Clinical Question: Used with opioids, is IV paracetamol better than oral paracetamol for managing moderate to severe pain in the Emergency Department?
Authors: Furyk, J. et al.
Published: EMJ Dec 2017 (online)
Population: Adults >18 years in the ED, with acute pain >40mm on a Visual Analogue Scale (VAS) (i.e. >4/10) 5 minutes after receiving an IV opioid
Interventions: all patients received an oral and IV substance. Randomised 1:1, half received active oral paracetamol and dummy IV, and half received active IV paracetamol and dummy oral.
Outcome: reduction in pain score on the VAS after 30 minutes
Summary: This is a single centre study, focussing on acute pain in the ED. The authors believed that the assumed benefits of IV paracetamol over oral, such as faster onset of action, greater analgesic efficacy, and reduced opioid use, required evidence of clinical superiority to justify the higher cost, time, and risk of possible complications.
Patients, nurses and doctors were blinded to allocation during treatment and data analysis. Pharmacy staff prepared each patient’s IV and oral preparations as required, using a sealed allocation envelope each time.
The sample size calculation was based on comparing the difference between two means. The authors were looking to detect a difference of 15mm between the VAS means of the two study groups, which was chosen as ‘a compromise between the commonly cited ‘minimum clinically significant’ difference of 13mm and 20mm’.
The final modified intention-to-treat (mITT) analysis included 87 patients, 47 in the IV group and 40 in oral group. They report that after 30 minutes the mean IV group VAS score was 51.5mm, and 54.2mm for the oral group. The difference in pain score was -2.6mm, with 95% CI -13.2 to 7.9 and p=0.62. The authors conclude that IV paracetamol is not superior to oral paracetamol in patients with moderate to severe pain.
Strengths, weaknesses, and clinical relevance
There have been many RCTs comparing oral to IV paracetamol in the past, and 2015 brought two systematic reviews of the evidence. Jibril et al. and Atkinson et al. both concluded there was no efficacy, pharmacokinetic, or safety benefit to IV dosing if the patient can take oral. However, the authors of this month’s paper state this is the first RCT in an ED environment, when managing acute pain is a large part of the workload.
In an ideal setting pain is assessed and managed step-wise up the WHO Analgesic Ladder. There is merit in evaluating fast acting IV preparations of ‘pre-opiate’ drugs for the management of acute pain in ED. It is unfortunate, then, that all patients included in this paracetamol trial have already had opiates, in the previous 5 minutes. The clinical question this study has answered is not the one I have been wondering.
There are a number of places where the analysis might have gone awry. Firstly, this study has been approached statistically as a study of the difference between two means, and the sample size calculation of just 44 per group reflects that. However, it is described as a ‘randomised controlled trial’, and uses RCT methodology. Given that established data finds limited difference in efficacy between oral and IV paracetamol, I believe a RCT sample size calculation would would require an enormous number of patients per group to establish statistical difference between the two groups.
Secondly, the primary outcome is stated to be the reduction in pain score from baseline. Baseline pain scores are reported as 65.0mm for the IV group and 71.3mm for the oral group. After 30 minutes the scores are 51.5mm and 54.2mm respectively. Further analysis compares the 30 minute pain scores of 51.5 and 54.2 rather than the amount of reduction from their baseline. (See Figure 2 for score reduction over time and note the different starting points.)
Unreported, mean pain reduction from baseline after 30 minutes for those receiving IV paracetamol was 13.5mm, and for oral paracetamol was 17.1mm. The mean difference is -3.6 and there remains no statistical significance between them (p=0.50).
Would the results be different in analgesic-naive acute pain?
Does the question of IV versus oral paracetamol need another clinical trial?(!!)
Could or should this study change practice here?