequence, created by the study statistician. Randomisation will be stratified for type of surgery. Each patient will receive a unique randomised test number corresponding to the specified drug, according to the group allocation. The randomisation list remains with the study statistician and the hospital pharmacy for the whole duration of the study. Hence, the patients participating in the trial, the treating physicians, the researchers dispensing the medication and assessing outcomes (i.e. four trained resident physicians and one study nurse) and the data managers will be blinded for group allocation. For test drug blinding, the metamizole tablets and the ibuprofen tablets will be made to be visually lookalike. Furthermore, the hospital pharmacy will package study medication into identical blister containers. Each container will be numbered according to the randomisation list. Only adverse events (AEs) that are considered serious, unexpected and at least possibly related to the medication would have to be unblinded.

The primary outcome measures are the average postoperative pain intensity measured by an 11-point Numeric Rating Scale (NRS) on the first postoperative day as well as the QOR profile. As QOR profile is strongly influenced by postoperative pain intensity, sample size calculation will be based on expected postoperative pain intensity. Based on previous studies, we assume a standard deviation of the NRS scores of 2.5 on the first postoperative day and 1.7 on the fourth postoperative day [3, 5]. A difference in mean average NRS score of 1 point or less is considered non-inferior. Therefore, the present study must have the power to detect a difference of more than 1 point to reject the null hypothesis that the analgesic power of a combination of metamizole and paracetamol is inferior compared to a combination of ibuprofen and paracetamol. Based on these assumptions, we will require 78 patients in each group to have a power of at least 80 % (β = 0.2). To determine non-inferiority, we will compute 95 % confidence intervals for the difference in primary endpoints. The sample size will be inflated to 100 participants per group (200 in total) to account for a possible 22 % loss to follow-up.

Participants’ data will be recorded in individual participant record booklets. Coded, depersonalised data will be entered into a web-based questionnaire (Questback) and then exported to SPSS version 21 (IBM Corp, Armonk, NY, USA). Database access will be restricted to the authorised research team. Participants’ study information will not be released outside of the study without the written permission of the participant.

All primary and secondary endpoints will be analysed on a per protocol basis according to a non-inferiority design. As a sensitivity analysis, we will compare these results to an intention-to-treat analysis. Data will be presented as mean values +/- SD, numbers (n), and percentages (%). P values < 0.05 will be considered statistically significant. Missing baseline values will be imputed using multiple imputation. The number of imputations will be set to 10. To determine non-inferiority for the difference in NRS score on the first day after surgery, we will compute 95 % confidence intervals. The QOR profiles will be assessed using linear mixed models, taking time, type of surgery and group assignment into account. Differences between the groups on secondary outcomes will be analysed using the Student’s t test for continuous outcomes, except for the pain scores, since these are often heavily skewed. For those outcomes, we will use the Mann-Whitney U test. All categorical variables will be compared using Pearson’s χ2 test. For multivariate analysis the following potential confounders will be assessed: surgical fear, preoperative pain (baseline NRS), expected pain, baseline FRI and EQ-5D, age, sex, work status, educational level, ASA classification, BMI, history of related surgery, type of surgery, and duration of surgery. In addition, changes in the QOR scores over time in the postoperative period will be analysed using linear mixed models and we will use logistic regression to explore possible predictors for QOR. All analyses will be performed using SPSS version 21.

Adverse events (AEs) will be recorded and severity and relation to study participation will be assessed. SAE data will be collected and handled by the DMC.