Pain management and sedation/original research
Oral Paracetamol Versus Combination Oral Analgesics for Acute Musculoskeletal Injuries

https://doi.org/10.1016/j.annemergmed.2019.05.030Get rights and content

Study objective

We compare paracetamol with a combination of paracetamol, ibuprofen, and codeine for pain relief in acute minor musculoskeletal injuries.

Methods

This was a prospective, double-blind, randomized, active-controlled, parallel-arm study at an urban tertiary hospital emergency department. Participants were aged 18 to 65 years and had acute (<48 hours) closed limb or trunk injuries with moderate pain (greater than 3/10). A single dose of 1 g of paracetamol, 400 mg of ibuprofen, and 60 mg of codeine was compared with a single dose of 1 g of paracetamol, placebo ibuprofen, and placebo codeine. The minimum detectable difference in pain was taken as 1.3.

Results

Baseline characteristics and pain were similar. There were clinically detectable reductions in pain at rest at 60 minutes for paracetamol: –1.6; 95% confidence interval (CI) –2.2 to –1.1); n=59 and the combination –2.0; 95% CI –2.5 to –1; n=59; difference –0.4; 95% CI –1.1 to 0.29; P=.26. At 120 minutes, the reduction in pain was –2.4; 95% CI –3.2 to –1.6 for paracetamol (n=30) and –2.9; 95% CI –3.7 to –2.2 for the combination (n=35); difference –0.5; 95% CI –1.6 to 0.5; P=.32. Rescue analgesia was required by 4 of 59 patients in the paracetamol group and 5 of 60 in the combination group (P>.99). More participants in the combination group had adverse events: 14 of 60 versus 5 of 59 in the paracetamol group, relative risk 2.8; 95% CI 1.1 to 7.2. No adverse events were serious.

Conclusion

Combining oral paracetamol, ibuprofen, and codeine as the initial treatment for pain associated with acute musculoskeletal injuries was not superior to paracetamol alone for pain reduction at 60 minutes or need for rescue analgesia, with more adverse events in the combination group.

Introduction

Prescribing opioids in the acute setting has been identified as a risk for subsequent long-term opioid use.1 Despite this, the use of opioids is common for the management of moderate to severe pain caused by acute musculoskeletal injuries. A recent audit in our department (unpublished data) found that more than a third of patients were prescribed oral opioids either alone or in combination with nonsteroidal anti-inflammatory drugs and paracetamol for moderate to severe pain related to such injuries. This practice is not supported by the available evidence, with a Cochrane review finding that using oral opioid compared with nonsteroidal anti-inflammatory drugs offered no benefit in terms of pain relief but may have increased the incidence of adverse events. This review also found that the combination of paracetamol and opioid did not provide better pain relief than nonsteroidal anti-inflammatory drugs alone.2 However, the quality of evidence was very low and few studies contributed to this body of evidence.2

Editor’s Capsule Summary

What is already known on this topic

The coadministration of different analgesics may be synergistic.

What question this study addressed

Does the combination of acetaminophen 1,000 mg, ibuprofen 400 mg, and codeine 60 mg provide greater analgesia than acetaminophen 1,000 mg alone?

What this study adds to our knowledge

In this adequately powered, randomized, double-blind trial of 118 adults with acute musculoskeletal pain, pain scores were similar at 60 minutes in both groups. There were more adverse events in the combination group.

How this is relevant to clinical practice

At the standard doses studied, supplementing acetaminophen with ibuprofen and codeine does not enhance analgesia.

Several studies compared paracetamol with a combination of paracetamol and nonsteroidal anti-inflammatory drugs, finding no clinically important differences in analgesic efficacy and adverse events.3, 4, 5, 6, 7 Another study compared the addition of opioids with paracetamol and nonsteroidal anti-inflammatory drugs in this setting, also finding no difference in analgesia.8

To our knowledge, no previous studies have compared the efficacy of paracetamol alone with a combination of paracetamol, nonsteroidal anti-inflammatory drugs, and an opioid for moderate and severe pain in the setting of acute musculoskeletal injury. If there were no difference between paracetamol alone compared with this combination of analgesics for moderate or severe pain, then there would be little reason to prescribe oral opioids in this setting.

The primary aim of this study was to determine whether adding nonsteroidal anti-inflammatory drugs and codeine at routinely prescribed doses to paracetamol provided superior analgesic efficacy in the setting of moderate or severe pain from acute musculoskeletal injury. The primary outcome was difference in pain relief between the groups at 60 minutes for pain at rest. The secondary outcomes were difference in pain relief at 60 minutes for pain on activity, rest and activity pain at 120 minutes, need for rescue analgesia, and the rate of adverse events between the groups.

Section snippets

Study Design and Setting

This was a prospective, double-blind, randomized, active-controlled, parallel-arm study, conducted between September 3 and November 25, 2018, in the adult emergency department (ED) at Auckland City Hospital. The hospital is an academic urban tertiary referral hospital, with an annual census of 72,000 patients aged 15 years and older.

Selection of Participants

We recruited adult patients presenting to the ED between 8 am and midnight 7 days per week, with at least moderate pain (pain scores >3 of 10). Other inclusion

Results

During the study period, 832 patients were approached in the ED to participate. Seven hundred thirteen were excluded because they did not meet the selection criteria. This included 5 who were missed during screening because of unavailability of research staff and 82 who declined consent. The remaining 626 patients had contraindications to participating in the study (Figure 1).

Sixty participants were enrolled into the combination group and 59 into the paracetamol-only group. One participant in

Limitations

Our study has several limitations. Not recruiting participants overnight meant that the sample was not consecutive. In the audit that preceded this study, we found that approximately 90% of potentially eligible patients presented during study hours, and it would not have been cost-effective to employ research staff overnight because of high likelihood of low recruitment. We believe this did not bias the study in favor of a particular group and will not limit the generalization of the results to

Discussion

We report the first study in the literature, to our knowledge, comparing a combination of paracetamol, ibuprofen, and codeine with paracetamol alone for the management of pain related to acute musculoskeletal injuries. There were no statistically significant or clinically important differences between the groups in pain reduction at rest or activity at 60 minutes. Although a slight difference in favor of the combination group approached the minimum clinically detectable threshold for activity

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Please see page 522 for the Editor’s Capsule Summary of this article.

Supervising editor: Steven M. Green, MD. Specific detailed information about possible conflict of interest for individual editors is available at https://www.annemergmed.com/editors.

Author contributions: PJ conceived the study. PJ, JG, MC, and CK designed the trial and obtained research funding. JG, MC, and PJ supervised the conduct of the trial and data collection. JG and MC undertook recruitment of patients and together with PJ, managed the data, including quality control. PJ and CK provided statistical advice on study design and PJ analyzed the data. JG and PJ drafted the manuscript, and all authors contributed substantially to its revision. PJ takes responsibility for the paper as a whole.

All authors attest to meeting the four ICMJE.org authorship criteria: (1) Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND (2) Drafting the work or revising it critically for important intellectual content; AND (3) Final approval of the version to be published; AND (4) Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. The study was funded by grants from the Auckland District Health Board A+ (study 7983), Auckland, New Zealand, and the Australasian College for Emergency Medicine Morson-Taylor Research Award 2018, Melbourne, Victoria, Australia

Trial registration number: ACTRN 12618000020280

The researchers had complete independence from funders. All authors, external and internal, had full access to all of the data (including statistical reports and tables) in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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